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Editorial CHICAGO MEDICAL SOCIETY. Jan. 18th. The regular meeting of the Society was almost wholly occupied with the subject of City Health Regulations. Dr. N. S. Davis, from the Special Committee on that subject, made the following report, which, after free discussion, was adopted. The Committee was instructed to present the same to the Common Council, with the draft of an amendment to the present laws, as indicated in the report. REPORT OF THE COMMITTEE ON THE HEALTH DEPARTMENT OF OUR CITY GOVERNMENT. Presented to the Chicago Medical Society, January 18th, 1867. The subject assigned to your Committee for consideration, is certainly one of the most important that can engage the of the people of this, or any other large city. The and enforcement of proper sanitary regulations is so closely connected with the preservation of health and the prolongation of life and happiness, that no community can ne,gleet them without, sooner or later, suffering the severest penalties. In fulfilling the duties assigned to your Committee, three questions require careful consideration. 1st. What are principles upon which a Municipal Health should be organized, in order to ensure the highest degree of enlightinent and efficient action? 2d. Is the present organization of the Health Department of our city defective; and if so, in what particulars? 3d. What changes are necessary to remedy its defects, and complete its efficiency? In answer to the first question, we would state, that the basis of a proper Health Organization, should consist of a Board of Commissioners, embodying in its members a high degree of ability or business capacity, and a thorough knowledge of sanitary science, as applied to the preservation of the health of communities and the prevention of the spread of contagious diseases. No board can embody these qualities, without composed in part, at least, of thoroughly-educated ; simply because, In our country, no other class of men are educated to an adequate extent, in reference to those subjects on which a Board of Health must continually act. The truth of this proposition is too plain to need either or illustration. A Board of Health Commissioners, composed of properly educated and qualified members, should be invested with power to devise and carry into prompt effect, all such measures as the safety and welfare of the community requires. The term of office of its members should be long enough to a reasonable degree of permanency in whatever sanitary measures or policy may be adopted. In no department of municipal affairs, is a vaccillating, temporizing policy more than in that relating to the preservation of the public health. A show of energy, or a display of zeal, or a prodigal expenditure of money just while some fearful epidemic disease is threatening to commence its work of death, and a negligent indifference at all other times, is but little better than no action at all. Sanitary measures, to be successful in lessening the sickness and mortality of communities, and in protecting them from the ravages of epidemics, must be founded on an accurate knowledge of all those local causes that tend to deteriorate the public health, and then they must be rigidly and perseveringly enforced from year to year. To enable a Board of Health Commissioners to devise such measures, and establish an enlightened and permanent sanitary policy, its members should not only possess the requisite and business capacity, with a term of office long enough to add experience to their previous knowledge, but they should be appointed in such a manner as to free them as far as possible from all partisanship, or feelings of dependence on the success or failure of mere political parties. And yet they should be fully accountable to the municipal government for all their official acts. Such are the principles on which a Board of Health Commissioners should be organized. The next question is, how far the present health department of our city government is organized in accordance with these principles, and in what particulars is it defective? Our present Health Department consists of a Board of three Commissioners, who are also at the same time Commissioners of the Police and Fire Departments; a Health-Officer; and a City Physician. The three members of the Board are elected by the people, one from each division of the city, and hold their offices for six years. The Health-Officer is appointed by the Board. The City Physician is elected by the Common Council, and holds office for two years. The present city charter confers on the Common Council power "to do all acts and make all regulations which may be necessary or expedient, for the preservation of health, and the suppression of disease." And, in accordance with this power, we find in the present laws and ordinances of the city full and ample powers conferred and duties enjoined upon the Board of of Health and Health-Officer, for the efficient and thorough regulation of everything relating to the public health and safety. After a full examination of the present laws and , we can see no need of further legislation, so far as relates to the conferring of power upon the Board of Health or its agents. Wherein, then, is the present organization defective? Chiefly in three important particulars. The first and most radical is, the absence of all provision for securing the selection of members of the Board of Health so thoroughly educated in matters as to fit them for an enlightened and efficient of their duties. To make up a Board of Health, charged with the duty of making and enforcing all such regulations as are necessary to mitigate or prevent the prevalence of diseases in a great city, of men who, neither by education, occupation, nor business habits, have acquired any special knowledge of the nature and causes of disease, or of the laws by which they are developed and diffused, is just as absurd as it would be to elect a practising physician to the office of City Attorney. If there is lack of efficiency in the practical working of our health organization, it is not because the members of the present Board of Police, acting as a Board of Health, are in integrity or business capacity, or from deficient legal authority to-act, but simply because they have not that special sanitary or medical education which enables them to clearly the nature, extent, and importance of the work entrusted to them. The second defect consists in an imperfect and injudicious distribution of duties between the Health-Officer, City , and Clerk of the Board of Health. The Health-Officer shall be simply an intelligent and efficient executive officer, to superintend the prompt enforcement of all the laws and orders of the Board of Health. The City Physician should keep at* all times a free vaccine dispensary for the poor, and have the immediate charge or superintendence of such sick persons as came under the care and authority of the Health and Police Departments of the City Government. And there should be a competent Clerk, who should perform the duties of Secretary to the Board of Health and the Health-Officer, and also the duties of Register of Vital Statistics. The third defect in the present organization is the absence of efficient regulations for the accurate registry of births, and deaths, with the causes of the latter. The of this needs no comment here. After a somewhat careful and candid examination of the whole subject, we feel certain that whatever inefficiency or defectiveness there is in the practical working of the present health organization of our city, can be traced directly or indirectly to the three sources just enumerated. This leads us to the third and last question' involved in this report, namely: What changes are necessary to remedy the defects to which we have alluded? We answer, so far as State legislation is concerned, we need but a single brief amendment to the laws now in force. If the present law relating to the action of the Board of Police, in the capacity of a Board of Health, was so amended as to provide for the of three thoroughly competent Physicians, (one from each Division of the City,) to act with said Police in all matters pertaining to health or sanitary regulations, to possess coequal powers and duties, and to constitute a part of said Board whenever acting in the capacity of a Board of Health, it would be all the legislation really required. This done, the other defects pointed out could be easily remedied under the authority already possessed by the Common Council and Board of Health. While the proposed amendment should leave the present mode of electing the three Police undisturbed, it should provide some other and less method of appointing the three medical members of the Board acting as a Board of Health. Those members of our profession who have acquired that education, experience, and 'reputation, which would enable them to impart that kind of and efficiency to a Board of Health, imperatively needed in all large cities, will never be found seeking from political parties, nor lobbying for appointments by a Governor and Senate, or a Mayor and Council. They must be sought ought and invited to accept the position, or their will not be obtained. We would suggest whether this would not be done more judiciously and with less reference to anything of a political or partisan character, by the Judges of the Superior Court of this city, than by any other authority. It will be seen that the defects we have pointed out and the remedies proposed are few and simple; yet they are really of vital importance to the practical working and beneficial of the Health Department of our city. Should the views thus far expressed in this report meet the approbation of this Society, an amendment could be in due form, relating to the appointment of three medical men as members of the Board of Health, and an ordinance in relation to the proper registry of vital statistics, and we have no doubt but both would meet the prompt sanction of the Mayor and Council. Before this report, it may be expected that some notice will be taken of the several amendments and health bills which have already been prepared and placed before the Legislature, the Council, and the public. There are three separate projects of this kind. The first consists in amendments to the present laws prepared and recommended by the Common Council. The only item in these, that relates to the important defects we have explained, is the section proposing to give the Common Council power, in cases of imminent danger from the of epidemic diseases, to appoint an additional number of members of the Board of Health, to act as such simply while such danger lasts. But it is not provided that even these appointees shall be medical men. And hence it does not in any degree remedy the radical defect in the constitution of of the present Board. The second project is in the form of a bill recently introduced into the State Senate by Senator Ward. By the provisions of this bill, everything pertaining to the Health Department, and sanitary regulations, is removed from the control of the people of the city and its municipal , and placed in the hands of a Board of Commissioners, consisting of the President of the Board of Police, and two Commissioners appointed by the Governor and Senate, one of whom must be a physician. The two persons thus appointed by the Governor and Senate are to hold office four years, and, with the President of the Board of Police, constitute a Board of Health, with full power to make all needful rules, , and appointments of agents, etc., sufficient to devise and execute a complete and independent sanitary system. There are two leading and fatal objections to this bill. The first is, that it deprives the people of this city of all power to regulate and control some of their most important local interests, and assumes that a Governor and Senate, at Springfield, are -better qualified to judge of the capacities and qualifications for office, of citizens of Chicago, than are the local authorities of the city, or the people themselves. The second, and more objection is, that it creates a large number of new and officers and employes, requiring a regular annual tax upon the city, of from $75,000 to $150,000, without regard to any extraordinary expenditures on account of the prevalence of severe epidemics. And yet it does not provide for the accomplishment of a single valuable object, that would not be as well and certainly accomplished, by simply adding hree thoroughly competent physicians to our present Board of Health. Serious objections could also be made to several items in the details of this bill. For instance, the section relating to the registration of births, marriages, and deaths, is utterly worthless. The third project is that presented by the Citizens' , and entitled the "Metropolitan Health Bill." This is amenable to precisely the same objections as we have made to the bill introduced by Senator Ward; while, practically, it would be far less efficient. Like Ward's bill, it takes from the people and local authorities the selection of a Board of Health, and confers it on the Governor and Senate, at Springfield. Like Ward's bill, it creates a long list of new and additional city officers and employees, requiring a correspondingly large additional expenditure of money annually. But, unlike Ward's bill, it does not fix the salary of the members of the Board of Health, or provide for the appointment of a full corps of Police. It allows the Common Council to fix their , thereby making the officers perform the difficult task of serving two masters; the Governor for their appointment, and the Council for their pay. Again, by depending in part upon the ordinary police for executing the orders of the Health Board, it places the police in the equally embarassing position of to the orders of two separate and independent Boards a plan that never has and never will work satisfactorily in practice. In conclusion, we cannot refrain from again expressing the opinion, that a single amendment to our present laws, for the addition of three competent and thoroughly members of the medical profession to the present Board of Health, with the aid of one additional Clerk, as Register of Vital Statistics, would result in rendering our Health as efficient and beneficial to the interests of the city, as it could be by any number of new and expensive schemes. It would require but one police organization, capable of being or diminished, as public exigencies might require, and practically amenable to but one Board. It would require a larger ratio of medical to the non- intelligence in the Board of Health, than is proposed in either Ward's bill, or that of the Citizens' Committee. of requiring an annual aggregate increased tax upon the city of $75,000 or $100,000 for salaries of new' officers and agents, it would require for the three additional members of the Board of Health and the Register of Vital Statistics an of not over $5,000. It would also,leave our City far less complicated in its details, and, in all its strictly local interests, under the control of its own citizens, where it properly belongs. All of which is respectfully submitted. N. S. DAVIS, ) R. C. HAMILL, V Committee. J. P. ROSS, J Medical Department of University of Michigan. We have seen in some of our exchanges, a statement of the number of Medical Students in the University of Michigan, by the assertion that the large number congregated there could not have been drawn thither by the small pecuniary charges, as the aggregate of attendance is greater, owing to the length of the Lecture-term, than in any other school in the North-west. The entire falsity of such a statement is shown by the following facts: The fee for admission to the Medical Department of the Michigan University is, for students in the State $10, from out of the State $20, paid but once. The Lecture-term being six months, allowing $25 per month for board, would make a total necessary expenditure for the full term of $160 for the student of the State, and $170 for students from other States. The Chicago Medical College, in this city, has a Lecture-term of full five months. If we put board here at the same rate as supposed for Ann Arbor, namely, $25 per month, the cost of attending the regular annual course here, would be as follows: Five months board, at $25 per month, $ 125 00 Lecture fees, 50 00 Matriculation fee, 5 00 Dissecting fee, 5 00 Hospital fee, 6 00 Total,_______________________________ $191 00 Clinical Items. A subscriber wishes to know how to cure "an obstinate, tormenting, intolerable itching, of years ," either in the genital organs of the female or around the anus of the male. The following cases may answer his purpose: Case I. Mrs. B., a married lady, aged about 25 years, had been for several years subject to periodical attacks of puritus pudendi, or intolerable itching of the labia and vulva. She generally suffered most from it after the menstrual periods, and it was generally accompanied by a thin leucorrhoeal discharge. She was placed on the following treatment: 1^. Ext. Hyoscyamus, SOgrs. Sulph Ferri, 30grs. Pulv. Aloes, 15grs. Blue Mass, lOgrs. Ext. Nux Vom., lOgrs. Mix and di vide, into thirty pills. One to betaken before breakfast and dinner each day. For local use she was directed a solution of borate of soda (borax), 5iij and sulphate of , 20grs., in water, one pint, the vulva to be wet with it , and a small quantity injected into the vagina each night and morning. Under this treatment the patient recovered, without any return of the disease. Case II. Mrs. W., aged 40 years, had been very severely troubled with the same disease several months, without any to the menstrual periods. The same solution of borax and morphine, applied locally, and the use of eight drops of Fowlers's arsenical solution, taken before each meal, in a spoonful of sweetened water, and continued for about four weeks, resulted in a cure. Both patients were required to live on plain food and to avoid all stimulating drinks. Case III. Mr. G., aged 30 years, sanguine temperament and full habit, had pruritis of the anus for three years. the itching would be intolerable for several days and then better for a week or ten days at a time. On examination, the skin, over a circle of an inch, around the opening of the , was thickened, slightly fissured, and whiter than usual, lie was directed to take eight drops of Donovan's solution each meal time, and the affected surface was wet with the liquid persulphate of iron, o.f the strength usually found in the drug stores, every third day. After four local applications he was entirely relieved. He continued to take the drops for three weeks, and although more than one year has elapsed the disease has not returned. I recollect treating several cases of old chronic cases of ani sucessfully, by applying locally, each night and , the following ointment: ly. Iodide Sulphur, 3ij Oil Tobacco, + 2gtts. Simple Crete, SSij Attention should always be paid to the general health, and especially to. the condition of the digestive organs. ^iie Chair of Surgery in Rush Medical College. According to statements in the daily papers of this city, the chair of Surgery made vacant by the death of the late Prof. I). Brainard, has been filled by the appointment of Moses Gunn, of Detroit, Professor of Surgery in the University of Michigan. It is also stated that Prof. Gunn has accepted the appointment. City Mortality. The following is the report of the of the mortality of the City of Chicago for the month of December, 1866: CAUSES OF DEATH. Accidents, u Asthma, 2 Bronchitis,____________________ 1 Burned,_________________________ 1 Cancer, 2 Childbed, 2 Cholera Infantum,_______________ 1 Consumption, 42 Convulsions,____________________35 Croup, 7 Cold____________________________ 2 Chicken Pox,____________________ 1 Congestion of Brain,____________ 3 Congestion of Lungs,____________ 2 Decline,________________________ 1 Delirium Tremens,______________ 1 Diarrhoea,______________________ 5 Diphtheria,___________________<<. 15 Disease of Heart, 8 Disease of Liver,______________ 2 Disease of Lungs,______________ 7 Disease of Brain,______________ 6 Dropsy,_________________________ 7 Drowned,________________________ 2 Erysipelas, 3 Fever, Childbed, 2 Fever, Remittent,_______________ 4 rever, scarlet,_______________ 13 Fever, Typhoid, 4 Fever, Typhus,_________________ 1 Fever, not stated, 1 Hydrocephelus,_________________ 7 Inflammation of Kidneys,_______ 1 Inflammation of Bowels,________ 9 Inflammation of Lungs,_________ 6 Inflammation of Liver,_________ 1 Marasmus,______________________ 1 Old Age, k 15 Palsy,_______________________ 2 Pneumonia,_____________________ 7 Phthisis Pulmonalis,___________ 1 Spasms,________,_______________ 1 Spinal Meningitis,_____________ 1 Suffocation,___________________ 2 Small Pox,_____________________ 2 Suicide, ______________________ 1 Stillborn,____________________ 10 Teething,______*_______________ 3 Whooping-Cough.________________17 Gun shot Wound,________________ 1 #White Swelling, 1 Unknown,______________________ 33 Total,_________________309 ages of the DECEASED. Under o years, loo ; over o and under 1U years, 19; over 10 and under 20, 15; over 20 and under 30, 28; over 30 and under 40, 34; over 4o and under 50, 16; over 50 and under 60, 11; over 60 and under 70, 11; over 70 and under 80, 12; over 80 and under 90, 6; unknown, 4. Total, 309. N \TTVTTTFS Chicago,____________128 Other States, 63 Belgium, 1 Bohemia, 2 Canada,__________1__ 2 England,____________ 5 Germany, 47 Ireland,____________38 Norway, 6 On the Sea,_________ 1 Sweden, 5 Scotland,___________ 4 Wales,______________ 1 Unknown,____________ 6 Total, 309 DIVISIONS OF THE CITY. North,..... 75 | South,....105 | West,....129 | Total,... 309 Total number during the month of November,_______________ 382 Decrease from last month, 73 Total number last year for the month of December,________ 333 Dr. Conneau. It bus been remarked that nearly every profession but that of medicine was represented in the French Senate. This anomaly has struck the Emperor, it would Appear, as the Evenement announces that his Majesty's physician, Dr. Conneau, is to be promoted forthwith to a seat at the . |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34766 Obstetrics/Gynecology Oncology Clear Cell Ovarian Carcinoma With C1 Lateral Mass Metastasis and Pathologic Fracture: A Case Report Muacevic Alexander Adler John R Sassine Dib 1 Rogerson Daniella 2 Banu Matei 3 Reid Patrick 4 St. Clair Caryn 1 1 Gynecologic Oncology, Columbia University Department of Obstetrics and Gynecology, New York, USA 2 Obstetrics and Gynecology, Columbia University Vagelos College of Physicians and Surgeons, New York, USA 3 Neurosurgery, Columbia University Department of Neurological Surgery, New York, USA 4 Neurosurgery, Columbia University, New York, USA Caryn St. Clair [email protected] 8 2 2023 2 2023 15 2 e347668 2 2023 Copyright (c) 2023, Sassine et al. 2023 Sassine et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Osseous metastasis (OM) in ovarian cancer (OC) are rare, with an incidence ranging from 0.8% to 2.6%, and are associated with poor prognosis. The available literature on their management and associated complications is scarce. We report a case of International Federation of Gynecology and Obstetrics (FIGO) stage IVB clear cell epithelial OC (EOC) who presented with neck pain. Imaging revealed multiple cervical spine metastases with left vertebral artery encasement and concurrent C1 lateral mass compression fracture, without neurological deficit, requiring occiput to C2 posterior instrumentation and fusion. Early OM may be associated with shorter overall survival, and survival after OM diagnosis is on the order of months. Management of OM should include a multidisciplinary team and may require surgical stabilization in addition to systemic chemotherapy, local radiotherapy, and osteoclast inhibitors. ovarian clear cell carcinoma vertebral fusion pathological fracture osseous metastasis ovarian carcinoma The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Ovarian cancer (OC) is the most common cause of gynecological cancer death . Direct spread to adjacent pelvic organs, peritoneal spread, and metastasis via the lymphatic route are common, while hematogenous spread to further sites such as the liver, lung, bone and brain occur less commonly and have a poor prognosis [2-4]. Osseous metastases (OM) in OC are among the rarest, with incidences between 0.82% and 4.0%, and may occur by direct invasion, hematogenous, lymphatic, and transperitoneal spread . The vertebral column is the most common site, though case reports document findings throughout the axial skeleton and pelvis . OMs are associated with shorter overall survival . A recent study found the 1-, 5-year survival after OM diagnosis were 33%, 15%, and 8%, respectively . Skeletal-related events (SREs) and neurovascular compromise secondary to OM have rarely been described. Here, we report a case of International Federation of Gynecology and Obstetrics (FIGO) stage IVB clear cell epithelial ovarian cancer (EOC) complicated by C1 vertebral metastases with vertebral artery involvement and C1 vertebral fracture, necessitating occiput to C2 posterior instrumentation and fusion and palliative C2 neurectomy. Case presentation A 59-year-old African American P0 (nulliparous) with a history of uterine leiomyoma presented with abdominal pain and bloating. A transabdominal sonogram demonstrated multiple large, complex adnexal masses. Staging computed tomography (CT) chest, abdomen and pelvis was suspicious for metastatic ovarian carcinoma, with bilateral complex adnexal masses, peritoneal carcinomatosis, omental caking, and pericardiac, abdominal, peripancreatic, mesenteric, retroperitoneal, and pelvic lymphadenopathy. No osseous lesions were identified at the time of the initial scan. An initial consult with gynecological oncology revealed an abdominal mass above the umbilicus, pelvic masses, and a palpable left supraclavicular node. Ca-125 was 6,773. Pathological examination of interventional radiology-guided peritoneal mass biopsies had an immunoprofile compatible with a high-grade adenocarcinoma of Mullerian origin, favoring clear cell carcinoma. The tumor showed preserved mismatch repair (MMR) proteins expression (positive for MLH1, PMS2, MSH2, MSH6). Immunostain for human epidermal growth factor receptor 2 (HER-2) was equivocal and difficult to interpret on the scant cell block material with mostly cytoplasmic staining, no convincing membranous staining, score 0-1, and immunostaining for PD-L1 was limited by scant cellularity in the cell block, focal positivity with an estimated combined positive score (CPS) 3-4. Further genetic testing did not show any mutations for possible targeted therapy. The patient was diagnosed with FIGO stage IVB clear cell EOC. She received her first cycle of carboplatin, paclitaxel, and bevacizumab, with a plan for 3-4 cycles of neoadjuvant chemotherapy and interval debulking pending clinical response. After her first cycle of chemotherapy, the patient endorsed persistent neck pain of moderate severity. Magnetic resonance imaging (MRI) cervical spine revealed contrast-enhancing osseous lesions within the anterior arch and left lateral mass of C1, as well as in the C4 and C7 vertebral bodies, left articulating facet of C6 and T4 vertebral body extending into the left pedicle. There was lateral tumor extension with encasement of the vertebral artery at the C1 level. There was no evidence of epidural disease or spinal cord impingement . CT angiogram (CTA) demonstrated multiple osseous lytic lesions and a C1 lateral mass compression fracture extending to the left transverse foramen, with asymmetry of the lateral atlantodental interval measuring 8 mm on the right and 2 mm on the left. There was circumferential tumor encasement of the left vertebral artery in the sulcus arteriosus, with severe narrowing with preserved flow and no evidence of dissection . Metastatic cervical and supraclavicular lymphadenopathy were confirmed. The total body bone scan did not show further OM. Figure 1 Sagittal (left) and axial (right) MRI of the patient A. T2-weighted and B. T1 fat saturation MRI sequences demonstrating C1 lateral mass lesion (red arrow) and displacement of the vertebral artery with no epidural tumor extension or cord compression. C. Parasagittal T1 sequence demonstrating lateral tumor extension with encasement of the vertebral artery (red arrow). D. Coronal (left) and axial (right) CT angiogram demonstrating osteolytic left lateral mass lesion encasing and narrowing the vertebral artery (red arrows). The patient was admitted to neurosurgery with gynecological oncology consultation, where she continued to endorse left-sided cervical pain radiating to the occiput which worsened with movement and improved with opioids, steroids and immobilization with a hard collar. There were no focal neurological deficits, paresthesias, anesthesia, gait difficulties, or bowel or bladder dysfunction. The patient had full strength in the upper and lower extremities and an intact gait. She had no signs of myelopathy and had a negative Hoffman's sign. Given normal cervical alignment, with imaging demonstrating articular facet involvement and lateral mass fracture, this pain was considered to be caused by cervical spine instability . Figure 2 Preoperative (A) and postoperative (B and C) radiographs A. Preoperative anterior-posterior (left) and upright lateral (right) radiographs demonstrating normal cervical spine alignment. B. Postoperative anterior-posterior (left) and lateral (right) cervical spine radiographs demonstrating appropriate instrumentation placement and alignment after posterior hardware fixation of the occiput to C2. C. Postoperative anterior-posterior (left) and lateral (right) standing scoliosis series illustrating normal alignment. Urgent surgery was not indicated without neurological deficits or compressive pathology. A multidisciplinary team discussed the case to determine if surgical decompression was required prior to local radiation, and surgical intervention with occiput to C2 instrumentation and fusion was decided upon. Surgery was performed two days after diagnosis. Intraoperatively, there was extensive tumor involvement of the C1 lateral mass and posterior arch, encasing the vertebral artery and extending towards the occipital condyle. A palliative C2 neurectomy was performed for pain control. A right C1 lateral mass screw, bilateral C2 pedicle screws, and occipital keel plate with three bicortical screws were placed. The fusion bed was prepared by decorticating the occiput and bilateral C1-2 joint spaces with the placement of allograft over the decorticated spaces. Intraoperative monitoring was stable throughout and the patient awoke at neurological baseline. Postoperatively, the patient endorsed significant improvement of her cervical pain. Incisional pain was controlled with methocarbamol, gabapentin and hydromorphone PCA (patient-controlled analgesia). Radiographs demonstrated excellent instrumentation placement and alignment . The patient ambulated without assistance on postoperative day (POD) 1 and was discharged in stable condition on POD3. Radiographs of the spine confirmed stable spinal fusion rods three weeks postoperatively . There was complete resolution of the cervical pain. The patient received her second cycle of carboplatin and paclitaxel four weeks postoperatively; at that time, progression of cervical lymphadenopathy was noted on exam. She since received two additional cycles three and six weeks later, with a downtrending CA-125 of 2,301. Bevacizumab has been held to allow for surgical healing. Denosumab injection of 120 mg every 4 weeks, calcium, and vitamin D were initiated postoperatively, with a plan for palliative radiation therapy (RT) of 20 Gy in 5 fractions to C1-2 and associated hardware to prevent disease progression. Discussion This report illustrates a unique complication of OM in EOC. Given the rare nature of these lesions, the literature is sparse. Four retrospective studies comment on OM in the context of other rare OC metastases . In these, the incidence of OM ranged between 1.2% and 4%. Deng et al. analyzed 1481 patients with stage 4 ovarian carcinoma using the Surveillance, Epidemiology, and End Results (SEER) database. OM was found in 3.74% of the entire cohort with a median survival time of 11 months for the patients with OM. Dauplat et al. examined 255 patients with EOC with stage 4 disease. Only four patients (1.6%) had OM with a median survival of 9 months. Gardner et al. used the SEER database to determine the pattern of the distant metastases at the initial presentation in patients with gynecological cancer and found that OM was present in 4% of the patients with ovarian carcinoma, vs 13% and 23% of patients with uterine and cervical cancer, respectively. Additionally, four retrospective studies looked specifically at OM in OC (Table 1). Table 1 Four retrospective studies examine osseous metastasis (OM) in ovarian carcinoma Publication - Author, Year Cohort - No OM - No (%) Overall Survival - Months Survival After OM Diagnosis - Months Most Commonly Involved Site Ak et al., 2021 (2) 736 19 (2.60) 38.1 13.6 Vertebral Sehouli et al., 2013 (5) 1,717 26 (1.50) 50.5 7.2 Vertebral Zhang, C. et al., 2019 (6) 32,178 352 (1.09) 50.0 5.0 Not Reported Zhang, M. et al., 2013 (7) 2,189 26 (0.82) Not Reported Not Reported Vertebral Ak et al. examined 736 OC patients and found OM in 2.6%; OM was mostly seen with clear cell histology similar to our case report. The vertebrae, as in our patient, were most commonly involved, though patients often had multiple sites of involvement. Pain was the most common presenting symptom, but was absent in over 50%. Unlike our case, out of the two patients presenting with pathologic fractures, one had neurologic deficit. Patients were managed with palliative RT and bisphosphonates. Only advanced, inoperable disease at presentation was associated with a shorter time to development of OM. Median overall survival in OC patients with OM was 38.1 months and median survival after OM diagnosis was 13.6 months. Patients who had OM at the time of diagnosis of their OC had a shorter median OS than those who developed OM later on, 6.1 vs 63 months, respectively. To note, although insignificant, overall survival was shorter in patients with clear cell histology after OM than in patients with a different histologic subtype ( 7 vs 22 months) . Sehouli et al. examined 1,717 patients and found OM in 1.5%. The vertebral column was the most common site, most frequently in the lumbar, followed by the thoracic and cervical regions. Multiple OM were seen in the majority of patients, as in our case. Pain was the presenting symptom in 66%; 9% had impaired mobility unlike our patient, and 4% had neurologic symptoms. Pathologic fractures were reported in 33%. Most patients were treated with bisphosphonates; of those treated, 26% went on to develop pathological fractures and required surgical intervention. RT of OM was performed in a minority of cases for pain control and for SRE prevention. OM was noted to progress in 75% of cases despite systemic and local therapy. The median overall survival of the entire cohort was 50.5 months; patients with early OM had significantly shorter overall survival than those with later OM, 11.2 vs 78.4 months; to note, the overall survival rates were calculated regardless of the histology of the disease. By far, the largest study on this topic, Zhang, C. et al. , examined 32,178 Surveillance, Epidemiology, and End Results (SEER) database OC patients and found the prevalence of OM was 1.09%. OM were more common in women over 65, Black and unmarried women. Similar to our patient, most of those patients had an advanced stage, poorly differentiated grade, non-serous type, elevated CA-125 and had concurrent distant metastasis. The median overall survival for the entire cohort was 50 months, whereas the median overall survival after OM diagnosis was 5 months only. Among examined variables, only surgery at the primary site was associated with significantly longer survival, 18 vs 3 months for primary site surgery versus no surgery. Survival was significantly shorter in patients with a non-serous histology without commenting specifically on the clear cell carcinoma histology . Lastly, Zhang, M. et al. found OM in 0.82% of 2,189 OC cases. The majority of OM were vertebral (12 cervical, 10 lumbar, seven thoracic), eight were pelvic, five were limb, two were sternal, and one was rib. Over half presented with pain, 35% with difficulty walking, and 15% were asymptomatic. Similar to our case report, the majority of cases with OM were in advanced disease and EOC, and most of them were managed with chemotherapy and RT. Cases that were managed with combined chemotherapy and RT had significantly longer survival than those treated with either agent alone, 14.2 versus 11 versus 8.4 months for combined therapy, RT alone, and chemotherapy alone, respectively . There is a paucity of data regarding the management of OM with or without SRE in OC, and the current management of lesions is based on that for other solid tumors. Diagnosis includes history and physical, and imaging options include radiographs, CT and MRI; MRI is the modality of choice for vertebral lesions. A multidisciplinary team approach is often needed for the management of such rare cases, including radiology, orthopedic surgery, neurosurgery, radiation oncology , gynecological oncology, palliative and pain medicine . All of these modalities were utilized as illustrated in this case. Conclusions In conclusion, we present a unique case of clear cell EOC with vertebral OM resulting in pathologic C1 fracture requiring surgical stabilization, further complicated by vertebral artery encasement and narrowing. OM secondary to OC are rare and often present with pain though rarely with neurologic deficit. The risk factors for the development of OM are poorly understood but may include clear cell EOC as in this case, and lesions are more commonly described in those with late-stage disease. Patients who present with OM at the time of diagnosis or early in their disease course may have shorter overall survival than those with later OM. However, survival after OM diagnosis is on the order of months. Surgery at the primary site and combination chemotherapy and RT may prolong survival. These findings are based on limited retrospective studies, and further examination of risk factors and prognostic implications of OM in OC is needed. Human Ethics The authors have declared that no competing interests exist. 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The increased attention drawn to the negative environmental impact of the cattle industry has fostered a host of research-driven initiatives among relevant actors. While the identification of some of the most problematic environmental impacts of cattle is seemingly more or less unanimous, solutions are complex and might even point in opposite directions. Whereas one set of solutions seeks to further optimize sustainability pr. unit produced, e.g., by exploring and altering the relations between elements kinetically moving one another inside the cow's rumen, this opinion points to different paths. While acknowledging the importance of possible technological interventions to optimize what occurs inside the rumen, we suggest that broader visions of the potential negative outcomes of further optimization are also needed. Accordingly, we raise two concerns regarding a focus on solving emissions through feedstuff development. First, we are concerned about whether the development of feed additives overshadows discussions about downscaling and, second, whether a narrow focus on reducing enteric gasses brackets other relations between cattle and landscapes. Our hesitations are rooted in a Danish context, where the agricultural sector mainly a large-scale technologically driven livestock production contributes significantly to the total emission of CO2 equivalents. critical kinetics planetary boundaries technical solutions feed additives livestock Jevons' paradox Denmark anthropology Independent Research Fund Denmark through the project Cattle Crossroads. Researching Danish Animal Production for the Future0217-00171B This research was funded by the Independent Research Fund Denmark through the project Cattle Crossroads. Researching Danish Animal Production for the Future accessed on 9 February 2023), Grant no. 0217-00171B. pmc1. A Commentary on Feed Additives as Solutions to Cattle's Climate Impact Since 2006, when the much-quoted FAO report Livestock's Long Shadow was published, increasing attention has been paid to the environmental challenges brought about by the cattle industry . Problems pile up. Today, agriculture occupies about 38% of Earth's terrestrial surface . Industrial livestock requires enormous amounts of feed, the production of which takes up more than three quarters of all agricultural land on the planet . This leads to massive deforestation, which proliferates into yet other problems such as soil erosion, nutrient leaching, and loss of biodiversity. Further, the gases emitted from the rumination processes of cattle make up a substantial portion of the greenhouse gases (GHG) that spread through the atmosphere, heating up our globe. In particular, enteric fermentation has been targeted and understood as key to controlling and potentially reducing the climate impact of cattle. In response, a host of research-driven initiatives among relevant actors has emerged. As this special issue suggests, the time has now come to collect knowledge on forage and feedstuff digestion kinetics in ruminants in order to meet the mounting pressures to reduce enteric methane production. The fact that domesticated animals produced around the world (mainly cattle, pigs, and poultry) now outnumber wild mammals and birds by a factor of ten no doubt adds pressure to this predicament . Yet, for all the weight this ratio puts on the world's ecosystems, the scientific knowledge base supporting the industry's transition towards more sustainable futures most often comes from very specific areas of the natural sciences. Nourishing this quantitatively large global production of a few domesticated animal species, then, is the continuous production of scientific knowledge and research related to issues such as feed intensification, genetics, and health. For cattle, the obvious aim is to further optimize and increase dairy and beef production industries that in Euro-American production systems are premised on principles of high cost efficiency, achieved by keeping large animal herds on small but intensively managed areas, with easy access to feed products that are often both nutritionally optimized and imported from overseas. While the identification of some of the most problematic environmental impacts of cattle is seemingly more or less unanimous, solutions are complex and might even point in opposite directions. As is clear from this special issue, one set of solutions points to interventions into the causal relations of elements kinetically moving one another inside the cow's rumen. More specifically, feed additives of various sorts are developed to decrease the generation of methane, thus targeting climate change. Surely, these interventions are valuable after all, in these critical, increasingly hot times, why oppose GHG reductions in whatever form and by whatever means? Nonetheless, in this short contribution, we raise two concerns regarding a focus on solving emissions through feedstuff development. Whereas knowledge about the possibilities of technological optimization is important, we suggest that broader visions of the possible negative outcomes of further optimization are also needed. Notably, we are concerned for two reasons: First, the development of feed additives may overshadow discussions about downscaling. Second, a narrow focus on reducing enteric gasses by manipulating a set of kinetic causal processes inside the rumen may bracket other relations between cattle and landscapes. Both of these consequences, we suggest, can potentially limit the scope of climate impact mitigation in relation to cattle. Below, we substantiate these reservations and go on to probe how the development of feed additives sit with ideas about absolute sustainability and safe operating spaces for humanity. Our approach to the issue of feed additives and cattle production is rooted in anthropology and cultural history. We thus work using a method of ethnographic fieldwork among stakeholders engaged in Danish cattle production, and we conduct document analysis of, e.g., policies and public discussions, just as we look to archival and historical literature to trace earlier connections between state making and livestock production in Denmark. 2. Intensified Danish Livestock Production With Feral Effects Within the agricultural sciences, an answer to the problematic climate impact of cattle has often been to further intensify animal production cf. . This response, however, rests on a modernistic assumption that more-than-human lives are essentially controllable by humans. The ecological crisis that we are presently witnessing does indeed testify to human activities and projects on a massive scale, but not to human control over causal relations in the more-than-human world. This is what we mean by feral kinetics in this opinion's title; we want to indicate that projects in which (causal) relations were once set in motion by humans through intentional projects often spur various unintended effects . Surely, no one set out to change the climate through animals. A brief historical look at the Danish context in which our research is rooted shows how intensification has come about gradually and in response to a host of societal, political, and historical circumstances that jointly make up what livestock came to be. In Denmark, the agricultural sector is responsible for 27.1% of national GHG emissions (excl. land use, land use change, and forestry (LULUCF)), of which intensive livestock production is a prominent contributor . Danish livestock production is often positively framed in public discourse as economically and environmentally cost-efficient when measured at the scale of singular products. Yet, there is reason to question the hidden costs of this mode of calculation, which often fails to include GHG emissions and global environmental impact derived from the livestock industry's dependency on feedstuffs, and thus, on land cultivation and deforestation both in Denmark and overseas, as scientists have also pointed out . In Denmark, as in other European countries, agricultural production has historically informed the organization of government, business, and civil society, and politicians still identify Denmark as "a farming country" see, for example, . It was through the workings and on-going development of the agricultural sector that Denmark as a nation underwent some of its most significant historical changes, not least that of industrial modernization . More specifically, 20th-century industrial modernization in the agricultural sector came about through the emergence of a strong, export-oriented livestock industry see, for example, . For instance, the number of pigs in Denmark has increased from 301,000 in 1860 to 12.2 million today, which is now more than twice the Danish population . The historical emergence of a strong livestock sector not only changed the welfare and fortuity of rural communities. It also changed the physical appearance of the animal bodies that would increase the reach of Danish industrial interests by yielding more meat and milk per animal than they ever had before, which was achieved, in particular, through the industry's adoption of scientific approaches to rational and optimized feeding . Our point is that during the same historical processes that have made Danish agriculture synonymous with a large livestock industry, the livestock industry has itself become synonymous with high export and feedstuff dependency, as both are integral to how cost efficiency is construed in the industry. However, if the purpose of novel feed additives is to mitigate the climate impact of cattle production, it seems pivotal to ask whether such a high dependency on feeds should itself become a site of scientific intervention in the industry. 3. The Issue of Scale and Re-Bound Effects Indeed, to pinpoint our first reservation, focusing on greening the enteric digestion process by making 'enhanced' rumens less harmful, and politically prioritizing this effort, may engender a so-called rebound effect where decreased methane emission pr. cow is evened out by an increased scale of production a mechanism sometimes summarized as Jevons' paradox. In other words, addressing the issue of methane emission through conceptualizing the rumen as a discrete and singular site of intervention may occlude the concern both with a potential rise in scale and with other the well-known, environmentally harmful effects of maintaining present-scale livestock production . Inadvertently, we fear, the development of feed additives may contribute to the status quo, thus foreclosing difficult discussions about how we might best use arable land (for feed or food), and about the number of cattle the world's ecologies (including atmospheric greenhouse gasses) can actually support. Aspiring for sustainability as genuine change on a planet with limited resources and imminent tipping points requires that we think in absolute terms. Adjustment and improvement miss the mark. 4. The Issue of Other Ecological Relations Our second hesitation is that a narrow focus on kinetics inside the rumen may eclipse wider ecological relations put into motion by the altered processes in the rumen. As the many ecological crises we are witnessing make clear, humans can no longer be seen as being in full control of various processes on earth what we referred to above as the 'feral' nature of the non-human world in this day and age. Processes once perceived as controllable have proven not to be so, resulting in unintentional global effects that are both distributed and caused by human actions . With regard to feed additives specifically, these may work on other relations than those within the rumen, making it urgent to widen the scope of research. We must be careful not to make yet another potent feral product by limiting our view of what the problems and solutions are. 5. Thinking with Absolute Sustainability To summarize, our hesitations with regard to feed additives concern, first, how additives may maintain status quo in terms of the scale of cattle production, and second, how they may engender unanticipated ecological effects. On both accounts, we suggest, there is a need to consider how technological and natural scientific solutions to the methane issue relate to a planet with boundaries that limit a safe operating space for humanity . In short, we want to question how feed additives as a means of reducing methane emissions sit with ideas about absolute sustainability . If, as we suggest, technological solutions 'work back' on the identification of what the problem even is, the result is too easily a circular argument; we can only see the problems that we think we can solve by way of technology rather than by a just and green societal transition, sanctioned in progressive politics. In making this argument, and exploring how it works in a Danish context, we draw on the model of planetary boundaries originally suggested by Rockstrom et al. . In 2017, Campbell et al. further worked with the model, arguing that agricultural production is, indeed, a main driver for the eco-system changes occurring, particularly within spheres where the planetary boundaries are transgressed. Our point is simply this: If the impact of agricultural production already exceeds 'permissible' limits, something has to change fundamentally. Making things relatively better is just not enough. This is particularly important in agro-industrially intensified countries such as Denmark where livestock industries are (dis)proportionately large; we must question both issues of scale and of unintended side effects. Choices remain to be made that observe planetary boundaries. Now, the scientists and companies who develop feed additives would probably agree that this is just one tool among many others. We want to stress that it is not feed additive development per se that we take issue with. Rather, looking to the recent political work of pushing for a green transition of the Danish cattle industry, we are concerned with the way feed additives have emerged on the political stage. Here, additives are presented as the obvious solution to a universal problem. However, the problem that additives are key to solving i.e. a massive cattle industry, nourished by feed that causes deforestation and in a monocultural logic can remain untouched. Further, the wider effects of the additives have yet to be documented. 6. A Couple of Examples To substantiate our argument, below we will look at a couple of instances where feed additives are discussed in a Danish context. We do so via ethnographic fieldwork, where we engage with stakeholders such as researchers and politicians, as well as with various written sources. Our method is ethnographic in the sense that we trace relations and generate analyses in dialogue with the field; as such, we explore what feed additives may be as they are produced and discussed by people who develop, implement, or entrust them with positive effects for mitigating climate change see also . In 2021, all political parties but one represented in the Danish parliament signed an agreement on the green transition of agricultural production in Denmark . The agreement, launched as historic and ambitious, commits to reducing GHG emissions from agriculture by 55-65% by 2030 compared to 1990 levels, in addition to reducing nitrogen and phosphorous run-off into waterways in order to comply with EU regulation. To reach this binding target, curiously, the agreement starts with listing a number of caveats, all to the effect that the goal must be achieved without decreasing agricultural productivity, nor compromising public finances and Denmark's competitive edge with regard to agriculture. Instead, the agreement highlights the continued prioritization of developing and implementing new technologies. Indeed, trust in (near) future technological solutions is so great that the historically ambitious deal, as it is now, ensures less than a third of the promised reduction. More precisely, the agreement specifies a reduction of 1.9 tons of CO2e out of the 6.1-8 tons which is the overall target for the agricultural sector, equaling a reduction in GHG emissions of 55-65% from 1990 emission levels. The rest of the required reduction, the agreement states, will be brought about by new technologies that have yet to be developed and implemented. Two overall arenas for technological innovation are singled out in the political agreement: namely, the curbing of emissions from manure from all production animals and enteric fermentation in livestock. The agreement states as follows: "It will be a continued priority that new tools, such as feed additives, are transferred as quickly as possible to the implementation track, and that the demand [for reduced GHG emissions] is adjusted according to what can be realized" (p. 4). What we want to point to here is that the means for a very large proportion of the CO2 reduction that the agreement commits to have yet to be invented, and that reduction targets are adjustable. In other words, the binding and historic agreement on the green transition of Danish agriculture is highly negotiable, and, further, dependent on uncertain technologies. All the while, the agreement lists a number of other priorities that are not up for negotiation such as productivity, employment, public finances, and rural development. This leaves it up to innovative technologies to find the remaining (majority) of the promised GHG reduction. Accordingly, as we see it, there is a substantial risk that the agreement's limited focus on climate change mitigation will lead to so-called "burden-shifting" see as the negative impacts of feed production and consumption are only considered with regard to a single planetary boundary, as opposed to asking how feeds can become sustainable in an absolute sense, heeding all biospheres. This is to say that optimizing feeds as a means to mitigate GHG emissions specifically risks overlooking equally important and environmentally detrimental processes such as the eutrophication or acidification of waterbodies. If global feed production and consumption on the whole are largely left unchanged, the use of feed additives to mitigate GHG emissions risks relocating instead of actually solving the problems caused by livestock production. By leaving it up to hopeful investments in future technologies to reduce GHG, we are not forced to consider the number of cows, nor the other effects of an unchanged scale. Another example from our fieldwork sheds light on the potential unintended effects of implementing feed additive solutions. Below, we provide more detail regarding some of the ways that feed additives work in the practices and discussions of industrial agriculture stakeholders. At the annual Cattle Congress 2022, the head of the Cattle Section in SEGES Innovation the Danish agricultural interest organization's independent research unit together with a researcher from the same organization, gave a talk under the headline "Climate Requirements in the Agricultural Agreement" the same deal mentioned above. From her point of view, climate requirements can be answered by two distinct means of action: the handling of digestion and manure while not compromising another distinct theme, namely animal welfare. In this way, she framed the problems involved in having an agricultural sector accounting for over one fourth of Danish GHG emissions by setting a very particular triangular frame within which one should think, talk, research, and act in relation to climate requirements: welfare, digestion, and manure. She mentioned that feeding with additives could reduce 20% of the 0.17 million tons CO2 that needed to be reduced by 2025, but also expressed frustration with the limited amount of money reserved to introduce and implement a new product approved by the European Union in the spring of 2022. New routines on farms need to be developed and supported, and potentially skeptical farmers should be convinced that milk yields will not decrease on account of the new additive. The researcher assisted her and elaborated on the tools needed to reach the goals in the climate law and the agreement discussed above. These were tools that altogether confirmed the dictum of 'more for less' (higher yield and more efficiency in feed and in producing bodies) that has made Danish livestock production competitive on a global market despite high production costs. Just as important, the presentation repeated a dictum that has recently become a standard answer to green goals: optimization equals sustainability. The researcher then went on to talk about the possibilities of reducing methane by changing diets rapeseed and a handful of feed additives were mentioned, along with the possibilities and challenges these feeding options spurred. He singled out one new product and stated that the climate impact of milk will decrease by 17%, adding that if all conventional producers would implement the additive, the reduction targets for 2030 could be met. Thus far, he continued, the additive has only been tested on Holstein cattle. He wrapped up his presentation by saying that if any of the farmers present were interested in testing the product on their animals, they should feel free to get in touch. What interests us here is that the talk can be seen as combining the launch of a solution with calling for further tests, thereby mimicking the agreement above in its expectations for future effects of something yet to be fully developed and tested. Interestingly, a person in the audience raised his hand and questioned the manure from cattle fed with the approved additive, asking whether the emissions from it altered when distributed on the fields. In response, the researcher answered that the amount of product used is so small, and further that the product is processed so quickly in the cow that it was very unlikely that it would have an effect elsewhere, outside the rumen. However, he continued, researchers in Canada have recently conducted a study where they pointed to higher emissions from manure in the fields as an effect of the application of feed additives. Interestingly, this Canadian study or hesitation, we could call it did not seem to 'alter' the Danish researcher's hopes for feed additives once they have been further tested. Chatting with the researcher after the talk, it became clear that potentially increased emissions on the fields were understood as a problem for another research field namely, that which deals with manure handling. For him, it seemed, there were so many kinetic relations to be explored within the rumen, and understanding what happens later, out on the fields, would be a theme to be researched once processes in the rumen are more fully understood. Our point here is to highlight the decoupling of what goes on in the rumen upon applying feed additives from the 'afterlife' of such an intervention. 7. Conclusion: Heeding all Biosphere Domains at Once To conclude, what we argue and the reason for our reservations towards the prevalent kind of solutionism offered by the development of feed additives is that it takes a very particular perspective on the cow for its rumen to be the sole target of any intervention. From this perspective, the cow is a singular unit from within which technology can decrease methane emission. To the contrary, as anthropologists, we would see any cow as a set of relations, ranging from the microbial level to global issues of deforestation . While we do not oppose feed additives as such, we do hold that they risk building on and maintaining a tunnel vision, as also described above, that allows for a curious disconnection of cattle's rumen from other cattle-related processes and decisions, including the discussion of scale and other effects than GHG emissions. In Denmark, and elsewhere, other biosphere problems are also apparent as seen from the model of planetary boundaries. Not least, we have huge problems with the leaching of N and P severely affected waterways in Denmark, as a result of the scale of animal production, regardless of its climate efficiency when measured pr. kilogram of, e.g., milk. Put bluntly, as we see it, if we care about the immediate threats to the safe operating space for humanity, it makes little sense to assess the climate impact of cattle pr. singular rumen. One direct insight from the principle of absolute sustainability is that all agricultural resource activities impact many of the nine biosphere domains. Accordingly, solutions need to follow suit. We cannot afford the luxury of solving one problem at a time. Acknowledgments We are very grateful to Hanne Helene Hansen for inviting us to contribute to this special issue, and to the three anonymous reviewers for helpful feedback. We also want to thank Liza Rosenbaum Nielsen, Kari Eriksson, and Camilla Kirketerp Nielsen for sustained and challenging discussions. Author Contributions Conceptualization, N.B., S.B., and F.H.; methodology, N.B., S.B., and F.H.; formal analysis, N.B., S.B., and F.H.; investigation, N.B., S.B., and F.H.; data curation, N.B., S.B., and F.H.; writing original draft preparation, N.B. and F.H.; writing review and editing, N.B., S.B., and F.H.; project administration, F.H.; funding acquisition, F.H. All authors have read and agreed to the published version of the manuscript. Institutional Review Board Statement Not applicable. Informed Consent Statement Not applicable. The article builds on publicly available sources. Data Availability Statement Not applicable. Conflicts of Interest The authors declare no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
A 13-year-old neutered, blue-eyed female Siamese cat with a bodyweight of 4.8 kg was admitted for enucleation of the right eye. An ultrasound guided retrobulbar block with 1 mL of ropivacaine was performed under general anaesthesia. When the tip of the needle was visualised inside the intraconal space, negative aspiration of the syringe before injection and no obvious resistance during injection were confirmed. Instantly, after ropivacaine was administered, the cat became apnoeic, and its heart rate and the blood pressure increased significantly for a short period of time. During surgery, the cat needed cardiovascular support to maintain blood pressure and was under continuous mechanical ventilation. Spontaneous breathing returned 20 min after the end of anaesthesia. Brainstem anaesthesia was suspected, and after recovery, the contralateral eye was examined. A reduced menace response, horizontal nystagmus, mydriasis, and absence of the pupillary light reflex were present. The following day, mydriasis was still present, but the cat was visual and was discharged. The inadvertent intra-arterial injection of ropivacaine was suspected to be the cause of the spread into the brainstem. To the current authors' knowledge, possible brainstem anaesthesia has only been reported in a cat 5 min after a retrobulbar block but never instantly. brainstem anaesthesia cat retrobulbar block intraarticular injection This research received no external funding. pmc1. Case Presentation A 13-year-old neutered, blue-eyed female Siamese cat with a bodyweight of 4.8 kg was scheduled for enucleation of the right eye due to panuveitis and secondary glaucoma. The menace response and dazzle reflex were normal on the left eye. Apart from being geriatric, the cat had no other comorbidities in her clinical history. Her preoperative clinical examination was normal without any nystagmus noticed or reported during her ophthalmological examination, and her biochemistry and haematological results were unremarkable. The cat's current medications included meloxicam and chloramphenicol ointment. For preanaesthetic medication, a combination of methadone (0.2 mg/kg) (Methadyne, Jurox, Leatherhead, UK), midazolam (0.3 mg/kg) (Hameln pharma Ltd., Gloucester, UK), and alfaxalone (1.5 mg/kg) (Alfaxan/Multidose, Jurox, Dublin, Ireland) was mixed in the same syringe and administered intramuscularly (IM). Anaesthesia was induced with a total of 1.8 mg/kg of alfaxalone administered through a right cephalic intravenous cannula. Intravenous fluid therapy was administered during anaesthesia at a rate of 3 mL/kg/h (Hartmann's solution; Aquapharm No. 11; Animalcare LTD; York, UK). Anaesthesia was maintained with sevoflurane (Sevohale, Chanelle, Galway, Ireland) in 100% oxygen administered through a Mapleson-D breathing system. Throughout anaesthesia, heart rate and rhythm with electrocardiography, haemoglobin oxygen saturation (SpO2), oscillometric blood pressure, oesophageal temperature, capnography, and spirometry were continuously monitored and recorded every 5 min using a multiparameter monitor (Datex-Ohmeda, GE, Helsinki, Finland). A retrobulbar block (RBB) was used as part of a multimodal analgesic plan. Following aseptic preparation of the periocular area and the area dorsal to the zygomatic process, an ultrasound (US)-guided RBB was performed using a 14 MHz linear transducer connected to a portable ultrasound device (Mindray bio-medical electronics Ltd., Shenzhen, China). Sterile ocular gel was applied to the globe, and the US transducer was placed over the cornea with the marker positioned laterally. The orientation was initially perpendicular to the transverse plane and parallel to the dorsal plane of the globe, and then it was oriented with an angle of 30deg approximately relative to the dorsal plane in order to position the US marker towards the junction between the zygomatic arch and the orbital ligament laterally. The depth and focus of the US were adjusted to achieve a good view of the retrobulbar space, the cone, and the optic nerve. The retrobulbar compartment was identified as a conic shape formed by the extraocular muscles positioned caudally to the eyeball. A 22 gauge, 50-mm ultrasound needle with extension tubing (USB 50 EVOLUTION, Temena GmbH) was introduced using a supra-temporal approach . The needle was inserted perpendicularly to the skin and oriented latero-medially behind the orbital ligament, dorsally to the zygomatic process of the temporal bone and ventral to the frontal bone, through the temporal muscle. When the tip and part of the needle were identified ultrasonographically using an oblique in-plane approach, the needle was advanced latero-medially to reach the intraconal space by crossing the extraocular muscles. In this case, the needle was visualised to go through the cone and appear in the medial aspect of it; therefore, it was slightly retracted until it was inside the cone again. At this level, negative pressure was applied to the syringe to exclude blood vessel penetration, and 1 mL of ropivacaine 0.75% (Naropin, Apen Pharma Trading Limited 0.75%, Dublin, Ireland) was injected without obvious resistance. The maximum recommended dose of ropivacaine of 2 mg/kg was calculated to be 1.28 mL . Immediately after the injection and before the needle had been removed, the cat became apnoeic. After a minute of apnoea, manual ventilation was initiated. At the same time, there was an immediate rise in the cat's heart rate (HR) from 102 to 140 bpm with a sinus rhythm. Unfortunately, there is no record of the concurrent blood pressure (BP), but we recall that it increased in parallel with the heart rate. Twenty minutes later, the cat was transferred to the operating theatre, and continuous mechanical ventilation (CMV) on a volume control mode was initiated using a veterinary ventilator (Merlin, Vetronic Services LTD, Devon, UK). During this time, no parameters were recorded on the monitoring sheet as the anaesthetist was involved in providing manual ventilation, but when the cat was moved to theatre, the blood pressure could not be measured with oscillometry or the flow Doppler technique. By that time, it was suspected that the administration of the local anaesthetic (LA) in the retrobulbar space could have been responsible for the occurrence of apnoea and the instability of the HR and BP. When the surgery started, the mean BP (MBP) was 50 mmHg, and the HR was 75 bpm. A dose of 0.01 mg/kg of glycopyronium (Accord Healthcare Limited, Durham, UK) was administered intravenously (IV) and was repeated after 5 min as there was no effect. Due to the lack of response to the anticholinergic, a dose of 0.1 mg/kg of ephedrine (MaCarthys Laboratories, Martindale Pharma, Brentwood, UK) was administered IV, and this was repeated again after 10 min, after which the MBP increased to 80 mmHg but only temporarily. The HR remained at levels >100 bpm after the above interventions, while the MBP increased again only after a dopamine (Martindale Pharma, UK) IV infusion at a dose of 5 mg/kg/min was initiated. During the whole anaesthetic, the SpO2 and the EtCO2 were maintained within the acceptable limits, while the oesophageal temperature was 34-36 degC. Anaesthesia ended at 75 min after induction, and the cat remained apnoeic. Twenty minutes following inhalant discontinuation, the cat was still apnoeic, and a decision was made to reverse the midazolam with 0.01 mg/kg of flumazenil IV (Hamlen Pharma gmbh, Gloucester, UK). The cat responded immediately and started breathing spontaneously following the administration of flumazenil. Dopamine was discontinued after extubation, as the cat was able to maintain MBP > 80 mmHg. During surgery, the cat lost approximately 29 mL of blood, which was 10% of her estimated total blood volume (4.8 kg x 60 mL/kg = 288 mL). On recovery, the cat remained on Hartman's solution at a rate of 3 mL/kg/h until the volume lost was replaced. After the cat had fully recovered, an ophthalmological examination of the left eye revealed a reduced menace response, horizontal nystagmus, mydriasis, and absence of the pupillary light reflex (PLR). The rest of the clinical examination was normal. She was responsive to stimulation and had a good appetite. The Glasgow Feline Composite Measure Pain Scale scores were between 0 and 2 postoperatively. The following day, she had a normal menace response, subtle horizontal nystagmus, mydriasis, and the PLR was present. The cat returned home on the day after surgery. One week later, at the follow-up examination, the left eye had a normal menace response, no nystagmus, a slightly larger than normal resting pupil size but was less mydriatic than postoperatively and within the normal limits for a blue-eyed Siamese cat, and with the PLR present. The owner reported no concerns, and the patient was discharged. 2. Discussion Regional anaesthesia of the eye is commonly applied in veterinary patients to provide analgesia during painful procedures, such as enucleation, or for akinesia of the extraocular muscles, which results in the globe maintaining a central position . Additionally, it reduces the incidence of the oculocardiac reflex during enucleation surgery by blocking the ophthalmic branch of the trigeminal nerve and the ciliary ganglion, as has been described in horses . The RBB and peribulbar blocks (PBB) are two different types of regional anaesthesia techniques in which the LA is either deposited in the retrobulbar or in the peribulbar space, respectively, with the final aim being for the LA to reach the intraconal space. The intraconal space is within the retrobulbar cone, and in the dog, the latter is formed by the ocular extrinsic muscles: the dorsal, ventral, lateral, and medial rectus muscles, the retractor bulbi with its four fascicles, and more superficially and medially, the dorsal oblique muscle . There is no fascia surrounding the muscles that form the cone. Within the retrobulbar cone are the ophthalmic nerve, the ciliary nerves, the optic nerve, the oculomotor nerve, and the abducens nerves. Additionally, the internal ophthalmic artery and the ciliary arteries run in the same space . Different techniques have been described for both blocks . In dogs, among other blind approaches to the RBB, the inferior-temporal-palpebral and the supra-temporal approaches have been described in cadavers. In one study with sedated dogs, the peribulbar technique was shown to be more reliable for producing anaesthesia than the RBB when using a bent needle inserted through the inferior eyelid . However, both methods produced adverse effects such as exophthalmos, chemosis, and anterior uveitis, which had resolved 14 h later . In cats, Shilo-Benzamini et al. described a superior-nasal approach for the retrobulbar block through the upper eyelid at the dorsomedial orbit using a curved needle. This was found to have a 70% success rate in cadavers, but this was only 50% when tested in sedated cats . Ultrasound-guided ophthalmic regional anaesthesia has been used recently in human ophthalmology, as it has the advantage of allowing visualisation of the retrobulbar structures and the needle at the same time as well as confirmation that the LA has been administered in the correct space. According to our knowledge, thus far, only extraconal deposition of the LA has been described in dog cadavers with US guidance . An US-guided PBB was shown to be as effective as a blind technique in anaesthetised dogs, although the dogs receiving the blind technique had a higher incidence of increased intraocular pressure (IOP) due to the possible wrong positioning of the needle, as the authors hypothesised . In cats, an US-guided RBB with a trans-palpebral approach, as mentioned above, was effective in only 50% of the animals , possibly due to "the difficulty in identifying the curved needle tip", as commented by the author in a review article on regional ophthalmic anaesthesia . More recently, the authors of a case report on a cat with microphthalmia described the use of an US-guided RBB using a modified technique similar to the supra-temporal approach, but in this case, the needle was introduced into the retrobulbar space from the subzygomatic area . Advocates of the PBB highlight the reduced risk of complications, such as the distribution of the LA in the central nervous system (CNS), retrobulbar haemorrhage, and globe penetration, compared to the RBB, as the needle is inserted further away from these structures . Indeed, the reported incidences of CNS complications in humans after a RBB are 0.09%, 0.27%, and 0.9% , whereas a much lower incidence of 0.007% has been reported with the PBB; however, the authors concluded that this incidence is probably underestimated . In veterinary patients, the incidence of complications is unknown. Only one case has been reported in a cat with suspected brainstem anaesthesia that occurred 5 min following the injection of LA into the retrobulbar space using a blind technique . The technique routinely performed at our hospital is the US-guided RBB using a supra-temporal approach with intraconal deposition of the LA. This preference is due to the perceived greater success rates when an US-guided technique with an in-plane approach is used and the correct deposition of the LA can be visualised. Additionally, a smaller volume of LA is necessary, as it is injected inside the cone. Humans receive regional ophthalmic blocks while awake, and the side effects vary from contralateral pupil dilation to amaurosis, convulsions, grand-mal seizures, hypertension/hypotension, tachycardia/bradycardia, and cardiopulmonary arrest . In veterinary medicine, the side effects reported in one cat following RBB were apnoea, increased HR and systolic blood pressure initially, and a reduction in blood pressure below normal values during surgery . A delay in recovery was also noticed, and after extubation, the cat presented with nystagmus, absence of the menace response, mydriasis, a lack of dazzle, and a negative PLR in the contralateral eye. There are three main potential mechanisms whereby a RBB or PBB may lead to CNS complications. First, these can occur due to penetration of the sheath of the optic nerve and the entry of LA into the subarachnoid space of the brainstem . If this occurs, symptoms appear 5 to 10 min after injection, depending on the onset of action of the LA. The second mechanism is through the inadvertent injection of the LA into the internal ophthalmic artery. The pressure of the injectate forces the LA to flow back into the internal carotid artery and into the brain. In such cases, clinical signs appear rapidly . Thirdly, complications can occur due to the systemic absorption of the LA . In the case presented here, tachycardia, hypertension, and apnoea appeared instantly before the removal of the needle, and the cat remained mechanically ventilated until recovery. No obvious resistance was noticed during the injection, and the needle did not seem to have penetrated the optic nerve on the US image. Given the rapid onset of the clinical signs, CNS spread of the local anaesthetic exclusively through penetration of the sheath of the optic nerve is less likely. Unfortunately, there are no saved images to corroborate this, as it is not common practice to save images for every patient, especially in routine cases. Similar to our case and to the other case report from a cat, the first manifestations of CNS spread in humans are often hypertension and tachycardia. This can be explained as a parasympathetic blockade through a combined vagal and carotid sinus reflex block . Although the immediate onset of symptoms in our case is in favour of inadvertent intra-articular injection, no blood appeared during the application of negative pressure to the syringe. Additionally, one would expect the duration of the symptoms to be transient due to the rapid redistribution of blood out of the brain, but this was only the case for hypertension and tachycardia. However, the cat remained apnoeic during the whole anaesthetic procedure and for 20 min after the end of anaesthesia. In dogs, the internal ophthalmic artery runs on the dorsal surface of the optic nerve . To the best of our knowledge, there is no published description of the ophthalmic vasculature in cats that mentions the exact pathway of the internal ophthalmic artery. In humans, because of an anatomical variation in the inferior ophthalmic artery in 15% of the population, there is a higher risk of inadvertent intra-arterial injection . The use of colour-flow Doppler could have helped us to identify the artery and avoid a possible intra-arterial injection of the LA, but this was omitted before the administration of ropivacaine. The rapid systemic absorption through the local capillaries could also explain this clinical presentation. However, the total dose administered (1 mL) was less than the maximum recommended dose in cats . The possibility that some of the LA was injected intra-arterially and some reached the subarachnoid space through penetration of the sheath could explain the quick onset of symptoms in combination with the increased duration of apnoea. In a similar case report in a human, an intra-arterial injection was suspected due to the instant occurrence of CNS toxicity. The same patient remained apnoeic for 40 min after seizures had resolved. The authors speculated that systemic absorption from the local capillaries or the spread of the LA in the subdural space along with the optic nerve could explain the sustained respiratory arrest . Following recovery from anaesthesia, the cat in the present case report had symptoms in the contralateral eye that could potentially be explained by brainstem exposure to the LA . Although nystagmus may be present during recovery from anaesthesia and opioids cause mydriasis in cats, the above symptoms were still present the following morning, although to a lesser degree. In contrast with humans, where convulsions or seizures are common, the cat in this report did not show any twitches, probably because general anaesthesia was masking this response. It is not clear why, upon administration of flumazenil, the cat started breathing spontaneously immediately, as midazolam causes minimal respiratory depression, and it did not compromise ventilation after administration in our case. However, when diazepam is administered with buprenorphine in rats, respiratory depression has been reported to be greater . Potentially, the impact of benzodiazepines on central ventilatory control after CNS dysfunction, as occurred in our case, is more pronounced compared with in a normal CNS. Additionally, the use of flumazenil has been reported to reduce the recovery time from anaesthesia in humans when no benzodiazepines have been administered . It is unknown as to whether it was the pharmacological action of flumazenil or the time that had elapsed since the retrobulbar block that caused the return to spontaneous breathing. Lipid emulsion therapy has been proven to be effective for treating local-anaesthetic-induced systemic toxicity , including a case of local-anaesthetic-induced seizures after a peribulbar block in humans . When brainstem anaesthesia was suspected in our case, the administration of a lipid emulsion could have potentially helped to resolve the cardiovascular and respiratory complications. 3. Conclusions We have presented a case report of a potential exposure of the CNS to ropivacaine after an US-guided RBB in a cat that showed sustained apnoea, cardiovascular instability, as well as nystagmus, mydriasis, and an absent PLR postoperatively in the contralateral eye. The early onset of symptoms, prior to needle withdrawal, indicates that an inadvertent intra-arterial injection of the LA was the possible cause, although we cannot exclude subarachnoid injection or a combination of the two. Although an US-guided technique was used and negative pressure was applied before the injection, this complication could not be avoided, and we highlight the importance of using colour-flow Doppler for better visualisation of the vasculature. Any medications that can be reversed could be beneficial for similar cases. Author Contributions Conceptualisation, A.P. and E.R.; writing original draft preparation, A.P.; writing review and editing, E.R.; supervision, E.R. All authors have read and agreed to the published version of the manuscript. Institutional Review Board Statement The presented case is not a prospective study and for that reason does not require ethical approval. The owner of the animal in the presented case gave consent to anonymously share the details of the case for publication purposes. Please see a blank consent form attached to the nonpublished materials section. Informed Consent Statement Informed consent was obtained from the owner of the animal involved in the case report. Data Availability Statement The presented case report is not a study, and no data were collected. Conflicts of Interest The authors declare no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
Animals (Basel) Animals (Basel) animals Animals : an Open Access Journal from MDPI 2076-2615 MDPI 10.3390/ani13050805 animals-13-00805 Editorial Editorial: Role of Non-Coding RNAs in Animals Do Duy Ngoc 12* Suravajhala Prashanth 34* 1 Faculty of Veterinary Medicine, Viet Nam National University of Agriculture, Hanoi 100000, Vietnam 2 Department of Animal Science and Aquaculture, Dalhousie University, Truro, NS B2N 5E3, Canada 3 Bioclues.org, Hyderabad 500072, India 4 Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Clappana 690525, India * Correspondence: [email protected] (D.N.D.); [email protected] (P.S.) 23 2 2023 3 2023 13 5 80526 12 2022 10 1 2023 21 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). pmcThe importance of non-coding RNAs (ncRNAs), such as microRNAs (miRNA), long non-coding RNAs (lncRNA), and circular RNAs (circRNA), in gene regulation is increasingly being appreciated in many species. Thanks to the next generation of sequencing methods, thousands of ncRNAs have been identified in different livestock species and their functions are undergoing characterization. Clearly, ncRNAs are involved in many gene regulation processes and pathways related to economically important traits in livestock species . In addition, ncRNAs are also considered to be potential biomarkers for infectious diseases in different farm animal species . This Special Issue contains 13 articles summarizing the diverse roles of ncRNAs in livestock . In particular, we report on different species of animal that have been used to study the functions of ncRNAs. These include chicken , pigs , goats , sheep , cattle , mice , and insects . Exploring the expression of ncRNAs in different biological conditions is an important step in understanding their function. Bo et al. identified 20,269 lincRNAs, including 16,931 novel lncRNAs, expressed in the testes of Yiling goats. The authors also suggested that ENSCHIT00000000777, ENSCHIT00000002069, and ENSCHIT00000005076 were the key lincRNAs in the process of testis development, a fact derived via co-expression analyses. Gan et al. used RNA sequencing to identify 302 miRNAs expressed in pig umbilical venous blood (UVB) and umbilical arterial blood (UAB). As a result, 106 and 22 miRNAs were specifically expressed in the UVB and UAB, respectively. The authors also suggested that miR-423 and miR-122-5p can be used as characteristic miRNAs of UVB and UAB, respectively. Hao et al. performed RNA-Seq to study the roles of lncRNAs in the mammary glands of lactating Small-Tailed Han (STH) ewes and Gansu Alpine Merino (GAM) ewes. The authors identified 1894 lncRNAs that were differentially expressed, among which 31 and 37 lncRNAs were up and downregulated respectively, when comparing STH ewes with GAM ewes. In addition, the authors also found that the development and proliferation of mammary epithelial cells via the enrichment of the target genes, followed by the morphogenesis of the mammary gland, ErbB signaling pathway, and Wnt signaling pathway could be important for mammary gland and milk yield regulation. To explore the function of lncRNAs in pig spleens at different stages of development, Li et al. profiled the systematic characters of mRNA and lncRNA repertoires in three groups of spleens from nine Yorkshire pigs, with three aged seven days, 90 days, and 180 days, respectively. The authors identified 19,647 genes in addition to 219 known and 3219 putative lncRNA transcripts; 1729 genes and 64 lncRNAs therein were found to express differentially. The authors also found that differentially expressed genes and the potential target genes of differentially expressed lncRNAs both performed the crucial roles of up-regulation in immune activation and hematopoiesis, and down-regulation in cell replication and division, in 180-day-old pigs compared to seven-day-old pigs. MiRNAs are the most well-studied molecules in the ncRNAs. Several studies contained within this Special Issue attempt to validate their functions. Guo et al. indicated the potential roles of miR-149-5b in the regulation of bovine adipocyte differentiation . Xu et al. show that, by targeting PTEN, MicroRNA-148a can regulate the proliferation and differentiation of ovine preadipocytes. Qiao et al. provided evidence of the role of miR-F4-C12 50 in the regulation of adipose accumulation, finding that it performed this role by targeting PIK3R1 in castrated male pigs . Wang et al. identified 852 known miRNAs and 179 novel miRNAs in female ICR mice mammary glands at the virgin stage, day 16 of pregnancy, day 12 of lactation, day 1 of forced weaning, and day 3 of forced weaning. The authors also discovered a novel miRNA (novel-mmu-miR424-5p) involved in regulating the expression of the CSN2 gene. Other studies also validated the function of circRNAs and lncRNAs . Regarding the circRNA function, Wang et al. indicated that circEZH2 can sponge miR-378b to regulate milk fat metabolism , while Shen et al. showed that circular PPP1R13B can target miR-9-5p to promote chicken skeletal muscle satellite cell proliferation and differentiation . Lastly, via RNA sequencing and the follow-up validation, Jian et al. confirmed that the roles of lncPGC in the regulation of primordial germ cell formation in chickens were mediated by TCF7L2. This Special Issue focused not only on livestock species but also on the roles of lncRNAs in insects. Choudhary et al. provided an updated review of the functions and molecular mechanisms of the mode of action of different insect lncRNAs. Taken together, these contributions enlighten the research community on contemporary breakthroughs and suggest approaches for performing future functional studies of the regulatory roles of ncRNAs in animals. We anticipate that both expert scientists and readers can benefit from the state-of-the-art studies addressing the roles of ncRNAs contained within this Special Issue. Acknowledgments We would like to thank all the authors who contributed their papers to this Special Issue. Author Contributions D.N.D. and P.S. wrote and edited the original draft of the manuscript. All authors have read and agreed to the published version of the manuscript. Conflicts of Interest The authors declare no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Williams A. Functional aspects of animal microRNAs Cell. Mol. Life Sci. 2008 65 545 562 10.1007/s00018-007-7355-9 17965831 2. Weikard R. Demasius W. Kuehn C. Mining long noncoding RNA in livestock Anim. Genet. 2017 48 3 18 10.1111/age.12493 27615279 3. Miretti S. Lecchi C. Ceciliani F. Baratta M. MicroRNAs as biomarkers for animal health and welfare in livestock Front. Vet. 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As one of the most abundant game species in Europe, European wild boar (Sus scrofa) populations prove highly adaptable to cultivated landscapes. The ongoing process of climate change and the high agricultural yields seem to further optimize the living conditions for this species. In long-term reproduction monitoring, we collected data on the body weight of wild boar females. Over an 18-year period, the body weight of wild boar females increased continuously, then stopped and decreased. It was possible to detect differences between the body weights of animals from forest and agricultural areas. For these areas, differences in body weight development also led to a significant distinction in the onset of puberty. We conclude that, even in a highly cultivated landscape, forested areas provide habitat characteristics that may strongly influence reproduction. Second, with dominant agricultural areas in Germany, wild boar reproduction has been favored in recent decades. Sus scrofa reproduction weight increase habitat climate factors Ministry of Food, Agriculture and Consumer Protection of Lower Saxony, Germany (Niedersachsisches Ministerium fur Ernahrung, Landwirtschaft und Verbraucherschutz)Verein der Forderer der Wildtierforschung an der Stiftung Tierarztliche Hochschule Hannover e. V.Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)491094227 University of Veterinary Medicine Hannover, FoundationThis research was funded by the Ministry of Food, Agriculture and Consumer Protection of Lower Saxony, Germany (Niedersachsisches Ministerium fur Ernahrung, Landwirtschaft und Verbraucherschutz) and by "Verein der Forderer der Wildtierforschung an der Stiftung Tierarztliche Hochschule Hannover e. V." This Open Access publication was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) 491094227 "Open Access Publication Funding" and the University of Veterinary Medicine Hannover, Foundation. pmc1. Introduction The wild boar (Sus scrofa) is a popular and widely abundant game species , and populations have increased throughout Europe in recent decades . It is an opportunistic omnivore with a high adaptability to changing environmental conditions . The wild boar has by far the highest reproductive potential and fecundity of all ungulate species worldwide in relation to its body mass . Combined with a low natural adult mortality rate in temperate climates , it can achieve high population densities in a very short time period . Due to its increasing population, it has become a very important species from an economical point of view . It can transmit diseases (like the African swine fever) to livestock and cause damage to agriculture . Several aspects that contribute to wild boar population growth have been studied and discussed. Among them, the most important factors are a reproductive success or lower juvenile mortality due to optimal feeding and mild climatic conditions . Several parameters of wild boar reproductive biology, such litter size , sex ratio and parturition time (unpublished own data) are positively related to maternal body weight. A body weight increase in free-living wild boar populations was reported from different European habitats , arising the question if similar developments could be observed from study areas situated in parts of Germany that were dominated by a high extent of cultivated landscape. Therefore, the aim of this research was to investigate whether the body weight of female wild boars in some areas of northern Germany increased over an 18-year period and whether the increase in body weight was different among age classes and habitats. Here, the influence of external (e.g., climate and mast) and internal (e.g., age and maturity) factors on body weight was tested, and, in addition we also tested for a possible effect on the onset of puberty. We hypothesized that body weight increased in all age classes over the years and that comparisons between forest and agricultural habitats showed a greater weight increase in the latter. 2. Materials and Methods 2.1. Study Area The study area was situated in the East of the federal state of Lower Saxony (northern Germany) (52.36deg N, 10.35deg E) and comprised about 5500 km2 with altitudes ranging from 60 to 130 m asl . Based on data from the German Meteorological Service, the average annual temperature since 2000 was 9.7 degC, and the average annual precipitation was about 800 mm. The trend of mean temperature is increasing, and mean precipitation is decreasing . The study area comprised either forestal-agricultural habitats (fah) or represented a large contiguous forestal habitat . Within the total area, one large block of forest (430 km2) was interpreted as a separate territory, containing only 3% of agricultural areas, and thus, agricultural food was available for wild boars only to a limited amount. Forest composition was almost the same as in the total area, while the forested area additionally comprised 2% of heathland and 5% of settlement and infrastructure. This area could be interpreted as forestal habitat , while the agriculturally dominated part of the study area was about 5500 km2, with 61% auf agricultural areas and 22% of forest. The remaining 17% were buildings and infrastructure. The agricultural land was characterized by 80% of energy-enriched products (e.g., grain, sugar beets, oilseed, rape, maize, leguminoses and potatoes) in 2020. The remaining 20% consisted of heathland, fallow land and horticultural products . Since 2007, only slight changes within the different field crops were reported . The forest consisted of 18.9% oak (Quercus spp.), 11.2% beech (Fagus sylvatica), 7.6% other deciduous trees (e.g., Betula spp, Acer spp., Tilia spp., Sorbus aucuparia), 45.5% pine (Pinus spp.) and 16.6% other coniferous trees (Larix spp., Picea abies, Pseudotsuga menziesii). 2.2. Data Collection Data were collected from 3517 free-ranging hunted wild boar females in the study area during the hunting years from 2003 until 2020. Each hunting year (indicated as "year" in the following text) started in April and ended in March. Since the majority of samples derived from November-January, we focused our analyses on these months of the hunting year (n = 3.367, Table 1). The age of the wild boar females was identified by tooth determination . Following the age identification, female wild boars were grouped into three classes (n = 2024 piglets: <=12 months; n = 866 yearlings: >=13-24 months; n = 477 adults: >=25 months, Table 1). Their dressed body weight (without digestive system, heart, lungs, liver, reproductive tract, and blood, hereafter "bw") was recorded. Dissection and examination of the reproductive tract (uterus and ovaries) was performed according to our own protocols . Consequently, the onset of sexual maturity was assumed when ovaries had follicles >=0.4 cm in diameter. 2.3. Statistical Analysis We described with Tukey's Honest Significance Difference (HSD) test differences between mean bw in the three age classes both overall and within the two habitat types. Then, we used generalized linear models (GLM, ) with identity link to analyze the development of bw over the hunting years, including age class, habitat type, tree crop and weather variables (Table 2). Explanatory variables were checked for correlations among each other , but multicollinearity did not affect our analyses, as checked by correlations and variance inflation. Testing for both linear and unimodal relationships with the dependent variable (bw), we used the AIC (Akaike Information Criterion) from univariate models with each numerical weather variable to decide about their inclusion in the GLM. We stopped when adding a new variable did not result in a lower AIC value. We also included the hunting index as a measure of hunting intensity for each hunting year. We used a GLM with logit link and binomial error structure to find predictors of wild boar puberty. All analyses were performed using R software version 4.1.0 . 3. Results 3.1. Overall Body Weight Tukey's HSD test revealed highly significant differences between age classes in the whole sample. Mean bw for piglets, yearlings, and adults was 27.6 kg [sd 8.6, n = 2024], 54.0 kg [sd 10.5, n = 866] and 66.7 kg [sd 12.9, n = 477], respectively. In all age classes, we found an increase in bw that resulted in significant differences between some months, following a seasonal pattern during autumn and winter. A bw difference (diff) between November and January was significant in yearlings (Tukey's HSD test: p = 0.05, diff = -2.3 kg) and adults (Tukey's HSD test: p < 0.01, diff = -4.2 kg). In piglets, there was a significant bw difference between November and December (Tukey's HSD Test: p < 0.0001, diff = 3.1 kg) and, like in the other two age classes, between November and January (Tukey's HSD Test: p < 0.0001, diff = -3.9 kg). The weight increase in piglets from November to December was especially pronounced in the fh (diff = 5.0 kg) and, to a lesser extent, in the fah (diff = 2.3 kg). 3.2. Effect of Habitat on Body Weight Mean bw was higher in fah compared to fh habitats . The difference of 2.8 kg was significant (Tukey's HSD p > 0.01). Differences between habitat types were particularly pronounced in yearlings. In this age class, the mean bw of animals from the agricultural habitat was 8.0 kg higher than that from forest habitat (Tukey's HSD p > 0.01). In piglets and adults, the weight difference between habitats was 5.2 kg and 5.5 kg, respectively. 3.3. Temporal Trends in Body Weight and External Factors Bw differed per age class and habitat, but the overall trend was similar in both factor variables. In all models, the relationship of bw with hunting year was best described by a fourth-order polynomial that visually suggested a slight increase until about 2017, followed by a decrease until 2020 . Fluctuations in bw were more pronounced for wild boar in fh. Strong beech mast benefited especially adult animals in fh , while oak mast did result in differences in bw without any significance. Among all age classes, climate factors such as frost periods in February negatively affected bw, while higher precipitation in May and July had a positive impact . The inclusion of the hunting index further improved the final model, with the bw being negatively correlated with this predictor of hunting pressure , which was again true for all age classes. 3.4. Predictors of Wild Boar Puberty In our data, piglets reached puberty approximately at a bw of 30 kg, and in fh, this was achieved at an age of 11 months, whereby piglets of fah seemed to achieve the crucial body weight at a lower age, i.e., about 8-9 months . As a result, in fah, 80 percent of the 8-month-old piglets had already reached puberty, while in forest areas, only 64 percent did. In years with beech masts, the probability of puberty was slightly higher than in years without mast . 4. Discussion During the last years, a permanent weight increase in female wild boars of all age classes in Lower Saxony culminated in 2017 and decreased from thereon for unknown reasons, therefore, partly supporting our hypothesis on a permanent weight increase of the species in the wild. The unexpected halt and decrease in body weight might be in line with extremely arid summers occurring since 2018 in the region . By highlighting a significant distinction of body weight between animals from forestal (fh) vs. agricultural (fah) habitats, our second hypothesis proved right. In Poland, a similar increase of wild boar body weight has been reported, and the distance to forestal areas also turned out to be a significant factor . Interestingly, the difference in body weight has an additional impact on puberty achievement, and here, mast seeding events significantly improve the condition of animals situated in forestal habitats. This is supporting our results from earlier studies, indicating that the occurrence of splendid masts of oak or beech result in a higher reproductive outcome, especially in forestal areas . Additionally, the precocious puberty of female and male wild boars in our study area supports the theory of a high share of piglets in reproduction. Anyway, the proven distinction of habitats longs for discussion. Various studies reflect that wild boars' spatial behavior is highly adaptive and diverse , especially among different European countries . In our study, we focused on adjacent areas of agricultural habitats and woodland, where the woodland was characterized by its consistency. We assume that wild boar populations inhabiting agricultural areas near the edge of the forest habitat do enter it and vice versa but that the majority of the animals inhabiting the pure forest area is concentrating on the forest, which is also providing enough forage, especially under climate change conditions . This is supported by the fact that puberty is reached by piglets inhabiting agricultural dominated areas at lower ages, while mast occurrence influences the onset of puberty, especially among forest-inhabiting animals. While the hybridization of domestic pigs and wild boars might lead to an adjustment in reproductive traits in the latter, there is no indication that hybridization might be responsible for the habitat-dependent differences we found in this study. In Europe, hybridization mainly occurred during the outside feeding of domestic pigs in the Roman Empire and Middle Ages , and in some countries, it was also observed after World War II or even recently . A wide variation in the degree of ongoing hybridization in European countries is stated, referring to the type of pig farming as one explaining factor . In this context, Germany is one of the countries where industrial pig farming is most common and, therefore, ongoing hybridization is less likely. Nevertheless, the differences in the reproductive performance of wild boars between Northern and Southwestern Germany that were found in former studies were not tested for differences in hybridization with domestic pigs so far , and studies that precisely perform German wild boar genome analyses would certainly be helpful to interpret reproduction in this species more accurately. While both sexes of wild boars seem to reach puberty on highly weight-dependent conditions and have gained weight continuously over the last years, it was surprising to observe that mast seeding events in forestal habitats appear to additionally influence the onset of puberty. The meaning of mast seeding events for wild boar reproduction is controversially discussed, and although, e.g., wild boars in France also seem to respond to mast seeding events positively through a higher breeding proportion, the effect seems to be caused mainly by their weight increase . This could be due to the difference in habitats, with the French Mediterranean forest seemingly serving as a main feeding source for wild boars , while our study area has been dominated by agricultural land use from the beginning of the monitoring. The high adaptability of wild boars might lead to aligned feeding strategies, in which the occurrence of mast seeding events might not provoke an imminent increase of body weight but resolve in a short-time adjustment of body fat and fatty acids, discussed as "flush feeding" in pigs , that also seems to have different outcomes depending on the timing and reproductive status of the animals . Few large contiguous forestal habitats are situated in Northern Germany, and with climate change, the persistence of comparable forests is threatened . Whether additional reproductive parameters, such as the time of farrowing and litter size of wild boars, will also prove to be habitat-dependent in our study areas will, therefore, be part of our future research. An additional impact could be shown for various external factors, such as precipitation in June and frost periods in February, leading to diminished body weights, whereas higher temperatures in March and April, as well as precipitation in May, were improving body weight. It seems reasonable that cold periods in February, with possibly farrowing females or piglets among the rut, lead to a reduced body weight of a high percentage of animals. Potentially, animals will search for shelter and be less active in foraging . Likewise, it can be assumed that strong precipitation in June may lead to crop failure or at least poor harvests as a consequence and thus also results in a decrease in body weight. The meaning of seasonality in wild living species is an important topic in wildlife research , and in the wild boar, questions about reproductive seasonality still remain unsolved . Additionally, little is known for weight development of wild boars in other European habitats, and further research can be helpful to evaluate the importance of these factors in Europe's future climate. 5. Conclusions Within a long-term study on the reproduction of female wild boars, we were able to gain outstanding results on basic features such as body weight development and received valuable insights on the impacts of external and internal factors on puberty. We, therefore, explicitly propose to establish long-term monitoring of wildlife species to a far greater extent. Acknowledgments We would like to thank The Forestry Seeds Advisory Board (FSB) at Oerrel, Lower Saxony, the Forestry Commission Offices in Lower Saxony, the state office for statistics (NLS), and the German Meteorological Service (DWD) for providing their data. We want to further thank all the hunters for their cooperation and help in collecting data, especially the Forestry Commission Offices Oerrel, Unterluss and Wolfenbuttel as well as the "Verwaltung Gunther Graf v. d. Schulenburg". Special thanks belong to Angelika Niebuhr for her support and care of the database and to all the volunteers, students and ITAW staff who helped to collect samples throughout all the years. Author Contributions Conceptualization, F.G. and O.K.; methodology, F.G.; software, T.L.; validation, T.L., O.K. and F.G.; formal analysis, F.G.; investigation, F.G. and C.M.; resources, U.S.; data curation, F.G.; writing original draft preparation, F.G.; writing review and editing, C.M. and O.K.; visualization, T.L.; supervision, U.S.; project administration, F.G. and O.K.; funding acquisition, F.G. and O.K. All authors have read and agreed to the published version of the manuscript. Institutional Review Board Statement Ethical review and approval were waived for this study due to animals' origin from regularly performed hunting. Informed Consent Statement Not applicable. Data Availability Statement Data for land use and climate are available online via and (accessed on 1 February 2023). Conflicts of Interest The authors declare no conflict of interest. Figure 1 Map of Germany (left), indicating the site of the study area in Lower Saxony, Germany (right part of the figure), showing forestal-agricultural habitat (fah, outlined in orange) around the large contiguous forestal habitat (fh, outlined in green) where wild boar females of this study were sampled. Figure 2 Bw (weight) of wild boar females (all ages) increased with hunting year until about 2017, followed by a decline that was less pronounced in agricultural dominated habitat fah (n = 2837). Figure 3 Strong beech mast (numbers represent levels according to categorization from forestry commission office Oerrel, Lower Saxony; 1 = no, 2 = part, 3 = half, 4 = full mast) resulted in (significantly) positive effects on bw only for adult wild boar females in fh (n = 680, p = 2.77 x 10-7 for beech = 4, age = adult, habitat = fh). Figure 4 Bw (weight) of wild boar females of all ages was negatively influenced by days of frost in February (FrostFeb), lower precipitation in May (Nmai, precipitation in mm) and July (Njuli, precipitation in mm) and strong hunting pressure (HI, ratio of hunting bag/hunting area). Figure 5 Different probabilities of puberty in the two landscape types (forest = fh, agriculture = fah), as described by age of piglets. Figure 6 Probability of puberty slightly decreased with increasing overall bw over years (left) and slightly increased with beech mast (right; numbers represent levels according to categorization from forestry commission office Oerrel, Lower Saxony; 1 = no, 2 = part, 3 = half, 4 = full mast). animals-13-00898-t001_Table 1 Table 1 Distribution of wild boar females according to age and habitat. Habitat Piglets Yearlings Adults Habitat Total fh 306 184 103 593 fah 1718 682 374 2.774 total 2024 866 477 3.367 animals-13-00898-t002_Table 2 Table 2 Predictors of wild boar body weight used in this study. Variable Measure/Explanation Year numerical (2003-2020) Age class three nominal levels: piglets, yearlings, adults Habitat two nominal levels: forested (fh), agricultural (fah) Oak crop four ordinal levels: (1-4) Beech crop four ordinal levels: (1-4) Precipitation monthly sum in mm Temperature monthly average (degC) Hunting Index wild boar annually shot per km2 Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
The thermal environment is a major factor influencing amphibians. For example, amphibian reproduction occurs in specific temperatures, and minor changes in this aspect could have negative impacts on this biological process. Understanding the potential effects of temperature on reproductive output is important from both an ecological and captive breeding colony point of view. I examined temperature effects on reproduction in axolotl reared from egg to adult at 4 temperatures (15 degC, 19 degC, 23 degC, and 27 degC) These adult axolotls (n = 174) were measured and weighed, dissected, and their gonads were removed and weighed to obtain an individual's reproductive allocation. Female axolotls reared at 23 degC had a greater Gonadosomatic Index (GSI) compared to axolotl reared at each of the other temperatures with axolotls reared at 27 degC having the lowest reproductive output. Moreover, all GSI pair-wise comparisons in the four temperature treatments were significantly different from each other (ANOVA, F (3, 66) = 61.681, p < 0.0001). Additionally male rearing temperature significantly influenced GSI (ANOVA, F (3, 89) = 10.441, p < 0.0001). Male axolotls reared at 19 degC had significantly greater GSI compared to males reared at the three other temperatures. There were no statistical differences among each of the other pair-wise comparisons. As seen in this experiment, axolotls may be especially sensitive to climate-driven warming due to their highly permeable skin and paedomorphic life history. Understanding how axolotls and other amphibian species adjust to the challenges of climate change is important in the management of this imperiled taxa. Gonadosomatic Index gametogenesis climate change amphibian This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. pmc1. Introduction Caudates are especially sensitive to changing temperatures due to their lack of thermal regulation. Aquatic temperatures influence growth and development during the larval period and may impact sexual development and induce sex reversal . Two literature reviews examined the influence of temperature on the developmental plasticity of amphibian larvae and determined that age and size at the onset of metamorphosis were generally lowest at the warmest temperatures. Amphibian larvae that develop faster and metamorphose at a smaller body potentially impact fitness-related traits . Further, larval amphibians may be more vulnerable than adults to temperature variations and are likely to encounter higher variation in temperature living in the aquatic environment. Larval amphibians often prefer specific temperatures in lab experiments and this behavior can change depending on developmental stage . Temperature preference also occurs in adult obligatory aquatic salamanders (Amphiuma tridactylum) , and acclimation temperature can influence larval and adult preferred temperature. For example, aquatic salamanders, Cryptobranchus alleganiensis (hellbenders) and Necturus maculosus (mudpuppies), selected the lower temperatures in a gradient when acclimated at 5 degC and avoided warmer temperatures . In hellbenders, water temperature can impact the pH and PCO2 , and in Ambystoma texanum (small-mouth salamanders), water temperature can influence physiological immune function , and metabolic rates , Rearing temperature can reduce growth and survival of Andrias davidianus (the Chinese giant salamander) and play an important role in the initiation of reproductive cycles , with low temperatures inducing early timing of female gamete maturation, as shown in Siberian salamanders (Salamandrella keyserlingii) captured during breeding migrations . Thus, seasonal temperatures may affect spermatogenesis and ovulation in temperate salamander species and their endocrine e and exocrine control and constraints . Notwithstanding these studies, little is known whether and how water temperature affects gonads growth in urodeles. This information is of importance for the development of temperature regimes for rearing amphibians in captive colonies (including germplasm repository development), and in understanding the effects of climate induced changes on life histories traits including reproduction. The present study examines the effect of water temperature on the Gonadosomatic Index (GSI) in the Axolotl, Ambystoma mexicanum. These salamanders are imperiled and near extinction in nature because of invasive predatory fish, pollution, and urbanization . Axolotls are thriving in domestication as exotic pets, or in laboratory colonies where they are used as model organisms for biological research. This species has been cultured in the lab as surrogates for wild Ambystoma species on the research of cold storage and cryopreservation of spermatophores and for examining temperature influence on reproductive physiology . Axolotls possess features typical of salamander larvae, including external gills, and are paedomorphic (i.e., retaining juvenile characteristics as adults), which allows them to exploit water throughout their entire lifespan. By living in water, however, the species may be more vulnerable to changes in water temperature or quality compared to amphibians that are both land and water dwelling. Thus, it is important to know how the effects of temperature can influence reproduction of this species and other cold-blooded vertebrates. 2. Materials and Methods 2.1. Animals This study took place at the Warm Springs Fish Technology Center, U. S. Fish and Wildlife Service, in Warm Springs, Georgia. Male and female adult axolotl originally obtained from the University of Kentucky's Ambystoma Genetic Stock Center (AGSC) were paired together in 20 degC water in three containers to obtain eggs for this experiment. Approximately 75 larvae (three weeks old) from each of three clutches were mixed and divided into four groups and put in four tanks (244 cm x 61 cm x 24 cm) that were filled with artesian spring water (pH x = 6.8 +- 0.2) and recirculated through a chiller/heater which maintained temperatures at 15 degC, 19 degC, 23 degC, and 27 degC. Temperatures were checked using a YSI Pro 20i digital meter every other day and thermostat was adjusted if needed. Rearing temperatures were within the range of temperatures (10 degC to 28 degC) that axolotl have been successfully cultured . Axolotls were exposed to a 12 h light and 12 h dark photoperiod and fed brine shrimp daily until larvae were approximately 5-6 cm in total length and thereafter fed ad libitum rations of a prepared pellet diet obtained from the AGSC. This feed was broadcast haphazardly throughout the tank 5-6 days a week and larvae ate freely. Periodically, the four systems were tested for ammonia (x < 0.1), nitrite (x = 0.05), and alkalinity (x = 15 mg/L). 2.2. Gonads Collection As axolotls matured in culture tanks, individuals were sampled starting at 12 months of age (starting in March 2022) those not sampled remained exposed to culture temperatures until collected at a later date (up to 15.5 month of age). When collected, individuals were euthanized by adding 10.0 g of Tricaine Methane-Sulfonate (MS-222) and two parts of sodium bicarbonate to 1 L of water. Salamanders were placed in the solution and 10 min after visible breathing stopped, Snout-Vent-Length (SVL, distance from the tip of the snout to the anterior angle of the vent)) (mm) was measured, then individuals were dried with a paper towel, and weighed (body mass: BM) to within 0.1 g using an electronic balance. Individuals were dissected, testis or egg masses removed, and these were weighed to 0.1 g and photographed. All axolotls were subsequently frozen individually. 2.3. Statistical Analysis Gonadosomatic index (GSI) was obtained by the dividing testis or eggs mass versus the body mass (in grams). GSI is widely used in studies of reproductive cycles of different groups of animals . These data were arcsine square root transformed to minimize the heterogeneity of variances among treatments . Body size data were log-transformed before analysis. An ANOVA was performed on these data using the Excel2016.lnk software package (Microsoft, Redmond Washington, DC, USA) to analyze the effect of rearing temperature on the GSI (p = 0.05 level of significance). If the p-value from the ANOVA was less than the significance level, a Tukey-Kramer post hoc test was done to examine which groups are different from each other. 3. Results 3.1. Females Female body size was significantly affected by rearing temperature. Axolotls reared at 15 degC and 23 degC and had a greater SVL and body mass compared to axolotls reared at 19 degC and 27 degC temperatures (Table 1). These body size differences were statistically different. SVL: ((ANOVA, F (3, 65) = 13.625, p < 0.0001), Body mass: (ANOVA, F (3, 65) = 31.907, p < 0.0001). Additionally, female axolotls reared at 23 degC had a greater GSI compared to axolotl reared at each of the other temperatures . All pair-wise comparisons in GSI in the four temperature treatments were significantly different from each other (ANOVA, F (3, 66) = 61.681, p < 0.0001, Figure 1), with axolotls reared at 27 C having the lowest reproductive output. 3.2. Males Male body size was significantly affected by rearing temperature. Axolotls reared at 23 degC had a greater SVL (115.4 mm) and body mass (93.4 g) compared to axolotls reared at other temperatures (Table 1). These body size differences were statistically different. SVL: ((ANOVA, F (3, 86) = 4.572, p = 0.0052), Body mass: (ANOVA, F (3, 86) = 14.143, p < 0.0001). Rearing temperature significantly influenced GSI (ANOVA, F (3, 89) = 10.441, p < 0.0001). Male axolotls reared at 19 degC had significantly greater GSI compared to males reared at the three other temperatures . Males in the warmest water temperature (27 degC) had the smallest GSI compared to axolotls reared at 15 degC and 23 degC temperatures, but these differences were not statistically different. 4. Discussion 4.1. Females Body size of females and the growth development of gonads depended strongly on temperature regime. Axolotls were larger both in length and weight when reared at 15 and 23 degC. Interestingly, gonads size of axolotls reared at the coldest temperature (15 degC) did not increase in proportion to body mass. These salamanders may have the capacity to allocate food energy to growth rather than to reproduction as temperature conditions at 15 degC may not be ideal. Alternatively, if temperature environments are optimal, females will growth larger and produce more eggs. This likely occurred in females reared at 23 degC as axolotls were larger and the GSI was significantly greater compared to females at the three other temperatures. 4.2. Males Similar to females, male body size was greatest at 15 degC and 23 degC, however males reared at 19 degC had a significantly greater GSI compared to males reared at the three other temperatures. Again, the potential for an energy trade-off between growth and reproduction is likely for males reared at different temperatures. 4.3. Effects of High Rearing Temperature and Climate Warming Both females and males were smaller in body size and produced relatively a smaller percentage of gonads when reared at 27 degC. This was particularly true for females. High temperatures may influence not only gonads production but may also affect gamete maturation or increase gamete mortality as seen in fish and mammals . Seasonal temperature variation can influence spermatogenesis and ovulation is some salamander species . I4 nature, axolotl growth and reproduction could be affected by increased water temperatures that arise from climate change. This species originated in cold water (<16 degC) lakes in Mexico and ideal water temperatures for rearing axolotls in the lab is 16-18 degC. Water temperatures above 24 degC can put stress on the animals and result in a loss of appetite (personal observation) and may make axolotls more vulnerable to parasites. A previous study suggested that maintaining axolotl at 24 degC or below can accelerate growth without serious detrimental effects but rearing temperatures above that would reduce axolotl developmental rates. This occurred in the present experiment as rearing temperatures of 27 degC resulted in axolotl reduced body size and decreased the relative mass of testis and the number of eggs. It is possible that the 27 degC water temperature affected hormonal function in these salamanders and suppressed gametogenesis. Future studies are needed to address the role of temperature on hormones, gamete quality, and paternal investment in offspring. 5. Conclusions These results suggest that the reintroduction and translocation of axolotls into former and new habitats should identify water temperature as an important component in conservation efforts. Previous research that examined axolotl distribution found this species in water temperatures ranging between 16 to 23 degC . As seen in this experiment, males and females should be reared at different temperatures to optimize reproductive output and may be especially sensitive to high temperatures. Whether temperature influences other maternal contribution to offspring, i.e., input into other fitness-related qualities (e.g., egg or hatching size) is presently unknown. While this study examined the effects of constant temperatures on axolotl reproduction, additional research should focus on the consequences of variable thermal environments. The ability of species to adapt to this extrinsic factor behaviorally or physiologically is little known. Understanding how axolotls and other amphibian species adjust to the challenges of temperature variation is important in the management of this imperiled taxa. Acknowledgments I thank William Wayman for the construction of systems for rearing axolotls and thank William Wayman, Jackie Zelco, and Isabel Veith for their help in feeding animals. I especially thank Sam Figiel and Aria Foster for assistance in dissecting axolotls and Yue Liu for reviewing an earlier version of the manuscript. I gratefully acknowledge the AGSC which received financial support (P40-OD019794) from the Office of Research Infrastructure Programs at the National Institutes of Health. Institutional Review Board Statement All procedures involving animals were reviewed and approved by the Animal Care and Use Committee of the U.S. Fish and Wildlife Service Warm Springs Fish Technology Center. All the animals used in this study were cared for in accordance with the Institutional Animal Care and Use Committee guidelines at the Warm Springs Regional Fisheries Center that conformed to standards established by the United States Office of Lab Animal Welfare and the United States Department of Agriculture. Approval code: WSFC 2021-05. Informed Consent Statement Not applicable. Data Availability Statement The data presented in this study are available upon request from the corresponding author. Additionally, data files have been uploaded to FigShare on Gonadosomatic Index (GSI) of female axolotls, Ambystoma mexicanum. Different letters indicate statistically significant differences among temperatures. Mean +- standard deviation. Figure 2 Effects of rearing temperature (15 degC, 19 degC, 23 degC, and 27 degC) on Gonadosomatic Index (GSI) of male axolotls, Ambystoma mexicanum. Different letters indicate statistically significant differences among temperatures. Mean +- standard deviation. animals-13-00874-t001_Table 1 Table 1 Effects of rearing temperature (15 degC, 19 degC, 23 degC, and 27 degC) on snout-vent-length (SVL) (mm) and body mass (g) of female and male axolotls, Ambystoma mexicanum. Different letters indicate statistically significant differences among temperatures. Mean +- standard deviation. Females 15 degC 19 degC 23 degC 27 degC n 25 21 16 21 SVL 110.6 +- 12.6 a 103.8 +- 5.4 b 114.4 +- 5.4 a 101.6 +- 8.9 b Body Mass 95.9 +- 12.6 a 70.6 +- 7.9 b 93.1 +- 12.7 a 57.0 +- 18.3 b Males 15 degC 19 degC 23 degC 27 degC n 27 30 20 12 SVL 111.1 +- 4.1 a 109.5 +- 5.6 a 115.0 +- 6.1 b 109.2 +- 8.6 a Body Mass 86.5 +- 7.8 a 72.3 +- 12.3 a 92.1 +- 17.8 b 72.1 +- 13.1 a Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
Cancers (Basel) Cancers (Basel) cancers Cancers 2072-6694 MDPI 10.3390/cancers15051354 cancers-15-01354 Editorial Editorial: Autologous and Allogeneic Stem Cell Transplant in Cancer Therapy Sharma Nidhi 1* Efebera Yvonne A. 2* 1 Division of Hematology, The Ohio State University, Columbus, OH 43210, USA 2 Department of Hematology, Blood and Marrow Transplant, OhioHealth, Columbus, OH 43214, USA * Correspondence: [email protected] (N.S.); [email protected] (Y.A.E.) 21 2 2023 3 2023 15 5 135413 2 2023 15 2 2023 19 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). pmcOver the last 10 to 20 years, there have been significant improvements in the fields of both autologous and allogenic transplantation. The upper age limit for hematopoietic stem cell transplantation continues to increase for both autologous SCT (ASCT) and allogeneic HCT (allo-HCT). The improvement in supportive management and development of novel agents has led to increases in survival outcomes in patients undergoing ASCT for multiple myeloma and lymphoma. Advances in conditioning regimens, the expanding use of alternative donor stem cell sources such as haploidentical stem cells and cord blood, and the use of modern T-cell depletion strategies such as post-transplant cyclophosphamide have led to better survival outcomes and a reduced incidence of graft versus host disease in patients undergoing allo-HCT. This special issue, which comprises 12 papers, addresses various aspects outlining the roles of ASCT and allo-HCT in the treatment of hematological malignancies, new advancements pertaining to their use and the challenges they pose when deciding on the optimal practice. The paper by Jiang et al. was a retrospective analysis on patients who underwent allo-HCT to better understand how survival has changed over the years. The authors divided the patients into groups based on the year of transplant. The data showed that both progression free and overall survival increased over the years. Five-year graft-versus-host disease/relapse-free survival (GFRS) also increased from 6% to 14% in the latter years. The authors attributed this change to advances in supportive care and treatments focused on the mitigation of graft versus host disease (GVHD) and relapse . For allogenic transplantation, tacrolimus, a calcineurin inhibitor that prevents T-cell activation, is often used for GVHD prophylaxis. However, there is variability in the serum concentrations of tacrolimus (TAC), and little is known on the impact of early TAC levels on acute GVHD (aGVHD). The retrospective study (2002-2016) by the same group studied the effect of early post-transplantation tacrolimus concentration on the risk of acute GVHD. It was reported that achieving >=10 ng/mL during the first week of allo-HCT may mitigate the risk of aGVHD. However, levels of >11 ng/mL beyond the first week may be associated with suppressed graft versus tumor effect and higher relapse . Graft versus host disease is a serious but common complication associated with allo-SCT as a result of donor T-cell mediated stem cells that attack immunocompromised host tissues. The treatment of aGVHD involves a high dose of corticosteroids, which suppress the immune system and put patients at an even greater risk of infectious complications , and potential viral reactivation complications. Despite this increased risk, there are little published data focused on the efficacy of cytomegalovirus (CMV) prophylaxis for patients who develop aGVHD. Wolfe et al. reported on the efficacy of letermovir to prevent clinically significant CMV infection (CS-CMVi) among allo-HCT patients who developed aGVHD in a single center retrospective study. Among aGVHD patients, letermovir prophylaxis decreased CS-CMVi in patients with aGVHD (p < 0.001), reduced non-relapsed mortality (p = 0.04) and improved overall survival (p = 0.04), suggesting that letermovir prophylaxis improves outcomes by preventing CS-CMVi in patients with aGVHD. Dybko et al. aimed to identify predictive and risk factors associated with the increased occurrence of the BK virus-related hemorrhagic cystitis (HC) following hematopoietic stem cell transplantation (HCT). A significant correlation was observed between HC incidences after HCT, BK viremia and viruria, and aGVHD occurrence. Furthermore, the level of BK virus DNA in serum at day +21 (>0.75 x 103) significantly impacted the patients' survival time . Allo-HCT therapeutic efficacy is mainly dependent on immune alloreactivity mediated by donor lymphocytes infused with the stem cell graft, the so-called graft versus leukemia (GVL) effect. Disease recurrence is the major obstacle to the success of allo-HCT, as patients with high-risk acute leukemia and MDS have a high risk of relapse after allo-SCT . Prophylactic donor lymphocyte infusion (DLI) has been shown to reduce the relapse rate but at the cost of increased GVHD . Tsirigotis et al. tested the safety and efficacy of a novel method of prophylactic DLI based on prolonged repetitive administration of low lymphocyte doses. When extended for up to 3 years, low-dose pro-DLI administered every two months is safe and effective in reducing relapse rate in patients with high-risk acute leukemia (AL). The data showed that repeated and prolonged DLI administration resulted in relapse prevention, perhaps by inducing a long-lasting anti-leukemic effect . Gutierrez et al., in a retrospective analysis, showed that it may be a curative option in relapsed/refractory (R/R) mantle cell lymphoma with a low cumulative incidence of relapse (CIR). They showed that it might be a better option for fit patients, using human leukocyte antigen (HLA)-identical (related or unrelated) or haploidentical related donors and without previous transplantation. In another study, Tsai et al. compared the outcomes of post cyclophosphamide with or without anti-thymoglobulin and GCSF-primed bone marrow plus peripheral blood stem cells (GIAC). They showed that the mGIAC approach may be a preferential choice for patients with low/intermediate-risk diseases in the view of non-relapse mortality (NRM), CIR, or overall survival (OS) . For multiple myeloma (MM), ASCT is more commonly used compared to allo-HCT. In this issue, three papers were published (two original article and one review). Jordan et al. performed a retrospective survival analysis on newly diagnosed MM (NDMM) patients receiving ASCT from 1992 to 2016 . Patients were split into five groups based on historic changes in novel agents for the treatment of MM. Across the years, there was a statistically significant improvement in both progression-free-survival (PFS) and OS, which was primarily attributed to the inclusion of novel therapies and post-transplantation maintenance. Importantly, significant survival improvements were seen in patients <=65 years and >65 years old. Baertsch et al. reported on the outcome after salvage high-dose chemotherapy (HDCT)/ASCT following re-induction treatment with carfilzomib/lenalidomide/dexamethasone (KRD). The authors conducted a retrospective analysis of patients that had previously undergone frontline HDCT/ASCT and reported that KRD followed by salvage ASCT were associated with favorable PFS and the response was enhanced by maintenance treatment. Deep remissions achieved with KRD followed by salvage autologous transplantation were associated with favorable PFS and were enhanced by maintenance treatment . In the past years, the therapeutic approaches for patients diagnosed with MM and their respective prognoses have decisively changed with the development of highly efficient new anti-myeloma drugs, such as protosome inhibitors (PI), immunemodulatory drugs (IMID), monoclonal antibodies and CAR-T cells. The review by Greil et al. addresses the role of allo-HCT in MM. The authors discuss data showing that a decreased risk of disease progression may outweigh this treatment-related toxicity for young, fit patients in high-risk constellations with otherwise often poor long-term prognosis. Salvage allo-HCT is recommended, preferentially within clinical trials, for patients with early relapse after first-line therapy including ASCT, and in high risk (HR) constellations according to cytogenetics and stage . Severe acute or chronic GVHD, systemic signs of inflammation and endothelial dysfunction with fluid overload are relatively common posttransplant conditions that are associated with an adverse prognosis and decreased survival due to increased NRM in allotransplant recipients. Previously, it has been shown that there is an association between systemic metabolic profiles and the risk of GVHD, and fluid retention post allo-HCT . Hatfield et al. studied the potential associations between lipidomic profiles and pretransplant inflammation, early fluid overload and later development of aGVHD. Ninety-two consecutive patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) were included in the analysis. The results showed that the pretransplant lipidomic profiles differed significantly when comparing patients with and without the risk factors: (i) pretransplant inflammation, (ii) early fluid overload, and (iii) patients with and without later steroid-requiring aGVHD . The pediatric population treated with allo-HCT most frequently develop endocrine complications. The treatments given, consequently, lead to impaired fitness, including exercise-induced shortness of breath, fatigue and reduced participation in physical activity . These symptoms may indicate frailty . Suominen et al. evaluated the physical fitness and prevalence of frailty in male long-term survivors of pediatric allo-transplant. Low muscle strength and a high incidence of frailty were observed in survivors of pediatric allo-HCT. There is a predominant risk of cardiovascular and metabolic diseases in the long-term . We hope that this Special Issue has responded to the clinical demand for up-to-date and in-depth information about the optimal management of patients undergoing hematopoietic stem cell transplantation for hematological malignancies. Conflicts of Interest The authors declare no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Jiang J. Sigmund A.M. Zhao Q. Elder P. Benson D.M. Vasu S. Jaglowski S. Mims A. Choe H. Larkin K. Longitudinal Survival Outcomes in Allogeneic Stem Cell Transplantation: An Institutional Experience Cancers 2022 14 5587 10.3390/cancers14225587 36428678 2. Sharma N. Zhao Q. Ni B. Elder P. Puto M. Benson D.M. 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Physical Fitness and Frailty in Males after Allogeneic Hematopoietic Stem Cell Transplantation in Childhood: A Long-Term Follow-Up Study Cancers 2022 14 3310 10.3390/cancers14143310 35884371 |
Energy security concerns require novel greener and more sustainable processes, and Paris Agreement goals have put in motion several measures aligned with the 2050 roadmap strategies and net zero emission goals. Renewable energies are a promising alternative to existing infrastructures, with solar energy one of the most appealing due to its use of the overabundant natural source of energy. Photocatalysis as a simple heterogeneous surface catalytic reaction is well placed to enter the realm of scaling up processes for wide scale implementation. Inspired by natural photosynthesis, artificial water splitting's beauty lies in its simplicity, requiring only light, a catalyst, and water. The bottlenecks to producing a high volume of hydrogen are several: Reactors with efficient photonic/mass/heat profiles, multifunctional efficient solar-driven catalysts, and proliferation of pilot devices. Three case studies, developed in Japan, Spain, and France are showcased to emphasize efforts on a pilot and large-scale examples. In order for solar-assisted photocatalytic H2 to mature as a solution, the aforementioned bottlenecks must be overcome for the field to advance its technology readiness level, assess the capital expenditure, and enter the market. The 2050 roadmap strategies and net zero emission goals are made possible through the adoption of novel greener and more sustainable processes. In this regard, exploiting solar irradiation (a plentiful energy source) is advantageous for developing green hydrogen technologies. Photocatalytic devices are suited for large-scale plants proliferation. Three case studies from France, Spain, and Japan are presented. hydrogen net zero emissions photocatalysis roadmap technological development source-schema-version-number2.0 cover-dateMarch 2023 details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.2.6 mode:remove_FC converted:10.03.2023 M. Isaacs , J. Garcia-Navarro , W.-J. Ong , P. Jimenez-Calvo , Is Photocatalysis the Next Technology to Produce Green Hydrogen to Enable the Net Zero Emissions Goal?. Global Challenges 2023, 7 , 2200165. 10.1002/gch2.202200165 pmc1 Introduction Today, humankind is confronted by a series of global challenges: energy/environmental crises, population growth, pandemics, and geopolitical wars, that simultaneously promote the depletion of natural resources and accelerate the contamination of sources of life: water, air, and soil. Among these challenges, energy production, and demand deserve special attention by the research and development communities who urgently need to devise tangible solutions. Notably, the continuous conversion of fossil fuels, such as oil, gas, and coal continue to contribute to greenhouse gases emissions, such as carbon dioxide (CO2). Ideally, certain criteria for selecting the future energy sources should be observed, namely, these sources should be abundant, easy to recycle or regenerate at the large scale, and their conversion should be CO2-free. The world's total net CO2 emissions, from 1850 to 2019, were 2400 +- 240 Gt(CO2). Between 2010 and 2019 alone, roughly 17% of the total cumulative net CO2 emissions (410 +- 30 GtCO2) were released, supporting Hubbert's predictions from 1970. The concentration of CO2 in the atmosphere has been directly measured by the Mauna Loa Observatory, exhibiting 417 ppm Figure 1 . Such CO2 increases result in damning and imminent consequences to the natural world. For example, increases to the surface temperature of the Earth consequently impact the average rate of sea levels (e.g., 20 cm rise between 1901 and 2018), desert dryness, melting of glaciers and ice caps, heat content and acidification of the ocean, and other negative effects to various ecosystems. Figure 1 a) Measurements of atmospheric CO2 since 1958 from the Mauna Loa Observatory in Hawaii (black) and from the South Pole (red) show a steady annual increase in atmospheric CO2 concentration. Reproduced with permission. Copyright 2022, Scripps CO2 Program. b) Illustrative scheme to represent the technological transfer from laboratory setups, pilot scale devices, and large-plants. For these reasons, an assessment of existing processes must be carried out to replace them with more efficient and sustainable technologies. For that, a shift from fossil fuels to clean energy has been suggested by the roadmap 2050 (the European Commission (EU)) and Net Zero by 2050 (the EU Green Deal and International Energy Agency). At the present time, fossil fuels still supply 80% of the world's energy. In this context, the use of solar energy is an appealing alternative due to the primary energy source being an effectively unlimited supply of great power. The diversity of emitted photons with different energies that can be selectively captured and thus used for chemical conversion to obtain solar clean fuels makes this a unique source. Nevertheless, the capture of solar photons is a challenge due to the day-night cycle, seasonal change, cloud presence, and geographical local distribution. Among several solar-driven fuels currently under investigation, hydrogen is primarily unlocking the potential of renewables as an energy source, and moving carbon neutrality toward a reality rather than a myth. The attractiveness of H2, as an energy vector, lies in three arguments: a) Its high energy content per unit mass (142 kJ mol-1), twofold to threefold increase compared with classical fossil fuels, such as gasoline, methane, propane, and natural gas, b) versatile energy storage medium because it can be used in electric only or combined heat and power fuel cells in stationary applications, internal combustion engines, and fuel cell vehicles, and c) despite its low self-discharge rate, regenerative hydrogen fuel cells may be cheaper than batteries in an optimized energy arbitrage system. H2 integration into the economic model became a serious consideration following the signing of the Paris agreement by the members of United Nations (UN). One of the goals of this agreement is to decarbonize heavy industry and, for that, reinviting or shifting existing technologies for optimized, greener, and more sustainable processes is a must. Thus, the European Commission, the World Economic Forum, the UN, Mission Innovation, and established industries are implementing new strategies to support net zero emissions and update their portfolio of technologies. With this integration scenario, emerging H2 technologies are achieving historical technology readiness levels (TRL), ranging from laboratory setups into pilot devices and large-plants . However, storage, transport, and safety hindrances must be addressed and refined to enable fully widespread integration into the socio-economical context. H2 safety is undoubtedly a topic to be addressed for a broader implementation and social acceptance. Briefly, the ignition energy of H2 mixed with air (0.017 mJ) is lower than natural gas (0.24-0.31 mJ). As natural gas is already handle in a large scale making a proof-of-concept. Thus, the ignition energy difference points out that theoretically H2 would cause lower flame propagation from the ignition point, thus is safer. Therefore, an ignition endanger will be consider when a source is close (e.g., spark or over heated contact). Experiments have shown that H2 does not ignite in cases where it was expected under specific circumstances, namely in presence of friction or energized devices. Still, more maturity in ignition tests is needed to mitigate and minimize inherent risks (essentially ignition), as reached for natural gas. 2 Hydrogen Production Context Worldwide political and scientific consensus have defined a color nomenclature for H2 in function of its source of production. There are eight different colors but for this article we limit the introduction of the three extreme cases, from the most and least contaminant and neutral sources. Please refer to Ajanovic et al. for details. Grey H2 is made with fossil-fuel-based technology, blue H2 is climate-neutral and made with carbon capture and storage technology, and green H2 is made with renewable energy (using renewables). To date, H2 is produced by mostly fossil fuels (98%) emitting nearly 900 million metric tons (Mt) of CO2 per year. By 2020 H2 production reached 90 Mt. It is forecasted, however, that H2 production may surpass 200 Mt in 2030. Steam methane reforming (76%) is the leading H2 production technology in the market, followed by coal gasification (22%), two energy-intensive and highly polluting methods. Electrolysis, a clean but relatively adolescent technology is already in the loop of existing technological processes contributing to 2% of total production, evidencing the need to decentralize H2 production to facilitate the integration with downstream processes to foster a sustainable energy transition. The output stream of electrolyzers is a mixture of H2 and O2. Thus, a common practice consists in using gas separation processes, (also in fuel cells and steam methane reforming with the equivalent or other by-product gases) in the end production point with possible recirculation for increasing the efficiency itself and obtained a higher H2 purity. The high-quality H2 with the desired low impurity levels is achievable with either adsorption and diffusion purification processes. The commercial technology widely used for adsorption-based H2 purification is Pressure Swing Adsorption (PSA), where porous solid adsorbents (e.g., zeolites and activated carbons) preferentially adsorb particular components from a gas stream in a pressurized vessel, later to be released after depressurization, that is, pressure cycles. Besides PSA, there are other methods based on temperature (TSA) and/or vacuum (VSA) but purities and cost differ. The amount of H2 made from renewable sources, like water or biomass, is a small part of the total amount produced. Fortunately, there are several methods to obtained H2 and O2 via water splitting (WS), namely electrolysis, electrocatalysis, photocatalysis (PC), photoelectrocatalysis, photovoltaic-electrochemical, solar thermochemical cycles, photothermal catalytic, or photobiological processes. WS is an uphill reaction that requires a significant Gibbs free energy, that is, 237 kJ mol-1. Interestingly, WS requires a very similar amount of energy as natural photosynthesis, with plants needing 1.24 eV (energy required per electron driven through the photosynthetic system) to make glucose, whereas to split water artificially requires 1.23 eV per electron. This thermodynamic requirement of PC H2 production is defined primarily by the water oxidation (oxygen evolution reaction) and then the proton reduction (hydrogen evolution reaction, HER) half-reactions requiring 1.23 and 0 V versus normal hydrogen electrode (pH = 0), respectively. On top of H2 production via WS, PC is an appealing approach for other energy applications, such as CO2 reduction and nitrogen fixation. As heterogeneous catalysis type, PC is particularly simple, requiring only light to activate the solid semiconductor (SC) and transform either a liquid or gas reactant. Unlike, typical electrolyzer connected with a photovoltaic panel, PC simplifies in its unassisted electricity possibility, potentially lowering costs in an operating expenses (OPEX) viewpoint. 3 Photocatalytic Water Splitting Principle PC WS is a heterogeneous surface catalytic reaction and possesses an attractive simplicity, requiring only light, a catalyst, and water to function. For that reason, PC WS is an appealing prospect, and considered one of the "holy grail" reactions in physical chemistry because can directly produce H2 from water. Should the technical barriers be removed whilst maintaining even a moderate capital expenditure (CAPEX), then one can presume it to challenge competitor methods, perhaps eventually reaching an even more attractive cost. Typically, PC WS starts when a SC is irradiated with a photon with equal or higher energy than its band gap. This generates an exciton: excited electron (e-) and a positive hole (h+). These two charge carriers dissociate and migrate to the surface of the catalyst. Some e-/h+ partners face undesirable recombination on the surface or in the bulk, but the e-/h+ pairs reaching the surface may undertake one of the two WS half-reactions. Figure 2 a) Photocatalyst scheme of activation, generation, and reactional water splitting steps. b) Summary of general photocatalytic steps. Successful h+ moieties avoiding recombination can oxidize water to create O2 and H+, while on the other hand, available can reduce the H+ to obtain H2. Therefore, the HER consumes 2 molecule of H2 formed. The four steps of the process (activation, exciton formation, recombination, redox) all involve different time scales, which are well-described by Takanabe et al. Figure 2b summarizes PC WS sequential steps: a) Activation of the catalyst (critical), b) generation of the charge carriers, and c) redox reactions in the interface between the catalyst and the substrate. Prior to catalyst activation there are two pre-reaction steps, first the reactant molecules must diffuse to the liquid-gas/solid interface to be adsorbed onto the catalyst surface. Once on the surface, they then wait to encounter a photo-generated charge carrier and react. Furthermore, after the catalyst's activation, two analogous post-reaction steps then happen. They initially desorb from the catalyst surface and then diffuse back into the reaction media. The critical step (activation of the catalyst) defines the overall efficacy of the material, which occurs mostly in the interior of the catalyst, but some sub-steps may proceed at its surface. Many leading scientists are currently improving the reaction medium/catalyst interface contact with sophisticated advanced material strategies (Z-scheme, Schottky junctions, and co-polymerization, among others) to tune key properties and increase efficiencies. 4 Photocatalytic Technological Developments This section will showcase three photocatalytic systems develop in Asia and Europe. One recently automated laboratory scale reactor, and two pilot devices: A panel photocatalytic array and a compound parabolic collector (CPC). The reasoning is to highlight the international efforts toward improving laboratory photocatalytic systems and the transition into pilot and large-scale processes. The first step toward large-plants, however, is the development and refinement of effective PC devices capable of promising performance on the pilot scale. Considerations of the complexities of benchmarking and effective engineering challenges in developing lab-scale PC materials was addressed in our recent work designing and constructing a compact automated stainless steel reactor, of 40 cm3 of volume. H2 photoproduction and quantum yields exhibited twofold increases when compared to literature equivalent materials. This result emphasizes that reactor geometry and configuration setup play a key role in the performance of PC materials and reveals insights into ideal (minimal losses) heat/mass/photonic profiles. An unprecedented 100 m2 arrayed panel system led by Professor Domen, comprising 1600 units has been recently launched at Kakioka Research Facility at the University of Tokyo. This system design has achieved 0.76% solar-to-hydrogen (STH) conversion, similar to ideal lab scale efficiency, 1% STH. The configuration attractiveness relies in being simple, cheaper, and more amenable to scale-up compared with solar cells and/or electrolysis systems. Each panel plate was sprayed with a modified aluminum-doped strontium titanate photocatalyst layer, one of the most efficient photocatalysts to date. The highlight of this panel array is its H2 recovery after several months of continuous operationality, starting with a moist gas product mixture, and H2 capture with a polyimide membrane. Another pilot device for solar H2 generation and removal of wastewater pollutants was tested at Plataforma Solar de Almeria. This setup consists of a CPC, which is a reactor type enabling highly efficient solar photon collection. Two materials were tested, Pt/(TiO2-N) and Pt/(CdS-ZnS), with the former outperforming the latter in combination with two sacrificial electron donors: formic acid and glycerol. This system evidences other proof-of-concept of H2 production, though this time using municipal wastewaters, enabling simultaneous waste water depollution and energy vector generation. Though several photocatalytic WS prototypes are available, their efficiency is still low (<1%). From a photochemical process perspective, reactor design and process optimization are needed to make this technology viable and feasible on a relevant scale. Furthermore, from a materials science perspective, higher-performing photocatalysts with better stability and H2 production efficiency (5-10% STH) are needed for economic viability. Public and private partnerships are proliferating internationally to tackle these bottlenecks; The Green Deal (European Union) in particular is investing a significant amount into finding tangible renewable solutions. 5 Conclusions and Outlook By maturing solar-assisted photocatalytic H2 technologies on a pilot scale, like in the three case studies, the proof-of-concept stage can be bypassed and thus enable the new chapter of TRL acceleration. The innovation of advanced H2 pilot devices in the next half-decade will be key to unlocking new engineering advances for large-scale that may foster both the commercialization of H2 from solar-fueled photocatalysis across the global market and the circular economy (while decarbonizing with clean energy). For solar scale up reactor design and dimensional technological transfer analysis, we propose a (non-exhaustive) list of parameters extracted from the selected case studies to implement in higher TRL projects, essentially in four axes: operational, photonic, mass, and heat transfer profiles. We suggest such considerations with the intention that WS PC pilot devices proliferate and unlock further technological barriers. Operational considerations include quantification of H2 (data acquisition) within an integrated on-line analytical equipment (gas chromatography) to reduce operational costs in human resources which is essential for scaling up to TRL >=3 (pilot prototypes). Reactor components should have resistance to pH, corrosion, and exposed environmental conditions. Furthermore, components must be easy to handle and accessible (with a modular assembly design providing an optimal solution to this point), and finally low-cost (low CAPEX and OPEX). Photonic considerations for catalyst activation focus on efficient photon capture and distribution, with suitable geometry to maximize collected light, suitable light absorbing materials, and maximizing use of the solar spectrum. Mass transfer considerations facilitate adsorption-desorption interactions, for example the reactor must guarantee minimal pressure from the gas flow, ensure suspended particle homogeneity in the contained volume, and avoid creation of pronounce vortexes of sufficient agitation to disrupt processes. Heat transfer considerations include the use of recirculating chillers directly in the path of the light source or inside the reactor (but not in contact with the particle dissolution) to guarantee a constant temperature, ideally of 20 degC, to avoid thermal catalysis contributions. Ultimately, for large-scale setups, the inclusion of wastewater and or organic pollutants as for substrate source and electron or proton donors or so-called sacrificial agents, respectively, should not be negligible while planning of building the plant. Contrarily, optimal processes envisage the simultaneous reuse of one of source (wastewater) resulting in the production of decontaminated (of organic pollutants) water and concomitant generation of energy solar carriers. Conflict of Interest The authors declare no conflict of interest. Acknowledgements Prof. Dr. Markus Antonietti is acknowledged for his support. The Max Planck Society supported this research financially. M. A. Juan Rodriguez is acknowledged for his graphical design contribution. The acknowledgements section was added and corrections made to references 19, 41 and 43 after initial online publication, on March 10, 2023. Open Access funding enabled and organized by Projekt DEAL. |
Cells Cells cells Cells 2073-4409 MDPI 10.3390/cells12050779 cells-12-00779 Editorial Rho GTPases in Model Systems Filic Vedrana * Weber Igor * Division of Molecular Biology, Ruder Boskovic Institute, Bijenicka 54, HR-10000 Zagreb, Croatia * Correspondence: [email protected] (V.F.); [email protected] (I.W.) 01 3 2023 3 2023 12 5 77922 2 2023 27 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). pmcSince the discovery of their role in the regulation of actin cytoskeleton 30 years ago, Rho GTPases have taken center stage in cell motility research. Over time, it has become clear that these "molecular switches" are also involved in the regulation of other cellular processes, such as cell polarization, cell differentiation and growth, membrane trafficking, and transcriptional regulation. The biological importance of Rho GTPases is exemplified by the fact that mammalian cells invest more than 150 genes that encode their direct regulators. Rho GTPases are essential signaling molecules in mammals and across the whole eukaryotic domain. This Special Issue of Cells represents a collection of review articles and original research papers covering Rho GTPases in model organisms and cell culture systems. It can be roughly divided into sections devoted to evolutionary aspects, screening and mechanistic approaches, and the roles of Rho GTPases in mammalian physiology and pathology. Evolutionary insight into the functional roles of Rho GTPases in simple model organisms can provide an invaluable perspective on their universal biological importance. Current knowledge and recent advances on how the fission yeasts Rho family GTPases regulate essential physiological processes, such as morphogenesis and polarity, cellular integrity, cytokinesis, and cellular differentiation, are presented by Vicente-Soler et al. . Although the genetic tools available in yeast are still unrivaled, the physiology of the actin cytoskeleton in these organisms is quite specific and distinct from metazoan cells. A much closer match is provided by the highly motile cells of amoebozoan protists, which share the composition and dynamics of the transient actin-based structures, in particular with mammalian cells of the hematopoietic lineage. Filic et al. provide an overview of the Rho signaling pathways that regulate the actin dynamics in Dictyostelium and compare them with similar signaling networks in mammals . Interestingly, although phylogenic algorithms do not identify strict homologies between Rho GTPases in the two groups, comprehensive functional studies established that canonical mammalian representatives, Rho, Rac and Cdc42, obviously have their functional analogues in Dictyostelium. Moving on into the realm of multicellularity, a review by Beljan et al. represents a compilation of the current knowledge concerning Rho-family GTPases in non-bilaterian animals, the available experimental data regarding their biochemical characteristics and functions, and an original bioinformatics analysis of their relationship with metazoan counterparts . Their findings provide a general insight into the evolutionary history of Rho-family GTPases in simple animals and support the notion that the ancestor of all animals probably contained Rho, Rac and Cdc42 homologs. Rho proteins of plants (ROPs) form a specific clade of Rho GTPases, which are involved in plant immunity and their susceptibility to diseases. In their review, Engelhard et al. summarize central concepts of Rho signaling in disease and immunity of plants and briefly compare them to important findings in the mammalian research field . Interesting similarities emerge, as follows: while invasive fungal pathogens may co-opt the function of ROPs for manipulation of the cytoskeleton that promotes pathogenic colonization, mammalian bacterial pathogens also initiate effector-triggered susceptibility for cell invasion via Rho GTPases. Zebrafish, as model vertebrates, offer a unique opportunity to explore the spatial and temporal dynamics of Rho GTPases within a complex environment at a level of detail unachievable in any other organism. Boueid et al. present a compilation of examples where the roles of Rho, Rac and Cdc42 in cell motility, developmental processes, angiogenesis, neural system and pathological processes in zebrafish were investigated using a set of powerful tools to follow and locally modulate Rho GTPases signaling and their function in real time, combined with rapidly evolving imaging and genetic techniques . Given the large complexity involved in the signaling networks centered on Rho GTPases, system-level research is required to fully grasp the extent of their biological roles and regulation. In their review article, Dahmene et al. highlight the recent large-scale studies, including proteomic approaches to map the full repertoire of Rho GTPases and Rho regulators protein interactions and high throughput screening strategies that unraveled new roles for understudied family members by using cell culture models and mouse embryos . An example of the high throughput screening approach is provided by Long et al., who developed and applied an image-based high-content screen using RNA interference to systematically perturb each of the 21 Rho family members and assess their importance to the overall organization of the Golgi complex . Their analysis revealed previously unreported roles for two atypical Rho family members, RhoBTB1 and RhoBTB3, in the endomembrane traffic events. In addition to their localization at the plasma membrane and endomembranes, recent research demonstrates that active pools of different Rho GTPases also localize to the nucleus. Navarro-Lerida et al. discuss how the modulation of Rho GTPases driven by post-translation modifications provides a versatile mechanism for their compartmentalization and functional regulation . They stress that understanding how the subcellular sorting of active small GTPase pools occurs and what its functional significance is will contribute to the exploration of Rho GTPases as important therapeutic targets in cancer and other disorders. Indeed, it is becoming increasingly clear that small Rho GTPases play essential roles in human physiology and pathology. In their review article, Sarowar and Grabrucker discuss the role of three archetypical Rho GTPases in the modulation of dendritic spine morphogenesis in the amygdala, the core brain region associated with fear learning and conditioning . Dendritic spines are tiny, dynamic, and heterogeneous actin-rich protrusions on the surface of neuronal dendrites that receive input from an axon at the synapse. RhoA inhibits dendritic growth and dynamics, while Cdc42 and Rac1 promote them. By doing so, Rho GTPases and some of their modulators expressed in the amygdala play an important role in fear-related processes. Another example of the influence of Rho signaling on synaptic plasticity is provided by Figiel and colleagues . Synaptic remodeling mediated by matrix metalloproteinase 9 (MMP-9) is essential for long-term memory formation. MMP-9 may contribute to the dynamic remodeling of structural and functional plasticity by cleaving ECM components and cell adhesion molecules. Rho GTPases seem to be downstream effectors of MMP-9, and the authors review current knowledge on their roles in MMP-9-dependent signaling pathways in the brain, with emphasis on the influence of their post-translational modifications. Mao et al. explored the function of Rho GTPases during phagocytosis of spent photoreceptor outer segment fragments by retinal pigment epithelial (RPE) cells, which is essential for visual function . This process is mediated by Mer tyrosine kinase (MerTK) receptor signaling, and MerTK mutations cause complete blindness in early adulthood, for which widely applicable therapy is still unavailable. In their research, the authors show that efficient RPE phagocytosis requires the activation of Rac1 and the simultaneous suppression of RhoA activity downstream from MerTK. In MerTK-deficient RPE cells, elevated RhoA activity blocks phagocytic cup formation. However, inhibition of RhoA downstream effector ROCK is sufficient to restore the phagocytic capacity of MerTK-deficient RPE. Since ROCK inhibitors are already approved for common, long-term use for ocular disease, this study supports future efforts toward their use in simple therapy, possibly as eye drops. Veluthakal and Thurmond systematically summarize the role of different Ras superfamily GTPases in the normal functioning of pancreatic islet b-cells . Pancreatic islet b-cells take up glucose and initiate glucose metabolism that, via a plethora of signaling events, induces insulin granule exocytosis. The authors review the roles of Rho, Arf and Rab family members in the islet insulin secretory process and describe how the altered activity of GTPases can lead to b-cell dysfunction. Considering the important roles that Rho GTPases play in the regulation of physiological processes, it is no surprise that their altered activities significantly contribute to numerous pathological conditions. Humphries et al. provide an overview of the current understanding of the regulation and functions of Rho GTPases specifically in breast cancer . They show that, similarly to findings in other tumors, there are conflicting data concerning the role of Rho GTPases in breast cancer. However, the prevalent notion is that increased activation of Rho GTPases has tumor-promoting roles in breast cancer initiation, metastatic progression, chemoresistance, and radioresistance. Furthermore, Rho GTPases have important roles in diseases whose major contributor is chronic inflammation. Kilian et al. summarize the role of RhoA in stress-induced signaling from damaged cardiomyocytes to immune cells, which leads to immune cell activation, chronic inflammation and cardiac disease progression . They discuss the possible roles of RhoA signaling in cardiomyocytes, macrophages, neutrophils, and dendritic cells, which are important in the pathogenesis and progression of cardiac dysfunction. Atherosclerosis is another example of a chronic inflammatory immune-mediated condition implicated in the pathogenesis of coronary artery disease, a major cause of mortality worldwide. Lee et al. highlight the role of Rac-mediated inflammatory signaling in the mechanisms driving atherosclerotic calcification . They also discuss the off-target effects of statins, the most widely used therapy for hypercholesterolemia, on Rac immune signaling. Inflammation also has a crucial role in the development of gastrointestinal diseases, such as inflammatory bowel disease (IBD) and colorectal cancer. IBD is marked by the uncontrolled activation of immune cells and alterations to intestinal epithelial cells (IECs), characterized by increased tight junction permeability and altered cytoskeletal rearrangements. Pradhan et al. summarize the current knowledge on the roles of classical Rho GTPases in the context of intestinal homeostasis and disease, focusing on IECs and T cells . Finally, Hahmeyer and da Silva-Santos provide a comprehensive overview of the current knowledge about the role of Rho signaling pathways in sepsis, a life-threatening organ dysfunction caused by a dysregulated response to infection . They describe how Rho proteins, mainly Rac1 and RhoA, are involved in the development of sepsis-specific symptoms in different systems and cells, including the endothelium, vessels, and the heart. Author Contributions Conceptualization, V.F. and I.W.; writing original draft preparation, V.F. and I.W.; writing review and editing, V.F. and I.W. All authors have read and agreed to the published version of the manuscript. Conflicts of Interest The authors declare no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Vicente-Soler J. Soto T. Franco A. Cansado J. Madrid M. The Multiple Functions of Rho GTPases in Fission Yeasts Cells 2021 10 1422 10.3390/cells10061422 34200466 2. Filic V. Mijanovic L. Putar D. Talajic A. Cetkovic H. Weber I. Regulation of the Actin Cytoskeleton via Rho GTPase Signalling in Dictyostelium and Mammalian Cells: A Parallel Slalom Cells 2021 10 1592 10.3390/cells10071592 34202767 3. Beljan S. Herak Bosnar M. Cetkovic H. Rho Family of Ras-Like GTPases in Early-Branching Animals Cells 2020 9 2279 10.3390/cells9102279 33066017 4. Engelhardt S. Trutzenberg A. Huckelhoven R. Regulation and Functions of ROP GTPases in Plant-Microbe Interactions Cells 2020 9 2016 10.3390/cells9092016 32887298 5. Boueid M. Mikdache A. Lesport E. Degerny C. Tawk M. Rho GTPases Signaling in Zebrafish Development and Disease Cells 2020 9 2634 10.3390/cells9122634 33302361 6. Dahmene M. Quirion L. Laurin M. High Throughput strategies Aimed at Closing the GAP in Our Knowledge of Rho GTPase Signaling Cells 2020 9 1430 10.3390/cells9061430 32526908 7. Long M. Kranjc T. Mysior M. Simpson J. RNA Interference Screening Identifies Novel Roles for RhoBTB1 and RhoBTB3 in Membrane Trafficking Events in Mammalian Cells Cells 2020 9 1089 10.3390/cells9051089 32354068 8. Navarro-Lerida I. Sanchez-Alvarez M. del Pozo M. Post-Translational Modification and Subcellular Compartmentalization: Emerging Concepts on the Regulation and Physiopathological Relevance of RhoGTPases Cells 2021 10 1990 10.3390/cells10081990 34440759 9. Sarowar T. Grabrucker A. Rho GTPases in the Amygdala A Switch for Fears? Cells 2020 9 1972 10.3390/cells9091972 32858950 10. Figiel I. Kruk P. Zareba-Koziol M. Rybak P. Bijata M. Wlodarczyk J. Dzwonek J. MMP-9 Signaling Pathways That Engage Rho GTPases in Brain Plasticity Cells 2021 10 166 10.3390/cells10010166 33467671 11. Mao Y. Finnemann S. Acute RhoA/Rho Kinase Inhibition Is Sufficient to Restore Phagocytic Capacity to Retinal Pigment Epithelium Lacking the Engulfment Receptor MerTK Cells 2021 10 1927 10.3390/cells10081927 34440696 12. Veluthakal R. Thurmond D. Emerging Roles of Small GTPases in Islet b-Cell Function Cells 2021 10 1503 10.3390/cells10061503 34203728 13. Humphries B. Wang Z. Yang C. Rho GTPases: Big Players in Breast Cancer Initiation, Metastasis and Therapeutic Responses Cells 2020 9 2167 10.3390/cells9102167 32992837 14. Kilian L. Frank D. Rangrez A. RhoA Signaling in Immune Cell Response and Cardiac Disease Cells 2021 10 1681 10.3390/cells10071681 34359851 15. Lee C. Carley R. Butler C. Morrison A. Rac GTPase Signaling in Immune-Mediated Mechanisms of Atherosclerosis Cells 2021 10 2808 10.3390/cells10112808 34831028 16. Pradhan R. Ngo P. Martinez-Sanchez L. Neurath M. Lopez-Posadas R. Rho GTPases as Key Molecular Players within Intestinal Mucosa and GI Diseases Cells 2021 10 66 10.3390/cells10010066 33406731 17. Hahmeyer M. da Silva-Santos J. Rho-Proteins and Downstream Pathways as Potential Targets in Sepsis and Septic Shock: What Have We Learned from Basic Research Cells 2021 10 1844 10.3390/cells10081844 34440613 |
Cells Cells cells Cells 2073-4409 MDPI 10.3390/cells12050814 cells-12-00814 Editorial Large-Scale Multi-Omic Approaches and Atlas-Based Profiling for Cellular, Molecular, and Functional Specificity, Heterogeneity, and Diversity in the Endocannabinoid System Aoki Jun 12 Isokawa Masako 3* 1 Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan 2 Laboratory for Cell Signaling Dynamics, Center for Biosystems Dynamics Research, RIKEN, Kobe 650-0047, Japan 3 Forefront Research Center, Graduate School of Science, Osaka University, Osaka 560-0043, Japan * Correspondence: [email protected] 06 3 2023 3 2023 12 5 81428 2 2023 02 3 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). pmcThe endocannabinoid system (ECS) is a widely-recognized lipid messenger system involved in many aspects of our our lives in health and diseases. The system consists of cannabinoid receptors, their endogenous ligands, and the enzymes that mediate their synthesis and metabolic processes. Research progress was recently reviewed regarding (i) the pharmacology of the ECS, (ii) the roles of ECSs in development and synaptic function, (iii) cannabinoid signaling in pathological conditions, and (iv) cell-type-specific and localization-dependent operations of cannabinoid receptors . Of particular interest may be the conceptual framework where biomedical consequences influenced by ECS are not necessarily monotheistic; instead, there exists cellular, molecular, and functional specificity, heterogeneity, and diversity in (endo)cannabinoid action. This Special Issue aims to discuss the multiplexity of endocannabinoid signaling mechanisms and functions considering large-scale multi-omic approaches and the way data are visualized for presentation. It is well accepted that lipidomic , transcriptomic , proteomic , or any combination of these data mining strategies and atlas-based data profiling methods helped identify the involvement of critical molecules throughout our lives. Methodological orientation provided typical standards for non-parametric dimensionality reduction, data visualization, and cluster analysis that ranged from traditional principal component analysis (PCA) to the currently popular uniform manifold approximation and projection (UMAP) method. Some researchers may feel that these approaches are still young and relatively underexplored in endocannabinoid research; however, fruitful applications have already emerged in the investigation of ligands, receptors, and related enzymes. The first example concerns the role of ECSs in the transition of retinal Muller glia (MG) into proliferating progenitor-like cells in health and diseases . Using single-cell RNA sequencing (scRNA-seq) libraries, the patterns and levels of eCB-related gene expressions across different retinal cells were presented with two-dimensional profiling methods, such as UMAP and violin plots. UMAP-ordered cells formed distinct clusters of neuronal cells, resting MG, and activated MG. The expression levels in Cnr1, MGLl, DAGLa, DAGLb, and FAAH were demonstrated using heatmaps, and the cell-type specificity was shown by violin plots. Furthermore, the involvement of fatty-acid-binding proteins and fatty acid synthase was shown in the formation of Muller-glia-derived progenitor cells (MGPCs) after NMDA-induced damage. UMAP analysis illustrated aggregates of damages and the formation of distinct MGPC clusters according to the expression of GLUL, RLBP1, and SLC1A3, or NESTIN, CDK1, and TOP2A. Heatmaps and violin plots showed patterns and levels of FABP5, FABP7, and PMP2. These reports strived for a fuller understanding of the contribution of ECSs and fatty acid signaling in the reactivity and dedifferentiation of Muller glia, as well as the proliferation of microglia and MGPCs. The second example is about the involvement of cannabinoid receptor type 1 (CB1R/Cnr1) and type 2 (CB2R/Cnr2) in nonalcoholic fatty liver disease (NAFLD) and melanoma , respectively. scRNA-seq and UMAP highlighted six clusters of transcriptomic data in main liver cells, and violin plots depicted the hepatocyte-zone-specific gene expression. In melanoma, UMAP dimensionality reduction processed 6381 B-cells and mapped the top 10 upregulated genes (highest-fold change). Although the deletion of Cnr1 (CB1R KO mice) was expected to prevent the development of NAFLD, scRNA-seq and UMAP analysis did not support the hypothesis, showing that Cnr1-/- mice failed to protect the liver from fibrosis. In melanoma, UMAP analysis portrayed a positive correlation between the upregulation of intra-tumoral CB2R gene expression and improved overall survival, as well as a reduction in the metabolic activity of tumor-infiltrating B cells in Cnr2-/- mice. Anandamide synthesis was targeted by global transcriptomic analysis in the partial hepatectomy (PHX) model . The result illuminated the up-regulation of cell-cycle proteins, such as cyclin-dependent kinase 1 (Cdk1), cyclin B2, and their transcriptional regulator forkhead box protein M1 (FoxM1), and provided molecular and genetic support to the pathophysiological observation that PHX increased biosynthesis of anandamide in the liver via conjugation of arachidonic acid and ethanolamine by fatty acid amide hydrolase. Last but not least, it may be worth mentioning that in pharmaceutical sciences, dimensionality reduction and cluster analyses, such as t-distributed stochastic neighbor embedding (t-SNE) and UMAP, have been frequently used on large-scale samples of cannabis sativa chemotypes for the purpose of modeling cannabinoids . Here, a dataset of 17,600 commercial cultivars was screened for unknown gene regulation and pharmacokinetics of dozens of cannabinoids. The concentration of tetrahydrocannabinol (THC) scattered against the concentration of cannabidiol (CBD) was plotted to segregate low-CBD and -THC cultivars. These approaches not only helped reveal complex interactions in cannabinoid biosynthesis but also advanced the phenotypical classification of cannabis cultivars. We introduced scRNA-seq, t-SNE, UMAP, heatmaps, and violin plots as examples among the popular methodological tools for data generation and analysis. scRNA-seq provides a way of comprehensively defining gene expression and identifying molecular trajectories by connecting transcriptomes. However, the reconstruction of molecular lineages from gene-expression cascades to cell-type-specific markers and regulators is still a major challenge. t-SNE, UMAP, heatmaps, dendrograms, and violin plots are the techniques in data science that reduce the dimensionality of raw data and visualize the outcomes in a pictorial format. They are routinely applied in a broad range of fields, including life sciences, where datasets of increasing sizes are handled. While these techniques have been used liberally in combination with transcriptomics and proteomics, less usage has been acknowledged in the detection of molecules that cannot be labeled with antibodies and/or genetic manipulation. Further applications are encouraged with all-inclusive measurement technologies such as imaging mass spectrometry in cells and organisms, as it can directly detect and visualize the identified and unidentified lipids and metabolites that often play key roles in the eCB system. We hope you will find the collection of papers in this Special Issue interesting and helpful for expanding methodological choices in the event of mining, summarizing, and presenting new ideas and perspectives for future eCB research. Conflicts of Interest The authors declare no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Busquets-Garcia A. Melis M. Bellocchio L. Marsicano G. Special issue editorial: Cannabinoid signalling in the brain: New vistas Eur. J. Neurosci. 2022 55 903 908 10.1111/ejn.15618 35118747 2. Busquets-Garcia A. Desprez T. Metna-Laurent M. Bellocchio L. Marsicano G. Soria-Gomez E. Dissecting the cannabinergic control of behavior: The where matters BioEssays 2015 37 1215 1225 10.1002/bies.201500046 26260530 3. Bhaduri A. Neumann E.K. Kriegstein A.R. Sweedler J.V. Identification of Lipid Heterogeneity and Diversity in the Developing Human Brain JACS Au 2021 1 2261 2270 10.1021/jacsau.1c00393 34977897 4. Bugeon S. Duffield J. Dipoppa M. Ritoux A. Prankerd I. Nicoloutsopoulos D. Orme D. Shinn M. Peng H. Forrest H. A transcriptomic axis predicts state modulation of cortical interneurons Nature 2022 607 300 338 10.1038/s41586-022-04915-7 35794483 5. Petrus-Reurer S. Lederer A.R. Baque-Vidal L. Douagi I. Pannagel B. Khven I. Aronsson M. Bartuma H. Wagner M. Wrona A. 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Diagnostics (Basel) Diagnostics (Basel) diagnostics Diagnostics 2075-4418 MDPI 10.3390/diagnostics13050946 diagnostics-13-00946 Interesting Images Interpreting Discordant Monosomy 3 FISH and Chromosomal Microarray Analysis Results in Uveal Melanoma Long Christopher P. 1* Coley Nicholas 2 Thorson John 3 Lin Jonathan H. 456 Ferguson Cole Academic Editor 1 Department of Ophthalmology, Roski Eye Institute, University of Southern California, 1450 San Pablo St #4400, Los Angeles, CA 90033, USA 2 Diagnostic Pathology Medical Group, 3301 C St, Suite 200E, Sacramento, CA 95816, USA 3 Department of Pathology, University of California, 9444 Medical Center Drive 1-200, La Jolla, CA 92037, USA 4 Department of Pathology, Stanford University, 300 Pasteur Dr., Palo Alto, CA 94304, USA 5 Department of Ophthalmology, Stanford University, 2452 Watson Ct, Palo Alto, CA 94303, USA 6 VA Palo Alto Healthcare System, 3801 Miranda Avenue, Palo Alto, CA 94304, USA * Correspondence: [email protected]; Tel.: +1-323-442-6335 02 3 2023 3 2023 13 5 94624 11 2022 21 2 2023 28 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). Uveal melanoma is the most common primary ocular tumor in adults and causes morbidity through lymphovascular metastasis. The presence of monosomy 3 in uveal melanomas is one of the most important prognostic indicators for metastasis. Two major molecular pathology testing modalities used to assess monosomy 3 are fluorescence in situ hybridization (FISH) and chromosomal microarray analysis (CMA). Here, we report two cases of discordant monosomy 3 test results in uveal melanoma enucleation specimens, performed using these molecular pathology tests. The first case is of uveal melanoma from a 51-year-old male that showed no evidence of monosomy 3 when assessed by CMA, but where it was subsequently detected by FISH. The second case is of uveal melanoma from a 49-year-old male that showed monosomy 3 at the limit of detection when assessed by CMA, but where it was not detected by subsequent FISH analysis. These two cases underscore the potential benefits of each testing modality for monosomy 3. Mainly, while CMA may be more sensitive to low levels of monosomy 3, FISH may be best method for small tumors with high levels of adjacent normal ocular tissue. Our cases suggest that both testing methods should be pursued for uveal melanoma, with a single positive result for either test interpreted as indicating the presence of monosomy 3. uveal melanoma monosomy 3 microarray FISH Stanford Vision Research CoreNIH P30EY026877 This research was funded by Stanford Vision Research Core (NIH P30EY026877). pmc1. Materials and Methods An oncoscan microarray was performed at the University of California San Diego (UCSD) Center for Advanced Laboratory Medicine (CALM), using the Affymetrix/Thermofisher OncoScan platform (catalog number: 902695), on DNA extracted from sections of formalin-fixed, paraffin-embedded (FFPE) tissue. Monosomy 3 FISH was performed at Mayo Clinic Laboratories (test ID: UMM3F), utilizing the D3Z1 centromeric probe (Abbot Molecular) and the BCL6 long-arm probe (Mayo Laboratories). Greater than 28% of 200 cells lacking two chromosome 3 signatures is requisite for a positive monosomy 3 result when using this assay. Next-generation sequencing (NGS) was performed at the UCSD CALM on DNA extracted from FFPE tissue using a laboratory-developed 397 gene hybrid capture-based assay, with analysis conducted on an Illumina HiSeq 2500 instrument (Illumina, San Diego, CA, USA). The images of FFPE, eosin (H&E)-stained whole-eye cross sections were taken using the Aperio AT2 whole-slide scanner. The remaining images were captured using the Olympus SC30 camera with cellSens software, attached to an Olympus BX43 microscope. The UCSD institutional review board approved the use of the collected tissue samples and associated clinical information for this study. The research was Health Insurance Portability and Accountability Act (HIPAA)-compliant and adhered to the principles of the Declaration of Helsinki. 2. Figure and Table Legends Patient #1 is a 51-year-old male who was referred to ophthalmology for progressive left-sided vision loss. Ophthalmoscopic examination revealed a mushroom-shaped pigmented lesion, emanating from the posterior uvea overlying the optic nerve, which was proven to be melanoma by the performance of a fine-needle aspiration (FNA) biopsy. He underwent a 7-day surgical placement of radioiodine plaque overlying the tumor 1 month after initial pathologic diagnosis. A clinically detected local recurrence at the periphery of the plaque site, detected 60 months after pathologic diagnosis, underwent multiple rounds of laser ablation. The patient ultimately underwent enucleation 79 months after pathologic diagnosis. His most recent imaging, taken 92 months after initial pathologic diagnosis, demonstrates numerous liver metastases and local left orbital tumor extensions, tracking along the optic nerve to involve the optic chiasm. As seen in Figure 1, the melanoma from patient #1 arises from the posterior uvea overlying the optic nerve. A focus on scleral invasion adjacent to the optic nerve is present, but no extrascleral extension is noted (A). The tumor assumes a primarily epithelioid morphology (B), with the expression of HMB45 in malignant melanocytes (insert). Patient #2 is a 49-year-old male who visited ophthalmology for an enlarging pigmented mass present on his right iris. He underwent surgical radioiodine plaque placement (removed after 7 days) at the time of an FNA biopsy that demonstrated uveal melanoma. He underwent a 7-month trial of sunitinib shortly after initial pathologic diagnosis. Fifteen months after pathologic diagnosis, magnetic resonance imaging (MRI) of the abdomen demonstrated two biopsy-proven metastatic liver lesions. These were subsequently treated with radioablation. He underwent enucleation 36 months after pathologic diagnosis and a right apical lung lesion, biopsied at 38 months, demonstrated metastatic melanoma. An enlarging right apical lung lesion was the only metastatic disease detected by computed tomography (CT) of the chest in the patient's most recent imaging scan, performed 48 months after pathologic diagnosis. As demonstrated in Figure 2, the melanoma from patient #2 (A) arises from the ciliary body (Insert). The tumor assumes a primarily spindle-cell morphology (B), characterized by extensive necrosis, and the presence of melanophages, secondary to radioiodine plaque treatment (Insert). Figure 3 demonstrates the raw CMA microarray relative fluorescence data for the uveal melanoma from patient #1 (A) and patient #2 (B). For each patient, chromosome position/array probe location is located on the x axis of each panel. Relative copy number is denoted on the y axis of the top panel of data for both patients (A and B), while B-allele frequency is depicted in the lower panel of data for each patient. The uveal melanoma from patient #1 shows segmental gain of chromosome 9q, as evidenced by (1) the slight spike in the relative copy number plot (circled) and (2) the same region of the B-allele frequency plot showing an allele frequency of approximately 0.4 or 0.6 (also circled). Whereas the normal genotypes of AA, AB, or BB produce the expected B-allele frequencies of 0, 0.5, or 1.0, segmental gains result in an AAB genotype (i.e., gain of a A allele copy), leading to a b-allele frequency of >0 but <0.5 or an ABB genotype (i.e., gain of a B allele copy), producing a B-allele frequency of >0.5 but <1.0. The uveal melanoma from patient #2 shows low frequency loss of chromosome 3, 4, 12, and 16q with gains of 7, 8, 18, 19, and 22. These changes can best be appreciated by inspection of the copy number plot for patient #2 where slight shifts of the average copy number above or below the 0 line indicate a loss (movement below the 0 line) or a gain (movement above the 0 line) of chromosomal material. As summarized in Table 1, no clinically significant sequence variants were detected by NGS for either tumor. The uveal melanoma from patient #1 showed focal gain of chromosome 9 and no detectable chromosomal losses. However, this tumor demonstrated monosomy 3 when examined by FISH analysis. The uveal melanoma from patient #2 showed several chromosomal gains in addition to monosomy 3 at the limit of detection. FISH analysis did not detect monosomy 3 for this tumor. These two cases highlight the diagnostic strengths and pitfalls of CMA and FISH for assessing monosomy 3 status in uveal melanoma . CMA utilizes DNA extracted from an entire tumor sample and inevitably includes some background or interspersed normal tissues . Consequently, CMA may fail to detect monosomy 3 in a small subclone or the DNA from normal tissue may obfuscate low-level loss of chromosome 3 within a tumor . The detection of monosomy 3 by FISH, while it was not detected by CMA in patient #1, may reflect this phenomenon. FISH, however, samples a narrow plane of tissue and requires a relatively high proportion of cells with a single probe signal to minimize false positive results . Thus, FISH may miss monosomy 3 at a low level that CMA can routinely detect . The detection of monosomy 3 by CMA, a substance not detected by FISH in patient #2, may reflect this phenomenon. Overall, these two cases highlight the strengths and weaknesses of FISH and CMA as assays to detect monosomy 3 in uveal melanoma. We suggest that both FISH and CMA should be performed for uveal melanoma, with a positive result for either test interpreted as indicating the presence of monosomy 3. Acknowledgments We thank the staff at the UC San Diego Center for Advanced Laboratory Medicine (CALM) for performing all microarray testing. We thank Mayo Laboratories in Rochester MN for performing all FISH testing. Author Contributions C.P.L. and N.C. authored the majority of the manuscript. N.C. interpreted the initial molecular tests and took all images. C.P.L. wrote the majority of the background sections with additional contributions by SS. J.H.L. and J.T. reviewed the finished manuscript and served as final editors/mentors. All authors have read and agreed to the published version of the manuscript. Institutional Review Board Statement Tissue derived from both patients in this retrospective study was consented for potential research use under the UC San Diego Health System consent for treatment forms. Informed Consent Statement No personal identification from either patient is presented in this manuscript per HIPAA regulations. Data Availability Statement FFPE tissue from either case can be obtained for additional studies following approval of a material transfer agreement. Microarray data from each case can be provided de-identified of HIPAA sensitive information upon request as well as the original FISH reports from Mayo laboratories. Conflicts of Interest The authors declare no conflict of interest. Figure 1 Melanoma from patient #1 without extrascleral extension (A). The tumor assumes a primarily epithelioid morphology (B), with the expression of HMB45 in malignant melanocytes (insert). Figure 2 Melanoma from patient #2 (A) originating from ciliary body (insert). Tumor sample with spindle-cell morphology (B), necrosis, melanophages, secondary to previous treatment (insert). Figure 3 Raw CGH microarray relative fluorescence data for the uveal melanoma from patient #1 (A) and patient #2 (B). diagnostics-13-00946-t001_Table 1 Table 1 Clinical Summary of CMA and FISH results of patient #1 and patient #2. Patient #1 Patient #2 Mutations No clinically significant variance detected. No clinically significant variance detected. Chromosomal Gains 2.27 Mb gain in 9q33.1 encompassing 6 genes (ASTN2, SNORA70C, LOC101928797, TLR4, LINC02578, BRINP1). Gain of chromosomes 7, 8, 18, 19, and 22. Chromosomal Losses No chromosomal losses detected. Monosomy 3 at limit of detection with additional losses of chromosomes 4, 12, and 16q. Monosomy 3 FISH Status Positive, 63.5% of 200 cells counted (28% cutoff). Negative. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Aronow M.E. Topham A.K. Singh A.D. Uveal Melanoma: 5-Year Update on Incidence, Treatment, and Survival (SEER 1973-2013) Ocul. Oncol. Pathol. 2018 4 145 151 10.1159/000480640 29765944 2. Damato B. Duke C. Coupland S.E. Hiscott P. Smith P.A. Campbell I. Douglas A. Howard P. Cytogenetics of uveal melanoma: A 7-year clinical experience Ophthalmology 2007 114 1925 1931 10.1016/j.ophtha.2007.06.012 17719643 3. Prescher G. Bornfeld N. Becher R. Nonrandom Chromosomal Abnormalities in Primary Uveal Melanoma JNCI J. Natl. Cancer Inst. 1990 82 1765 1969 10.1093/jnci/82.22.1765 2231772 4. Bornfeld N. Prescher G. Becher R. Hirche H. Jockel K.H. Horsthemke B. Prognostic implications of monosomy 3 in uveal melanoma Lancet 1996 347 1222 1225 10.1016/S0140-6736(96)90736-9 8622452 5. Scholes A.G. Damato B.E. Nunn J. Hiscott P. Grierson I. Field J.K. Monosomy 3 in uveal melanoma: Correlation with clinical and histologic predictors of survival Investig. Ophthalmol. Vis. Sci. 2003 44 1008 1011 10.1167/iovs.02-0159 12601021 6. Theisen A. Microarray-based comparative genomic hybridization (aCGH) Nat. Educ. 2008 1 45 7. Sisley K. Rennie I.G. Parsons M.A. Jacques R. Hammond D.W. Bell S.M. Potter A.M. Rees R.C. Abnormalities of chromosomes 3 and 8 in posterior uveal melanoma correlate with prognosis Genes Chromosomes Cancer 1997 19 22 28 10.1002/(SICI)1098-2264(199705)19:1<22::AID-GCC4>3.0.CO;2-2 9135991 |
Diagnostics (Basel) Diagnostics (Basel) diagnostics Diagnostics 2075-4418 MDPI 10.3390/diagnostics13050831 diagnostics-13-00831 Case Report Subcapsular Biloma following Endoscopic Retrograde Cholangiopancreatography and Endoscopic Biliary Sphincterotomy: A Case Report with a Mini Review of Literature Pentara Natalia Valeria 1* Ioannidis Aristidis 2 Tzikos Georgios 2 Kougias Leonidas 1 Karlafti Eleni 34 Chorti Angeliki 2 Tsalkatidou Despoina 2 Michalopoulos Antonios 2 Paramythiotis Daniel 2 de Haas Robbert J. Academic Editor 1 Department of Radiology, AHEPA General University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece 2 1st Propaedeutic Department of Surgery, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece 3 1st Propaedeutic Department of Internal Medicine, AHEPA Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece 4 Emergency Department, AHEPA University General Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece * Correspondence: [email protected] 22 2 2023 3 2023 13 5 83129 1 2023 13 2 2023 17 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). A biloma is a loculated, extrahepatic, intra-abdominal bile collection. It is an unusual condition with an incidence of 0.3-2% and is usually a result of choledocholithiasis, iatrogenic injury or abdominal trauma causing disruption to the biliary tree. Rarely, it will occur spontaneously, resulting in spontaneous bile leak. We herein present a rare case of biloma as a complication of endoscopic retrograde cholangiopancreatography (ERCP). A 54-year-old patient experienced right upper quadrant discomfort, following ERCP, endoscopic biliary sphincterotomy and stenting for choledocholithiasis. Initial abdominal ultrasound and computed tomography revealed an intrahepatic collection. Percutaneous aspiration under ultrasound guidance of yellow-green fluid confirmed the diagnosis, indicated infection and contributed to effective management. Most likely, a distal branch of the biliary tree was injured during the insertion of the guidewire through the common bile duct. Magnetic resonance image/magnetic resonance cholangiopancreatography contributed in the diagnosis of two seperate bilomas. Even though post ERCP biloma is an unusual complication, differential diagnosis of patients with right upper quadrant discomfort following an iatrogenic or traumatic event should always include biliary tree disruption. A combination of radiological imaging for diagnosis and minimal invasive technique to manage a biloma can prove to be successful. biloma bile leakage endoscopic retrograde cholangiopancreatography percutaneous drainage This research received no external funding. pmc1. Introduction The term "biloma" was first introduced by Gould and Patel in 1979 in order to describe a loculated, encapsulated, extrahepatic biliary collection of bile . However, the term was extended to include any intra-abdominal bile collection, external to the biliary tree and although many of them are encapsulated, the current definition does not require it to be as such . Biloma is a rare condition with an incidence of 0.3% to 2.0% and is usually presented in patients aged 60 to 70 years old . Biloma formation is most commonly a result of choledocholithiasis, iatrogenic injury and abdominal trauma, causing disruption to the biliary tree and furthermore bile leakage into the peritoneal cavity . Although it is not common, bile leakage could also occur spontaneously, known as spontaneous bile leak (SBL), which is usually a diagnosis of exclusion . ERCP is a combined endoscopic and fluoroscopic operation, incorporated with contrast material injection, allowing for radiologic imaging and if necessary therapeutic interventions. Some ERCP indications are obstructive jaundice, biliary or pancreatic ductal system condition treatment or biopsy, pancreatitis of unknown cause, nasobiliary drainage and biliary stenting among many others . ERCP complications include post-ERCP pancreatitis (PEP) with a frequency of 3.5% which is the most common complication, and infections, such as cholangitis, gastrointestinal bleeding and duodenal or biliary perforations . 2. Case Report Our patient, a 54-year-old female, had a history of chololithiasis after an ultrasound exam of the abdomen thirty years ago, due to non-specific abdominal pain, which revealed multiple echogenic shadowing stones within the gallbladder. During a recent visit to her personal physician, she was advised to have a magnetic resonance image (MRI) scan in order to evaluate the current state of her reported history of chololithiasis. MRI revealed multiple calculi in the gallbladder as well as within the common bile duct. The patient had a surgical history of right leg amputation due to an accident and was not taking any medication. The diagnosis was followed by ERCP. During this procedure, a guidewire under fluoroscopy was passed into the common bile duct, and contrast was injected, highlighting multiple filling defects (>4). Endoscopic papillary balloon dilation of the common bile duct was performed resulting in the gradual exit of bile duct stones. Subsequently, a plastic stent 10 fr-9 cm was placed in the common bile duct to ensure bile drainage . During the first day of her hospitalization, the patient started complaining of pain radiating to her back. Ultrasound examination of the abdomen revealed a collection of fluid with thickened hyperechoic walls compressing the liver parenchyma. The possibility of a tear of the biliary tree was considered. An abdomen computed tomography (CT) scan revealed a well-circumscribed subcapsular collection (5.7 x 3.5 cm) with an air-fluid level in segment VII of the liver, containing a contrast agent that was previously used in ERCP. It was firstly attributed to an intrahepatic biloma as a complication of the previously performed ERCP. Laboratory workup showed elevated white cell count (13,630 per microliter) and CRP at 231.3 mg/L. However, liver function tests (LFTs) remained within normal levels during the first two days: alanine transaminase(ALT) of 20.0 IU/L, aspartate transaminase (AST) of 32 IU/L, g-GT of 10.0 IU/L, and bilirubin of 0.39 IU/L. Antibiotic treatment was initiated, Piperacillin/Tazobactam (4 + 0.5) g x 4 and Amikacin 375 mg x 2. Percutaneous drainage of the biloma was scheduled, as it was deemed necessary in order to fully manage this complication. On the third day of admission, a CT exam was repeated, revealing an increase in size of the forenamed subcapsular collection, as well as a rounded water-attenuation fluid collection with an air-fluid level in contact with the previous one. Differential diagnosis included an extension of the already existing collection or a completely different one . Percutaneous drainage of the biloma was performed under ultrasonography guidance. After the injection of 15 cc of lidocaine 1%, the collection was punctured through an intercostal approach with an 18 G Chiba needle. Aspiration of yellow-green fluid confirmed the diagnosis and the correct placement of the needle. An Amplatz superstiff guide wire was then inserted through the needle, and finally, an 8 F pigtail drainage catheter was placed in the collection. Injection of contrast was performed through the pigtail catheter, which opacified the subcapsular collection. Contrast material leak in the peritoneal cavity was not identified . Reduced drainage throughout the next days (ninth to twelfth day of admission), a repetitive CT scan and a magnetic resonance image/magnetic resonance cholangiopancreatography (MRI/MRCP) revealing minimal change in the size of the biloma strengthened the case of two separate bilomas . Percutaneous drainage was once more performed under ultrasound guidance, inserting a second 8 Fr pigtail drainage catheter, which passed through the first biloma and ended inside the second one. Contrast injection indicated no communication between the two bilomas . A sample of the drained fluid was collected, followed by laboratory analysis indicating E. coli infection. Follow-up CT showing both drainage catheters revealed capsular ring enhancement, designating inflammation and abscess formation. However a significant reduction in the size of the bilomas was detected . Over time, the amount of bile drainage decreased. The patient was discharged from the hospital after twenty-two days of hospitalization and came back seven days later in order to remove the two pigtails based on a follow-up CT, which revealed further size reduction of the bilomas and of the two pigtails' drainage, which stopped. Thirty-eight days later, the patient came back in order to have a cholocystectomy. She had an uncomplicated postoperative course and was discharged from the hospital. Twenty days after her release, she underwent successful ERCP in order to remove the stent that was previously placed in the common bile duct and has been carefully monitored ever since. 3. Discussion There are only some cases reported in the literature of this complication after ERCP . A study by Enns et al. of ERCP-related perforations showed that the incidence of ERCP-related perforations is less than 1%. Clinical presentation is variable, ranging from an incidental finding on imaging to right upper quadrant discomfort, abdominal fullness, nausea, vomiting, fever, jaundice, peritonitis without fever, or even severe biliary sepsis . Reported causes of biloma formation following ERCP consider modalities of the endoscopic procedure, meaning the injection of contrast medium through the catheter inducing high pressure in proximal biliary ducts, the modification of the biliary epithelium by persistent cholangitis, or both . In our case, the most likely scenario is that a distal branch of the biliary tree was injured by the tip of the guidewire. Its formation is thought to be via two mechanisms based on the pace of bile leakage. Secondary to slow leakage bile acids, which are known to have detergent and tissue destroying properties, cause mild inflammation in the neighboring abdominal tissues or liver parenchyma, prompting fibrosis and encapsulation. Additionally, rapid bile leaks could result in biliary peritonitis, where encapsulation may be present as a result of inflammatory adhesions . Taking into account bilomas' variable clinical presentation, radiological imaging was shown to be the foundation of diagnosis. Ultrasound exam, due to its non-invasiveness and rapid evaluation, is usually the primary medical imaging, revealing a wide range of findings from anechoic, well-circumscribed collections to large, complex fluid with multiple fine internal septa, but most frequently a cystic lesion . Smaller bilomas can be missed, making abdominal CT the optimal method for its identification, usually showing a well-circumscribed, hypo-attenuated collection with clear margins and a density of less than 20 Hounsfield units . Even though CT imaging has the benefit of providing us with useful information, such as the biloma's location and surrounding structures, it is not the most effective diagnostic imaging modality to distinguish between differential diagnoses, such as postoperative hematoma, seroma, abscess, lymphocele, liver cyst or pseudocyst, making MR imaging and MRCP in some cases required . A biloma typically produces a variable signal on T1-weighted images and high signal intensity on T2-weighted images, corresponding to the signal intensity of gallbladder fluid . High T1 signal intensity and low T2 signal intensity material within the collection indicates concentrated bile layering . MRI combined with MRCP provides convenient anatomical details of the extrahepatic bile ducts, sometimes identifying the location of the leakage . Rim enhancement could be present as a consequence of reactive inflammation . Hepatobiliary cholescintigraphy, which is a diagnostic nuclear medicine procedure using a radiotracer called Tc-99 m iminodiacetic acid to evaluate the biliary system, also known as HIDA scan, is considered an exceptionally effective radiological modality. Its profitability is based on the fact that the radiotracer follows the bilirubin metabolic pathway and is eventually excreted into the bile ducts, making it a beneficial tool in the diagnosis of gallbladder and biliary tree pathology . The HIDA scan can reveal whether an active biliary leak is present and also helps to guide additional therapy . Single positron emission computed tomography (SPECT) could also provide helpful details concerning the location of a possible active leak . Invasive imaging techniques, such as ERCP and PTC, are useful where management is needed . Imaging guided percutaneous transhepatic biliary drainage has both diagnostic and therapeutic roles by determining the proximal extent of biliary duct injury and providing fluid for laboratory analysis to confirm the diagnosis which is often required. In our case, percutaneous drainage of the biloma was performed under US guidance, preventing surgery. A study by Fatima et al. concluded that most biliary perforations can be managed nonoperatively, and when operative treatment is required, the mortality rate increases. Nonetheless, further surgical management may be needed if percutaneous drainage is unsuccessful, multiloculated lesions are present or bile leaks are ongoing . When it comes to blood testing, results vary from patients with no abnormalities to raised inflammatory markers and abnormal liver function tests. When a biloma is infected, blood cultures may unveil Gram-negative bacteremia. The most typical organisms found in the microbiological culture of biloma fluid are Enterobacteriaceae, followed by Enterococcus species . Author Contributions Conceptualization, N.V.P. and A.I.; methodology, A.C. and G.T.; software, N.V.P.; investigation, G.T. and D.T.; resources, N.V.P. and D.T.; data curation, A.C. and D.T.; writing original draft preparation, N.V.P. and L.K.; writing review and editing, L.K. and E.K.; visualization, A.I.; supervision, D.P.; project administration, A.I., D.P. and A.M. was the Director of the Department of Surgery and provided his permission for this study. All authors have read and agreed to the published version of the manuscript. Institutional Review Board Statement Ethical review and approval were waived for this study due to Informed consent was obtained from the patient and all sensitive data was made anonymous. Informed Consent Statement Informed consent was obtained from all subjects involved in the study. Written informed consent has been obtained from the patient to publish this paper. Data Availability Statement The data and materials/figures used in the current study are available from the corresponding author on reasonable request. Conflicts of Interest The authors declare no conflict of interest. Figure 1 Endoscopic retrograde cholangiopancreatography fluoroscopy images. (a) Cannulation of the common bile duct and cholangiogram which shows intraluminal filling defects consistent with stones (green arrows). (b) Filling defects in the gallbladder (green arrows). (c) Biliary stent deployed (green arrows). Figure 2 (a,b) Computed tomography scan of the abdomen: (a) axial, (b) sagittal and (c) coronal section showing a subcapsular collection as well as a rounded water-attenuation fluid collection with an air-fluid level in contact with the previous one (green arrows). Figure 3 Contrast opacification of the subcapsular collection through the 8F pigtail catheter (green arrow). Previously placed stent in the common bile duct (black arrow). Figure 4 (a) Abdominal computed tomography scan, (b) magnetic resonance image/T2-weighted image of the abdomen and (c) magnetic resonance cholangiopancreatography of the abdomen revealing two separate bilomas. Figure 5 (a,b) Contrast opacification of the subcapsular collection through the 8F pigtail. Figure 6 Computed tomography of the abdomen (a) axial (b) coronal and (c) sagittal section showing both pigtail drainage catheters as well as a capsular ring enhancement of the biloma (green arrow). Reduction in size of the two bilomas can also be seen. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Gould L. Patel A. Ultrasound detection of extrahepatic encapsulated bile: "Biloma" Am. J. Roentgenol. 1979 132 1014 1015 10.2214/ajr.132.6.1014 108953 2. Copelan A. Bahoura L. Tardy F. Kirsch M. Sokhandon F. Kapoor B. Etiology, Diagnosis, and Management of Bilomas: A Current Update Tech. Vasc. Interv. Radiol. 2015 18 236 243 10.1053/j.tvir.2015.07.007 26615164 3. Faisaluddin M. Bansal R. Iftikhar P.M. Arastu A.H. A Rare Case Report of Biloma After Cholecystectomy Cureus 2019 11 e5459 10.7759/cureus.5459 31656709 4. Balfour J. Ewing A. Hepatic Biloma StatPearls [Internet] StatPearls Publishing Treasure Island, FL, USA 2022 5. Yadav A. Condati N.K. Mukund A. Percutaneous Transhepatic Biliary Interventions J. Clin. Interv. Radiol. ISVIR 2018 2 27 37 10.1055/s-0038-1642105 6. Yousaf M.N. D'Souza R.G. Chaudhary F. Ehsan H. Sittambalam C. Biloma: A Rare Manifestation of Spontaneous Bile Leak Cureus 2020 12 e8116 10.7759/cureus.8116 32542169 7. Meseeha M. Attia M. Endoscopic Retrograde Cholangiopancreatography StatPearls Publishing Treasure Island, FL, USA 2022 8. Kwon C. Song S.H. Hahm K.B. Ko K.H. Unusual complications related to endoscopic retrograde cholangiopancreatography and its endoscopic treatment Clin. Endosc. 2013 46 3 10.5946/ce.2013.46.3.251 23424711 9. Dupas J.L. Mancheron H. Sevenet F. Delamarre J. Delcenserie R. Capron J. Hepatic subcapsular biloma. An unusual complication of endoscopic retrogade cholangiopancreatography Gastroenterology 1988 94 1225 1227 10.1016/0016-5085(88)90017-0 3280390 10. Alkhateeb H.M. Aljanabi T.J. Al-azzawi K.H. Alkarboly T.A. Huge biloma after endoscopic retrogade cholangiopancreatography and endoscopic biliary sphincterotomy Int. J. Surg. Case Rep. 2015 16 7 11 10.1016/j.ijscr.2015.08.039 26402876 11. Jafari A. A rare case of hepatic subcapsular biloma after laparoscopic cholecystectomy and subsequent endoscopic retrograde cholangiopancreatography Caspian J. Intern. Med. 2018 9 198 200 29732041 12. Szary N.M. Al-Kawas F.H. Complications of endoscopic retrograde cholangiopancreatography: How to avoid and manage them Gastroenterol. Hepatol. 2013 9 496 504 13. Harshna V.V. Ronald S.A. Imaging and Intervention of Biliary Leaks and Bilomas Dig. Dis. Interv. 2017 1 014 021 14. Weerakkody Y. Jones J.B. Reference Article Available online: (accessed on 1 September 2022) 15. Snyder E. Banks K.P. Hepatobiliary Scintigraphy StatPearls [Internet] StatPearls Publishing Treasure Island, FL, USA 2022 16. Fatima J. Baron T.H. Topazian M.D. Houghton S.G. Iqbal C.W. Ott B.J. Farley D.R. Farnell M.B. Sarr M.G. Pancreaticobiliary and Duodenal Perforations After Periampullary Endoscopic Procedures: Diagnosis and Management Arch Surg. 2007 142 448 455 10.1001/archsurg.142.5.448 17515486 |
Diagnostics (Basel) Diagnostics (Basel) diagnostics Diagnostics 2075-4418 MDPI 10.3390/diagnostics13050828 diagnostics-13-00828 Editorial Editorial on Special Issue "Artificial Intelligence in Pathological Image Analysis" Tsuneki Masayuki Medmain Research, Medmain Inc., 2-4-5-104, Akasaka, Chuo-ku, Fukuoka 810-0042, Japan; [email protected]; Tel.: +81-92-707-1977 21 2 2023 3 2023 13 5 82817 2 2023 20 2 2023 (c) 2023 by the author. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). This research received no external funding. pmcThe artificial intelligence (AI), especially deep learning models, is highly compatible with medical images and natural language processing and is expected to be applied to pathological image analysis and other medical fields. In routine pathological diagnosis, the histopathological and cytopathological examination of specimens is conventionally performed under a light microscope. Whole slide images (WSIs) are the digitized counterparts of the conventional glass slides obtained using specialized scanning devices. In recent years, digital pathology has been steadily introduced into clinical workflows, such as intraoperative consultations and secondary consultations. Pathology diagnosis support systems (computer-aided detection/diagnosis: CAD) using AI are useful for various classification tasks, such as histopathological subtyping, tumor grading, immunohistochemical scoring, and predictions of genetic mutation and protein expression profiles . It is becoming possible to develop AI that can not only perform image classification and detection tasks, but also infer histopathological findings from images by combining pathological images with natural language. In a time of distinct paradigm shifts and novel technological innovations, it is necessary for us to establish a unified comprehension(s) of AI approaches in experimental and clinical pathology. In this Special Issue "Artificial Intelligence in Pathological Image Analysis", we collected a review and thirteen research articles in the areas of AI models in clinical and experimental pathology and computer vision in pathological image analysis. The published studies in this Special Issue provide great insights into the latest knowledge about the application of AI for pathological image analysis. Kim et al. summarized the current trends and challenges to the application of AI in pathology . In this review article, the authors described the development of computational pathology (CPATH), its applicability to AI development, and the challenges it faces, such as algorithm validation and interpretability, computing systems, reimbursement, ethics, and regulations. Further, the authors presented an overview of novel AI-based approaches that could be integrated into the pathology laboratory workflow. As the authors described, explainable AI and ethics and security issues are important topics in CPATH. To develop safe and reliable AI, the pathology community needs more clinical research and laboratory practices. This review paper provides the current research status of AI in pathology and future perspectives for successful applications. Our research article demonstrated a deep learning model for prostate adenocarcinoma classification in core needle biopsy WSIs using transfer learning . In routine clinical practice, diagnosing 12 core biopsy specimens using a microscope is time-consuming, manual process, and it is limited in terms of human resources. The authors trained deep learning models capable of classifying core needle biopsy WSIs into adenocarcinoma and benign (non-neoplastic) lesions and achieved an ROC-AUC of up to 0.978 in the core needle biopsy test sets for adenocarcinoma. Deep learning-based computational algorithms might be useful as routine histopathological diagnostic aids for prostate adenocarcinoma classification in core needle biopsy specimens. Rakovic et al. conducted a survey of prostate cancer UK supporters for the use of digital pathology and AI in the histopathological diagnosis of prostate cancer . A total of 1276 responses to the online survey were analyzed. It was revealed that most of the respondents were in favor of advances in prostate cancer diagnosis by means of digital pathology and AI-assisted diagnostics as adjuncts to current clinical workflows. However, a small minority of them were not in favor of the use of AI in histopathology for reasons which are not easily addressed. Importantly, the patients are more comfortable with the overall responsibility for a histopathology report remaining with the histopathologist and relying on their decision making to use AI and integrate its findings into the final report. Baek et al. demonstrated the AI-assisted image analysis of acetaminophen-induced acute hepatic injury in Sprague-Dawley rats . The aim of this study was to apply deep learning models for the assessment of toxicological pathology in a non-clinical study. Authors trained the model for various hepatic lesions, including necrosis, inflammation, infiltration, and portal triad at the WSI level. The deep learning model achieved an overall model accuracy of 96.44%. Importantly, the model predicted lesions of portal triad, necrosis, and inflammation with high correlations with annotated lesions by toxicologic pathologists. This study suggested that the deep learning algorithm (Mask R-CNN algorithm) can be applied to implement diagnosis and prediction of hepatic lesions in toxicological pathology. Zurac et al. developed the AI-based method for identifying mycobacterium tuberculosis in Ziehl-Neelsen-stained tissue specimen WSIs . In routine histopathological diagnosis, detecting mycobacterium tuberculosis in Ziehl-Neelsen-stained slides is difficult and time consuming because of the bacillus size. The developed deep learning model achieved an ROC-AUC of 0.977, an accuracy of 98.33%, a sensitivity of 95.65%, and a specificity of 100% for identifying mycobacterium tuberculosis bacilli on WSIs, which were better than or similar to those data of a team of pathologists who manually inspected slides and WSIs. By using the developed deep learning algorithm, the pathologists saved at least one-third of the total examining time. Park et al. proposed a new training method called MixPatch, which was designed to improve a CNN-based classifier by specifically addressing the prediction uncertainty problem and examine its effectiveness at improving the diagnosis performance in the context of histopathological image analysis . MixPatch generates and uses a new sub-training dataset, which consists of mixed patches and their pre-defined ground-truth labels. Importantly, by specifically considering the mixed region variation characteristics of the histopathology images, MixPatch augments the extant mixed image methods for medical image analysis, in which the prediction uncertainty is a crucial issue. MixPatch provides a new way to systematically alleviate the overconfidence problem of CNN-based classifiers and improve their prediction accuracy, contributing toward more calibrated and reliable histopathology image analysis. Serbanescu et al. demonstrated the morphological difference between nodular (low-risk subtype) and micronodular (high-risk subtype) basal cell carcinomas using a classical morphometric approach (a gray-level co-occurrence matrix and histogram analysis) and a deep learning semantic segmentation approach . The authors identified distinct pathological patterns of the tumor component in random fields of the tumor island that did not contain peripheral palisading. They demonstrated that the most significant difference between the morphology of the two (nodular and micronodular) subtypes was represented by the peritumoral cleft component. Importantly, the deep learning semantic segmentation approach provided new insight into the morphologies of nodular and micronodular subtypes of basal cell carcinoma. Nofallah et al. demonstrated the potential application of the semantic segmentation of clinically important tissue structures for improving the diagnosis of skin biopsy WSIs . It has been revealed that including a clinically important tissue structure along with WSIs improves the learning of the model, especially in challenging diagnostic classes, such as melanoma in situ and invasive melanoma (T1a). The model showed a 6% improvement in the F-score when whole slide images were used along with epidermal nests and cancerous dermal nest segmentation masks compared to that which was achieved using WSIs alone in training and testing the diagnosis pipeline. Importantly, comparing scores with 187 pathologists' performance on the same test set showed that the model can outperform or have comparable performance in the cases with the aforementioned diagnostic classes. Legnar et al. investigated the possibility to predict a final diagnosis based on a written neuropathological description using various natural language processing (NLP) methods . Certain diagnoses or groups of diagnoses (e.g., amyloid-deposition-associated diseases) could be predicted very well; however, in several cases, the morphological description was apparently not sufficient to make accurate predictions. This is because some diagnoses are associated with one pattern, but for others, there is a complex pattern combination which makes the prediction difficult without patho-physiological knowledge. Overall, it has been revealed that the morphological description texts, used as a surrogate for image analysis, enable the correct diagnosis to be achieved for some entities. Cazzato et al. trained the fast random forest (FRF) algorithm to be able to support the specialist to automatically highlight the anomalous pixel regions and to estimate a possible risk by quantifying the percentage of these regions with atypical morphological features starting from routine histopathological images . An important tool for melanoma diagnosis is the probability image estimated by the processed FRF output image. The probability image is useful to discriminate between information about ambiguous lesions. The FRF algorithm proved to be successful, with a discordance of 17% with respect to the results of the dermatopathologist, meaning that this type of supervised algorithm to can help the dermatopathologist in achieving the challenging diagnosis of malignant melanoma. VanBerlo et al. developed a deep learning solution for automatic lung ultrasound view annotation that effectively improves the efficiency of downstream annotation tasks, which can distinguish between parenchymal and pleural lung ultrasound views with 92.5% accuracy . The automatic partitioning of a 780 clip lung ultrasound dataset by view led to a 42 min reduction of the downstream manual annotation time and resulted in the production of 55 +- 6 extra relevant labels per hour. This deep learning-based automated tool considerably improved the annotation efficiency, resulting in a higher throughput relevant to the annotating task at hand, which can be applied to other unannotated datasets to save considerable manual annotation time and effort. Kawazoe et al. demonstrated an automated computational pipeline to detect glomeruli and to segment the histopathological regions inside of the glomerulus in a WSI . The computational pipeline automatically detects glomeruli on PAS-stained WSIs, followed by segmenting the Bowman's space, the glomerular tuft, the crescentic, and the sclerotic region inside of the glomeruli. To predict the estimated glomerular filtration rate (eGFR) in cases of immunoglobulin A nephropathy (IgAN), it is important to quantify the sclerotic region using the developed pipeline. Importantly, the developed automated computational pipeline could aid in diagnosing renal pathology by visualizing and quantifying the histopathological feature of the glomerulus and potentially accelerate the research in order to better understand the prognosis of IgAN. Fauzi et al. demonstrated a cell detection and classification system based on a deep learning model for use with the Allred scoring system for breast carcinoma hormone receptor status testing . The computational pipeline first detects all of the cells within the specific regions and classifies them into negatively, weakly, moderately, and strongly stained ones, followed by Allred scoring for the estrogen receptor (ER) status evaluation on WSIs. The automated Allred scores matches well with pathologists' scores for both the actual Allred score and hormonal treatment cases. The proposed system can automate the exhaustive exercise to provide fast and reliable assistance to pathologists and medical personnel. Palm et al. examined the performance of a digitalized and artificial intelligence (AI)-assisted workflow for HER2 status determination in accordance with the American Society of Clinical Oncology (ASCO)/College of Pathologists (CAP) guidelines . The HER2 4B5 algorithm in the uPath enterprise software and the HER2 Dual ISH image analysis algorithm (Roche Diagnostic International, Rotkreuz, Switzerland) were used in this study. The authors demonstrated the feasibility of a combined HER2 IHC and ISH AI workflow in the primary and metastatic breast cancers, with a Cohen's k of 0.94 when it was assessed in accordance with the ASCO/CAP recommendations. In summary, in this Special Issue, there are wide varieties of valuable scientific papers including a review article and papers on deep learning models in pathological applications, human and toxicological pathology, and various methodologies. AI-based computational algorithms, including deep learning models, are taking digital pathology beyond mere digitization and telepathology . The incorporation of AI-based computer vision and natural language processing algorithms in routine clinical workflows is on the horizon, reducing processing time and increasing the detection rate of anomalies . It is necessary to continue to share the latest findings and updated methodologies in "Artificial Intelligence in Pathological Image Analysis" and continue to conduct valuable research. Conflicts of Interest M.T. is the employee of Medmain Inc. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Tsuneki M. Deep learning models in medical image analysis J. Oral Biosci. 2022 64 312 320 10.1016/j.job.2022.03.003 35306172 2. Kim I. Kang K. Song Y. Kim T.J. Application of Artificial Intelligence in Pathology: Trends and Challenges Diagnostics 2022 12 2794 10.3390/diagnostics12112794 36428854 3. Tsuneki M. Abe M. Kanavati F. A Deep Learning Model for Prostate Adenocarcinoma Classification in Needle Biopsy Whole-Slide Images Using Transfer Learning Diagnostics 2022 12 768 10.3390/diagnostics12030768 35328321 4. Rakovic K. Colling R. Browing L. Dolton M. Horton M.R. Protheroe A. Lamb A.D. Bryant R.J. Scheffer R. Crofts J. The Use of Digital Pathology and Artificial Intelligence in Histopathological Diagnostic Assessment of Prostate Cancer: A Survey of Prostate Cancer UK Supporters Diagnostics 2022 12 1225 10.3390/diagnostics12051225 35626380 5. Baek E.B. Hwang J.H. Park H. Lee B.S. Son H.Y. Kim Y.B. Jun S.Y. Her J. Lee J. Cho J.W. Artificial Intelligence-Assisted Image Analysis of Acetaminophen-Induced Acute Hepatic Injury in Sprague-Dawley Rats Diagnostics 2022 12 1478 10.3390/diagnostics12061478 35741291 6. Zurac S. Mogodici C. Poncu T. Trascau M. Popp C. Nichita L. Cioplea M. Ceachi B. Sticlaru L. Cioroianu A. A New Artificial Intelligence-Based Method for Identifying Mycobacterium Tuberculosis in Ziehl-Neelsen Stain on Tissue Diagnostics 2022 12 1484 10.3390/diagnostics12061484 35741294 7. Park Y. Kim M. Ashraf M. Ko Y.S. Yi M.Y. MixPatch: A New Method for Training Histopathology Image Classifiers Diagnostics 2022 12 1493 10.3390/diagnostics12061493 35741303 8. Serbanescu M.S. Bungardean R.M. Georgiu C. Crisan M. Nodular and Micronodular Basal Cell Carcinoma Subtypes Are Different Tumors Based on Their Morphological Architecture and Their Interaction with the Surrounding Stroma Diagnostics 2022 12 1636 10.3390/diagnostics12071636 35885545 9. Nofallah S. Li B. Mokhtari M. Wu W. Knezevich S. May C.J. Chang O.H. Elmore J.G. Shapiro L.G. Improving the Diagnosis of Skin Biopsies Using Tissue Segmentation Diagnostics 2022 12 1713 10.3390/diagnostics12071713 35885617 10. Legnar M. Daumke P. Hesser J. Porubsky S. Popovic Z. Bindzus J.N. Siemoneit J.H.H. Weis C.A. Natural Language Processing in Diagnostic Texts from Nephropathology Diagnostics 2022 12 1726 10.3390/diagnostics12071726 35885630 11. Cazzato G. Massaro A. Colagrande A. Lettini T. Cicco S. Parente P. Nacchiero E. Lospalluti L. Cascardi E. Giudice G. Dermatopathology of Malignant Melanoma in the Era of Artificial Intelligence: A Single Institutional Experience Diagnostics 2022 12 1972 10.3390/diagnostics12081972 36010322 12. VanBerlo B. Smith D. Tschirhart J. VanBerlo B. Wu D. Ford A. McCauley J. Wu B. Chaudhary R. Dave C. Enhancing Annotation Efficiency with Machine Learning: Automated Partitioning of a Lung Ultrasound Dataset by View Diagnostics 2022 12 2351 10.3390/diagnostics12102351 36292042 13. Kawazoe Y. Shimamoto K. Yamaguchi R. Nakamura I. Yoneda K. Shinohara E. SHintani-Domoto Y. Ushiku T. Tsukamoto T. Ohe K. Computational Pipeline for Glomerular Segmentation and Association of the Quantified Regions with Prognosis of Kidney Function in IgA Nephropathy Diagnostics 2022 12 2955 10.3390/diagnostics12122955 36552963 14. Fauzi M.F.A. Ahmad W.S.H.M.W. Jamaluddin M.F. Lee J.T.H. Khor S.Y. Looi L.M. Abas F.S. Aldahoul N. Allred Scoring of ER-IHC Stained Whole-Slide Images for Hormone Receptor Status in Breast Carcinoma Diagnostics 2022 12 3093 10.3390/diagnostics12123093 36553102 15. Palm C. Connolly C.E. Masser R. Sgier B.P. Karamitopoulou E. Simon Q. Bode B. Tinguely M. Determining HER2 Status by Artificial Intelligence: An Investigation of Primary, Metastatic, and HER2 Low Breast Tumors Diagnostics 2023 13 168 10.3390/diagnostics13010168 36611460 |
Diagnostics (Basel) Diagnostics (Basel) diagnostics Diagnostics 2075-4418 MDPI 10.3390/diagnostics13050955 diagnostics-13-00955 Interesting Images A Familial Case of Multiple Endocrine Neoplasia 2A: From Morphology to Genetic Alterations Penetration in Three Generations of a Family Chen Lan 1* Zhang Jing-Xin 1 Liu Dong-Ge 1 Liu Hong-Gang 2* Tar-Choon Aw Academic Editor 1 Pathology Department, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, China 2 Pathology Department, Beijing Tongren Hospital, Capital Medical University, Beijing Key Laboratory of Head and Neck Molecular Diagnostic Pathology, Beijing 100730, China * Correspondence: [email protected] (L.C.); [email protected] (H.-G.L.); Tel.: +86-10-85133913 (L.C.); +86-18811612227 (H.-G.L.) 02 3 2023 3 2023 13 5 95509 1 2023 21 2 2023 22 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). This paper illustrates a rare syndrome of multiple endocrine neoplasia type 2A (MEN2A) in a family of three generations. In our case, the father, son and one daughter developed phaeochromocytoma (PHEO) and medullary thyroid carcinoma (MTC) over a period of 35 years. Because of the metachronous onset of the disease and lack of digital medical records in the past, the syndrome was not found until a recent fine needle aspiration of an MTC-metastasized lymph node from the son. All resected tumors from the family members were then reviewed and supplemented with immunohistochemical studies, previously wrong diagnoses were then corrected. Further molecular study of targeted sequencing also revealed a RET germline mutation (C634G) in the family tree including the three members with onset of the disease and one granddaughter who had no disease at the time of testing. Despite the syndrome being well-known, it may still be misdiagnosed because of its rarity and long disease onset. A few lessons can be learned from this unique case. Successful diagnosis requires high suspicion and surveillance and a tri-level methodology including a careful review of family history, pathology and genetic counselling. medullary thyroid carcinoma pheochromocytoma multiple endocrine neoplasia type 2A RET germline mutation Beijing Key Laboratory of Head and Neck Molecular Diagnostic Pathology, Capital Medical UniversityOpen Grant 2016-2017 This research was funded by the Beijing Key Laboratory of Head and Neck Molecular Diagnostic Pathology Open Grant, Capital Medical University, grant number Beijing Key Laboratory of Head and Neck Molecular Diagnostic Pathology Open Grant 2016-2017. pmcFigure 1 The cytology of a metastasized medullary thyroid carcinoma (MTC) in the neck lymph node and its primary MTC in the son born in 1968. A 49-year-old male in the outpatient clinic had a right lymphadenopathy, 1.2 cm in diameter, in area III. He had ultrasound-guided fine needle aspiration. The smear was composed of a large amount of monomorphic, small, round cells in large aggregates or dispersed ((a), HE, 100x). The cells were plasmacytoid with eccentric nuclei, which had fine chromatin or small nucleoli. There was no mitosis or necrosis ((b), HE, 400x). Immunohistochemistry on smears showed strong immunopositivity for chromogranin A ((c), 400x), TTF-1 and CEA (not shown). There was moderate positivity for calcitonin ((d), 400x) and no expression of thyroglobulin ((e), 400x). It was consistent with metastasized thyroid medullary carcinoma. He was diagnosed with bilateral multiple MTC with right neck lymph node metastasis in 1/2 in our hospital 8 years ago when he was 41. Tumors infiltrated thyroid tissues in a solid and trabecular growth pattern and there was amyloid deposition in the background ((f), 50x). It was composed of small monomorphic cells with fine chromatin or small nucleoli in a syncytial pattern ((g), 200x). Immunohistochemistry showed a strong expression of chromogranin A ((h), 100x) and calcitonin ((i), 100x) and absence of thyroglobulin ((j), 25x). The cell morphology of his recent lymph node aspiration was consistent with his previous pathology. The patient was then admitted into the ward for further treatment. A family syndrome of multiple endocrine neoplasia type 2A (MEN2A) surfaced when we dug into his family history and previous pathology. His father and one of his elder sisters used to have intermittent hypertension, cardiac palpitation, dizziness and epileptic seizure, etc. He was 31 when he first suffered similar symptoms and was then hospitalized and diagnosed with left adrenal pheochromocytoma (PHEO) and right thyroid adenoma. We suspected the thyroid adenoma might have been misdiagnosed as application of immunohistochemistry was in its early stage in the late 1990s during his first onset of the disease. His pathology materials were not kept due to the long time period in a different local hospital where he received surgical resections. We proceeded to review the pathology of his father and sister who had surgeries in our hospital. Figure 2 The pathology of thyroid and adrenal gland tumor of his elder sister born in 1964. One of his elder sisters, who was 4 years older than him, was diagnosed with left adrenal PHEO and right thyroid follicular carcinoma at the age of 28 and left thyroid MTC at 45. As per her previous pathology, her PHEO diagnosed at 28 ((a), HE, 200x) was composed of zellballen-like nests of tumor cells separated by vascular sinuses. The tumor cells were spindle-like with amphophilic granular cytoplasm. The small and monomorphic nuclei were vacuolar with small nucleoli. Immunohistochemistry showed that tumor cells were positive for chromogranin A ((b), 50x). The small spindle-like sustentacular cells were outlined by S100 positivity at the periphery of tumor nests ((c), 200x). The proliferative index was less than 1% as indicated by Ki67 ((d), 100x). Her left MTC diagnosed at 45 ((e), HE, 200x) was composed of trabecular solid growth patterns of spindle or polygonal tumor cells. The tumor cells had round nuclei that varied in size with amyloid substance deposition in the background. They were strongly positive for chromogranin A ((f), 100x) and calcitonin ((g), 100x) and negative for thyroglobulin ((h), 100x). When we reviewed her right thyroid follicular carcinoma diagnosed at 28 ((i), 200x), it was also composed of a similar pathology as her left MTC showing nests of syncytial cell aggregates with monomorphic, round nuclei. There was also nuclei variation in size ((j), 200x). Supplementary immunohistochemistry demonstrated immunopositivity of chromogranin A and calcitonin (not shown). The thyroid follicular carcinoma diagnosis was wrong and it should be MTC instead. Therefore, the elder sister had both MTC and PHEO in a time span of 17 years. The misdiagnosis was not recognized earlier as her first medical record in early 1990s was not digitalized and was disconnected with her second record until we manually discovered it this time. The syndrome was missed then due to the metachronous onset of the disease that was misdiagnosed as thyroid adenoma or follicular carcinoma in the brother and sister. MTC can mimic any thyroid tumor and requires immunohistochemistry for accurate diagnosis; however, immunohistochemistry back then was not comprehensive. Figure 3 The pathology of left MTC and left adrenal PHEO in the father diagnosed in our hospital. Born in 1940, the father had surgeries for PHEO and MTC at 42. His previous medical file and pathology were searched manually, reviewed carefully and supplemented with immunohistochemistry. The left thyroid tumor was 4 x 3.5 x 2.5 cm in size and composed of a trabecular growth pattern of spindle-like cells with monomorphic, round or spindle nuclei ((a), HE, 200x). They were strongly positive for calcitonin ((b), 200x) and CEA ((c), 200x), and weakly positive for chromogranin A ((d), 200x) and the diagnosis was consistent with MTC. His PHEO was composed of nested polygonal cells with abundant amphophilic cytoplasm separated by rich vascular sinuses ((e), HE, 100x). They were strongly positive for chromogranin A ((f), 100x) and sparsely positive for Ki67 ((g), 200x). The sustentacular cells at the periphery of tumor cells were strongly positive for S100 ((h), 200x). The syndrome was missed because our knowledge for this rare syndrome was limited in early 1980s. His children had not had onset of the disease back then. Figure 4 RET germline mutation detected in the family of three generations. In 1968, Steiner first reported multiple endocrine neoplasia type 2. The syndrome is classified into MEN2A, 2B and familial MTC depending on the presence and type of additional symptoms. Virtually all MEN2A patients have MTC and 50% of them have concurrence of PHEO, and 15-30% have hyperparathyroidism. It accounts the most common variation of MEN2 with an incidence of 1/1,973,500 . The major molecular alterations of RET in MEN2A lie in codons 609, 611, 618 or 620 of exon 10 or codon 634 of exon 11. The latter accounts for 80% of germline mutations of MEN2A . For our cases, 4 mL blood was taken for each person from the three generations of the family as shown in the family tree. It included the parents, their four children and two grandchildren outlined in red. DNA was purified using a QIAmp Blood DNA kit (Qiagen, Germantown, MD, USA). Targeted next-generation sequencing was successfully performed for the RET proto-oncogene by Gene Plus, Beijing, China, according to manufacturer's protocol. A missense mutation c.T1900G in exon 11 causing protein alteration of p.C634G was discovered in all three members with onset of the disease and one granddaughter who had no disease at the time of testing. The family members with the mutation are labeled as RET in the figure, while those with onset of MEN2A are labeled in blue. The granddaughter with the RET mutation, was 18 years old and is the daughter of the son. A close monitoring was undertaken for the girl according to the American Thyroid Association guidelines for adults, that requires surveillance of serum calcitonin . The family tragedy might be stopped thereafter. MEN2-associated RET mutations have a gain of function effect to promote activation of the kinase and oncogenic conversion via downstream signaling pathways . RET tyrosine kinase inhibition will provide targeted therapy for the family members with established RET-positive cancers . Selpercatinib, one kinase inhibitor, has been approved by the U.S. Food and Drug Administration for patients with advanced or metastatic RET-mutant MTC . It inhibits wild-type RET and multiple mutated RET isoforms and may benefit the son who had repeated recurrence of the cancer. In conclusion, misdiagnosis of thyroid tumor and metachronous onset of the disease in the family hampered our recognition of this well-documented but rare disease. A few lessons can be learned from this case. High suspicion was a critical starting point in our diagnosis. A careful review of previous medical records helped connect the dots. Molecular screening then played a key role in reaching our eventual diagnosis. Acknowledgments The authors thank the technicians in the Pathology Department of Beijing Hospital for their technical support. Author Contributions Conceptualization, L.C.; methodology, J.-X.Z.; validation, D.-G.L.; formal analysis, L.C.; investigation, L.C.; resources, J.-X.Z.; data curation, J.-X.Z.; writing original draft preparation, L.C. and J.-X.Z.; writing review and editing, L.C. and D.-G.L.; visualization, J.-X.Z.; supervision, H.-G.L.; project administration, H.-G.L.; funding acquisition, L.C. and H.-G.L. All authors have read and agreed to the published version of the manuscript. Institutional Review Board Statement Ethical review and approval were waived for this study because the study was under a normal procedure to perform clinical pathology, molecular diagnosis and genetic counseling to the patients. Genetic diagnosis was paid for by a government grant due to rarity of the disease and the poor economic conditions of the patients. Informed Consent Statement Informed consent was obtained from all subjects involved in the study. Written informed consent has been obtained from the patient(s) to publish this paper. Data Availability Statement The authors declare that all datasets on which the conclusions of the paper rely are available to editors and reviewers without unnecessary restriction. The datasets can be obtained from the corresponding author Lan Chen on reasonable request. Conflicts of Interest The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. 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Introduction Hyperglycaemic hyperosmolar state (HHS) is a known complication of type 2 diabetes mellitus; however, carbonated carbohydrate fluid intake may precipitate a more severe presentation of type 1 diabetes mellitus with hyperosmolar state. The management of these patients is not easy and can lead to severe complications such as cerebral venous thrombosis. Methods We present the case of a 21-month-old boy admitted for consciousness disorders revealing a hyperglycaemic hyperosmolar state on a new-onset type 1 diabetes and who developed cerebral venous thrombosis. Results and Conclusion Emergency physicians should be aware of HHS in order to start the appropriate treatment as early as possible and to monitor the potential associated acute complications. This case highlights the importance of decreasing very gradually the osmolarity in order to avoid cerebral complications. Cerebral venous thrombosis in HHS paediatric patients is rarely described, and it is important to recognize that not all episodes of acute neurological deterioration in HHS or diabetic ketoacidosis are caused by cerebral oedema. Emergency physicians should be aware of HHS in order to start the appropriate treatment as soon as possible and to think about its acute complication. This case highlights the importance to restore euvolemia before insulin treatment and decrease very gradually the osmolarity in order to avoid cerebral complication. Cerebral venous thrombosis in HHS paediatric patients is rarely described, and it is important to recognize that not all episodes of acute neurological deterioration in HHS or DKA are caused by cerebral oedema. case report cerebral thrombophlebitis diabetes hyperglycaemic hyperosmolar state source-schema-version-number2.0 cover-dateMarch 2023 details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.2.6 mode:remove_FC converted:10.03.2023 Injeyan M , Baron S , Lauzier B , Gaillard-Le Roux B , Denis M . Hyperglycaemic hyperosmolar state and cerebral thrombophlebitis in paediatrics: A case report. Endocrinol Diab Metab. 2023;6 :e389. doi:10.1002/edm2.389 pmc1 BACKGROUND Diabetic ketoacidosis (DKA) and hyperglycaemic hyperosmolar state (HHS) are acute metabolic complications that occur in children with type 1 diabetes mellitus. Diabetic ketoacidosis is the most common hyperglycaemic crisis 1 but HHS is associated with higher mortality 2 , 3 , 4 and its incidence is increasing. 5 , 6 , 7 HHS is a known complication of type 2 diabetes mellitus 8 ; however, carbonated carbohydrate fluid intake may precipitate a more severe presentation of type 1 diabetes mellitus with hyperosmolar state. 4 , 9 , 10 The main objective is to correct electrolyte disorders and avoid neurological complications. The common cerebral complication associated with HHS is cerebral oedema. While the risk of developing peripherical venous thromboembolism has already been described 11 , 12 , 13 in DKA or HHS, cerebral venous thrombosis has been rarely described. 14 , 15 We present the case of a 21-month-old boy admitted for consciousness disorders revealing a hyperglycaemic hyperosmolar state for a new-onset type 1 diabetes and who developed cerebral venous thrombophlebitis (CVT). 2 CASE PRESENTATION A 21-month-old boy, weight 11 kg, presented at the emergency room with an unconscious and hypotonic state. He was born at 39 weeks of gestational age, with a birth weight of 3440 g and birth length of 51 cm. There was no family history of diabetes mellitus. He was previously healthy, presenting only a slight delay in psychomotor development as he could not sit up at 9 months nor stand alone at 21 months. He presented a rhinopharyngitis treated with amoxicillin one week before the hospitalization. He had a 3-day history of polyuria and lethargy and a great alteration of the general condition for 2 days. His parents hydrated him only with sugar water. On the morning of the third day, he was found to be unresponsive in his bed. Upon admission, he presented normal temperature (36.8degC), tachycardia (heart rate: 150 bpm), hypotension (blood pressure: 61/37 mm Hg), cold extremities, tachypnoea (respiratory rate: 40 cycles/min, SaO2: 100%) and dehydration signs objectified by dried mucous membranes. He presented unconscious (Glasgow coma scale [GCS]: 5) with no signs of localization and his pupils were in reactive mydriasis. Rapid glucose test was higher than 33 mmol/L. Blood tests reported hyperglycaemia (138 mmol/L), metabolic acidosis (pH 7.30, bicarbonate 16 mmol/L), hyperlactatemia (5.20 mmol/L), ketosis (0.9 mmol/L) and ketonuria. Electrolyte test revealed hypernatremia (sodium chloride 128 mmol/L and corrected sodium chloride 167 mmol/L) and hyperkalaemia (7.9 mmol/L). Creatinine and blood urea nitrogen were 159 mmol/L and 39 mmol/L, respectively, and serum osmolarity was 511 mOsm/L. Prothrombin rate and fibrinogen were 80% and 1.6 g/L, respectively. The electrocardiogram showed a regular sinus rhythm without any conduction disorder but hyperkalaemia signs including very large and sharp T waves and a diffuse ST shift. An injected brain computed tomography scan (CT-scan) was performed and showed a permeable veinous sinus and a hypodensity of the white matter in front of the temporal horn and the right ventricular carrefour. The patient received a volume expansion of 250 ml of isotonic fluid NaCl 0.9% followed by a rehydration with 110 ml/kg/day of NaCl 0.9%. Hyperkalaemia was treated by calcium gluconate 10% (4 ml), Terburtaline aerosol (1 aerosol of 2.5 mg), and sodium bicarbonate 8.4% (10 ml). His mental status required intubation under sedation by 2 mg/kg of ketamine and 1 mg/kg of rocuronium. He was then referred to the paediatric intensive care unit (PICU) and regular insulin (Insulin analogue [Lispro] 0.02 UI/kg/h) was started. During PICU hospitalization, volume expansion was continued intravenous by 150 ml of NaCl 0.9% and 50 ml of ringer lactate and maintain intravenous fluid was changed for Glucose 5% with NaCl 20% 4 g/L and KCl 10% 3 g/L. Laboratory examinations were performed in order to check and modulate electrolyte changes . The serum sodium concentration and the serum osmolarity increased to a maximum of 167 mmol/L (corrected natremia) and to 511 mOsmol/L, respectively. Serum glucose level decreased and normalized to 7.6 mmol/L in 24 h, which led to a gradual decreased in serum osmolarity and sodium. This corresponded to an average drop of 1 mmol/L/h of sodium in the first 24 h, with a maximum of 3.5 mmol/L/h between H10 and H12, and of 7.37 mOsm/L/h of osmolarity with a maximum of 13.5 mOsm/L/h between H10 and H14. His hemodynamic status remained stable, without any vasopressor support requirement. The echocardiography showed normal cardiac function. The transcranial Doppler (TCD) performed did not show any anomalies. The patient was sedated by morphine and midazolam which was stopped on Day 2. At the initial examination without sedation and before extubation, the child presented a rolling of the lower and upper limbs, a pyramidal syndrome including bilateral Babinsky's sign, sharp reflexes with increased reflexogenic area and a withdrawal reaction to pain. Seizures were detected on Day 2 and treated by clonazepam (0.05 mg/kg) and then levetiracetam (40 mg/kg/day). No clinical signs of intracranial hypertension (ICH) were found and TCD was normal (pulsatility index (PI): 0.9 and diastolic velocity (Vd): between 30 and 40 cm/s). Electroencephalogram showed a marked encephalopathy pattern without epileptic activity, possibly of metabolic origin and related to sedation. His brain magnetic resonance imaging (MRI) reported an extensive thrombophlebitis of the superior sagittal sinus and of several cortical veins in the vertex, the torcular, the left transverse sinus as well as presence of small thrombi in the right transverse sinus. Significant bilateral and symmetrical signal abnormalities of the fronto-parieto-temporo-occipital subcortical white matter and of the external capsules were also visible in diffusion restriction, which seemed rather to be related to metabolic disorders . He was immediately treated by anticoagulant (unfractionated heparin, 20 UI/kg/h, target antiXa: 0.3-0.5). The mental status improved and extubation was possible on Day 3. FIGURE 1 Changes in biological parameters and medical interventions over time upon admission. H, Hours FIGURE 2 Magnetic resonance imaging performed on Day 2 and at 3 months. (A) MRI performed on Day 2, extensive thrombophlebitis of the superior sagittal sinus and of several cortical veins in the vertex, the torcular, the left transverse sinus and presence of small thrombi in the right transverse sinus. Significant bilateral and symmetrical signal abnormalities of the fronto-parieto-temporo-occipital subcortical white matter and of the external capsules were also visible in diffusion restriction, which seemed rather to be related to metabolic disorders. (B) MRI at 3 months, partial permeabilization of the superior sagittal sinus with persistence of a heterogeneous aspect of the sinus, seat of some linear images probably corresponding to residual filiform thrombi, a complete permeabilization of the transverse sinuses and the torcular and cortical veins, and an appearance of FLAIR signal abnormalities of the periventricular white matter, probably sequelae of the abnormalities visualized in diffusion on the first MRI. Five days after PICU admission, the neurological examination showed no focal signs, symmetrical osteo-tendon reflexes, no Babinski's sign, no peripheral hypertonia, no epileptoid tremor and some upper limb stereotypies. The brain CT-Scan showed an absence of haemorrhagic remodelling and a stability of the extent of the thrombophlebitis reaching the superior sagittal sinus, torcular, left transverse sinus and some cortical veins. The white matter signal abnormalities described on the MRI were not visible on the CT scan. A Doppler ultrasound of the lower limbs showed a deep venous thrombosis in superficial femoral vein, to the location of the central catheter. Serology revealed positive antibody against insulin (4 unit/ml; normal high <0.4 unit/ml) and no antibody against GAD, IA2, ICA, Zn8. A central hypothyroidism was found (T4 3.7 pg/ml [9.4-18 pg/ml], TSH 0.46 mUI/ml [0.2-4 mUI/ml]). We did not find any abnormality on the other pituitary axes except a low IGF1 level (27 ng/ml [49-297 ng/ml]), controlled at 38 ng/ml two days later, which may be related to dehydration and acute malnutrition. The infant was transferred to the general paediatric ward on Day 5 and discharged home on Day 26. Initially, he was treated with a regimen of basal and rapid insulin and then transitioned to an insulin pump. L-Thyroxine treatment was stopped at 1 month with normalization of the thyroid balance (TSH 0.21 mUI/ml; T4 10.6 pg/ml); without any antibodies stating a transient acute central hypothyroidism; and diabetes was well balanced. Chromosomal analysis by CGH-Array was normal and the search for fragile X syndrome was negative. The metabolic workup was unremarkable (mucopolysaccharides, urinary oligosaccharides, plasma lysosphingolipids and Gaucher disease). In addition, the mitochondrial DNA study was normal. He was treated with anticoagulants (antivitamin K: coumadin 2 mg per day) for 3 months. The brain MRI performed at 3 months showed partial repermeabilization of the superior sagittal sinus with persistence of a heterogeneous aspect of the sinus, seat of some linear images probably corresponding to residual filiform thrombi, a complete repermeabilization of the transverse sinuses and the torcular and cortical veins, and an appearance of FLAIR signal abnormalities of the periventricular white matter, probably sequelae of the abnormalities visualized in diffusion on the first MRI . The neurological examination returned to baseline, and he is followed up in a specialized neurodevelopment centre. 3 DISCUSSION We report the first case of HHS revealing a new-onset type 1 diabetes complicated by cerebral thrombophlebitis in a young boy. In France, diabetes mellitus incidence increases by 4% each year since 1988. 16 HHS remained a rare diagnosis in paediatrics but hyperosmolar events had higher rates of complications. 4 In this case, the little boy was thirsty, and his parents gave him only sugar water. That probably contributed to an increase in blood sugar and the hyperosmolar state. Several case reports have shown that carbonated carbohydrate fluid intake may precipitate a more severe presentation of type 1 diabetes mellitus in adolescents, 10 but this presentation is rarely described in children. The mortality rate in patient with HHS varies between 20% and 60% and timely diagnosis as appropriate treatment prevent complications and death. 2 , 3 , 17 The child presented with hyperglycaemia without acidosis, which could have led to a delayed diagnosis of diabetes 1. Contrary to diabetic ketoacidosis, HHS is characterized by development of a severe hyperglycaemia without acidosis, these patients maintain a low insulin production leading to the absence or underproduction of ketones via lipolysis. The pathophysiology of HHS is further compounded by a disordered renal response. HHS commonly occurs after polyuria and polydipsia, resulting in profound dehydration. This is accompanied by severe electrolyte imbalance, greater than in DKA because of the longer duration of osmotic diuresis. The hypertonicity of the hyperosmolar state preserves intravascular volume, which contributes to masking clinical signs of dehydration which can lead to a difficult and delayed diagnosis. 7 , 18 HHS is a life-threatening emergency. The treatment of HHS requires rehydration, electrolyte balance, intravenous insulin and management of complication. The patient received a volume expansion of 250 ml of isotonic fluid NaCl 0.9% followed by a rehydration with 110 ml/kg/day of NaCl 0.9% and then insulin after his transfer in PICU. The priority is to restore euvolemia before the use of insulin. Fluid replacement should be started with 0.9% saline in order to maintain circulatory volume, restore renal perfusion and gradually correct hyperosmolarity. 19 It is commonly admitted that hypotonic maintenance intravenous fluids lead to a greater risk of developing cerebral oedema in children, and thus its use should be avoided. 3 We monitored for signs of ICH through clinical examination and DTC during the first 48 h. Adequate fluid replacement must begin before insulin administration for many reasons. First, early insulin is unnecessary in HHS, because ketosis is usually minimal. 20 Secondly, insulin bolus could induce shifts of potassium to the intracellular space and hypokalaemia 20 ; move intravascular water into the cells, then exacerbating hypotension and increasing the risk of brain oedema. 19 Furthermore, fluid administration alone promotes dilution and decreases serum glucose. Finally, the osmotic pressure exerted by glucose may fall rapidly then leading to circulatory compromise and venous thrombosis. 20 HHS can cause many complications. The main risks of severe dehydration and hyperviscosity are brain oedema, rhabdomyolysis, pancreatitis, renal failure, malignant hyperthermia and thromboembolism. This state can lead to death with refractory arrhythmia or multisystem failure (cardiac, pulmonary oedema and renal failure). 21 The severity of altered mental status correlates with the level of hyperosmolarity. 3 In our case, the patient presented a severe dehydration with hyperosmolarity and hyperviscosity that altered mental status. The brain MRI and doppler ultrasound showed an extensive cerebral thrombophlebitis and thrombosis in superficial femoral vein, respectively. Adult literature reported that patients with diabetes and hyperosmolarity had a significantly higher risk of venous thromboembolism (VTE). 11 Several studies showed that young children (<3 years old) with DKA have an increased incidence of clinical VTE associated with the placement of femoral central venous catheters (CVC) 12 , 13 and these patients had significantly higher glucose and corrected sodium concentrations. 13 Cerebral venous thrombosis in the course of diabetic hyperglycaemia seems to be extremely rare. Only two reports were described in the literature. In the first one, venous thrombosis was interpreted as a consequence of the combination of dehydration and iron deficiency anaemia but no hyperosmolarity was reported. 14 The second one reported an 8-year-old male patient with CVT at early stage of management and was associated with hyperosmolarity. 15 In the context of cerebral thrombophlebitis, anticoagulation is effective in reducing the risk of death, sequelae in acute phase and of recurrence. 22 There is no recommendation for prophylactic anticoagulation for patients with HHS. Anticoagulation treatment should be reserved for children who require CVC and are immobile for more than 24 to 48 hours. 23 4 CONCLUSION HHS is an increasingly common complication of T1D but its diagnostic and management remains difficult. Emergency physicians should be aware of HHS in order to start the appropriate treatment as soon as possible and to think about its acute complication. This case highlights the importance to restore euvolemia before insulin treatment and decrease very gradually the osmolarity in order to avoid cerebral complication. Cerebral venous thrombosis in HHS paediatric patients are rarely described, and it is important to recognize that not all episodes of acute neurological deterioration in HHS or DKA are caused by cerebral oedema. Thromboprophylaxis is not recommended but early anticoagulation in case of cerebral thrombophlebitis may improve prognosis. AUTHOR CONTRIBUTIONS Maud Injeyan: Conceptualization (equal); data curation (equal); investigation (equal); resources (equal); writing - original draft (equal). Sabine Baron: Writing - review and editing (supporting). Benjamin Lauzier: review and editing (supporting); validation (supporting). Benedicte Gaillard-Le Roux: Data curation (supporting); resources (supporting); writing - original draft (supporting); writing - review and editing (supporting). Manon Denis: Conceptualization (equal); data curation (equal); supervision (lead); validation (lead); writing - original draft (lead); writing - review and editing (lead). CONFLICT OF INTEREST The authors declare that they have no competing interest to disclose. CONSENT FOR PUBLICATION Written informed consent was obtained from the patient's legal guardians for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. DATA AVAILABILITY STATEMENT All data supporting the findings of this article are included in the article. |
Cancers (Basel) Cancers (Basel) cancers Cancers 2072-6694 MDPI 10.3390/cancers15051534 cancers-15-01534 Editorial Merkel Cell Carcinoma: An Update and Review Stockfleth Eggert Department of Dermatology, Venereology and Allergology, St. Josef Hospital, Ruhr University Bochum, Gudrunstrasse 56, 44791 Bochum, Germany; [email protected] 28 2 2023 3 2023 15 5 153407 2 2023 23 2 2023 (c) 2023 by the author. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). pmcMerkel cell carcinoma (MCC) is a rare, very aggressive skin cancer with a high mortality rate and a high tendency of metastatic spread . MCC mainly affects elderly and immunosuppressed individuals. Thus, in a population with a growing life expectancy and consequent age-related immunological impairment, MCC cases are likely to increase in the near future. Merkel cell polyomavirus (MCPyV) infection, UV radiation and the impairment of cellular immunity have been identified as important factors in MCC development , but the oncogenic mechanisms in MCC are still not fully understood. However, the exploration of carcinogenic mechanisms is of pivotal importance with respect to the development of preventive and therapeutic measures. As MCCs are frequently misdiagnosed, biomarkers are needed to improve their detection, in order to prompt biopsy to confirm diagnosis by histology and immunohistochemistry, respectively. In addition, biomarkers are required for prognostic evaluation, including for the patient-specific risk of metastatic spread, as well as for decisions about treatment. Recently, immune checkpoint inhibitors (ICI) have significantly improved the management of advanced MCC, with durable response rates in many (50-70%), but not all, metastatic cases . Considering the high costs of ICI therapy and the potential development of various immune-related adverse events, there is an urgent need to characterize biomarkers for the indication and monitoring of specific therapies, finally resulting in a personalized management of MCC patients. In this Special Issue of Cancers, entitled "Merkel Cell Carcinoma: An Update and Review", the interested reader is provided with concise review articles reflecting the current knowledge of MCC epidemiology, pathogenesis and T cell immunity. In addition, clinical studies, including patient profiles with primary MCC and rare manifestations of MCC such as nodal MCC and cardiac metastases are included. The issue of MCC treatment is covered in several contributions and includes the evaluation of current treatment modalities, as well as the characterization of potential new drugs that may be used for MCC in the future. Finally, the topic of molecular markers (biomarkers) that may be used for prognostic evaluation or to guide MCC therapy is addressed in some articles. The article series starts with a review by Silling et al. presenting an update on the epidemiology of MCPyV and MCC, as well as the characteristic features and risk factors of MCC. The authors report on the two entities of MCC, UV radiation-induced and MCPyV-induced, and summarize the differences and similarities in pathogenesis as well as prevalence variations in different geographical regions and patient populations. Studies on MCPyV detection and viral gene expression in skin malignancies other than MCC were also reviewed. Lower prevalence, lower viral load and the rarely detected expression of large T antigens do not support a causal role of MCPyV in non-MCC skin cancer . The association of MCPyV with other malignancies was also addressed by Dimitraki and Sourvinos, who reviewed studies about the presence of the virus in various cancer types of different human organ systems . As in non-MCC skin cancers, MCPyV DNA has been detected in the tissues of different tumours, but again with low prevalence and in low amounts. The authors conclude that the results of these studies do not provide evidence for a substantial role of the virus in the pathogenesis of malignancies other than MCC. Based on studies in other cancers indicating the uptake of extracellular citrate by a plasma membrane variant of the mitochondrial citrate transporter pmCIC supporting cell proliferation, Drexler et al. examined the role of citrate homeostasis in MCC . They report novel interesting data about citrate and pmCIC in the biology and pathogenesis of MCC. The proliferation of MCC tumour cells is stimulated by extracellular citrate, and this effect can be blocked by the inhibition of pmCIC using Na-gluconate. These findings characterize pmCIC as an attractive therapeutical target. The important role of T cells in MCC pathogenesis was illustrated in a comprehensive review of Ouyang et al. . In particular, the impact of tumour-infiltrating lymphocytes (TILs) including different T cell subtypes in tumour initiation, progression and clearance, was outlined, and interacting factors of the TME were discussed. Based on the present knowledge of the T cell immunity of MCC, the authors highlight the importance of understanding T cell-mediated reactions to design effective strategies of immunotherapy. Following these articles on epidemiology and pathogenesis, the next papers of the Special Issue mainly consider the clinical aspects of MCC. Gualdi et al. report data from six Italian dermatological clinics regarding the primary diagnosis of MCC, including clinical and demographic data. The physicians primarily involved in the MCC assessment belong to various medical specialties and differ with respect to the initial management of patients, indicating a lack of standardization and the need for strategies to increase awareness among physicians, in order to improve MCC diagnosis . Whereas MCC typically manifests as a skin nodule, rare cases may present with just a lymph node localization without a cutaneous primary site and no distant metastases (nodal MCC-UP). Fazio et al. present in their paper informative data from a single centre about the management of this rare MCC phenotype. Their findings suggest favourable outcomes (relapse-free survival and cancer-specific survival) of adjuvant radiotherapy after curative surgical treatment with lymphadenectomy . Cardiac metastases of MCC represent another unusual manifestation, as distant metastases of MCC are mainly located in non-regional lymph-nodes, skin, liver and bone . In the article of Akaike et al. , nine cases of cardiac metastatic MCCs were identified in a registry of almost 600 patients with metastatic MCC. Despite the small number of cases, the detailed evaluation with respect to clinical presentation, course of disease, therapy/management and prognosis suggests that the survival of patients with cardiac metastases is not worse than that of patients with metastases at other sites, and that patients with cardiac metastases show a good response to immunotherapy and cardiac radiotherapy. The efficiency of postoperative radiotherapy and the role of regional lymph node irradiation in localized MCC is addressed in the study of Dinges et al. . They report data from a single-centre retrospective analysis comparing patients with and without lymph node irradiation (LNI). Relapses mainly occurred in regional lymph nodes, and regional relapse was more frequent in patients without LNI, indicating that the inclusion of regional lymph nodes in postoperative radiotherapy may reduce the risk of regional relapse. In another paper on MCC treatment, Dudzisz-Sledz et al. present the findings of a prospective multi-centre study from Poland . Therapies currently used in four polish cancer centres to treat locally advanced MCC are unsatisfactory, and patients have a poor prognosis. The authors emphasize the need to improve the management of these patients in reference centres with experienced multidisciplinary teams available. Although the management of advanced MCC has been improved by the introduction of immune checkpoint inhibitors, a significant portion of patients do not benefit from immunotherapy, indicating the need for further treatment options . There are several new drugs in the pipeline for future MCC therapy. Among them, fumaric acid esters represent potentially useful compounds. Gambichler et al. studied the anti-neoplastic effects of dimethylfumarate (DMF) in MCPyV-negative MCC cell cultures and provide functional data concerning the mode of action as a precondition for potential clinical application in the future . Finally, the Special Issue concludes with two papers dealing with the characterization of biomarkers that support disease management. By comparing the transcriptomes of primary MCC from patients with good and poor prognosis, Sundqvist et al. identified several differentially expressed genes, mainly involved in pathways promoting tumour progression (death-associated) and immune responses (survival-associated) . These dysregulated genes may provide targets for future therapeutic interventions and potentially represent biomarkers for the prognostic evaluation and initiation of specific treatments. The value of circulating tumour DNA (ctDNA) for the management of MCC patients was addressed in a review of Gao et al. . Although the number of published studies on ctDNA in MCC is still small, ctDNA detection may have the power to become a useful tool to identify patients that may require specific therapies and to monitor the treatment response. Whereas commercial assays are already available for tumour agnostic testing, the use of tailored assays to detect patient-specific tumour mutations is still challenging and requires the identification of tumour-associated mutations by comprehensive investigations, such as whole-exome sequencing, which is not easily implemented in routine laboratories. As with all rare diseases, rare tumours such as MCC also face the problem of insufficient awareness and are, consequently, afflicted by misdiagnosis and inadequate treatment. 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Front Genet Front Genet Front. Genet. Frontiers in Genetics 1664-8021 Frontiers Media S.A. 1038606 10.3389/fgene.2023.1038606 Genetics Data Report Whole genome sequencing of a wild swan goose population Ni et al. 10.3389/fgene.2023.1038606 Ni Hongyu 1 + Zhang Yonghong 1 + Yang Yuwei 1 Yin Yijing 1 Xie Hengli 1 Zheng Jinlei 1 Dong Liping 1 Diao Jizhe 1 Wei Meng 1 Lv Zhichao 2 Yan Shouqing 1 Li Yumei 1 Sun Hao 1 * Sun Xueqi 1 3 * 1 College of Animal Science, Jilin University, Changchun, China 2 Jilin Province Economic Management Cadre College, Changchun, China 3 Jilin Academy of Agricultural Sciences, Changchun, China Edited by: Nuno Carolino, Instituto Nacional Investigaciao Agraria e Veterinaria (INIAV), Portugal Reviewed by: Juan Vicente Delgado Bermejo, Juan Vicente Delgado bermejo, Spain Elena Ciani, University of Bari Aldo Moro, Italy *Correspondence: Hao Sun, [email protected]; Xueqi Sun, [email protected] + These authors have contributed equally to this work and share first authorship This article was submitted to Livestock Genomics, a section of the journal Frontiers in Genetics 24 2 2023 2023 14 103860607 9 2022 20 1 2023 Copyright (c) 2023 Ni, Zhang, Yang, Yin, Xie, Zheng, Dong, Diao, Wei, Lv, Yan, Li, Sun and Sun. 2023 Ni, Zhang, Yang, Yin, Xie, Zheng, Dong, Diao, Wei, Lv, Yan, Li, Sun and Sun This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. swan goose whole genome sequencing (WGS) SNP linkage disequilibrium genetic resource This study was supported by the Key Projects of Jilin Province Science and Technology Development Plan (Grant No. 20220203084SF). pmcIntroduction It was reported that Chinese goose breeds are thought to have originated from wild swan geese (Anser cygnoides) (Shi et al., 2006). The wild swan goose, as a migratory waterfowl, has many different characteristics compared to the domestic goose breeds. Most notable is that the wild swan goose has long-distance flight ability. At present, the swan goose has two biological migration routes, namely inland migration routes and coastal migration routes. The majority of swan goose individuals in northeastern Mongolia (Inner Mongolia, Heilongjiang, and Jilin province) relocated to the Chinese Yangtze River, and the Russian Far East relocated to the coast of southeast China for winter (Zhu et al., 2020). Due to the lack of analysis of the genomic characteristics and selection signals of wild swan geese, the genetic basis underlying these characteristics is still not well investigated. The swan goose has been listed as vulnerable in the Red List of Threatened Species of the International Union for Conservation of Nature (IUCN), and the swan goose's global population has been estimated at c.60,000-90,000 ). In China, the wild swan goose has been designated as a Class II national protected species. Therefore, it's difficult to obtain wild swan goose samples to carry out genomic studies. Xianghai wetland national nature reserve (44deg55'-45deg09'N, 122deg05'-122deg31'E), located in the Jilin province (the northeast region of China), was one of the wild swan goose's habitats. In 1981, the Xianghai wetland national nature reserve was established, and it is the habitat of many protected migratory birds e.g. Grus japonensis, Otis tarda. We are working at the front line of geese breeding in the Xianghai wetland national nature reserve. Our team consists of researchers from Jilin University and Jiuzhou Flying Goose Husbandry&Technology Co., Ltd., which holds a license to domesticate swan geese in the Xianghai Wetlands. In 1999, their farm was established for domesticating and breeding wild swan geese in Yanya lake in the Xianghai wetland national nature reserve. In recent years, we are working on hybrid goose breeding (swan goose x local domestic goose). We are interested in investigating the genetic difference between the wild swan goose and the domestic goose. Considering that sequencing the wild swan goose provides a valuable resource not only for researchers working on animal conservation but also for those focusing on goose genomic breeding and further genomic investigation. With this in mind, we report and make publicly available whole genome sequencing data for 10 wild swan geese. Samples collection and sequencing The Jiuzhou Flying Goose Husbandry&Technology Co., Ltd. holds a license to domesticate swan geese in the Xianghai Wetlands. The experienced staff randomly picked up wild swan goose eggs from the Xianghai Wetland National Nature Reserve for incubation and rearing. About 2 mL of blood samples were collected from the veins under the wings of the adult swan geese by the experienced staff, and all the swan geese remained healthy after blood collection. Genomic DNA was extracted from the blood following the standard phenol-chloroform extraction procedure. For genome sequencing, at least 0.5 mg of genomic DNA from each sample was used to construct a library with an insert size of 350 bp. Paired-end sequencing libraries were constructed according to the manufacturer's instructions (Illumina Inc., San Diego, CA, United States) and sequenced on the Illumina HiSeq platform. Data quality control and variant calling The FASTP (Chen et al., 2018) software was used to perform quality control on the raw data. The clean reads were aligned to the swan goose genome (PRJNA826973) using Burrows-Wheeler Alignment Maximal Extract Matches algorithm (Li and Durbin, 2009) with default parameters. The SNPs (Single Nucleotide Polymorphisms) were called using the GATK software (McKenna et al., 2010). For these to be called, the calling quality had to be greater than 20 (base recognition accuracy >99%). The SNPs were filtered with minor allele frequency <0.05 and missing rate >0.10 using the VCFtools (Danecek et al., 2011). The distribution of the SNPs on the chromosomes was plotted using the R "CMplot" package. Data description A total of 162.6 Gbp clean data was obtained. The sequence data were deposited in the NCBI Sequence Read Archive (SRA) and the accession number of the sequencing data is PRJNA814334. One individual was deeply sequenced with 39.6 Gbp data obtained, and the other samples were sequenced with about 13.7 Gbp data obtained. The sequencing information of each sample is shown in Supplementary Table S1. The average mapping rate was 0.90 (mapping quality value >=20). Finally, a total of 10,727,005 SNPs (minor allele frequency >=0.05) were obtained, and a total of 7,646,295 (71.28%) transitions (Ts) and 3,080,710 (28.72%) transversions (Tv) were observed. The distribution of the SNPs in 10 kb non-overlapping windows on the chromosomes is provided in Figure 1A. From the information of the SNPs, Linkage disequilibrium (r2) measures were calculated based on the PopLDdecay (Zhang et al., 2019). The decay of LD (linkage disequilibrium) according to distance, for pair-wise SNPs up to 300 kb is shown in Figure 1B. The LD value (r2 = 0.2) was about 200 bp in the wild swan goose, and the levels of LD at different distances were presented in Supplementary Table S2. FIGURE 1 (A) Distribution of the SNPs on the chromosomes. The x-axis represents the chromosome position (Mb), and the y-axis represents the chromosomes. The number of SNPs presented in each 10 kb genome block is displayed by the different colors. (B) Extent of LD average r2 values at distances up to 300 kb. (C) The neighbor-joining tree based on 1-IBS distance. To provide future researchers with an understanding of the genetic difference between the wild swan goose and the domestic goose, here we compared the swan goose populations with a domestic goose breed, the Zi goose, a local domesticated breed in northeast China. The PCA and LD analysis results are provided in Supplementary Figure S1. The plot of the first two PCA components showed a clear genetic differentiation, along the first component, between the swan geese and Zi geese. In addition, the PCA patterning highlighted a wider genetic differentiation among the swan geese samples than among the Zi geese . Historically, the wild swan geese have not undergone intensive selection as experienced in Zi geese. Hence, it is reasonable to assume that the Swan geese mantain higher levels of genetic variability than Zi geese. This assumption is also supported by the LD analysis. In our study, we find that the LD extend of the Zi geese is higher than the Swan geese . It is known that the LD extent could reflect the history of the population. The strong artificial selection could contribute to increasing the LD extent, although we can't exclude the possibility of other factors such as gene flow. To provide future researchers with an understanding of the genetic relationship among samples, we constructed an inter-individual neighbor-joining (NJ) tree of the ten swan geese samples using the (1-IBS) genetic distances, with the identity-by-state (IBS) values being estimated using PLINK v1.9 (Purcell et al., 2007). Genetic distances between individuals ranged from 0.184 to 0.291, and the average value was 0.272. Moreover, we calculated the inbreeding coefficient of each individual using PLINK v1.9 (Purcell et al., 2007) with the command "het." The inbreeding coefficient (Supplementary Table S3) ranged from -0.01 to 0.12, and the average value was 0.07. This result indicated that the extent of inbreeding of the wild swan goose population is low. In conclusion, this paper provides the whole genome resequencing data of ten swan geese, which can serve as a theoretical reference for future exploration of genetic variation or characteristics between swan geese and domestic goose populations, and is of great value in revealing the genetic mechanism of phenotypic differences. For example, by comparing the genome of the wild swan goose to the local goose, researchers may find the clue to the genetic background of the special characteristics of the swan goose, e.g., long-term flying ability. Data availability statement The sequence data presented in the study are deposited in the NCBI Sequence Read Achieve (SRA) repository, accession number PRJNA814334. The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/Supplementary Material. Ethics statement The animal study was reviewed and approved by the Institutional Animal Care and Use Committee of Jilin University. Author contributions YZ and HS designed the research. YZ, XS, YL, SY, ZL, JD, and LD collected the samples. HN, YuY, YiY, HX, MW, and JZ performed the experiment. HS and HN analyzed the data and wrote the manuscript. All authors read and approved the manuscript. Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher's note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Supplementary material The Supplementary Material for this article can be found online at: Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file. References Chen S. Zhou Y. Chen Y. Gu J. (2018). fastp: an ultra-fast all-in-one FASTQ preprocessor. Bioinformatics 34 , i884-i890. 10.1093/bioinformatics/bty560 30423086 Danecek P. Auton A. Abecasis G. Albers C. A. Banks E. DePristo M. A. (2011). The variant call format and VCFtools. Bioinformatics 27 , 2156-2158. 10.1093/bioinformatics/btr330 21653522 Li H. Durbin R. (2009). Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25 , 1754-1760. 10.1093/bioinformatics/btp324 19451168 McKenna A. Hanna M. Banks E. Sivachenko A. Cibulskis K. Kernytsky A. (2010). The genome analysis toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data. 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Healthcare (Basel) Healthcare (Basel) healthcare Healthcare 2227-9032 MDPI 10.3390/healthcare11050745 healthcare-11-00745 Editorial Public Health Palliative Care and Public Palliative Care Education Bollig Georg 12* Rosenberg John P. 23 1 Department of Anesthesiology, Intensive Care, Palliative Medicine and Pain Therapy, HELIOS Klinikum, 24837 Schleswig, Germany 2 Last Aid Research Group International (LARGI), 24837 Schleswig, Germany 3 School of Health, University of the Sunshine Coast, Caboolture, QLD 4510, Australia * Correspondence: [email protected] 03 3 2023 3 2023 11 5 74524 2 2023 27 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). pmcThis Special Issue, "Public Health Palliative Care (PHPC) and Public Palliative Care Education (PPCE)", highlights recent advances and challenges in PHPC and PPCE. The articles demonstrate the breadth and diversity of local responses from across the globe, including Europe, Asia, Australia and South America. The COVID-19 pandemic clearly shows how collaboration between healthcare services and communities is an essential component of public health. This collaboration, initially described in the Ottawa Charter for Health Promotion and the growing body of literature about public health approaches to palliative and end-of-life care, demonstrates the importance of the broad implementation of palliative care in all communities and societies. If most people want to die at home, the public must take a role in the support of seriously ill and dying people. The participation of the public is essential to enable more people to die at home. According to Allan Kellehear's "95% rule" , seriously ill and dying people spend little more than 5% of their final year of life in the direct care of healthcare services; the other 95% relies upon relatives, friends or others without healthcare backgrounds to provide support. Public health palliative care (PHPC) and public palliative care education (PPCE) approaches attempt to address this provision of support. However, public awareness of palliative care is generally low, and although public education has been recommended by a number of authors, PPCE is rarely implemented in most communities . Often, this education like clinical care is provided by healthcare services with familiarity with the issues of dying, death and loss. Although this is not unreasonable, it is more consistent with the principles and practices of PHPC to provide such education in partnerships between services and communities, demonstrating responses to local needs. Five papers highlight different aspects and experiences of the implementation of the Last Aid Course (LAC) from different countries and settings. LACs demonstrate a standardised approach to PPCE that has been implemented in 20 countries worldwide, including Germany, Switzerland, Scotland, Lithuania, Australia, Canada and Brazil. LAC was introduced in 2014 to educate the public about death, dying and end-of-life care, to encourage and to empower people to participate in end-of-life care at home, and to enhance the public discussion about these themes . Mueller and colleagues report on LACs in a German university hospital , where they were very well accepted by the whole staff (both healthcare and non-healthcare professions) in general, but healthcare staff sought extended content and opportunity for group discussions. These findings led to the formation of an extended "LAC Professional" for healthcare professionals comprising ten teaching hours . In Slovenia, Zelko et al. demonstrate that web-based delivery is very well received and favourably rated by LAC participants . They recommend that the LAC should also address the cultural diversity and characteristics of local settings and populations; they describe early experiences with an LAC for deaf people. Macaden at al. report from Scotland that LAC could serve as the foundational core training to promote death literacy in communities to enhance personal knowledge, skills and confidence of community members . In a cross-border pilot study from Denmark and Germany, Bollig et al. showed that LAC participants find individual differences more important than cultural differences in end-of-life care . They describe differences in regulations and organisation of services across the border that people need to be informed about; some suggest the topics of organisation and support across the border, religions and cultures, and supporting people in grief could be added to the LAC. This pilot study has influenced the work of the revision of LAC content during the 3rd International Last Aid Conference in Maribor, 2022. Interviews with German participants of the LAC presented by Giehl et al. inform us about the effects that LAC can have on palliative care provision at home and empowerment of participants . The LAC helps to provide knowledge, guidance and recommendations for action in palliative care situations. These articles on LACs add to our understanding of the impact of LAC training of both the public and professionals. They show that the LAC concept is feasible in different settings in a range of countries. Indeed, LAC may contribute to increased death literacy in communities, where the development of personal skills to strengthen community action underpins PHPC . In the context of Compassionate Communities, LACs can be seen as practical support offered by fellow citizens to relieve suffering. Recognition of palliative care as everyone's responsibility also enables universities to play a role in the development of Compassionate Communities. Librada Flores et al. recognise that, with minimal death awareness in universities, a university that sensitises, trains and mobilises students and professionals to develop care networks around people at the end of life is highly beneficial . Including universities as partners in Compassionate Communities may contribute to social change with the sensitisation of future leaders educated there. Aoun and her colleagues report on a large community-focused study of bereaved and current carers, and patients, of palliative care . They observe that those with the greatest awareness of palliative care are the 'winners' in receiving best quality care and the 'losers' were the opposite; however, in both cases, wider social networks are key to providing appropriate support. The importance of communities supporting their members in times of need is very clear, and this reiterates the necessity of public awareness. This is perhaps most clear in communities with a strong, shared cultural identity. Kroik et al. explore this in the indigenous Sami of Fennoscandia . Where community coherence is high, capacity for well-functioning palliative and end-of-life care is increased; yet the greatest challenge lies in the establishment of supportive interactions with healthcare services. Developing meaningful care relies upon this partnership. The implementation of the Compassionate Cities charter in downtown Taipei, Taiwan, guided the development of a compassionate community in a local district . A culturally sensitive and holistic program was developed using health and social services, universities and community representatives, which enabled a sustainable approach to community connection and greatly increased awareness of palliative and end-of-life care issues. In South Korea, Bae and Kim also demonstrate the importance of regional knowledge in designing appropriate responses to local needs . Interestingly, this clear sense of common purpose can be created between previously disparate groups. Kleijberg and his colleagues explored the application of the arts to intergenerational groups where community partners, children and older adults were drawn together for intentional 'play' . These activities engaged with end-of-life issues, and illustrate a powerful alternative to didactic pedagogy in building knowledge and connections. Rumbold and Aoun's review of the literature provides an informative overview of the consumer experience of palliative care, including consumer contribution to service and policy design . Arguably, it is from a community where citizens' engagement with palliative and end-of-life care issues is high that these experiences are more positive; however, this review demonstrates minimal use of consumer perspectives in the models of palliative care. This is true not only in the low usage of generalised evidence but also in the notable absence of community representation in the co-creation of services. This Special Issue adds to the growing body of knowledge, based on practice, theory and research, about PHPC and PPCE. It is clear that global perspectives of PHPC are best expressed through both international, national and local activities including PPCE, such as Last Aid. Partnerships between healthcare services, civic organisations and communities are essential to increase awareness, skills and practice. It is evident that PHPC and PPCE are needed to improve palliative care support by the public in communities. These examples show that encouraging work on this important theme is ongoing worldwide, although more effort for implementation and research is needed. Author Contributions Both authors have contributed equally. All authors have read and agreed to the published version of the manuscript. Conflicts of Interest The authors declare no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. World Health Organization The Ottawa Charter for Health Promotion WHO Geneva, Switzerland 1986 2. Kellehear A. The social nature of dying and the social model of health Oxf. Textb. Public Health Palliat. Care 2022 22 29 3. Bollig G. Bauer E.H. Last Aid Courses as measure for public palliative care education for adults and children: A narrative review Ann. Palliat. Med. 2021 10 8242 8253 10.21037/apm-21-762 34353105 4. Gopal K.S. Archana P.S. Awareness, knowledge and attitude about palliative care, in general, population and health care professionals in tertiary care hospital Int. J. Sci. Study 2016 3 (Suppl. S10) 31 35 5. McIlfatrick S. Slater P. Beck E. Bamidele O. McCloskey S. Carr K. Muldrew D. Hanna-Trainor L. Hasson F. Examining public knowledge, attitudes and perceptions towards palliative care: A mixed method sequential study BMC Palliat. Care 2021 20 44 10.1186/s12904-021-00730-5 33731087 6. Westerlund C. Tishelman C. Benkel I. Furst C.J. Molander U. Rasmussen B.H. Sauter S. Lindqvist O. Public awareness of palliative care in Sweden Scand. J. Public Health 2018 46 (Suppl. S4) 478 487 10.1177/1403494817751329 29301481 7. Kozlov E. McDarby M. Reid M.C. Carpenter B.D. Knowledge of Palliative Care among Community-Dwelling Adults Am. J. Hosp. Palliat. Care 2018 35 647 651 10.1177/1049909117725725 28819986 8. Bollig G. Brandt Kristensen F. Wolff D.L. Citizens appreciate talking about death and learning end-of-life care: A mixed-methods study on views and experiences of 5469 Last Aid Course participants Prog. Palliat. Care 2021 29 140 148 10.1080/09699260.2021.1887590 9. Mueller E. Bollig G. Becker G. Boehlke C. Lessons learned from introducing Last Aid Courses at a university hospital in Germany Healthcare 2021 9 906 10.3390/healthcare9070906 34356284 10. Bollig G. Schmidt M. Aumann D. Knopf B. Der Letzte Hilfe Kurs professionell Erste Erfahrungen mit einem eintagigen niedrigschwelligen Palliative Care Fortbildungsangebot fur Personal aus dem Gesundheitswesen Z. Palliativmed 2023 24 31 39 10.1055/a-1905-2423 11. Zelko E. Vrbek L. Koletnik M. Last Aid Course The Slovenian Experience Healthcare 2022 10 1154 10.3390/healthcare10071154 35885681 12. Macaden L. Broadfoot K. Carolan C. Muirhead K. Neylon S. Keen J. Last Aid Training online: Participants' and facilitators' perceptions from a mixed-methods study in rural Scotland Healthcare 2022 10 918 10.3390/healthcare10050918 35628055 13. Bollig G. Safi M. Schmidt M. Ewald H. Is there a need for cultural adaptation of the Last Aid Course? A mixed-methods study across the Danish-German border Healthcare 2022 10 658 10.3390/healthcare10040658 35455837 14. Giehl C. Chikhradze N. Bollig G. Vollmar H.C. Otte I. "I needed to know, no matter what I do, I won't make it worse" expectations and experiences of Last Aid Course participants in Germany A qualitative pilot study Healthcare 2023 11 592 10.3390/healthcare11040592 36833126 15. Mills J. Rosenberg J.P. Bollig G. Haberecht J. Last Aid and Public Health Palliative Care: Towards the development of personal skills and strengthened community action Prog. Palliat. Care 2020 28 343 345 10.1080/09699260.2020.1829798 16. Librada Flores S. Roa Trujillo S.H. Torrejano Gonzalex N. Garcia Buitrago M.d.P. Lucas Diaz M.A. A survey of attitudes and beliefs about care, compassion and communities networks in palliative care. a preliminary study for the development of a compassionate university Healthcare 2021 9 946 10.3390/healthcare9080946 34442083 17. Aoun S.M. Jiang L. Rumbold B. Winners and losers in palliative care service delivery: Time for a public health approach to palliative and end-of-life care Healthcare 2021 9 1615 10.3390/healthcare9121615 34946341 18. Kroik L. Tishelman C. Stoor K. Edin-Liljegren A. A salutogenic perspective on end-of-life care among the Indigenous Sami of Northern Fennoscandia Healthcare 2021 9 766 10.3390/healthcare9060766 34205402 19. Kellehear A. Compassionate Cities Routledge London, UK 2012 20. Liu C.-J. Huang S.J. Wang S.S.-C. Implementation of Compassionate Communities: The Taipei experience Healthcare 2022 10 177 10.3390/healthcare10010177 35052340 21. Bae S.H. Kim Y.H. The First Step to Initiate Pediatric Palliative Care: Identify Patient Needs and Cooperation of Medical Staff Healthcare 2022 10 127 10.3390/healthcare10010127 35052291 22. Kleijberg M. Hilton R. Ahlberg B.M. Tishelman C. Play elements as mechanisms in intergenerational arts activities to support community engagement with end-of-life issues Healthcare 2021 9 764 10.3390/healthcare9060764 34205346 23. Rumbold B. Aoun S.M. Palliative and end-of-life care service models: To what extent are consumer perspectives considered? Healthcare 2021 9 1286 10.3390/healthcare9101286 34682966 |
J Synchrotron Radiat J Synchrotron Radiat J. Synchrotron Rad. Journal of Synchrotron Radiation 0909-0495 1600-5775 International Union of Crystallography 36891858 yi5132 10.1107/S1600577523000814 JSYRES S1600577523000814 Short Communications Mapping the 3D position of battery cathode particles in Bragg coherent diffractive imaging 3D positioning of battery cathode particles in Bragg CDI Shabalin A. G. ab* Zhang M. c Yao W. c Rysov R. b Ren Z. b Lapkin D. b Kim Y.-Y. b Assalauova D. b Mukharamova N. b Sprung M. b Vartanyants I. A. b Meng Y. S. c Shpyrko O. G. a a Department of Physics, University of California San Diego, La Jolla, CA 92093-0319, USA b Deutsches Elektronen-Synchrotron DESY, Notkestrasse 85, 22607 Hamburg, Germany c Department of NanoEngineering, University of California San Diego, La Jolla, CA 92093-0448, USA Yabashi M. Editor RIKEN SPring-8 Center, Japan Correspondence e-mail: [email protected] 01 3 2023 16 2 2023 16 2 2023 30 Pt 2 s230200 445448 12 7 2022 30 1 2023 (c) A. G. Shabalin et al. 2023 2023 This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited. A full version of this article is available from Crystallography Journals Online. A method to determine the 3D position of particles in Bragg coherent diffractive imaging experiments is proposed. Test measurements demonstrate depth-resolution with a precision of 20 mm along the beam. In Bragg coherent diffractive imaging, the precise location of the measured crystals in the interior of the sample is usually missing. Obtaining this information would help the study of the spatially dependent behavior of particles in the bulk of inhomogeneous samples, such as extra-thick battery cathodes. This work presents an approach to determine the 3D position of particles by precisely aligning them at the instrument axis of rotation. In the test experiment reported here, with a 60 mm-thick LiNi0.5Mn1.5O4 battery cathode, the particles were located with a precision of 20 mm in the out-of-plane direction, and the in-plane coordinates were determined with a precision of 1 mm. extra-thick battery cathodes Bragg coherent X-ray diffractive imaging battery cathodes Bragg diffraction sphere of confusion 3D mapping US Department of Energy, Office of ScienceDE-SC0001805 DE-EE0008442 Funding for this research was provided by the US Department of Energy, Office of Science (contract no. DE-SC0001805). The electrode fabrication effort is supported by the US Department of Energy's Office of Energy Efficiency and Renewable Energy (EERE) and US Army Tank and Automotive Research Development and Engineering Command (TARDEC) under the award number DE-EE0008442. pmc1. Introduction Imaging of local strain in the bulk of polycrystalline samples requires a probe with high penetration depth and sensitivity to the crystal structure deformations at the nanoscopic level. This became possible with major advances in synchrotron instrumentation, in particular coherent scattering methods that have been developed within the last two decades. Bragg coherent diffractive imaging (CDI) (Robinson et al., 2001 >; Miao et al., 2002 >; Pfeifer et al., 2006 >; Robinson & Harder, 2009 >) is now established as a powerful tool for imaging the structure deformation and structure defects in individual nanocrystals (Ulvestad et al., 2015 >; Kim et al., 2021 >). As the crystals are usually diverse, several particles at different locations are measured to collect sufficient statistical information across the sample (Singer et al., 2018 >). The precise location of the measured particles is usually unknown in such experiments, and thus homogeneity of the sample is often assumed. For systems in which the material response is not uniform, it is important to obtain the location information. For example, in Li-ion batteries with extra-thick cathodes, the charging behavior is expected to depend on the depth under the cathode surface (Zheng et al., 2012 >; Lee et al., 2018 >). Strengthening the capabilities of operando Bragg CDI with the possibility to map the measured particles would provide a missing link between the performance of individual nanoparticles and the 3D structure of extra-thick electrodes. As a general solution to this problem, here we suggest a method to determine the 3D position of the measured particles in Bragg CDI experiments. Our method has some similarities with the procedure involving the detection of rotational centers from cross-correlations in micro-tomography (Pan et al., 2012 >), which uses optical contrast as a measure of alignment, whereas our work uses the integrated intensity of a Bragg diffraction spot. The fundamental difference is that in tomography the full 180deg angular range is available for sample rotations. In Bragg CDI, each particle is observed only in the angular range of about 1deg in which the Bragg condition is satisfied. Despite this limitation on the angular range, in which the particle is observed in the beam, our method allows us to determine where exactly along the beam the particle is. This adds new information to the Bragg CDI method. 2. Method In a typical Bragg CDI experiment, a finite crystalline sample is illuminated with a focused X-ray beam and oriented to fulfill the Bragg diffraction condition (Vartanyants & Yefanov, 2015 >). The resulting far-field interference pattern around the Bragg peak is recorded with a 2D detector (see the schematic in Fig. 1 >). Different cross-sections through reciprocal space are accessed by rocking the sample in the beam so that a typical dataset consists of a few tens of diffraction patterns (Williams et al., 2003 >). In such a geometry, the crystal is on the instrument axis of rotation aligned to be perpendicular to the X-ray beam. Since the particle must stay in the beam during the scan, bringing the particle precisely to the instrument axis of rotation is an important step. To describe the alignment procedure, let us assume that the nanoparticle is initially located off the axis of rotation. First, we adjust the rotation of the sample (o) and the translations perpendicular to the beam (x and y) to maximize the diffracted intensity of the peak. Then, o is scanned near the position of the highest intensity (o p ), as shown in Fig. 2 >(a). For two angular positions on the opposite sides of the resulting intensity profile (o1 and o2), we maximize the intensity by scanning the x spatial position. By that we determine how much the sample moved [see Fig. 2 >(b)]. Finally, we move the sample along the beam by These steps are repeated until Dz = 0, which means the particle is located exactly at the axis of rotation. 3. Experiment We performed our experiment at the P10 Coherence Applications beamline of PETRA III facility (Hamburg, Germany), using an X-ray beam with a photon energy of 11.89 keV that was focused to a 2 mm x 2 mm spot. The sample was an Li-ion battery cathode consisting of a roughly 60 mm-thick layer of LiNi0.5Mn1.5O4 (LNMO) material deposited on a roughly 20 mm-thick Al foil. The cathode was mounted in a way that the X-ray beam was incident normal to the front side (LNMO surface) leaving Al foil downstream as shown in Fig. 1 >. First, we selected an Al (111) reflection and measured 12 particles for positional reference to use our mapping method. After that, we switched to the LNMO (111) reflection and measured 30 LNMO particles. Then, to confirm that choice of reflection does not affect the consistency of the results, we switched to the LNMO (222) reflection and measured four more particles. The resulting 3D positions are presented in Figs. 3 >(a) and 3 >(b). We can see that the z positions of LNMO particles fit well into the 60 +- 20 mm range. The Al particles appear within the expected size of the sample and fit into the 20 +- 30 mm range. The positions of Al particles are less precise due to the much lower quality of the Bragg peaks that were less intense and would often overlap. This can be explained by the significantly smaller grain size of Al. Overall, the positions are consistent with the cathode geometry and dimensions. We did not apply any bias when choosing the particles and selected them using only two criteria. The first was that there should be no peak overlap with other particles in the beam, and this should not depend on the position in the sample because the sample material was pristine and therefore uniform. The second was high peak intensity, which should also not depend on the position, as the total optical path would be roughly the same for any position along the beam, at least for scattering angles in the range 10-15deg, used in our work. Using equation (1), the precision of the positioning in our method can be estimated from the angular difference Do (0.8deg in our case) and the precision of the measurement of Dx (about 0.3 mm in our case). This provides 20 mm precision along the beam, which is confirmed by the experimental data presented in Figs. 3 >(a) and 3 >(b). Instrumental inaccuracies of the rotational and translational positioning can potentially bring systematic errors to our method. At the P10 beamline, we used a six-circle Huber diffractometer with high-precision translational piezo mechanisms. Beforehand, for the measurements, we aligned the beam and the axis of rotation using a metal pin with sharp edges. Considering that all sample rotations in the method were performed within a narrow range of about 1deg, we can confidently state that, throughout the measurements, the axis of rotation remained in the beam center with a precision better than 1 mm. Therefore, instrumental errors did not contribute significantly in our case. 4. Discussion and conclusions In our experiment, it was difficult to find particles with isolated and intense Bragg peaks because the diffraction rings from such a thick sample were densely populated with peaks. In future work, this can be mitigated by employing a smaller X-ray beam and choosing higher-order reflections. We note that the low transmission of X-rays in thick samples makes alignment difficult, thus limiting the applications of our method. Future advances in coherent scattering methods toward using higher photon energies would help overcome this problem. We suggest that our method can be used to explore the difference in charging behaviors of underlying nanoparticles at different depths in extra-thick Li-ion battery cathodes. On one hand, such cathodes are significantly thicker than the depth-resolution of the method (20 mm). On the other hand, they are still thin enough for a hard X-ray beam to penetrate. Such an experiment could help explain the origin of thick electrode electrochemical performance deterioration. We proposed a simple method for mapping the 3D position of particles in Bragg CDI experiments, which is based on the precise alignment of the selected particles with the instrument axis of rotation. We carried out an experiment in which positions of LiNi0.5Mn1.5O4 battery cathode particles were measured with a precision of 1 mm in the plane perpendicular to the beam and 20 mm in the direction along the beam. In future experiments, our method can help to study inhomogeneous systems in which the structural behavior of composing nanocrystals depends on their location in the sample interior. We acknowledge DESY (Hamburg, Germany), a member of the Helmholtz Association HGF, for the provision of experimental facilities. Parts of this research were carried out at the PETRA III synchrotron facility and we would like to thank all the beamline staff for assistance in using the Coherence Application beamline P10. Open access funding enabled and organized by Projekt DEAL. Figure 1 Schematic of the depth-resolved Bragg CDI approach. Before the measurements, the axis of rotation of the instrument (o) is aligned to intersect with the focused X-ray beam. The sample (in our case, a battery cathode in a coin cell) is searched for particles that have bright and isolated Bragg peaks on the 2D detector. We use the right-hand coordinate system with the z axis along the direction of the X-ray beam and the y axis aligned with the sample rotation axis. Figure 2 Alignment for the longitudinal position in the depth-resolved Bragg CDI. (a) After the x and y coordinates have been aligned, the Bragg peak intensity is scanned with the o-scan rotation providing the rocking curve data. Then, x profiles are measured on the opposite sides of that curve: o1 and o2. (b) If the particle was seated off the axis of rotation, the x position of the peak would shift between these two scans. The misalignment along the beam direction is calculated as the amount of that shift divided by the angular difference expressed in radians. Figure 3 Measured 3D positions of particles in a 60 mm-thick battery cathode. The cathode consisted of the LNMO material (yellow area), deposited on 20 mm-thick Al foil (gray area). Slopes of the red and black dashed contours illustrate the thickness uncertainties for the LNMO and Al layers, respectively, which are estimated to be about 10 mm on each side. LNMO (111) (red markers) and LNMO (222) (blue markers) reflections were used. For Al, we used the (111) reflection (shown by black markers). (a) yz projection. (b) xz projection. References Kim, Y. Y., Keller, T. F., Goncalves, T. J., Abuin, M., Runge, H., Gelisio, L., Carnis, J., Vonk, V., Plessow, P. N., Vartaniants, I. A. & Stierle, A. (2021). Sci. Adv. 7, 757. Lee, B.-S., Wu, Z., Petrova, V., Xing, X., Lim, H.-D., Liu, H. & Liu, P. (2018). J. Electrochem. Soc. 165, A525-A533. Miao, J., Ishikawa, T., Johnson, B., Anderson, E. H., Lai, B. & Hodgson, K. O. (2002). Phys. Rev. Lett. 89, 088303. Pan, Y., De Carlo, F. & Xiao, X. (2012). Proc. SPIE, 8313, 645-653. Pfeifer, M. A., Williams, G. J., Vartanyants, I. A., Harder, R. & Robinson, I. K. (2006). Nature, 442, 63-66. Robinson, I. & Harder, R. (2009). Nat. Mater. 8, 291-298. Robinson, I. K., Vartanyants, I. A., Williams, G., Pfeifer, M. & Pitney, J. (2001). Phys. Rev. Lett. 87, 195505. Singer, A., Zhang, M., Hy, S., Cela, D., Fang, C., Wynn, T., Qiu, B., Xia, Y., Liu, Z., Ulvestad, A., Hua, N., Wingert, J., Liu, H., Sprung, M., Zozulya, A. V., Maxey, E., Harder, R., Meng, Y. S. & Shpyrko, O. G. (2018). Nat. Energy, 3, 641-647. Ulvestad, A., Singer, A., Clark, J. N., Cho, H. M., Kim, J. W., Harder, R., Maser, J., Meng, Y. S. & Shpyrko, O. G. (2015). Science, 348, 1344-1347. Vartanyants, I. A. & Yefanov, O. M. (2015). X-ray Diffraction. Modern Experimental Techniques, ch. 12, pp. 341-384. Singapore: Pan Stanford Publishing. Williams, G. J., Pfeifer, M. A., Vartanyants, I. A. & Robinson, I. K. (2003). Phys. Rev. Lett. 90, 175501. Zheng, H., Li, J., Song, X., Liu, G. & Battaglia, V. S. (2012). Electrochim. Acta, 71, 258-265. |
During radiation therapy (RT) of glioblastoma, daily MRI with combination MRI-linear accelerator (MRI-Linac) systems has demonstrated significant anatomic changes, including evolving post-surgical cavity shrinkage. Cognitive function RT for brain tumors is correlated with radiation doses to healthy brain structures, especially the hippocampi. Therefore, this study investigates whether adaptive planning to the shrinking target could reduce normal brain RT dose with the goal of improving post-RT function. We evaluated 10 glioblastoma patients previously treated on a 0.35T MRI-Linac with a prescription of 60 Gy delivered in 30 fractions over six weeks without adaptation ("static plan") with concurrent temozolomide chemotherapy. Six weekly plans were created per patient. Reductions in the radiation dose to uninvolved hippocampi (maximum and mean) and brain (mean) were observed for weekly adaptive plans. The dose (Gy) to the hippocampi for static vs. weekly adaptive plans were, respectively: max 21 +- 13.7 vs. 15.2 +- 8.2 (p = 0.003) and mean 12.5 +- 6.7 vs. 8.4 +- 4.0 (p = 0.036). The mean brain dose was 20.6 +- 6.0 for static planning vs. 18.7 +- 6.8 for weekly adaptive planning (p = 0.005). Weekly adaptive re-planning has the potential to spare the brain and hippocampi from high-dose radiation, possibly reducing the neurocognitive side effects of RT for eligible patients. radiotherapy glioblastoma resection cavity hippocampi cognitive function dose reduction National Institutes of Health (NIH)R37CA262510 National Cancer Institute (NCI)K12CA226330 University of Miami Sylvester Comprehensive Cancer CenterResearch reported in this publication was supported by the National Institutes of Health (NIH)/National Cancer Institute (NCI) under award numbers R37CA262510 and K12CA226330. Additional support was provided by the University of Miami Sylvester Comprehensive Cancer Center. pmc1. Introduction Glioblastoma is the most common primary brain cancer worldwide and is frequently fatal. The standard of care for glioblastoma is maximal safe surgical resection followed by daily radiation and chemotherapy for 6 weeks, and then continued chemotherapy with temozolomide for 6 months . Brain tumors and their treatment (surgery, chemotherapy, and radiation) can affect the patient in multiple ways. For example, cognitive decline can be a delayed side effect of radiation therapy, which can include attention problems, memory, and the speed of processing information. Approximately 30% to 50% of brain tumor patients present with cognitive decline symptoms 6 months after radiation therapy (RT) . Studies suggest that the irradiation of the hippocampus and healthy brain tissue is correlated to post-treatment cognitive dysfunction . Hybrid MRI-linear accelerator (MRI-Linac) systems have gained in popularity since their initial 510(k) marketing authorization in 2012 . Such systems offer improved soft tissue delineation over cone beam computed tomography (CBCT)-guided RT . A previous study has shown the possibility of the daily tracking of glioblastoma resection cavity (RC) volumes during RT . RC volumes play a significant role in the treatment planning process, as RT guidelines for glioblastoma include the treatment of the RC plus additional margins . Changes to the RC volume have consequences for the RT dose distribution in structures surrounding the RC. The standard of care for glioblastoma RT is based on one plan after the surgical resection of the tumor, and is usually generated about a week or more prior to the RT start date. However, the daily MRI-Linac treatments have permitted the visualization of significant anatomical changes during RT, including evolving RC shrinkage . Here, we demonstrate that RC shrinkage can be adapted on the MRI-Linac platform with savings in seemingly normal brain structure doses. 2. Materials and Methods 2.1. Daily Set up Images Daily set-up images were acquired before treatment delivery on a 0.35-T MRI-Linac (ViewRay MRIdian, Cleveland, OH, USA). Patients were immobilized in a custom thermoplastic mask, and they were imaged with a vendor-supplied head and neck anterior flexible coil and torso posterior flexible coil wrapped around the thermoplastic mask and baseplate (total 11 channels). Images were acquired using a balanced steady-state free procession pulse sequence (bSSFP), characterized by its short acquisition time and high signal-to-noise ratio. Images acquired with this pulse sequence combine T1/T2 contrast behavior ; however, at the high flip angles used here the images are predominantly T2-weighted as we have previously demonstrated . The set-up MRI scans used for this study were acquired with 1.5 x 1.5 x 1.5 mm voxel dimension, TR/TE = 3.35/1.45 ms, flip angle = 60 degrees and bandwidth = 536 Hz/pixel. The field-of-view for the set-up scans was chosen to fit the entire head and the acquisition time was 172 s. 2.2. Patient Data Base and Analysis Ten patients were selected from a prospective non-interventional study of 0.35-T MRI-Linac glioblastoma RT. Thirty-six patients were evaluated for possible inclusion in this study. Of the 36 patients analyzed, 26 had a gross total or near-total resection defined as resection cavity only on MRI (no enhancing tumor lesion) or resection cavity with small tumor lesion and/or a postoperative change of less than 20 mL. Near total resection or gross total resection was defined by an attending radiation oncologist after evaluating the surgery note from the neurosurgeon, the radiology notes from the radiologist, and the post-surgery imaging. Of those 26 patients, 13 had cavity shrinkage during RT, defined as any volume decrease with a volume reduction range from the planning of the MRI RC to the beginning of Week 5 of treatment MRI RC of: -0.88 mL to -12.47 mL. Of those 13 patients, 3 were excluded from analysis due to the location of the tumor involving both hippocampi. Daily T2-weighted TRUFI bSSFP treatment set-up MRI scans from the MRI-Linac were transferred to radiation oncology software (MIM Software, Cleveland, OH, USA) where RC, planning tumor volume (2 cm clinical target volume expansion within brain followed by 3 mm expansion of RC), brain, and organs at risk (OARs) were contoured on the planning scan and last day of every treatment week (Fractions 5, 10, 15, 20, 25). These contours were reviewed by a senior radiation oncologist. Figure 1 shows the structures that were contoured for most patients. Constraints for brainstem, optic structures, eyes, and lenses are typically included on modern cooperative group protocols for brain radiotherapy, as excess dose can cause vision loss, cranial neuropathies, or paralysis . We also include hippocampi, as emerging data suggest that hippocampal doses are correlated to neurocognitive function after radiotherapy , and lacrimal glands, as excess doses can cause permanent xeropthalmia . Fractionated RT plans were created for every patient, with a prescription of 60 Gy to the planning target volume (PTV). The PTV is the sum of the clinical target volume (CTV), a 2 cm expansion from the resection cavity within the normal brain confined by anatomic barriers such as dura, plus 3 mm for daily setup error. Treatment was delivered over a period of six weeks (5 days per week, 2 Gy per day). These plans that were not adapted are denoted as static plans. Diagnostic and MRI-Linac MRIs and computed tomography (CT) scans taken pre-RT were used to plan the individual static plans for the MRI-Linac planning system . The dose distribution to organs at risk and the brain were recorded. For the adaptive plans, MRI-Linac set-up scans from fractions 5, 10, 15, 20, and 25 (the last days of each week of treatment) were used to calculate treatment plans for the following five fractions of treatment. Contours were created for each fraction to account for changes in RCs and shifts in OARs. For consistency, constraints on each weekly plan were kept constant (including the threshold and importance values). Each plan was normalized to 95% coverage at prescription dose to the PTV. The weekly plans were divided in dosage, prescribing 10 Gy per week for six weeks, summing a total of 60 Gy . The adaptive plans were then transferred to MIM software. After fusing all plans to the pre-RT scan as a reference, a summation of dose was performed. The accumulated dose was then recorded for OARs and healthy brain. Dose values to the hippocampus recorded from non-adaptive plans and adaptive plans were compared using a paired t-test, and the statistical analysis was conducted in Minitab. We considered p values < 0.05 to be statistically significant. 3. Results The mean and max doses for the static and adaptive plans for the uninvolved hippocampi and brain (Table 1) and a summary of statistical values (Table 2) are shown. For every patient, there is a dose reduction to the hippocampus and brain tissue, with dose to healthy tissue trending downwards and isodose lines freeing the hippocampi as the weeks progressed (Table 1). Only in patients 3 and 5 did the dose to OARs not change significantly during treatment due to cavity position superior in the brain, far from the hippocampi. The difference between the hippocampus mean (p = 0.003) and max (p = 0.036) and brain mean (p = 0.005) for the static and adaptive plans all reached statistical significance . From the 10 patients evaluated, 9 also showed dose reductions to optic structures (mean static plan 96.7 Gy, mean adaptive plan 84.5 Gy, p = 0.044) and brainstem (mean static plan 18.21, mean adaptive plan 14.5, p = 0.041). 4. Discussion MRI-guided RT can reduce doses to healthy tissue by adapting treatment plans to changes during RT . Brain tumor resection cavities are clearly visible on hybrid MRI-RT systems without exogenous contrast, and the cavities of a significant percentage of patients with gross or near total resection (36% of patients analyzed) shrink during treatment. This study demonstrates that weekly adaptive re-planning in glioblastoma can lower the dose to healthy brain tissue by adapting to shrinking resection cavities. Adaptive RT might improve glioblastoma RT toxicity as hippocampal RT doses have been correlated with worsened neurocognitive outcomes, while sparing the hippocampi from irradiation has been correlated with improved neurocognitive outcomes . Studies have shown that increasing the hippocampal dose correlates with declines in neurocognitive outcomes , and sparing the hippocampi from doses above 55 Gy improves neurocognitive outcomes. Similarly, for normal-appearing uninvolved brain, radiation doses beyond 35 Gy cause cortical atrophy on serial imaging that may lead to decreased neurocognition . Furthermore, doses as low as 10 Gy disrupt white matter connectivity . Another technique that limits brain RT dose is proton therapy . A randomized trial of protons vs. photons in glioblastoma for improved brain sparing reduced grade 2 toxicities and high-grade lymphopenia , which might also be possible with other brain-sparing techniques such as this one. Adaptation as demonstrated here should not negatively impact tumor control, as tumor cells would be expected to shift with the normal-appearing brain towards the shrinking resection cavity. As an alternative to hybrid MRI-RT systems, standalone MRI during RT has been proposed to reduce boost margins during RT to reduce the volume of brain treated in efforts to limit toxicity. This has been shown to improve target coverage and reduce the dose to the normal brain . One study has even suggested that such an adaptive strategy could improve patient overall survival . The current work expands on these existing studies to demonstrate feasibility on an integrated MR-Linac system with integrated adaptive radiotherapy capabilities, and demonstrates improvement in hippocampal sparing, which could improve patient quality of life. The main limitation for the integration of standalone MRI during RT in clinical practice is the cost, availability, and coordination of standalone MRIs for patients during RT as well as the extra effort for re-simulation and planning. Hybrid MRI-RT systems essentially nullify these concerns since they allow for treatment and MRI in the same session and include an adaptive online radiotherapy workflow . To this end, the UNITED trial (NCT04726397) uses a hybrid MRI-RT system with weekly adaptation to intact disease and cavity based on T1 post-contrast MRI with 5 mm CTV margins. In this study, we propose weekly adaptation on non-contrast T2-weighted or FLAIR images, as the US Food and Drug Administration has advised to "minimize repeated [gadolinium contrast] imaging studies when possible, particularly closely spaced MRI studies ". In the case of rapid tumor recurrence during RT, an expansion of edema on T2 or FLAIR would be visible around the resection cavity, and this could trigger gadolinium contrast administration in select patients. 5. Conclusions The weekly adaptive MRI-guided re-planning of shrinking glioblastoma resection cavities has the potential to spare brain and hippocampi from high-dose radiation, reducing RT toxicity. Clinical trials of MRI-guided adaptive RT should measure its impact on neurocognition and other toxicities. Acknowledgments I: Beatriz Guevara, am grateful to all of those with whom I have had the pleasure to work during this project. Without the help of Jenniffer Donoso, who provided administrative support, William Amestoy, who provided the guidance to learn to use the planning systems, Kyle Padgett, who provided guidance during the methodology of this article, this project would not have been possible. Author Contributions Conceptualization, D.M., K.C. and E.A.M.; methodology, B.G. and K.B.; validation, B.G. and E.A.M.; formal analysis, B.G.; investigation, B.G., K.C., D.M. and A.V.; resources, G.A.A., M.I.D.L.F., A.V., J.M., A.B., J.C.F. and E.A.M.; data curation, K.C.; writing original draft preparation, B.G.; writing review and editing, K.C. and E.A.M.; visualization, B.G.; supervision, E.A.M.; project administration, A.V. and E.A.M.; funding acquisition, E.A.M. All authors have read and agreed to the published version of the manuscript. Institutional Review Board Statement The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board of Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine (protocol code 20190678, date of approval 9 December 2019, protocol code 20160817, date of approval 17 April 2017). Informed Consent Statement Informed consent was obtained from all subjects involved in the study. Data Availability Statement The data presented in this study will be submitted to The Cancer Imaging Archive pending acceptance of this manuscript. Conflicts of Interest Mellon is the principal investigator of NCI Academic-Industrial Partnership grant R37CA262510, and as part of this and other work receives research support from ViewRay, Inc. He is also a consultant for ViewRay, Inc and receives travel funding from ViewRay. Mellon receives no personal funds from and holds no interests in ViewRay, Inc. There was no role for ViewRay, Inc. or any other sources outside of the University of Miami, in the collection, analysis, or interpretation of data; writing of data; or decision to publish the results. There are no other conflict of interest. Figure 1 Contoured structures on the MRI scan: RC (red), PTV (green), Brainstem (yellow), right hippocampus (red), left hippocampus (pink), optic nerves (magenta), eyes (magenta), lenses (blue, green), lacrimal glands (blue, green). Figure 2 (A): Flow chart for static plan (60 Gy prescription to the PTV). (B): Flow chart for Adaptive planning (10 Gy prescription to the PTV with a total of 6 different plans and accumulated dose of 60 Gy). W1-W6 stands for Week 1-Week 6 of RT. Figure 3 (A): Resection cavity shrinkage visualized on MRI-Linac: T2-weighted bSSFP treatment set-up scans This shows the PTV and RC volume trending downwards as the weeks progressed. Week 1: Volume of RC is 3.0 mL and mean dose to brain is 3.3 Gy. Week 2: Volume of RC is 1.3 mL and dose to brain is 2.7 Gy. Week 3: Volume of RC is 0.8 mL and dose to brain is 2.7 Gy. Week 4: Volume of RC is 0.6 mL and dose to brain is 2.5 Gy. Week 6: Volume of RC is 0.5 mL and dose to brain is 2.5 Gy. (B): Example adaptive replanning comparing the dose distribution for the first week of treatment (left) and the dose distribution for the sixth week (right). Isodose lines are shown in color surrounding the PTV (area shaded in blue). Both left and right hippocampi are contoured, shown in pink (left) and red (right). During the first week of treatment, the 4 Gy isodose line (light blue) completely covers the right hippocampus. Comparing the 4 Gy isodose line between the two scans, at Week 6, this line has reduced radius sparing the right hippocampus from radiation dose. The dose also decreases to healthy tissue surrounding the PTV outside of the hippocampi. Figure 4 Static plan vs. adaptive re-planning (bars represent standard deviation). * Indicates statistical significance between the static and adaptive plans. cancers-15-01555-t001_Table 1 Table 1 Static vs. adaptive plans for all patients. Mean and maximum (max) dose to hippocampus and brain. All numbers shown are in units of Gy. PATIENT # SUM HIPPOCAMPUS BRAIN UNINVOLVED HIPPOCAMPUS Static Plan Adaptive Plan Static Plan Adaptive Plan mean max mean max mean mean 1 23.8 44.4 11.8 19.9 23.0 18.5 both 2 12.2 16.8 8.9 11.2 14.3 9.7 left 3 2.4 3.7 2.0 2.9 13.0 11.2 both 4 11.0 13.7 7.6 12.1 26.4 26.0 left 5 4.6 9.6 3.9 6.9 19.5 17.9 both 6 10.4 17.0 7.2 15.6 19.4 15.9 right 7 22.8 29.2 16.4 21.5 22.7 22.4 both 8 13.1 43.6 9.5 32.4 21.3 19.2 both 9 12.3 16.2 8.7 15.1 14.3 13.7 both 10 12.9 15.9 8.4 14.5 32.5 32.1 right cancers-15-01555-t002_Table 2 Table 2 Statistical data for static and adaptive plans. All numbers shown are in units of Gy. Sum hippocampus refers to the accumulated dose between the left and right hippocampi (involved hippocampi excluded). STATIC PLAN (SP) ADAPTIVE RE-PLANNING STDEV SP STDEV AP p-VALUES Hippocampus mean 12.5 8.4 6.7 3.96 0.003 Hippocampus max 21 15.2 13.7 8.19 0.036 Brain mean 20.6 18.7 6.0 6.81 0.005 Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
Cancers (Basel) Cancers (Basel) cancers Cancers 2072-6694 MDPI 10.3390/cancers15051481 cancers-15-01481 Editorial Special Issue "Cutaneous Lymphomas" Wobser Marion * Goebeler Matthias Department of Dermatology, Venereology and Allergology, University Hospital Wurzburg, 97080 Wurzburg, Germany * Correspondence: [email protected] 26 2 2023 3 2023 15 5 148121 2 2023 22 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). pmcCutaneous lymphomas comprise heterogeneous subtypes of hematological neoplasms that primarily manifest in the skin . A close correlation of histological, immunophenotypical and clinical findings is mandatory in order to attribute the respective lymphoma subtype, especially owing to the fact that clinical prognosis and consequently the appropriate therapeutic regimen vary significantly between different entities. During the last years, tremendous success in delineating the molecular pathogenesis of cutaneous lymphomas has been achieved. Especially with respect to the most common skin lymphomas, i.e., mycosis fungoides and Sezary syndrome, a better comprehension of the cell of origin , its molecular alterations and the interaction with the tumor microenvironment could translate into improved evaluation and development of novel therapeutic concepts . Nevertheless, cutaneous lymphomas are rare tumor entities and, therefore, during the last years relatively few large randomized clinical trials have been conducted. Consecutively, collaborative data compilation within national or international registries as well as the evaluation of real-world data with respect to diagnosis, prognosis and treatment of cutaneous lymphomas are of paramount importance . Taking this background into mind, this Special Issue, entitled "Cutaneous Lymphomas", aimed to addressing all of these multifaceted issues within the field of cutaneous lymphomas. One focus of this Special Issue was to present epidemiological and real-world data on different subtypes of cutaneous lymphomas arising from collaborative national and international projects. Within this context, a comprehensive review and meta-analysis including more than 16,000 cases of different subtypes of cutaneous T-cell lymphomas is presented which describes key epidemiological features from a global perspective . In addition, the article of K. Wojewoda and colleagues summarizes epidemiological, diagnostic and clinical data on patients with mycosis fungoides in a monocentric national setting (Sweden), clearly underlining the importance of stage-adapted treatment as provided by national and international guidelines . Of note, retrospective data from a multicenter chart review compiling entries between 2017-2018 delineated significant variations in treatment choice for relapsed/refractory (R/R) cutaneous T-cell lymphomas in a real-world setting in European countries . In particular, the choice of chemotherapeutic protocols as well as applied combinatory approaches differed widely between the 27 contributing European centres with respect to first-, third-line treatments as well as to R/R conditions. In this retrospective analysis, beyond interferon, retinoids and phototherapy, chemotherapy as a first-line treatment option turned out to be more frequently applied in the clinical routine when compared to previously published data that have delineated extracorporeal photopheresis, bexarotene, phototherapy and methotrexate as the main first-line treatment modalities . Although novel treatment options were uncommonly used according to this retrospective chart review (that considered data collected between 2017 and 2018) , the authors conclude that a wider application of novel targeted therapies such as brentuximab vedotin and mogamulizumab might alter treatment patterns and outcomes in the future. Another focus of the Special Issue was to present novel insights into the molecular pathogenesis of different subtypes of cutaneous lymphomas. While previous investigations have delineated key molecular alterations as well as distinct immunophenotypes of the different cutaneous B-cell lymphomas subtypes, namely cutaneous marginal zone lymphoma and cutaneous diffuse large B-cell lymphoma , up to now there had only limited data been available that addressed the molecular pathogenesis of cutaneous follicular B-cell lymphoma . The article contributed by our research group adds additional deep sequencing data to close this gap in elucidating the mutational landscape of cutaneous follicular B-cell lymphoma. Genetic alterations within 15 of the selected target genes were identified, with prevailing somatic mutations present in TNFRSF14, CREBBP, STAT6 and TP53 genes. While several of these molecular findings show overlap with genetic alterations in systemic follicular B-cell lymphoma, the presence of any of these mutations was not associated with biological behaviour of cutaneous B-cell lymphoma. Nevertheless, such molecular profiling might serve to facilitate discriminating cutaneous B-cell lymphoma from pseudolymphoma in the future. Owing to the indolent behaviour of cutaneous follicular B-cell lymphoma, skin-directed treatment options are mainstays of care. Taking this into account, intralesional versus intravenous applications of rituximab were retrospectively assessed in a monocentric analysis of indolent cutaneous B-cell lymphomas . Neither treatment response nor relapse rate showed statistically significant differences between either treatment regimen. In addition, potential adverse effects were amenable, indicating that intralesional administration of rituximab might be a feasible therapeutic option for indolent cutaneous B-cell lymphoma of a limited extent. Taking translational aspects into account, two further articles and one comprehensive review add further data on the molecular pathogenesis of cutaneous T-cell lymphomas to this Special Issue. Although large-cell transformation (LCT) of mycosis fungoides has been associated with a higher risk of relapse and progression and, consequently, restricted prognosis , its molecular pathogenesis had not been elucidated yet. Novel data published herein demonstrate that the large-cell transition of mycosis fungoides is associated with a higher frequency of somatic mutations in cancer-associated genes . In particular, the activation of RAS signaling together with epigenetic dysregulation may orchestrate the altered phenotype of LCT and provide the molecular basis for potentially adverse clinical behavior. F. Karagianni et al. evaluated the chick embryo chorioallantoic membrane model (CAM) assay as a preclinical in vivo model for cutaneous T-cell lymphoma that allows for pharmacological testing . Combining the HDAC inhibitor resminostat with the JAK-inhibitor ruxolitinib displayed significant antitumor effects in established cell lines of mycosis fungoides and Sezary syndrome. Taking into account the presence of frequent alterations in JAK/STAT signalling as well as in epigenetic regulation in cutaneous T-cell lymphoma, such a combinatory therapeutic approach might be feasible for further evaluation in the clinical setting. The biological behaviour of cutaneous T-cell lymphomas is not only determined by characteristics of the neoplastic cell itself as exemplarily depicted above but, more-over, also by its close interaction with the tumor microenvironment and by influences imparted by the skin microbiome . To further account for this complexity, this Special Issue includes a review article that gives an overview on the role of the cutaneous microbiome for cutaneous T-cell lymphomas. Defective skin barriers and chronic antigen exposure by microbial components or superantigens have been determined to have a crucial role in stimulating the disease progression of mycosis fungoides and vice versa, indicating that antimicrobial strategies might hence be exploited for the treatment of therapeutic issues . In summary, this Special Issue comprises informative research articles and reviews, written by international experts in the field, which pinpoint key milestones of current research within the field of cutaneous lymphomas. Moreover, open questions and future tasks are comprehensively discussed with the aim of tackling diagnostic and therapeutic challenges in the future. Author Contributions Conceptualization, M.W. and M.G.; writing original draft preparation, M.W.; writing review and editing, M.G. All authors have read and agreed to the published version of the manuscript. 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Foods Foods foods Foods 2304-8158 MDPI 10.3390/foods12051013 foods-12-01013 Editorial Current Research on Antioxidant, Anti-Inflammatory and Anti-Obesity Potential of Food Extracts Rivero-Pino Fernando Writing - original draft Millan-Linares Maria C. Writing - review & editing Montserrat-de la Paz Sergio Writing - review & editing * Department of Medical Biochemistry, Molecular Biology, and Immunology, School of Medicine, Universidad de Sevilla, Av. Sanchez Pizjuan s/n, 41009 Seville, Spain * Correspondence: [email protected]; Tel.: +34-955-421-051 27 2 2023 3 2023 12 5 101317 2 2023 22 2 2023 24 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). This research received no external funding. pmcThe immune-inflammatory, glucose homeostasis, and antioxidant response have a crucial role in the prevention of non-communicable chronic diseases, according to the World Health Organization (WHO). As people live longer in society, the lifestyle of human changes and the prevalence of age-related degenerative diseases and obesity is likewise rising quickly. One of the subfields of nutritional sciences, which covers the study of nutrients and other food ingredients with an emphasis on how they affect mammalian physiology, health, and behaviour, is nutritional biochemistry. Immunonutrition is a new and interdisciplinary field within Nutritional Biochemistry since it encompasses many elements of nutrition, immunity, inflammation, oxidation, and illnesses with an immunometabolic basis. One of the promising ingredients that are currently being assessed by scientists in terms of immunonutrition is food extracts. Food vegetable extracts are produced directly from fruits, vegetables, seeds, or roots of a plant and contain components that can perform a beneficial function in the body when ingested through food (fortified) or as a dietary supplement. These extracts can be used, for instance, as flavourings, natural dyes, stabilizers, or antioxidants. Over the past few decades, a thorough screening of dietary components has been carried out, and a wide spectrum of antioxidant, anti-inflammatory, and anti-obesity actions has been noted. These bioactivities exerted by food extracts could help promote a healthier lifestyle in humans by preventing and/or pre-treating many diseases, from diabetes or cardiovascular diseases to neurological diseases such as Alzheimer's. In this regard, several ingredients have been reported as potential nutraceuticals from a wide variety of extracts, including hemp oil , artichoke by-products , red rice bran , chia , Fabaecea beans , mulberry branches , and cocoa . These results indicate the potential of vegetable sources as health-promoting ingredients that can be used as food for humans. The production and consumption of extracts from vegetable sources satisfy the sustainable development goals (SDGs) established by Agenda 2030, including zero hunger, good health and well-being, responsible consumption and production, and climate action. It is well known that vegetable sources possess an environmentally friendly character, aside from the health benefits that their consumption has on human beings . In addition, the use of by-products can also promote the circular economy, which is the ideal objective that will be used to define the food system in the near future . In this regard, parts of botanicals which at the beginning are not used for any purpose can be revalued by applying processing techniques, releasing, or purifying bioactive compounds, such as alkaloids, flavonoids, and coumarins obtained from branches or chlorogenic acid, naringin, and rutin , among other phenolic compounds, obtained from stems. Each part of the plant has a different composition of bioactive compounds, and the season in which these are collected can have an impact on the profile of bioactive molecules that the extract can have. Different processes can be employed to extract bioactive ingredients, such as enzymatic hydrolysis , which can promote the release of peptides from native proteins using specific proteases that mimic the specificity of digestive proteases or not. Concerning conventional extraction, these include ethanol extraction , methanol extraction , and aqueous extraction . Different solvents lead to the concentration of different components. In addition, some of the reports hereby included also take advantage of pre-treatments that are considered sustainable processing techniques, such as pulsed-electric fields or ultrasound , which have been proved to promote the release of bioactive compounds compared to the direct extraction without pre-treatment and, thus, increasing the added-value of these extracts. These green extraction techniques have emerged to increase the extractability of valuable intracellular compounds from plant cell tissues with shorter extraction times, less energy, and solvent consumption while maintaining the integrity of the major labile extracted bioactive. In the screening of several compounds, and as the first approach in choosing which compounds should be subjected to further analysis, in vitro/characterization studies can be carried out to establish which compound/extract could be more potent. Tungmunnithum et al. indicated that Vigna unguiculata subsp. sesquipedalis populations (n = 50) showed low variability in their total phenolics (628.3 to 717.3 mg/100 g DW gallic acid equivalent), whereas the flavonoid and anthocyanin contents were highly variable (ranging from 786.9 to 1536.1 mg/100 g DW quercetin equivalent, and 13.4 to 41.6 mg/100 g DW cyanidin equivalent). The anti-obesity properties identified by in vitro analysis were reported for the mulberry branch extract, which was indicated to inhibit alpha-glucosidase (half maximal inhibitory concentration (IC50) of 1.90 +- 0.05 mg/mL), acetylcholinesterase and butyrylcholinesterase (IC50 of 179.47 +- 0.38 mg/mL and 101.82 +- 3.37 mg/mL) and to be antioxidant with scavenging DPPH and ABTS radicals. Most of the analysis reported in the published papers in this Special Issue refers to cell-based assays , which help unravel the underlying mechanisms by which specific compounds exert bioactivities. Cell-based assays garner a lot of interest as a better compromise between in vivo investigations and in vitro chemical assays because both in vivo and in vitro assays have limitations. By measuring cytokines, (proinflammatory and anti-inflammatory), usually in macrophages, the beneficial effects on the immune response due to the specific compounds can be described and quantified. Chia (Salvia hispanica L.) seed peptides, which are considered a novel food in Europe, were reported to reduce reactive oxygen species and nitrite output and enhance the expression and release of anti-inflammatory cytokines . Furthermore, the chia peptides reversed LPS-associated M1 polarization into M2, which could be related to a variety of human inflammatory diseases. Animal studies precede human trials and are extremely useful in confirming the potential bioavailability and bioactivity of ingredients. In this Special Issue, in vivo anti-adipogenic, anti-hypertrophic, and anti-inflammatory activities of red rice bran extract were evaluated , highlighting the role of phenolics, flavonoids, anthocyanins, and proanthocyanidins in an obese mouse model. The extract was effective against high-fat diet-induced pathological changes in white adipose tissue via the down-regulation of genes involved in adipogenesis, lipogenesis, lipolysis, and inflammation after the consumption of 1 g/kg/day over 6 weeks . Furthermore, the in vivo antihypertensive properties of cocoa peptides were reported, likely due to the inhibition of the angiotensin-converting enzyme . In the investigation, the consumption of the cocoa extract, consisting of peptides, resulted in a decrease in systolic blood pressure by 5% and diastolic blood pressure by 7%. In addition, recently, the relevance of in silico analysis has gained interest within the research community, and this shows in the evaluation carried out by Coronado-Caceres et al. , who identified 26 cocoa peptides with alignment in the Blast(r) analysis. The identification of specific peptides and the molecular docking analysis revealed that LSPGGAAV, TSVSGAGGPGAGR, and TLGNPAAAGPF could be the most potent sequences of the test item evaluated. Some relevant results are reported in this Special Issue, for the first time, such as (i) the reprogramming and anti-inflammatory activity of phytol (obtained from hemp seeds (Cannabis sativa L.) for non-drug varieties, which are widely used as a source of medicines, foods, or fibres in human monocyte-macrophages ; (ii) the mechanisms by which the red rice bran extract attenuates adipogenesis and inflammation on white adipose tissues in high-fat diet-induced obese mice ; (iii) the application of the PEF-assisted extraction of phenolics from artichoke stems and the subsequent evaluation of the biological effects of these extracts using human cell lines . These reports can be considered cutting-edge research in terms of the extraction, characterization, and evaluation of food extracts since together they report the use of ingredients considered as novel or from residues (not previously evaluated), in addition to the use of novel non-thermal extraction techniques (ultrasound or PEF) and making use of advanced bioactivity evaluation technologies such as cell cultures (of human cells) and animals. The "Farm to Fork" Strategy aims to foster a circular economy; one of its goals is to lessen the agri-food industry's negative environmental effects. It also aims to adopt measures that can boost the capacity of researchers to develop new sustainable food products and to promote access to nutritious food for all. These results, such as vegetable products and/or by-products, are employed to produce health-promoting ingredients that encompass and try to solve both the environmental problem and the development of diseases, which have been increasing in the human population recently due to lifestyle changes. The research papers published in this Special Issue represent the potential of novel bioactive ingredients in the nutraceutical industry, addressing their biochemical, physiological, and molecular processes underlying mechanisms of action by different types of analysis. These reports offer an idea of how different food extracts that can be obtained from vegetable sources are adequate ingredients to be used as an antioxidant, anti-obesity, and/or anti-inflammatory nutraceutical based on their ability to modulate different physiological processes. However, the complexity of these extracts (considering the variety of compounds of different natures that are contained) makes it difficult to draw global conclusions on which compounds are more likely to exert certain bioactivity. For that purpose, some of the following studies also evaluate the potential of single compounds that can be identified as major compounds in the extracts. Nonetheless, further research is required, by all interested parties (academia, industry, consumers, risk assessors), to ensure that these ingredients are feasible for use in the long-term in humans, modulating physiological status and health. Acknowledgments The authors acknowledge the research Grants P20_00661 and US-1381492 (Andalusian Ministry of Economy, Knowledge, Business, and University, Government of Andalusia, Spain) into the European Regional Development Fund Operational Programme 2014 to 2020. The authors acknowledge the research grant TED2021-130521A-I00 from the Spanish Ministry of Science and Innovation. Author Contributions Writing original draft preparation, F.R.-P.; writing review and editing, M.C.M.-L. and S.M.-d.l.P. All authors have read and agreed to the published version of the manuscript. Conflicts of Interest The authors declare no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Claro-Cala C.M. Grao-Cruces E. Toscano R. Millan-Linares M.C. Montserrat-de la Paz S. Martin M.E. Acyclic Diterpene Phytol from Hemp Seed Oil (Cannabis sativa L.) Exerts Anti-Inflammatory Activity on Primary Human Monocytes-Macrophages Foods 2022 11 2366 10.3390/foods11152366 35954130 2. Carpentieri S. Augimeri G. Ceramella J. Vivacqua A. Sinicropi M.S. Pataro G. Bonofiglio D. Ferrari G. Antioxidant and Anti-Inflammatory Effects of Extracts from Pulsed Electric Field-Treated Artichoke By-Products in Lipopolysaccharide-Stimulated Human THP-1 Macrophages Foods 2022 11 2250 10.3390/foods11152250 35954020 3. Munkong N. Lonan P. Mueangchang W. Yadyookai N. Kanjoo V. Yoysungnoen B. Red Rice Bran Extract Attenuates Adipogenesis and Inflammation on White Adipose Tissues in High-Fat Diet-Induced Obese Mice Foods 2022 11 1865 10.3390/foods11131865 35804681 4. Villanueva-Lazo A. Montserrat-de la Paz S. Grao-Cruces E. Pedroche J. Toscano R. Millan F. Millan-Linares M.C. Antioxidant and Immunomodulatory Properties of Chia Protein Hydrolysates in Primary Human Monocyte-Macrophage Plasticity Foods 2022 11 623 10.3390/foods11050623 35267256 5. Tungmunnithum D. Drouet S. Lorenzo J.M. Hano C. Characterization of Bioactive Phenolics and Antioxidant Capacity of Edible Bean Extracts of 50 Fabaceae Populations Grown in Thailand Foods 2021 10 3118 10.3390/foods10123118 34945669 6. Xiang W. Xia Z. Xu L. UPLC-MS/MS Profiling, Antioxidant, a-Glucosidase Inhibitory, Cholinesterase Inhibitory, and Cardiovascular Protection Potentials of Jialing 20 (Morus multicaulis Perr.) Mulberry Branch Extract Foods 2021 10 2659 10.3390/foods10112659 34828948 7. Coronado-Caceres L.J. Hernandez-Ledesma B. Mojica L. Quevedo-Corona L. Rabadan-Chavez G. Castillo-Herrera G.A. Lugo Cervantes E. Cocoa (Theobroma cacao L.) Seed-Derived Peptides Reduce Blood Pressure by Interacting with the Catalytic Site of the Angiotensin-Converting Enzyme Foods 2021 10 2340 10.3390/foods10102340 34681387 |
Foods Foods foods Foods 2304-8158 MDPI 10.3390/foods12050976 foods-12-00976 Editorial Toward Exploring and Utilizing the Nutritional and Functional Properties of Cereal Crops Wang Yaqiong 1+ Tu Min 2+ He Guangyuan 1 Li Yin 1* Chang Junli 1* 1 The Genetic Engineering International Cooperation Base of Chinese Ministry of Science and Technology, The Key Laboratory of Molecular Biophysics of Chinese Ministry of Education, College of Life Science and Technology, Huazhong University of Science & Technology, Wuhan 430074, China 2 Hubei Technical Engineering Research Center for Chemical Utilization and Engineering Development of Agricultural and Byproduct Resources, School of Chemical and Environmental Engineering, Wuhan Polytechnic University, Wuhan 430023, China * Correspondence: [email protected] (Y.L.); [email protected] (J.C.) + These authors contributed equally to this work. 25 2 2023 3 2023 12 5 97613 2 2023 22 2 2023 23 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). National Major Projects of China2016ZX08010004-004 National Natural Science Foundation of China31771418 32272126 Natural Science Foundation of Hubei2016CFB549 Fundamental Research Funds for Central Universities, HUST2021XXJS070 3004170157 Wuhan Knowledge Innovation Project2022020801010073 Opening Fund of Key Laboratory of Forage and Endemic Crop Biology, Ministry of EducationFECBOF2021002 Opening Fund of Hubei Key Laboratory of Bioinorganic Chemistry & Materia MedicaBCMM202205 Start-Up Research Funding of Wuhan Polytechnic University2021RZ100 53210052172 Research Project of Wuhan Polytechnic University2023Y24 This research was funded by the National Major Projects of China (2016ZX08010004-004), the National Natural Science Foundation of China (31771418, 32272126), the Natural Science Foundation of Hubei China (2016CFB549), the Fundamental Research Funds for Central Universities, HUST (2021XXJS070, 3004170157) and Wuhan Knowledge Innovation Project (2022020801010073). This work was also supported by the Opening Fund of Key Laboratory of Forage and Endemic Crop Biology, Ministry of Education (FECBOF2021002), the Opening Fund of Hubei Key Laboratory of Bioinorganic Chemistry & Materia Medica (BCMM202205), the Start-Up Research Funding of Wuhan Polytechnic University (2021RZ100, 53210052172) and the Research Project of Wuhan Polytechnic University (2023Y24). pmc1. Introduction Cereal crops are of great importance in the development of human civilization and fall into two groups, major crops and minor crops. Wheat (Triticum aestivum L.), maize (Zea mays L.), and rice (Oryza sativa L.) belong to major cereal crops, as they are the top three most produced cereals in the world. The minor cereals usually include sorghum (Sorghum bicolor L.), rye (Secale cereal L.), oats (Avena sativa L.), foxtail millet (Setaria italica L.) and teff (Eragrostis Tef), as well as many other under-utilized cereals preferentially cultivated in certain countries or regions. Recently, increasing attentions have been drawn to the nutritional and functional properties of not only the major cereals but also those minor crops. Along with economic development, the demands from modern consumers for healthy diets with improved nutritional and functional properties have been greatly expanded. These consumers' demands, in turn, impact on both basic and applied research related to major and minor cereals. Correspondingly, the emerging trend of "eat full" to "eat well" holds the potential to become "mainstream". Cereal grains are composed of three major components, starches, proteins, and lipids, with other minor albeit important ingredients, such as minerals, fibers, vitamins and bioactive compounds. Numerous bioactive compounds (for example, phenolic acids, flavonoids, tannins, carotenoids, and saponins) have been identified and characterized in different cereal seeds, especially those from the minor cereals. Studies have generally established that although the seeds of major cereals are rich in starch and storage proteins, they have less healthy grain ingredients (e.g., fibers, minerals, vitamins and bioactive compounds) compared to seeds from the minor cereals. Therefore, these minor cereals have re-gained the attentions of consumers, breeders and scientists owing to their excellent nutritional properties. Nutritional studies have recognized that increased consumption of healthy grain ingredients through the addition of these minor cereals (pseudocereals as well) into our daily diet has been associated with protection against diseases such as cancer, type II diabetes, obesity, cardiovascular diseases (CVDs) and celiac disease, or anemia. In this background, the present Topic "Nutritional and Functional Properties of Cereal Crops" provides a forum for researchers to communicate their latest findings related to the nutritional and functional properties of cereal. We expect a diverse set of studies covering multi-disciplines, and therefore collaborate with several related journals, including Foods, Antioxidants, Nutrients, Metabolites and Crops. This topic have collected a cohort of diverse, high-quality articles with a relatively low acceptance rate (~26%), falling into two categories: (1) the "upstream" studies related to cereal nutritional and functional properties, for instance to compare the diversity of metabolites between different cereal grains, and to investigate the effects of technological steps on the nutritional compounds in the cereals; (2) the "downstream" studies, such as those evaluating the effects of healthy cereal ingredients on human diseases. This Editorial paper aims to showcase the eight papers (including two reviews and six original research papers) and discuss related perspectives. 2. "Upstream" Studies Related to the Nutritional and Functional Properties of Cereals Tang et al. compared flavonoid and carotenoid metabolites in the seeds of six Poaceae species (i.e., wheat, maize, rice, sorghum, foxtail millet, and broomcorn millet), identified a total of 201 flavonoids and 29 carotenoid metabolites with flavone, anthocyanins, flavanone and polyphenol being the major metabolic differences between the species. Carcea et al. performed comparative studies of the effects of stone milling and roller milling techniques on the nutritional indicators (e.g., phytic acid and trans-fatty acid contents, and starch damage) and revealed that starch damage, but not the other two indicators, was associated with the milling method. With the recent advancements in modern analytical technologies and the recognition of agricultural sustainability, minor cereals (such as millets) or even pseudocereals (for example, amaranth and quinoa) have attracted increasing attentions because they are environmental-friendly and offer a plethora of nutritional benefits. These advantages and the recent exploration and application of the benefits have been reviewed by Balakrishinan et al. . This comprehensive review covers the nutritional significance of these crops, their emerging food applications and a summary of the current clinical trial evidence on the consumption of amaranth, quinoa and millets. As detailed examples for the application of minor crops, Aung et al. explored the application of germinated wheat as a beneficial ingredient of plant-based beverages and evaluate the sensory properties and consumer acceptability. In another example, Zhang et al. demonstrated that the oil extraction method of field muskmelon seeds affects the physiochemical and functional properties of the extracted proteins as well, potentially influencing the applications of those proteins as food ingredients. 3. "Downstream" Studies Related to the Nutritional and Functional Properties of Cereals This topic also collected several studies focused on the influences of cereal ingredients on health benefits. Sorghum is the world's fifth largest cereal crop and in some sorghum varieties polyphenols are rich in the seeds with potential health benefits in the management of obesity and diabetes. Lee et al. employed cell biology approaches and showed that the sorghum bran extracts with high phenolic contents, rather than those low in phenols, repress adipogenesis through repression of ROS production, MAPK signaling, and insulin signaling adipogenesis through repression of ROS production, MAPK signaling, and insulin signaling. These mechanistic insights justify the health benefits and potential use of highly phenolic sorghum varieties. Another meta-analysis also focused on a cereal secondary metabolite, the oat b-glucan. Yu et al. reviewed the randomized controlled trials of oat b-glucan interventions in hypercholesterolemia and concluded that oat b-glucan intake may significantly reduce the level of total cholesterol and low-density lipoprotein-cholesterol, supporting the health benefits of minor cereal-rich diets. In contrast to the focus on secondary metabolism (polyphenols in sorghum), Huang et al. investigated the effects of different types of carbohydrates (i.e., simple, refined and unrefined carbohydrate-rich diets) on plasma metabolites by using a randomized and controlled cross-over trial, discovering that individual variation, but not the carbohydrate type, impacting more on the plasma metabolic profiles . 4. Concluding Remarks Increasing medical trials are uncovering the health benefits of the consumption of minor cereal grains. However, the intra-species diversity of nutritional and functional properties has not been fully discovered in cereal crops. Advancements in multi-omic technologies offer powerful tools to fulfill such purposes, as exemplified by Tang et al. . A combination of advanced techniques from multi-omics, plant science, food science and technology will further our knowledge of the nutritional and functional properties of cereals. Acknowledgments We thank all authors who submitted their work for this Research Topic, the support of professional editorial staff, and the invaluable time and efforts of reviewers in manuscript evaluation. Author Contributions Y.W., M.T., G.H., J.C. and Y.L. drafted and revised this editorial based on this Research Topic's contributions. All authors approved the submitted version. All authors have read and agreed to the published version of the manuscript. Data Availability Statement Data is contained within the article. Conflicts of Interest The authors declare no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Tang J.Y. Li X.K. Zhang Y.K. Yang Y.L. Sun R. Li Y.J. Gao J.H. Han Y.H. Differential Flavonoids and Carotenoids Profiles in Grains of Six Poaceae Crops Foods 2022 11 2068 10.3390/foods11142068 35885312 2. Carcea M. Narducci V. Turfani V. Finotti E. Stone Milling versus Roller Milling in Soft Wheat (Part 2): Influence on Nutritional and Technological Quality of Products Foods 2022 11 339 10.3390/foods11030339 35159489 3. Balakrishnan G. Schneider R.G. The Role of Amaranth, Quinoa, and Millets for the Development of Healthy, Sustainable Food Products-A Concise Review Foods 2022 11 2442 10.3390/foods11162442 36010444 4. Aung T. Kim B.R. Kim M.J. Optimized Roasting Conditions of Germinated Wheat for a Novel Cereal Beverage and Its Sensory Properties Foods 2022 11 481 10.3390/foods11030481 35159631 5. Zhang H.J. Xu R.Z. Yuan Y.S. Zhu X.X. Li W.H. Ge X.Z. Shen H.S. Structural, Physicochemical and Functional Proerties of Protein Extracted from De-Oiled Field Muskmelon (Cucumis melo L. var. agrestis Naud.) Seed Cake Foods 2022 11 1684 10.3390/foods11121684 35741881 6. Lee H.S. Santana A.L. Peterson J. Yucel U. Perumal R. De Leon J. Lee S.H. Smolensky D. Anti-Adipogenic Activity of High-Phenolic Sorghum Brans in Pre-Adipocytes Nutrients 2022 14 1493 10.3390/nu14071493 35406112 7. Yu J.H. Xia J.Y. Yang C. Pan D. Xu D.F. Sun G.J. Xia H. Effects of Oat Beta-Glucan Intake on Lipid Profiles in Hypercholesterolemic Adults: A Systematic Review and Meta-Analysis of Randomized Controlled Trials Nutrients 2022 14 2043 10.3390/nu14102043 35631184 8. Huang N.K. Matthan N.R. Matuszek G. Lichtenstein A.H. Plasma Metabolite Response to Simple, Refined and Unrefined Carbohydrate-Enriched Diets in Older Adults-Randomized Controlled Crossover Trial Metabolites 2022 12 547 10.3390/metabo12060547 35736480 |
Cancers (Basel) Cancers (Basel) cancers Cancers 2072-6694 MDPI 10.3390/cancers15051549 cancers-15-01549 Editorial New Perspectives on Endoscopic Management of Liver and Pancreatic Cancer Lattanzi Barbara 1 Ramai Daryl 2 Galentino Maura 3 Martino Beatrice 3 Facciorusso Antonio 3* 1 Gastroenterology and Emergency Endoscopy Unit, Department of Emergency, Sandro Pertini Hospital of Rome, 00157 Rome, Italy 2 Gastroenterology & Hepatology, University of Utah Health, Salt Lake City, UT 84044, USA 3 Section of Gastroenterology, Department of Medical Sciences, University of Foggia, 71122 Foggia, Italy * Correspondence: [email protected] 01 3 2023 3 2023 15 5 154906 2 2023 13 2 2023 27 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). This research received no external funding. pmcLiver and pancreatic cancers are major health issues which represent a clinical and economic burden worldwide. Hepatocellular carcinoma (HCC) arises from the primary cells of the liver and is the third most common cause of cancer-related death as well as the leading cause of mortality in cirrhotic patients . Cholangiocarcinoma (CCA) is the second most frequent primary liver malignancy and arises from the epithelial cells lining the biliary tree. This cancer exhibits a poor prognosis and resistance to chemotherapeutic agents . Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent neoplastic disease of the pancreas and represents the fourth leading cause of cancer-related mortality . It is projected to become the second leading cause of cancer-related mortality by 2030 . Due to their high incidence rate and aggressive nature, an early diagnosis of these tumors is very important to ensuring improved survival outcomes . Improvements in diagnostic tools and therapeutic strategies have led to consistent progress in the life expectancy of patients affected by these neoplasms. Nevertheless, a considerable proportion of patients present with advanced tumors or metastases which are not suitable for curative treatments. Endoscopy, in particular endoscopic ultrasound (EUS) and endoscopic retrograde cholangio-pancreatography (ERCP), represent valuable tools for the evaluation and diagnosis of pancreatic and several gastrointestinal tumors . Moreover, endoscopy might represent a useful therapeutic option for selected patients . In this Special Issue, we present five original papers which demonstrates the diagnostic and therapeutic uses of endoscopy for liver and pancreatic cancers. Concerning diagnostic tools, liver biopsy (LB) represents the gold standard method for the definitive diagnosis of focal and parenchymal diseases of the liver. Traditionally, LB has been commonly performed using a percutaneous approach (PC-LB) (under CT scan or ultrasonographic guidance) or through a transjugular (TJ) approach. In recent years, endoscopic ultrasound (EUS)-guided liver biopsy has been adopted as a good alternative to PC and TJ approaches . Facciorusso et al. compared PC-LB and EUS-LB methods in terms of diagnostic outcomes including accuracy and safety for both focal and parenchymal liver diseases . Fifty-four patients undergoing endoscopic ultrasound for different primary EUS indications, who also benefited from a liver biopsy, were compared to 62 patients who underwent PC-LB. The results did not show any statistically significant difference in terms of diagnostic adequacy or accuracy, and no differences in severe adverse events were observed in both groups. On the other hand, the total sample length appeared to be greater in the PC-LB group and EUS-LB was associated with a significantly longer procedure time. Thus, the authors concluded that there was no evidence to support the widespread use of EUS-LB except in cases where it is used in conjunction with other endoscopic procedures. Within the biliary tract, differentiating between benign and malignant biliary stenosis (BS) is challenging, and tissue diagnosis plays a crucial role. The paper by Troncone et al. aimed at evaluating the diagnostic yield of EUS-guided fine-needle aspiration (FNA)/ fine-needle biopsy (FNB) plus ERCP with brushing or forceps biopsy in BS . The authors analyzed 47 patients with BS who underwent endoscopic procedures. Patients with BS secondary to pancreatic cancer were excluded to analyze data relating to a more homogeneous population. They concluded that the combination of EUS and ERCP tissue sampling increased diagnostic accuracy in defining the etiology of BS. Moreover, repeating EUS or ERCP-based tissue sampling increased the diagnostic potential of both procedures; thus, reducing the risk of referring non-malignant cases for surgery. Concerning pancreatic tumors, EUS FNA/B represents the most accurate method of diagnosing these lesions; nevertheless, this technique is not without its flaws. In this Special Issue, Togliani and colleagues aimed to identify factors that impaired EUS tissue sampling diagnostic adequacy . In this paper, the authors analyzed the performance of tissue acquisition in 316 EUS-FNA and 91 EUS-FNB patients with a suspicion of having pancreatic neoplasms. A four-level score measuring the degree of adequacy and a score for the grade of fibrosis were applied in this study. The authors found that the adequacy of pancreatic EUS tissue acquisition was directly correlated with the performance of three or more needle passes and the cell block, regardless of the type of needle used. Moreover, sample adequacy was negatively affected by the location of the lesion in the head/uncinate process; this result is probably due to the finding of a higher grade of tissue fibrosis in lesions located in the head/uncinate process . Following the widespread adoption of EUS for pancreatic tissue acquisition in recent decades, prior reports on the risk of seeding after EUS appears to be lower when compared to the percutaneous route . However, concerns on this topic still lingered. Recently, a systematic review and meta-analysis determined that the incidence of pancreatic adenocarcinoma needle-tract seeding was estimated at 0.4%, albeit without an apparent impact on prognosis . However, little is known about the natural history of this disease and its management. In this scenario, Archibugi et al. elaborated through a systematic review case of needle-tract seeding and analyzed their management and outcomes . The authors reported 46 cases in which PDAC seeding on the needle track was deemed extremely likely. Most cases were in the gastric wall. The data shows that this is a rare complication and usually occurs late (median 19 months from EUS-FNA). Furthermore, this phenomenon should be distinguished from "typical" distant disease recurrence, since, when treated more aggressively with repeated surgery, the overall survival seems longer compared to that of patients treated with palliative treatments. Lastly, endoscopy might represent a useful therapeutic instrument in patients affected by locally advanced PDAC. Several ablative therapies have been proposed and tested in clinical practice . However, the lack of definitive evidence for a survival advantage as well as its high costs represents barriers for adoption and requires additional studies. Testoni et al. contributed to this Special Issue with a phase II randomized controlled trial aimed at investigating the efficacy of thermal ablation with the HybridTherm probe under EUS guidance as a complement to chemotherapy versus standard chemotherapy alone, in locally advanced and borderline resectable PDAC . A total of 17 and 20 patients were randomized in combined and chemotherapy-alone arms, respectively. The authors found an improved 6-month progression-free survival rate in the combined arm (chemotherapy + endoscopic thermal ablation). However, the overall survival was similar regardless of the type of treatment and thus not statistically significant. Moreover, the study confirmed the safety of the EUS HybridTherm probe in patients with PDAC. As the study was underpowered, larger randomized trials are needed to investigate the role of EUS-guided localized ablation after induction with chemotherapy. In conclusion, this Special Issue deepens our understanding of various aspects of endoscopic diagnosis and treatment for liver and pancreatic cancers. Since these tumors are characterized by a high incidence rate and aggressiveness, diagnostic tools with high accuracy and adequacy of sampled materials are vital to high quality patient care. Moreover, prompt individualized oncologic treatment with promising endoscopic techniques is a multidisciplinary field that deserves the efforts of endoscopists together with oncologists and surgeons . Conflicts of Interest The authors declare no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. 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(1) Background: EWS fusion genes are associated with Ewing sarcoma and other Ewing family tumors including desmoplastic small round tumor, DSRCT. We utilize a clinical genomics workflow to reveal real-world frequencies of EWS fusion events, cataloging events that are similar, or divergent at the EWS breakpoint. (2) Methods: EWS fusion events from our next-generation sequencing panel (NGS) samples were first sorted by breakpoint or fusion junctions to map out the frequency of breakpoints. Fusion results were illustrated as in-frame fusion peptides involving EWS and a partner gene. (3) Results: From 2471 patient pool samples for fusion analysis at the Cleveland Clinic Molecular Pathology Laboratory, we identified 182 fusion samples evolved with the EWS gene. They are clustered in several breakpoints: chr22:29683123 (65.9%), and chr22:29688595 (2.7%). About 3/4 of Ewing sarcoma and DSRCT tumors have an identical EWS breakpoint motif at Exon 7 (SQQSSSYGQQ-) fused to a specific part of FLI1 (NPSYDSVRRG or-SSLLAYNTSS), ERG (NLPYEPPRRS), FEV (NPVGDGLFKD) or WT1 (SEKPYQCDFK). Our method also worked with Caris transcriptome data, too. Our primary clinical utility is to use this information to identify neoantigens for therapeutic purposes. (4) Conclusions and future perspectives: our method allows interpretation of what peptides result from the in-frame translation of EWS fusion junctions. These sequences, coupled with HLA-peptide binding data, are used to identify potential sequences of cancer-specific immunogenic peptides for Ewing sarcoma or DSRCT patients. This information may also be useful for immune monitoring (e.g., circulating T-cells with fusion-peptide specificity) to detect vaccine candidates, responses, or residual disease. fusion gene analysis cancer-specific sequence EWS-FLI1 EWS-ERG EWS-WT1 mRNA polypeptide breakpoint next generation sequencing (NGS) information and education virtual visit Cleveland Clinic Anderson Sarcoma ResearchT56428 Morden Foundation, Spin for Gin, Little Warriors Foundation, and a Velosano Kids Impact awardThis research was funded by the Cleveland Clinic Anderson Sarcoma Research Fund T56428 with contributions by the Morden Foundation, Spin for Gin, Little Warriors Foundation, and a Velosano Kids Impact award. pmc1. Introduction Ewing sarcoma treatment has become relatively standardized with the vincristine, dexrazoxane + doxorubicin, and cyclophosphamide + mesna cycles alternating with ifosfamide + mesna and etoposide cycles . Dose intensification using higher doses of chemotherapy or consolidation with high-dose chemotherapy and autologous transplant has been performed with no or modest improvement, respectively . Despite apparent immunogenicity in a study of EWS-FLI1 consolidative immunotherapy , Ewing sarcoma vaccines against EWS peptides or mRNA coding for EWS peptides have not become part of standard-of-care or are not in clinical trials yet. Patients with excellent (100%) necrosis have a much better prognosis; Ewing sarcoma patients with pelvic tumors or poor chemotherapy response have a poor prognosis . Similarly, poor necrosis, axial location, relapsed, and/or metastases continue to have poor survival . How the EWS-fusion genes translate into biologic behavior is an active area of research (this issue of Cancers, Ewing Sarcoma: Basic Biology, Clinical Challenges and Future Perspectives, and references ). In our pediatric and medical oncology practice, we see many high-risk and metastatic Ewing sarcoma and DSRCT patients, both in person and also using informational/educational virtual visits. Our pathologists also have extensive experience in diagnosing bone and soft tissue sarcomas, including the use of an in-house sarcoma NGS panel and the use of whole exome RNA sequencing reports from Caris since January 2022. An unmet need exists to not just diagnose Ewing sarcoma and DSRCT using molecular tools but also to learn more about the nature of the EWS fusion genes and potential best targets in the context of HLA in each Ewing sarcoma or DSRCT patient . Collecting real-world information about EWS gene fusions and resulting peptides may be leveraged to help design future immunologic approaches including identifying in a more precise manner (e.g., with HLA binding assays, T-call and B-cell recognition assays) what constructs to include in personalized cancer vaccines. The first step is to understand which cancer-specific peptides (neoantigens) are present in a real-world clinical practice setting and then seek to routinely obtain more information (e.g., HLA type). The HLA type is now routinely available on Caris reports. Then, we can better understand similarities and differences between how patients -may possibly stimulate the most effective T-cell and B-cell responses to EWS neoantigens. Different breakpoints, or "types", in the fusion genes have been identified for some time now, and their prognostic significance has been speculated upon previously . With the routine availability in our clinical practice of NGS and transcriptome sequencing panels (e.g., Caris) as part of sarcoma pathology and molecular reports detailing the presence of fusion genes, we have developed practical tools to investigate whether identical, similar, or very different peptides are made from the EWS-partner fusion genes in Ewing sarcoma and DSRCT in our clinical population. Our team is also interested in immunogenicity analysis of EWS fusion peptides and other cancer-specific peptides (neoantigens) to use as neoantigen targets for new therapies . From this perspective, we share current efforts and data on EWS-FLI1, EWS-ERG, EWS-FEV, and EWS-WT1 gene fusions from our Cleveland Clinic NGS sarcoma panel as well as Caris transcriptome data. Thus, we are at an early stage of using this information to facilitate ongoing analysis and prediction of the immunogenicity of EWS fusion peptides in the context of HLA. This information may help to overcome barriers to effective new immunologic approaches against cancer-specific neoantigens in Ewing sarcoma and DSRCT . 2. Materials and Methods Pathology reports and gene fusions were analyzed using the Cleveland Clinic NGS sarcoma panel from January 2019. Since January 2022, we also have available data from Caris reports for transcriptome analysis. The Cleveland Clinic sarcoma NGS panel is based on anchored multiplex polymerase chain reaction (PCR) enriched for 34 gene targets . The amplicons were subjected to massively parallel sequencing with 151x2 cycle pair-end reads. An informatics pipeline was used for read alignment (GRCh37 as reference genome), fusion identification, and annotation. For in-house NGS or Caris analysis, the sequenced short reads were aligned to the reference genome (hg19 or GRCh37) by either Archer Analysis or Caris transcriptome analysis pipeline. To obtain DNA and peptide sequences around the fusion junction, result alignment bam file (s) were loaded into Integrative Genome Viewer (IGV). Breakpoints were manually examined, and DNA sequences were extracted. This sequence was then translated to a peptide sequence. For ease of comparison, both fusion partner DNA and peptide sequences were represented with a different color to identify the exact point of fusion. Figure 2 shows EWS genomic (hg19) breakpoint distribution. This in-house reporting system was used to display data as the DNA sequence spanning the fusion gene breakpoint and the amino acid sequence of an in-frame peptide spanning the gene fusion breakpoint. For ease of interpretation, the data was displayed to allow "at-a-glance" pattern recognition of identical, similar, or unique EWS-FLI1, EWS-ERG, EWS-FEV, and EWS-WT1 gene fusions through visual examine fusion data via Integrative Genome Viewer . DNA sequences across the gene fusion breakpoint and translational amino acid sequences were compared in Ewing sarcoma and DSRCT patients seen in the clinic and during virtual visits who had provided paraffin blocks of tumor samples for analysis using our in-house NGS and/or Caris analysis. We also had both In-house NGS using Archer and Caris transcriptome using STARfusion data compared in 18 patients [EWS-FLI1 (n = 14), EWS-WT1 (n = 3), and EWS-FEV (n = 1)] This allowed us to demonstrate that the generalization of our methods pertain not only out NGS but other platforms that can help oncologists and others know "at-a-glance" similarities and difference in individual EWS gene fusions. 3. Results From 190 identified fusion samples with the EWS gene, the breakpoints in a genomic location are plotted in Figure 2. Most of the fusions are clustered in several breakpoints including chr22:29683123 (65.9%), chr22:29684775 (9.3%), chr22:29688158 (8.2%), chr22: 29692358 (4.9%), and chr22:29688595 (2.7%), . Additional comparison data using Caris transcriptome was available for EWS-FLI1 (n = 14), EWS-WT1 (n = 3), and EWS-FEV (n = 1). A typical analysis is depicted in Figure 3. The presence of start (green) or stop (red) codons at the bottom of Figure 3 shows out-of-frame sequences compared to read-through regions for the in-frame sequences. Table 1 shows the frequencies and sequence details of the most common 24 amino acid polypeptides that span the EWS breakpoints in EWS-FLI1 fusion. Table 2 details the in-frame sequence of EWS-ERG, and EWS-WT1 fusions. In-frame analysis showed the EWS motif from exon 7 (SQQSSSYGQQ) accounted for over 80% of gene fusions involving EWS-FLI1, EWS-ERG, EWS-FEV, and EWS WT1, while the remaining gene fusions involved other parts of the EWS gene. In a real-world clinical practice (PA), using in-frame analysis of EWS-FLI1 peptides that span the breakpoint showed the EWS breakpoint sequence SQQSSSYGQQ to be the most common in our analysis (Table 1). The most common FLI1 sequence was NPSYDSVRRG. Some samples yielded an aspartate (D) instead of asparagine (N) at the FLI1 fusion point, but on manual inspection, this is related to breakpoint yielding asparagine. Although many EWS-FLI1 gene fusion events are possible, it seems that a limited number occur. Furthermore, the majority have identical breakpoints as identified by in-frame peptide analysis. Using Caris transcriptome data, we confirmed that our method is a general one as depicted in Figure 4. Similarly, for EWS-ERG, EWS-FEV, and EWS-WT1, gene fusion analysis using in-frame peptide sequences, a common EWS sequence in EWS-ERG, EWS-FEV, and EWS-WT1 fusions was also SQQSSSYGQQ (Table 2). Thus, although many EWS-ERG, EWS-FEV, and EWS-WT1 gene fusion events are possible, it appears a few are more frequently associated with the development of Ewing sarcoma and DSRCT, respectively. 4. Discussion EWS fusion genes are critical mutations associated with Ewing sarcoma and DSRCT. How these events translate into the malignant phenotype has and continues to be an area of very active investigation with many downstream effects resulting from the action of the EWS fusion genes . We sought to try to learn whether EWS-FLI1, EWS-ERG, EWS-FEV, and EWS-WT1 gene fusions would result in identical, similar, or very different polypeptides using in-frame analysis. It seems that our method identified identical polypeptides for a particular fusion event (e.g., EWS-FLI1 exon 7-7). As expected, some types of fusions were more common than others (Table 1 and Table 2). In particular, the EWS gene breaks and fuses to a partner in a way to often yields SQQSSSYGQQ fused to a partner sequence for both Ewing sarcoma and DSRCT in 83% of cases. Nevertheless, both Ewing sarcoma and DSRCT can result from a variety of different fusions involving EWS and a partner gene. Thus, a unifying pathway of fusion gene action resulting in protein action (s) may be one of the numerous actions of fusion genes and/or polypeptides leading to the Ewing sarcoma and DSRCT cancer phenotypes (many paths lead to Rome analogy). Since effective epitopes for B cells may be different from T cells as reported by Liu et al. , precise knowledge of sequences that span EWS breakpoints to augment the additional study of best neoantigens will be important for both humoral as well as T-cell responses to neoantigens. Our in-frame analysis could have several important future clinical applications including (1) identification of different sequences and lengths of peptides that span the specific breakpoint to test for patient-specific HLA binding to the cancer-specific peptide (e.g., selection of best neoantigens for personalized cancer vaccines); (2) analysis of T-cell and B-cell immune responses prior to immunization, during therapy, after therapy, and in response to chemotherapy, radiation, cryoablation, or immunologic interventions. These could include immune-stimulatory drugs, reduction in the tumor inhibitory microenvironment (e.g., inflammation reduction, stereotactic body radiotherapy (SBRT), freezing of tumors, and depletion of regulatory t-cells ). This information could also increase the success of priming and boosting the immune system with vaccines composed of fusion peptides mRNA for the unique fusion gene sequence in the context of a particular HLA type and neoantigen binding (personalized mRNA vaccines using precision data). Furthermore, using Caris transcriptome data, we showed that our method has general applicability for others interested in helping physicians, genetic counselors, patients, and caregivers to increase their understanding about cancer-specific sequences resulting from somatic genetic events in Ewing sarcoma and DSRCT in the oncology clinic. Thus, we are in at an early stage in the process of starting to obtain more personal and precise data for better future interventions, the next generation of evidenced based medicine in oncology as recently described by Subbiah . Not only gene fusions, but also frameshift mutations create neoantigens that start with a normal sequence and then transition to an unexpected cancer-specific sequence as part of early or late mutational events in cancer. Thus, our method may have applications not only for gene fusions such as EWS-FLII1, EWS-ERG, EWS-FEV, and but also for other gene fusions which are commonly found in sarcomas and also somatic frameshift mutations. Since the best choice of neoantigens in the context of HLA is vital, the collection of both in-frame fusion peptide data as well as HLA type may someday become a more routine Ewing sarcoma and DSRCT practice as part of tumor and host testing to f additional immunologic interventions in higher-risk, metastatic, and relapsed Ewing sarcoma, DSRCT, and other solid tumor patents (such as fusion-related sarcomas). Since acid decalcification does not allow for DNA analysis, this is one barrier to general applications for bone sarcomas such as Ewing sarcoma. Thus, we are currently in the process of implementing improved methods of tissue fixation (e.g., EDTA) that will facilitate both pathologic and genetic analysis of bone biopsies and resected samples. This should facilitate future studies in not only Ewing sarcoma but also osteosarcoma and analysis of samples from bone metastases, too. 5. Conclusions Our current sarcoma NGS panel as well as Caris transcriptome data was suitable for learning additional basic biology about EWS fusion genes including the exact breakpoint and intergroup similarities and differences involving EWS-FLI1, EWS-ERG, EWS-FEV, and EWS-WT1 in-frame polypeptides predicted by the fusion genes. Furthermore, our method of analysis also has possible future applications including analysis of immunogenicity of fusion peptides and cancer-specific genes such as frameshift mutations, point mutations, insertions, and deletions to yield cancer-specific neoantigens in the context of a patient's HLA type. Although at an early stage, our paradigm of obtaining in-frame information may then facilitate the better design of more personal, precise, and effective data-driven immunologic interventions against Ewing sarcoma and DSRCT and other solid tumors including designing mRNA vaccines using the sequences and peptide size and HLA binding affinities with the highest chances of success . 6. Patents The TC and Cleveland Clinic Foundation has a patent pending for the prediction of cancer-specific neoantigens such as EWS fusion peptides to HLA. Acknowledgments We acknowledge the support of the Cleveland Clinic Sarcoma program and Laboratory Medicine and Pathology Institute, Learner Research Institute, and the Pediatric Institute to learn more about Ewing family tumors. Author Contributions Conceptualization, P.M.A., Z.J.T., R.H. and T.C. methodology, P.M.A., S.E.K. and Z.J.T.; software, Z.J.T.; validation, P.M.A., M.T. and Z.J.T.; analysis P.M.A. and Z.J.T.; investigation, P.M.A. and S.E.K.; resources, R.H. and T.C.; data curation, Z.J.T. and P.M.A.; writing original draft preparation, P.M.A.; writing review and editing, M.T.; visualization, R.H. and T.C.; supervision, R.H.; project administration, P.M.A. and R.H.; funding acquisition, P.M.A. and T.C. All authors have read and agreed to the published version of the manuscript. Informed Consent Statement Patient consent was waived due to no interventions and analysis of existing data. Data Availability Statement Data supporting reported results can be obtained by contacting P.M.A. and Z.J.T. Zheng Jin Tu can provide additional details about in-frame analysis upon request ([email protected]). Conflicts of Interest The authors declare no conflict of interest. Figure 1 Current sarcoma NGS panel at Cleveland Clinic detects many gene fusions (same color) including 14 involving the EWS gene (Purple at 4 o'clock) . Clinical NGS reports detail which exons are involved in a fusion gene such as EWS-FI1, EWS-ERG, and EWS-WT1. Since January 2022 Caris transcriptome reports are also obtained for additional information. Figure 2 EWS fusion genomic (hg19) breakpoint distribution from 190 Fusion samples. Each breakpoints on the genomic location with samples/total are labeled on the EWS gene. The top five locations are further annotated with fusion gene in the box linked with dash line. Figure 3 Determination of breakpoint and in-frame analysis to determine polypeptide sequences corresponding to fusion gene products in a single patient with Ewing sarcoma. (A) EWS gene IGV view against hg19 reference genome; (B) FLI1 gene IGV view against hg19 reference genome; (C) fusion reads IGV view against fusion contig reference. The first translational frame is the in-frame fusion with peptide sequence of SSSYGQQNPSYDSV between EWS and FLI1 gene. Figure 4 Data analysis diagram of how to depict EWS fusion junction breakpoints and corresponding amino acids. Top: flow diagram of how genomic data is depicted for in-house NGS using Archer Analysis or Caris transcriptome with STAR fusion detection. Middle and bottom: two examples of in-frame analysis of Caris transcriptome data to yield fusion peptide data with manual review of breakpoints of both fusion genes. cancers-15-01623-t001_Table 1 Table 1 Frequencies of Common EWS-FLI1 Fusion genes and corresponding polypeptides that span the EWS breakpoint. EWS-FLI1 Breakpoint Fusion Peptide Analysis Number (Per Cent) SQQSSSYGQQ NPSYDSVRRG 19 SQQSSSYGQQ SSLLAYNTTS 12 SQQSSSYGQQ NPYQILGPTS 1 SQQSSSYGQQ RSGQIQLWQF 1 33/40 (83%) Other EWS-FLI1 Fusions Peptides PMDEGPDLDL GSLLAYNTTS 5 GERGGFNKPG GPPLGGAQTI 1 CVEFSSLIDQ PVYPDVLASG 1 7/40 (17%) cancers-15-01623-t002_Table 2 Table 2 EWS-ERG, EWS-FEV, and EWS-WT1 sequences and corresponding fusion polypeptides that span the breakpoints in Ewing sarcoma and DSRCT. Ewing Sarcomas with EWS-ERG Fusions EWS-ERG exon 7-9 (N = 3/6, 50%) SQQSSSYGQQNLPYEPPRRS Ewing sarcomas with EWS-FEV fusions EWS-FEV1 exon 7-2 (2/3; 67%) SQQSSSYGQQNPVGDGLFKD DSRCT with EWS-WT1 fusions EWS-WT1 exon 7-7 (N = 9/12, 75%) SQQSSSYGQQSEKPYQCDFK EWS-WT1 exon 9-7 (N = 3/12 25%) GERGGFNKPGGEKPYQCDFK Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
Diagnostics (Basel) Diagnostics (Basel) diagnostics Diagnostics 2075-4418 MDPI 10.3390/diagnostics13050959 diagnostics-13-00959 Interesting Images Dynamic Ultrasound Examination for Extensor Pollicis Longus Tendon Rupture after Palpation-Guided Corticosteroid Injection Chen Ying-Chun Conceptualization 1 Wu Wei-Ting Writing - original draft 12 Mezian Kamal Validation 3 Ricci Vincenzo Validation 4 Ozcakar Levent Validation Writing - review & editing 5 Chang Ke-Vin Conceptualization Methodology Writing - review & editing Funding acquisition 126* Barile Antonio Academic Editor 1 Department of Physical Medicine and Rehabilitation, College of Medicine, National Taiwan University, Taipei 10048, Taiwan 2 Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, Bei-Hu Branch, Taipei 10845, Taiwan 3 Department of Rehabilitation Medicine, Charles University, First Faculty of Medicine and General University Hospital in Prague, 12800 Prague, Czech Republic 4 Physical and Rehabilitation Medicine Unit, Luigi Sacco University Hospital, ASST Fatebenefratelli-Sacco, 20157 Milan, Italy 5 Department of Physical and Rehabilitation Medicine, Hacettepe University Medical School, Ankara 06100, Turkey 6 Center for Regional Anesthesia and Pain Medicine, Wang-Fang Hospital, Taipei Medical University, Taipei 11600, Taiwan * Correspondence: [email protected] 03 3 2023 3 2023 13 5 95928 1 2023 28 2 2023 01 3 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). This report aimed to present a case of wrist-tendon rupture and to discuss a rare complication after corticosteroid injection. A 67-year-old woman had difficulty extending her left-thumb interphalangeal joint several weeks after a palpation-guided local corticosteroid injection. Passive motions remained intact without sensory abnormalities. Ultrasound examination showed hyperechoic tissues at the site of the extensor pollicis longus (EPL) tendon at the wrist level and an atrophic EPL muscle stump at the forearm level. Dynamic imaging demonstrated no motion in the EPL muscle during passive thumb flexion/extension. The diagnosis of complete EPL rupture, possibly due to inadvertent intratendinous corticosteroid injection, was therefore confirmed. extensor tendon wrist ultrasonography blind intervention Community and Geriatric Medicine Research Center, National Taiwan University Hospital, Bei-Hu Branch, Taipei, TaiwanMinistry of Science and TechnologyMOST 106-2314-B-002-180-MY3 109-2314-B-002-114-MY3 109-2314-B-002-127 Taiwan Society of Ultrasound in MedicineThis study was made possible by (1) research funding from the Community and Geriatric Medicine Research Center, National Taiwan University Hospital, Bei-Hu Branch, Taipei, Taiwan; (2) Ministry of Science and Technology (MOST 106-2314-B-002-180-MY3, 109-2314-B-002-114-MY3, and 109-2314-B-002-127), and (3) the Taiwan Society of Ultrasound in Medicine. pmcThis report aimed to present a case of wrist-tendon rupture and to discuss a rare complication after corticosteroid injection. A 67-year-old female complained of difficulty in extending the left thumb for several months. The medical history comprised radial wrist pain after a contusion injury one year ago, for which corticosteroid injection under palpation guidance had also been performed, with gradual symptom relief. The physical examination revealed loss of the active extension of the left-thumb interphalangeal joint with normal passive motions . Other finger joints were not affected, nor were there any sensory abnormalities over the distal upper extremity. Plain radiographs of the left wrist showed no evidence of fracture or joint dislocation. The ultrasound examination of the left wrist showed hyperechoic tissue between the Lister's tubercle and the extensor digitorum communis tendons where the extensor pollicis longus (EPL) tendon should normally reside . Herewith, the EPL tendon was clearly visualized at the right wrist . The posterior interosseous nerve (PIN) remained bilaterally intact based on dynamic tracking from the level of the supinator tunnel to the dorsal wrist . Moving the transducer more proximally toward the distal forearm, a hyperechoic region was seen at the ulnar aspect of the first extensor compartment, representing the atrophic EPL muscle . On the normal side, the intact EPL muscle could be explicitly recognized . Dynamic ultrasound was applied to trace the left EPL tendon distally to proximally, whereby no excursion was observed for the EPL muscle during passive thumb flexion/extension (Video S2). As a complete rupture of the left EPL tendon was diagnosed/confirmed, the patient was referred for surgical repair. Finger drop can ensue due to neurological and orthopedic causes . In cases with more generalized weakness or sensory signs, neurological causes, such as PIN palsy, cervical radiculopathy or multifocal neuropathy, should be considered . More specifically, PIN palsy may result in the loss of finger and thumb extension, without wrist drop. Four types of PIN palsy have been reported. Among them, (although uncommon) type 4 exclusively involves the branch supplying the EPL, with isolated difficulty in extending the IP joint of the thumb . Orthopedic causes, on the other hand, include rupture, subluxation or entrapment of the finger extensor tendon. The absence of the tenodesis effect, i.e., finger automatic extension during wrist passive flexion, would indicate an abnormality of the tendons instead of nerves . In patients with an isolated loss of thumb extension, the EPL tendon (responsible for the extension of the thumb interphalangeal joint) should be investigated. Static ultrasound examination can serve as a helpful tool for scrutinizing tendon injury, whereas dynamic imaging can be employed to validate motion problems. The most common sonographic finding of tendon rupture is loss of fiber continuity with the formation of a retracted stump. The absence of normal tendon gliding during passive motion further confirms the diagnosis . In chronic cases, the proximal muscle part would become thinned and hyperechoic due to fat infiltration and disuse atrophy. In the case of a ruptured EPL tendon, the tubular-shaped hypoechoic area might be seen, corresponding to fluid, hemorrhage, and scar tissue . In addition, a bulging contoured hypoechoic lesion (also referred to as a pseudo-mass), located between the Lister's tubercle and the carpometacarpal joint, has been reported as being more frequent over the ruptured EPL than other finger tendons . One of the important etiologies of spontaneous EPL tendon rupture is intratendinous corticosteroid injection. Other causes include distal radial fracture, repetitive friction against metal implants, and contusions . Local corticosteroid injection is associated with rupture, not only in the EPL tendon, but also in other locations, such as the rotator cuff, common extensor, patellar, and Achilles tendons . Intratendinous corticosteroid injection in animal models was found to inhibit connective-tissue formation and lead to a reduction of tendon mass and biomechanical integrity . Lu et al. reported 13 patients with tendon rupture after corticosteroid injection on the wrist region. The most common injected site was the radial styloid under the clinical impression of De Quervain's tenosynovitis. The injection times over the same sites ranged from 1 to 4, whereas the periods from the last injection ranged from 3 to 32 weeks. Needless to say, ultrasound is a preferred tool for guiding the needle, in order to avoid unwanted intratendinous corticosteroid injection . Peritendinous or intrabursal corticosteroid injection, even in the highest dose, do not affect the tendon's elasticity when properly performed under ultrasound guidance . Compared to palpation guidance, ultrasound guidance provides fewer local complications, e.g., fat atrophy and depigmentation . Furthermore, . palpation-guided corticosteroid injection has been proven to have better accuracy and clinical outcome in bicipital tendinosis . In short, this case of ours revealed that static/dynamic ultrasound played a vital role in the management of (thumb) tendon disorders. This is true not only for a precise diagnosis or targeting during an intervention, but is therefore also paramount to the indirect avoidance of adverse effects, e.g., an intratendinous injection. Supplementary Materials The following supporting information can be downloaded at: Video S1: Physical examination of bilateral thumb motions. Video S2: Dynamic tracking of EPL tendons and muscles. Click here for additional data file. Author Contributions Conceptualization, Y.-C.C. and K.-V.C.; methodology, K.-V.C.; validation, K.M., V.R. and L.O.; writing original draft preparation, W.-T.W.; writing review and editing, K.-V.C. and L.O.; funding acquisition, K.-V.C. All authors have read and agreed to the published version of the manuscript. Institutional Review Board Statement Not applicable. Informed Consent Statement Patient consent was obtained. Data Availability Statement Data are contained within the main text of the manuscript. Conflicts of Interest The authors declare no conflict of interest. Figure 1 (A) Inability to extend the interphalangeal joint of the left thumb (black arrow), with the normal right side. (B) Normal passive movement of the same joint. Figure 2 Ultrasound imaging (transverse view) and schematic drawing of (A) left and (B) right wrists at the level of Lister's tubercle. Compared to the right side, EPL tendon was absent with hyperechoic fibrofatty tissues (white arrow and pink shade) instead. Asterisks, Lister's tubercle; EPL and red shade, extensor pollicis longus tendon; EDC and blue shade, extensor digitorum communis tendon; EIP and green shade, extensor indicis proprius tendon; arrowheads and yellow shade, posterior interosseous nerve. Figure 3 Ultrasound imaging (transverse view) and schematic drawing of the (A) left and (B) right distal forearm. Compared with the normal side, the left EPL muscle, located at the ulnar aspect of EPB muscle, was hyperechoic and atrophic. APL and orange shade, abductor pollicis longus; ECRB and blue shade, extensor carpi radialis brevis; EPB and brown shade, extensor pollicis brevis; ED and green shade, extensor digitorum communis; EDM and yellow shade, extensor digiti minimi; EI and gray shade, extensor indices; EPL and pink/red shade, extensor pollicis longus. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Wu C.H. Chang K.V. Ozcakar L. Hsiao M.Y. Hung C.Y. Shyu S.G. Wang T.G. Chen W.S. Sonographic tracking of the upper limb peripheral nerves: A pictorial essay and video demonstration Am. J. Phys. Med. Rehabil. 2015 94 740 747 10.1097/PHM.0000000000000344 26135374 2. Varatharaj A. Pinto A. Manning M. Differential diagnosis of finger drop Neurologist 2015 19 128 131 10.1097/NRL.0000000000000021 25970834 3. Kudlac M. Cummings R. Finocchiaro J. Finger Drop: Cervical Radiculopathy, Peripheral Nerve Lesion, or Multifocal Neuropathy? A Case Report JOSPT Cases 2022 2 112 116 4. Horton T. 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Diagnostics (Basel) Diagnostics (Basel) diagnostics Diagnostics 2075-4418 MDPI 10.3390/diagnostics13050871 diagnostics-13-00871 Interesting Images 68Ga-Pentixafor PET/CT May Fail to Detect Recurrent Multiple Myeloma with Extramedullary Disease Pan Qingqing 12 Luo Yaping 12* Cao Xinxin 3 Li Jian 3 Li Fang 12 Vinjamuri Sobhan Academic Editor Pant Vineet Academic Editor 1 Department of Nuclear Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College Hospital, Beijing 100730, China 2 Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Beijing 100730, China 3 Department of Hematology, Chinese Academy of Medical Sciences and Peking Union Medical College Hospital, Beijing 100730, China * Correspondence: [email protected]; Tel.: +86-10-69155513 24 2 2023 3 2023 13 5 87129 1 2023 22 2 2023 23 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). Two patients with a history of multiple myeloma experienced a recurrence of the disease.18F-FDG PET/CT revealed prominent extramedullary disease as well as multi-foci in the bone marrow, both with increased FDG uptake. However, on 68Ga-Pentixafor PET/CT, all the myeloma lesions showed significantly lower tracer uptake in comparison with 18F-FDG PET. This false-negative result of recurrent multiple myeloma with extramedullary disease may be a potential limitation of 68Ga-Pentixafor in assessing multiple myeloma. multiple myeloma extramedullary disease 68Ga-Pentixafor PET/CT National High Level Hospital Clinical Research Funding2022-PUMCH-A-127 2022-PUMCH-B-070 2022-PUMCH-B-071 CAMS Initiative for Innovative MedicineCAMS-I2M 2017-I2M-3-001 Beijing Natural Science Foundation7202160 This work is supported by National High Level Hospital Clinical Research Funding (2022-PUMCH-A-127, 2022-PUMCH-B-070, 2022-PUMCH-B-071), the CAMS Initiative for Innovative Medicine (CAMS-I2M, 2017-I2M-3-001), and the Beijing Natural Science Foundation (7202160). pmcFigure 1 A 64-year-old man with a history of multiple myeloma (MM) for 8 years, recently presented with a parasternal mass and blindness of the right eye. Serum protein electrophoresis and immunofixation electrophoresis showed positivity for the monoclonal protein (16.2 g/L, IgA-l). A biopsy of the parasternal mass confirmed plasmacytoma. Considering the recurrence of MM, 18F-FDG PET/CT was referred. The maximum intensity projection (MIP) of the PET (A) detected multi-foci with intense radioactivity all over the body. The axial fusion images (B,C, bone window) showed most of the FDG-avid foci were located in bone marrow, most prominently in the sternum and pelvis (SUVmax 34.0), accompanied by lytic bone destruction and paramedullary masses. Additionally, the axial fusion images (D,E, soft tissue window) demonstrated extramedullary disease (EMD) with intense FDG uptake in the right kidney and paranasal sinus (SUVmax 22.3), which also involved the right orbit and temporal lobe. Since 68Ga-Pentixafor has been reported to be advantageous over 18F-FDG in assessing MM1,2, he was included in the clinical trial of 68Ga-Pentixafor (NCT03436342). In the MIP (F) and corresponding axial fusion images of 68Ga-Pentixafor PET (G-J), the above hypermetabolic foci showed significantly lower tracer uptake as compared with 18F-FDG PET (bone marrow lesions: SUVmax 16.5; EMD: SUVmax 7.4). Figure 2 A 70-year-old woman with smoldering MM was found to have a solitary plasmacytoma in the frontal bone that was surgically resected one year ago. Recently, she complained of backache and was found with a retroperitoneal mass. Elevation of the monoclonal protein (19.0 g/L) and the presence of IgA-l in serum immunofixation electrophoresis and infiltration of plasma cells (17.5%) in bone marrow aspiration confirmed the recurrence of MM. 18F-FDG PET/CT was then performed. The MIP image (A) showed an FDG-avid mass in the abdomen. The axial fusion images (B,C) showed the mass was located in the retroperitoneum with uneven FDG distribution (B, SUVmax 5.7). Furthermore, several bone marrow lesions with increased FDG uptake and lytic bone destruction were found in the occipital bone, C4 vertebra, and right 8th rib (C, SUVmax 4.1). She was also included in the clinical trial and underwent 68Ga-Pentixafor PET/CT (D, MIP image; E,F, axial fusion images). However, the retroperitoneal mass and the bone marrow lesions did not demonstrate increased uptake of 68Ga-Pentixafor. She then received chemotherapy against MM, and the retroperitoneal mass disappeared after 2 cycles of chemotherapy. 68Ga-Pentixafor, a CXCR4-targeted agent, has recently been introduced in MM . Our recent study demonstrated 68Ga-Pentixafor had a significantly higher sensitivity than 18F-FDG in detecting newly diagnosed MM2. However, 68Ga-Pentixafor was inferior to 18F-FDG in the current two cases of recurrent MM with extensive EMD. CXCR4 is overexpressed in myeloma cells and is responsible for plasma cells' homing to the bone marrow niche . Development of EMD in MM is associated with CXCR4/CXCL12 downregulation through cell adhesion disruption . In line with the current cases, Lapa C. et al.'s study found that some EMDs were exclusively identified by 18F-FDG and were not sensitive to 68Ga-Pentixafor . Thus, the significantly lower uptake than 18F-FDG of recurrent MM with EMD may be a potential limitation of 68Ga-Pentixafor in assessing MM. Author Contributions Conceptualization, Y.L.; investigation, Q.P.; writing original draft preparation, Q.P.; writing review and editing, Y.L.; visualization, X.C., J.L. and F.L.; supervision, X.C., J.L. and F.L.; funding acquisition, Q.P., Y.L. and X.C. All authors have read and agreed to the published version of the manuscript. Institutional Review Board Statement The study was conducted in accordance with the Declaration of Helsinki, and approved by the institutional review board of Peking Union Medical College Hospital (IRB protocol #ZS-1113). Informed Consent Statement Informed consent was obtained from all subjects involved in the study. Written informed consent has been obtained from the patients to publish this paper. Data Availability Statement No new data were created or analyzed in this study. Data sharing is not applicable to this article. Conflicts of Interest The authors declare no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Lapa C. Schreder M. Schirbel A. Samnick S. Kortum K.M. Herrmann K. Kropf S. Einsele H. Buck A.K. Wester H.J. [(68)Ga]Pentixafor-PET/CT for imaging of chemokine receptor CXCR4 expression in multiple myeloma-Comparison to [(18)F]FDG and laboratory values Theranostics 2017 7 205 212 10.7150/thno.16576 28042328 2. Pan Q. Cao X. Luo Y. Li J. Feng J. Li F. Chemokine receptor-4 targeted PET/CT with (68)Ga-Pentixafor in assessment of newly diagnosed multiple myeloma: Comparison to (18)F-FDG PET/CT Eur. J. Nucl. Med. Mol. Imaging 2020 47 537 546 10.1007/s00259-019-04605-z 31776631 3. Philipp-Abbrederis K. Herrmann K. Knop S. Schottelius M. Eiber M. Luckerath K. Pietschmann E. Habringer S. Gerngross C. Franke K. In vivo molecular imaging of chemokine receptor CXCR4 expression in patients with advanced multiple myeloma EMBO Mol. Med. 2015 7 477 487 10.15252/emmm.201404698 25736399 4. Pan Q. Luo Y. Cao X. Ma Y. Li F. Multiple myeloma presenting as a superscan on 68Ga-Pentixafor PET/CT Clin. Nucl. Med. 2018 43 462 463 10.1097/RLU.0000000000002067 29538035 5. Alsayed Y. Ngo H. Runnels J. Leleu X. Singha U.K. Pitsillides C.M. Spencer J.A. Kimlinger T. Ghobrial J.M. Jia X. Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma Blood 2007 109 2708 2717 10.1182/blood-2006-07-035857 17119115 6. Roccaro A.M. Mishima Y. Sacco A. Moschetta M. Tai Y.T. Shi J. Zhang Y. Reagan M.R. Huynh D. Kawano Y. CXCR4 regulates extra-medullary myeloma through epithelial-mesenchymal-transition-like transcriptional activation Cell Rep. 2015 12 622 635 10.1016/j.celrep.2015.06.059 26190113 7. Stessman H.A.F. Mansoor A. Zhan F. Janz S. Linden M.A. Baughn L.B. Van Ness B. Reduced CXCR4 expression is associated with extramedullary disease in a mouse model of myeloma and predicts poor survival in multiple myeloma patients treated with bortezomib Leukemia 2013 27 2075 2077 10.1038/leu.2013.148 23728080 8. Ghobrial I.M. Myeloma as a model for the process of metastasis: Implications for therapy Blood 2012 120 20 30 10.1182/blood-2012-01-379024 22535658 9. Blade J. Fernandez de Larrea C. Rosinol L. Extramedullary disease in multiple myeloma in the era of novel agents Br. J. Haematol. 2015 169 763 765 10.1111/bjh.13384 25825255 |
Diagnostics (Basel) Diagnostics (Basel) diagnostics Diagnostics 2075-4418 MDPI 10.3390/diagnostics13050815 diagnostics-13-00815 Interesting Images Unilateral Orbitopathy Caused by Skull Base Chordoid Meningioma Yang Jia-He 1 Li Meng-Syuan 2 Shen Ming-Jin 3 Lin Yu-Hsuan 1456* Okazawa Hidehiko Academic Editor 1 Department of Otolaryngology, Head and Neck Surgery, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan 2 Department of Ophthalmology, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan 3 Department of Pathology & Laboratory Medicine, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan 4 Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan 5 School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan 6 School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan * Correspondence: [email protected]; Tel.: +886-978-608396; Fax: +886-7-3422121 21 2 2023 3 2023 13 5 81504 2 2023 17 2 2023 19 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). Chordoid meningioma (CM) makes up only 1% of all meningiomas. Most cases of this variant are locally aggressive, have high growth potential, and are likely to recur. Although CMs are known to be invasive, they rarely extend into the retro-orbital space. Herein, we report a case of a central skull base CM in a 78-year-old woman whose only manifestation was unilateral proptosis with impaired vision resulting from the tumor extending into the retro-orbital space through the superior orbital fissure. The diagnosis was confirmed by analysis of specimens collected during endoscopic orbital surgery, which simultaneously relieved the protruding eye and restored the patient's visual acuity by decompressing the oppressed orbit. This rare presentation of CM reminds physicians there may be lesions outside the orbit that can cause unilateral orbitopathy and that endoscopic orbital surgery can be used to confirm its diagnosis as well as treat it. orbit skull base meningioma endoscopy Yen Tjing Ling Medical FoundationCI-111-26 This study was supported by Yen Tjing Ling Medical Foundation (CI-111-26). pmcFigure 1 Pre-treatment fundoscopy and brain magnetic resonance imaging (MRI). (A) The fundus photo of the left eye showed blurring of the disc margin. (B) Axial T1-weighted gadolinium-enhanced MRI showed a vividly enhanced, relatively homogenous skull base lesion extending into the orbit through the superior orbital fissure (yellow arrowheads). (C) The coronal view of the T1-weighted sequence showed the tumor grossly infiltrating the intraconal space and encircling the optic nerve (yellow arrowhead). A 78-year-old woman visited our clinic complaining of progressive blurred vision and proptosis of the left eye that had begun two months prior. She reported no previous trauma or additional neurologic deficits. The best corrected left visual acuity was found to be 20/100. Other ophthalmic findings of the left eye included positive relative afferent pupil defect and impaired color vision. Subsequent fundoscopy showed optic disc edema (A), confirming left optic neuropathy. Her thyroid blood tests were all within normal limits. Magnetic resonance imaging showed an extensive skull base tumor invading the left retrobulbar space through the superior orbital fissure (B,C). We then arranged endoscopic endonasal surgery to confirm the diagnosis and decompress the orbit, bringing about immediate recovery of eye protrusion, visual acuity, and color perception. Histopathology revealed meningothelial cells with a chordoma-like appearance , confirming the diagnosis of chordoid meningioma (CM). Because curative surgical resection has been associated with high comorbidity, the patient opted to receive Gamma knife radiosurgery (GKRS) instead. The patient remained asymptomatic at 14-month after the definite treatment. Orbital tumors typically originate from the orbit itself, but if they come from the adjacent structures, the most common neoplasms that invade the orbit have been found to be meningiomas from the cranial base . Chordoid meningioma is a rare WHO grade II meningioma that commonly occurs sporadically in females in their forties ; however, although uncommon, CM has been linked to Castleman disease . CM biologically behaves with local aggressiveness and destructiveness, high putative growth potential, and a strong propensity for recurrence and malignant transformation . Current evidence demonstrated no significant difference between the typical MR imaging features of CM and other subtypes of meningiomas; both showed hyper-intense signals in the T2-sequence and noticeably homogeneous enhancement after contrast administration. However, one study comparing advanced MRI metrics of eight CMs and 102 WHO grade I-III meningiomas revealed that the apparent diffusion coefficient (ADC) value and normalized ADC ratios of CM were higher than those of other subtypes . A subsequent study additionally found that the proportion of chordoid histology in a whole tumor was positively correlated with its ADC value, suggesting that ADC metrics can be a valuable tool to distinguish CM from different meningioma variants . Once diagnosed, the standard treatment for cranial meningioma was surgical resection . Total tumor resection was one of the most crucial prognostic factors, although the intent may cause significant comorbidity. In contrast, the role of radiotherapy (RT) remains debated, with some clinicians prescribing adjuvant radiotherapy in cases where the tumor cannot be completely resected or has high proliferative potential scored by the Mindbomb E3 ubiquitin protein ligase 1 (MIB-1) labeling index . However, a recent review of 221 surgically-treated CM patients demonstrated that adjuvant radiotherapy was not beneficial for disease control . Future well-designed investigations are warranted to clarify the relevance of radiotherapy, particularly in adjuvant RT, for CM patients at high risk of recurrence. Figure 2 The intraoperative pictures and the histopathological findings. (A) The medial rectus muscle (MR) and inferior rectus muscle (IR) were clearly exposed after removing the lamina papyracea and the periorbita. The 0deg endoscope revealed the tumoral tissues (asterisk) through the intraconal surgical corridor created between the two muscles. (B) The hematoxylin-eosin staining demonstrated syncytial meningothelial cells with eosinophilic cytoplasm arranged in characteristic cords and embedded in a myxoid stroma (original magnification x400). The immunohistochemistry of the tumor cells was diffusely positive for the epithelial membrane antigen (EMA) (C, original magnification x100) and the progesterone receptor (PR) (D, original magnification x100), and focally positive for somatostatin receptor 2A (SSTR2A) (E, original magnification x400). (F) The Mindbomb E3 ubiquitin protein ligase 1 (MIB-1) labeling index of the tumor was 2% (original magnification x200). We employed transnasal endoscopic orbital surgery (EOS) to retrieve tumoral tissues. The EOS was considered safe and effective because it offered similar or improved surgical visualization and manipulation space than the traditional approach . Additionally, its minimally invasive nature reduces external incisions and associated complications, leading to improved postoperative recovery to facilitate subsequent treatment . Another reason for using EOS in this patient was to relieve the compression on the orbit and optic nerve through the established surgical corridor . In conclusion, this study reminds physicians that unilateral orbitopathy can be caused by lesions beyond the orbit, in this case, CM, which is a rare presentation. It also highlights endoscopic orbital surgery as a minimally invasive approach to diagnose and relieve compressive symptoms in this disease entity. However, close and continuous follow-up is mandatory to evaluate the effectiveness of GKRS in controlling the growth of this aggressive variant of meningioma. Author Contributions Conceptualization, J.-H.Y. and Y.-H.L.; methodology, J.-H.Y. and Y.-H.L.; investigation, J.-H.Y.; resources, M.-S.L., M.-J.S. and Y.-H.L.; data curation, J.-H.Y. and Y.-H.L.; writing original draft preparation, J.-H.Y. and Y.-H.L.; writing review and editing, Y.-H.L.; visualization, J.-H.Y. and Y.-H.L. All authors have read and agreed to the published version of the manuscript. Institutional Review Board Statement The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board of Kaohsiung Veterans General Hospital (KSVGH 22-CT12-06). Informed Consent Statement Written informed consent has been obtained from the patient to publish this paper. Data Availability Statement The data presented in this article are available on request from the corresponding author. Conflicts of Interest The authors declare no conflict of interest. Abbreviations MR, medial rectus muscle; IR, inferior rectus muscle; EMA, epithelial membrane antigen; PR, progesterone receptor; SSTR2A, somatostatin receptor 2A; MIB-1, Mindbomb E3 ubiquitin protein ligase 1. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Jorgensen M. Heegaard S. A review of nasal, paranasal, and skull base tumors invading the orbit Surv. Ophthalmol. 2018 63 389 405 10.1016/j.survophthal.2017.07.001 28739401 2. Choy W. Ampie L. Lamano J.B. Kesavabhotla K. Mao Q. Parsa A.T. Bloch O. Predictors of recurrence in the management of chordoid meningioma J. Neurooncol. 2016 126 107 116 10.1007/s11060-015-1940-9 26409888 3. Kepes J.J. Chen W.Y. Connors M.H. Vogel F.S. "Chordoid" meningeal tumors in young individuals with peritumoral lymphoplasmacellular infiltrates causing systemic manifestations of the Castleman syndrome. A report of seven cases Cancer 1988 62 391 406 10.1002/1097-0142(19880715)62:2<391::AID-CNCR2820620226>3.0.CO;2-7 3383139 4. Tahta A. Genc B. Cakir A. Sekerci Z. Chordoid meningioma: Report of 5 cases and review of the literature Br. J. Neurosurg. 2020 37 41 44 10.1080/02688697.2020.1861436 33332220 5. Pond J.B. Morgan T.G. Hatanpaa K.J. Yetkin Z.F. Mickey B.E. Mendelsohn D.B. Chordoid Meningioma: Differentiating a Rare World Health Organization Grade II Tumor from Other Meningioma Histologic Subtypes Using MRI AJNR Am. J. Neuroradiol. 2015 36 1253 1258 10.3174/ajnr.A4309 25882286 6. Baal J.D. Chen W.C. Solomon D.A. Pai J.S. Lucas C.H. Hara J.H. Oberheim Bush N.A. McDermott M.W. Raleigh D.R. Villanueva-Meyer J.E. Preoperative MR Imaging to Differentiate Chordoid Meningiomas from Other Meningioma Histologic Subtypes AJNR Am. J. Neuroradiol. 2019 40 433 439 10.3174/ajnr.A5996 30819773 7. Bleier B.S. Castelnuovo P. Battaglia P. Turri-Zanoni M. Dallan I. Metson R. Sedaghat A.R. Stefko S.T. Gardner P.A. Snyderman C.H. Endoscopic endonasal orbital cavernous hemangioma resection: Global experience in techniques and outcomes Int. Forum. Allergy Rhinol. 2016 6 156 161 10.1002/alr.21645 26623968 8. Berhouma M. Jacquesson T. Abouaf L. Vighetto A. Jouanneau E. Endoscopic endonasal optic nerve and orbital apex decompression for nontraumatic optic neuropathy: Surgical nuances and review of the literature Neurosurg. Focus 2014 37 E19 10.3171/2014.7.FOCUS14303 |
Diagnostics (Basel) Diagnostics (Basel) diagnostics Diagnostics 2075-4418 MDPI 10.3390/diagnostics13051000 diagnostics-13-01000 Communication Rise of the BQ.1.1.37 SARS-CoV-2 Sublineage, Italy Focosi Daniele 1*+ Spezia Pietro Giorgio 2+ Capria Anna-Lisa 2+ Gueli Federico 3 McConnell Scott 4 Novazzi Federica 5 Pistello Mauro 256 Baraniak Anna Academic Editor 1 North-Western Tuscany Blood Bank, Pisa University Hospital, 56124 Pisa, Italy 2 Division of Virology, Pisa University Hospital, 56124 Pisa, Italy 3 Independent Researcher, 2210 Como, Italy 4 Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA 5 Laboratory of Microbiology, ASST Sette Laghi, 21100 Varese, Italy 6 Retrovirus Center and Virology Section, Department of Translational Research, University of Pisa, 56100 Pisa, Italy * Correspondence: [email protected] + These authors contributed equally to this work. 06 3 2023 3 2023 13 5 100007 2 2023 02 3 2023 05 3 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). BQ.1.1 has dominated the Europe and Americas COVID-19 wave across the 2022-2023 winter, and further viral evolution is expected to escape the consolidating immune responses. We report here the emergence of the BQ.1.1.37 variant in Italy, peaking in January 2022 before suffering competition by XBB.1.*. We attempted to correlate the potential fitness of BQ.1.1.37 with a unique two-amino acid insertion within the Spike protein. SARS-CoV-2 COVID-19 BQ.1.1.37 Cerberus Italy bando Ricerca Salute 20182020KSY3KL This work was supported by bando Ricerca Salute 2018 "Tuscany Antiviral Research Network (TUSCAVIR.NET)"; bando PRIN: Progetti di ricerca di rilevante interesse nazionale, Bando 2020, Prot. 2020KSY3KL: "DissectINg the complex network of virus-cell Host interactions controlling virAL replication and inflammatory response to identify novel host-targeted Approaches against severe respiratory virus infections (INHALA)". pmcThe BA.5-derived BQ.1.1 Omicron sublineage has been the eighth SARS-CoV-2 sublineage to achieve global absolute dominance (>50% of all sequences in a given week) during the ongoing COVID-19 pandemic. Its dominance has so far been restricted to Europe and the Americas, with increased circulation facilitating the emergence of descendant sublineages. As of 24 February 2023, 60 BQ.1.1 sublineages have been designated by PANGOLIN , some of them requiring further aliases (CZ, DU, DN, DK, DP, CW, DM, DT). We report here on the emergence of the recently (23 January) designated BQ.1.1.37 , where the defining nucleotide mutation is T1453C (following A17039G (ORF1b:N1191S)), and the most interesting feature is a unique two-amino acid (AE) insertion at the indel hotspot in the fifth loop (N5) of the N-terminal domain (NTD) of the Spike protein (S:Y248D ins_S:247:SAE). On 25 February 2023, we retrieved from GISAID and CoV-Spectrum database the exact same set of 215BQ.1.1.37 sequences. Notably, the query for the GISAID database (Spike_ins248AED + Spike_Y248S) is slightly different from the one for the CoV-Spectrum database (S:Y248D + ins_S:247:SAE), the latter having an average 5-day lag from GISAID. The sequences are available as EPI_SET_230225ku at the link (accessed on 25 February 2023). We generated a phylogenetic tree using Molecular Evolutionary Genetic Analysis (MEGA) software v.1.11.09 (accessed on 25 February 2023)); the Maximum Composite Likelihood method was used to compute evolutionary distances, expressed as the number of base substitutions per site. The isolates that were sequenced in our laboratories were labeled in red and the tree was edited using the interactive Tree of Life (iTOL) tool v.6 (accessed on 25 February 2023)). The first sequence appeared in Lombardy on 15 November 2022. More than half of those sequences (135) were reported from Italy (mostly from Emilia-Romagna, Umbria and Lombardy regions), with the incidence rate reaching 4.8% on 6 February. A total of 67 more sequences were deposited from other European countries (Germany 13, Spain 11, Austria 8, Netherlands 7, Sweden 6, Belgium 5, Ireland 4, France 3, Denmark 3, Portugal 2, Luxembourg 2, Poland 1, Switzerland 1, Czechia 1), and 13 more from other continents. Eventually, because of partial labeling in metadata, we could not document whether some of the cases outside Italy had been locally imported from Italy. Of interest, in the past 4 months BQ.1.1.37 has a current relative growth advantage across Europe of 38% (CI 32-44%) . As of 26 January 2023, CoV-Spectrum collection #24 analysis, maintained by one of the authors , showed that BQ.1.1.37 was the fourth fastest growing sublineage worldwide compared to an S:F486P baseline, but the arrival of the wave led by the much fitter XBB.* lineages moved BQ.1.1.37 to the 25th rank on 25 February 2023; hence, BQ.1.1.37 is likely to be outcompeted soon (e.g., XBB.1.5 having a relative growth advantage of 19% and XBB.1.9 of 39% over BQ.1.1.37). BQ.1.* was dominating Italy as of January 2023 (BQ.1.1 22%, BQ.1.22 13.5%, BQ.1 5.8%). Italy has a sequencing rate much less than 1% of positive samples, making the occurrence of the BQ.1.1.37 peak highly significant. Furthermore, the growth of BQ.1.1.37 partly continued in Italy even after the arrival of the XBB.1.5 . BQ.1.1.* sublineages are already baseline resistant to the RBD-binding monoclonal antibodies (mAb) cilgavimab, tixagevimab, sotrovimab and bebtelovimab. Figure 3 shows that the two-amino acid insertion is unlikely to further disrupt the receptor binding site (RBD) of the Spike protein, but can instead cause immune escape to NTD-directed mAbs according to the classification by Finkelstein et al. , i.e., those that prevent conformational changes necessary for fusion or cause steric interference. For example, Andreano et al. reported that an 11-amino acid insertion between Y248 and L249 emerging after 13 passages in the presence of convalescent serum caused total lack of neutralization . Genome insertions play a relevant role in the evolution of coronaviruses in general , and of SARS-CoV-2 in particular . A 12-nt insert was at the origin of SARS-CoV-2, generating a second furin-cleavage site (FCS). Several lineages contain insertions in their Spike proteins, e.g., A.2.5 and B.1.214.2 variants which both have insertions in the aa~210 insertion hotspot region , VOI Mu (YY144-145TSN, contributing to immune resistance ), VOC Omicron BA.1 (ins214EPE), and several sublineages of Omicron BA.2 such as BA.2.52 (ins_S:247:SGE). Among the BA.2-paraphyletic BA.4/5 lineages, XBB.1.8 has ins_S:186:SGG, and BS.1 has ins_S:212:NGE. Interestingly, five out of the fastest BQ.1.1 sublineages so far have one or two mutations/insertions at 247/248, namely: EH.1 (with S:S247N and S:Y248S, which is now the 14th fastest lineage in the world), BQ.1.1.45 (with S:Y248D, which is now the 21th fastest lineage), EA.1 (with ins_S:247:SKWL, which is the 24th fastest lineage), BQ.1.1.37 (the 25th fastest lineage worldwide) and BQ.1.1.63 (S:Y248H). Another BQ.1.* sublineage, BQ.1.28, harbors a different insertion in the Spike protein, namely ins248RWMD. Remarking on the importance of the residues 247 and 248, in Spring 2022 in India, in the middle of the BA.2.75 and BA.5 wave, only two sublineages were able to compete, notably BA.2.76 (S:Y248N, also causing a notable outbreak in China ) and BA.2.38.1 (S:S247N + S:Y248S). Most insertions cluster in the Spike NTD and at the S1/S2 cleavage site: while many insertion sequences appear to be viral in origin, a subset of insertions show homology to RNA sequences from host transcripts, implying incorporation of short host RNA sequences during viral genome replication . Analysis of homology of Omicron ins214EPE and flanking regions suggests that the template switching event could have involved the genomes of SARS-CoV-2 variants (e.g., B.1.1 strain), other human coronaviruses that infect the same host cells as SARS-CoV-2 (e.g., HCoV-OC43 or HCoV-229E), or a human transcript expressed in a host cell that was infected by the Omicron precursor . Despite the fact that the growth rates of BQ.1.1.37 are likely to be tapered along the XBB.1.* wave, BQ.1.1.37 has represented a clear example of a geographically restricted diversification and of the impact of Spike deletions on growth rates. Figure 1 Relative growth advantage of BQ.1.1.37 in Europe since 1 November 2022 to 25 February 2023, calculated using CoV-Spectrum.org over a S:F486P baseline . The model assumes that the increase or decrease of the proportion of a variant follows a logistic function. It fits a logistic model to the data by optimizing the maximum likelihood to obtain the logistic growth rate in units per day . Figure 2 Comparison of BQ.1.1.37 and XBB.1.5 expansions in Italy. Chart generated using CoV-Spectrum . Figure 3 Localization of the BQ.1.1.37 NTD insertion with respect to a neutralizing antibody specific to the NTD. All three-dimensional molecular representations were generated with PyMOL 2.5.2 (Schrodinger). (A) SARS-CoV-2 S protein is displayed as cartoon representation overlaid on the space-filling surface. RBD, NTD and S2 are colored as black, dark grey and light grey, respectively. The position of the insertion at position S246, and residues C-terminal to that position in the loop are highlighted in yellow and red, respectively. (A, inset) An expanded view of the NTD, rotated 90 degrees about the x-axis is displayed to visualize the loop residues that would be displaced by the insertion in the BQ.1.1.37 S protein variant. (B) The structure of the complex between NTD and nAb 4A8 is displayed as before with the 4A8 Fab structure colored orange. (B, inset) An expanded view of the nAb interaction, rotated 90 degrees about the x-axis is displayed to highlight the probable perturbation of the 4A8 epitope caused by the S246 insertion in NTD. Supplementary Materials The following supporting information can be downloaded at: Click here for additional data file. Author Contributions A.-L.C. performed genome sequencing; P.G.S. performed genome sequences and designed Supplementary Figure S1; S.M. designed Figure 3; D.F. wrote the first draft; F.G. proposed the lineage on GitHub, and performed GISAID searches; F.N. and M.P. revised the manuscript. All authors have read and agreed to the published version of the manuscript. Institutional Review Board Statement Not applicable. Informed Consent Statement Not applicable. Data Availability Statement This manuscript did not generate any dataset. Conflicts of Interest The authors declare no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. PANGO Lineage Notes Available online: (accessed on 25 January 2023) 2. BQ.1.1 + T1453C Sublineage with Insertion at S:247/248 Available online: (accessed on 24 January 2023) 3. Elbe S. Buckland-Merrett G. Data, disease and diplomacy: GISAID's innovative contribution to global health Glob. Chall. 2017 1 33 46 10.1002/gch2.1018 31565258 4. Smith D.J. Lapedes A.S. de Jong J.C. Bestebroer T.M. Rimmelzwaan G.F. Osterhaus A.D. Fouchier R.A. 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Analysis The study applied LDA to the titles and abstracts to classify them into 10 research topics (Table 2). Among the publications, age group (children, adolescents, college students, adults) was the most commonly visited topic in studies on intervention programs for smartphone addiction (n = 90, 30.61%), followed by mental state (well-being, boredom, loneliness, fear of missing out, mental disorders, inattention) (n = 58, 19.73%). The third was usage behavioral problems (dependence, attachment, gaming, social media) (n = 51, 17.35%). The fourth was living conditions (stress, learning, society, sleep, family, bullying) (n = 45, 15.31%). The fifth was physical problems (obesity, bone problems, posture), the sixth was supervision and management system, and the seventh was personality factors (emotional imbalance), each one of which was visited at identical rates (n = 11, 3.74%). The eighth was gender (n = 8, 2.72%); the ninth was work (n = 5, 1.7%); and the tenth was COVID-19 (n = 4, 1.36%). These are recurring research themes in interventions for smartphone addiction. Additionally, most of the studies were related to multiple topics, such as age group and mental state, age group and usage behavioral problems, usage behavioral problems and living conditions, living conditions and physical problems, age group and gender, usage behavioral problems and gender, etc. This demonstrates that smartphone addiction is associated with a range of psychological, physical, and social factors. Understanding the influencing factors of specific subjects and tailoring intervention programs can improve their effectiveness. 3.1.4. Research Subject Analysis The LDA analysis showed that among 104 studies, students (children, adolescents, college students) (n = 59, 56.7%) were the most studied subjects (Table 3) since young people are globally recognized to be subjects with the highest daily usage rate of smartphones . This has prompted scholars to conduct multi-faceted research on young people, focusing on psychological and physical disorders and life stress, as well as their relationships with schools and families, suggesting that social environments and interpersonal relationships both have an impact on their lives . The second group was the general public (n = 34, 32.7%), followed by parents (n = 6, 5.77%), general workers (scholars, farmers, craftsmen, and merchants) (n = 4, 3.85%), and patients with mental disorders (n = 1, 0.96%). 3.1.5. Analysis and Definitions of Intervention Program Classifications This section applies the LDA analysis to the intervention program of each study, classifying 10 types of programs based on 104 studies. Table 4 "Psychological interventions" (n = 48, 26.97%) were the most commonly applied intervention method, indicating that smartphone addiction is associated with psychological factors. People vulnerable to depression, suicidality, and social disconnection may desire a sense of security by using their smartphones . "Social support" interventions (n = 27, 15.17%) show that smartphone addicts need support from peers or the surrounding environment to overcome loneliness and to emerge from a "dark cloud" to ultimately establish good relationships with others and experience a sense of happiness . "Lifestyle interventions" (n = 25, 14.04%) focus on regulating smartphone usage through restricting behaviors, such as limiting the time spent on gaming applications and prohibiting users from becoming "smartphone zombies" . "Technological interventions" (n = 19, 10.67%) aim to create apps to remind smartphone users of their prolonged usage and response software for vehicle drivers who use smartphones, as well as to integrate medical treatments in the intervention of smartphone addiction . "Family interventions" (n = 18, 10.11%) encourage family members to place restrictions on and influence addicts to help them feel cared for, thereby increasing family interactions . "Medical interventions" (n = 14, 7.87%) concentrate on psychological and physical treatments for depression, anxiety, bad posture, and sleep problems . "Educational intervention" programs (n = 12, 6.74%) use counseling sessions to teach children and adolescents to use smartphones correctly and organize psychosocial education courses . "Exercise interventions" (n = 8, 4.49%) allow subjects to focus on exercise and reduce their temptation to use their phones, thus, promoting weight loss and health benefits . "Mindfulness interventions" (n = 5, 2.8%) enhance self-belief, facilitate social adjustment, and reduce the occurrence of smartphone addiction . "Meditation interventions" (n = 2, 1.12%) help exercise the body and mind and reduce smartphone obsession through seated meditation (Table 4). These studies on intervention programs may not only focus on one program but instead test the benefits of a combination of programs, for example, psychological and exercise, technological and medical, and lifestyle and educational with social support. 3.2. Time In this section, "time" refers to the development trajectory of publications in different time periods. As shown in Figure 3, the earliest studies on intervention programs "technological intervention," "social support," and "medical intervention" emerged in 2014, based on analyses and screenings. In 2021, the direction of research on social support intervention shifted toward social anxiety, advocating social networking and relationships to maintain well-being, thereby reducing problematic smartphone use . Studies on "psychological intervention" and "educational intervention" emerged in 2015. In 2015 and 2019, researchers proposed a combination of psychological and exercise interventions to reduce the occurrence of smartphone addiction using weight loss as a goal . Studies on "lifestyle intervention" appeared in 2016, when scholars discussed the association between smartphone addiction intervention and gender differences in sleep quality . In this research domain, "family intervention" and "mindfulness intervention" began receiving attention in 2018. Parental intervention in the use of smartphones among children and adolescents may improve well-being in the parent-child relationship and enable a desirable childhood environment . Similarly, in 2018, studies increasingly showed the impact of a mindfulness intervention on smartphone addiction . "Exercise intervention" was proposed in 2019 and integrated with psychological and family interventions. Additionally, studies in 2020 suggested that exercise can also enhance physical and mental states and offer early intervention for smartphone addiction . Recently, a few academics have proposed "meditation intervention." In 2020, researchers suggested that meditation can be applied to intervene in mental health to reduce smartphone addiction . In particular, a 2021 study suggested that the impact of COVID-19 has led to a substantial rise in smartphone addiction and proposed mediation as a way to help alleviate smartphone addiction and fear of the pandemic . During this period, it is observed that the research on intervention programs increasingly focused on non-medical methods as physical and mental treatments and relaxation activities available in society were innovated each year. 3.3. Space "Space" refers to the international geographical distribution of academic research. China had the highest research volume in terms of articles on smartphone addiction published in international academic journals, followed by South Korea, Taiwan, Spain, the UK, the US, India, Canada, Hong Kong, Iran, Australia, Italy, Saudi Arabia, the Caucasus region, France, the Hebrew region, Lebanon, Tunisia, the Philippines, Switzerland, Nigeria, Germany, Bangladesh, Oman, Sudan, Austria, Palestine, Vienna, Germany, Switzerland, Peru, and Brazil . Information on the spatial distribution showed that stronger attention was placed on the issue in the East Asian region. In addition to Spain, the non-Asian countries mentioned above are mostly English-speaking countries. This is also possibly because the journal database mainly comprises studies published in English. 3.4. Composition In this section, "composition" refers to understanding the structure of professional knowledge in a certain domain through exploring research topics and the types of relationships. Figure 5 illustrates the citation structure relationships among studies and indicates that the research of intervention programs for smartphone addiction is recognized by many academic journals and that they are interconnected in this field. Computers in Human Behavior has the highest number of citations. Similarly, the visualization shows that this journal has the strongest connections and mutual influence with other journals. According to a VOSviewer analysis, the top-three researchers out of the 4935 in the total citations were the US clinical psychologist Jon D. Elhai, the Swiss experimental psychopathologist J. Billieux, and M. Kwon, who is a quantum optics scholar based in Boston . The visualization analysis depicted in Figure 5 shows clusters around lead researchers in the field, indicating that their research has a high degree of association with others. The high concentration of researchers suggests cooperative relationships among multiple authors, as evidenced by the co-citations. After analyzing 41 countries, China was found to have the highest number of citations in research on intervention programs for smartphone addiction, followed by South Korea, Taiwan, the US, the UK, Israel, Australia, Singapore, Spain, and Austria (Table 6). In Figure 7, denser dots and stronger connections indicate higher cooperation. China and South Korea not only showed high research capacity but also had highly influential and cooperative relationships. Finally, a co-occurrence analysis of keywords was performed on the studies on intervention programs for smartphone addiction. According to the VOSviewer results, there were a total of 420 keywords. Smartphone addiction and problematic smartphone use appeared the most, totaling 62 occurrences (Table 7). Figure 8 shows that certain keywords are intimately related to the intervention of smartphone addiction and represent related phenomena in that domain. Recently, researchers have proposed to replace "smartphone addiction" with "problematic smartphone use". Most studies are related to mental health conditions such as depression and anxiety, and social media is also evidently related to smartphone addiction. Young people are the most common research subjects, and a few studies even suggest that an eating addiction among young people is related to smartphone addiction . 4. Discussion and Conclusions This study extracted research studies available on the WoS and applied bibliometric methods to analyze the research trends of the intervention of smartphone addiction over the past eight years. The results support three conclusions. First, intervention programs can be classified into 10 types, namely psychological, social support, lifestyle, technological, family, medical, educational, exercise, mindfulness, and meditation. In particular, meditation is the latest addition, whereas psychological intervention has always been an essential intervention method for smartphone addiction, thereby indicating that addictions are significantly associated with psychological factors. Second, based on the analysis results of 104 studies, the research volume of intervention programs has gradually increased, showing that researchers are becoming increasingly aware of the significance of smartphone addiction intervention. Additionally, during the search and analysis, we found that the number of studies on intervention programs for smartphone addiction, up to August 2022, was even greater than that of the year 2021. Owing to the increase in usage, smartphone addiction will become a more prominent issue and there will be more intervention programs in the future. Third, from a geographical perspective, China and South Korea were found to be the countries with the most research on smartphone addiction intervention. Whether in terms of the number of publications or citations, both countries are the leaders and most influential in this research field. Moreover, the literature review showed that China, Saudi Arabia, and Malaysia were the countries with the highest population of smartphone addicts . China produces the most research on interventions; however, Saudi Arabia and Malaysia, which have the third-highest populations of smartphone addicts, produce very few studies on this domain. Finally, by analyzing the most influential journals publishing articles on smartphone addiction, we identified that the researchers mainly had a human behavior or social science academic background. Additionally, we found that the influence and quality of journals are positively correlated. Studies have not regarded smartphone addiction as a disorder; instead, the phenomenon has generally been defined in terms of individual behaviors and social relationships. Yet, many studies have shown that smartphone addiction is related to physical and mental disorders. The most influential and cited researcher was Jon D. Elhai, a professor of clinical psychology at the University of Toledo. His research focuses on smartphone addiction and psychological issues such as anxiety, depression, and boredom. This study explored the academic field of smartphone addiction intervention methods through data analysis, and the results serve as a significant reference for research in this domain. In addition to clarifying the key scholars, academic journals, and advancements of intervention programs, it provides insights into intervention in smartphone addiction worldwide. In light of this, we propose our recommendations for future research based on the results. First, in the analysis of each study, we found that qualitative and quantitative research methods accounted for the majority; however, the effectiveness of intervention methods requires further discussion. Second, this study conducted bibliometric analyses of research studies on the intervention of smartphone addiction using WoS and VOSviewer. Despite many significant findings, there may be differences in other databases, as each database has its own subset of literature available. Therefore, future studies may utilize other databases to widen the range of exploration. Finally, this study classified and analyzed the trend of research on intervention programs for smartphone addiction, which is an unprecedented attempt. Our analysis found that many studies relied on students as research subjects because of convenience, disregarding smartphone addiction in middle-aged and elderly groups. Hence, future studies may focus on a wider range of subjects to investigate the reasons behind the occurrence of smartphone addiction and expand the scope of research. 5. Research Limitations One limitation of this study is that larger and more complete datasets are not available. As the authors are still in the exploratory stage, only the Web of Science database was retrieved, and because of the diverse nature of this database, it was included in the retrieval of the study. However, since the research articles submitted at the end of 2021 would only be published in full in 2022, they were retrieved on 30 June 2022, to make the data more complete. Moreover, this study only examines the trend of interventions for smartphone addiction research and does not provide additional knowledge. The most accurate answer to the question of whether China is the most researched country is not yet available, although this study's analysis and related research indicate that China is currently the country with the greatest interest in smartphone addiction intervention and the highest rate of addiction. 6. Future Directions and Outlook In any future research, the authors will consider more comprehensive issues and hope to find different intervention options. Furthermore, they hope to improve their own research and consider the innovation and effectiveness of interventions for smartphone addiction. The discussion and analysis of this study may be premature, although if new findings emerge in time, they will be included in follow-up research. In addition, this study's analysis drew on certain current research on interventions for smartphone addiction, and the related topics of intervention studies were also classified; however, the analysis of the relevance of various articles may suffer from some shortcomings, which will be extensively explored in the future. Author Contributions Conceptualization, Y.-Y.W. and W.-H.C.; methodology, Y.-Y.W. and W.-H.C.; software, Y.-Y.W. and W.-H.C.; validation, Y.-Y.W. and W.-H.C.; formal analysis, Y.-Y.W. and W.-H.C.; investigation, Y.-Y.W. and W.-H.C.; resources, Y.-Y.W. and W.-H.C.; data curation, Y.-Y.W. and W.-H.C.; writing original draft preparation, Y.-Y.W. and W.-H.C.; writing review and editing, Y.-Y.W. and W.-H.C.; visualization, Y.-Y.W. and W.-H.C.; supervision, Y.-Y.W. and W.-H.C.; project administration, Y.-Y.W. and W.-H.C.; funding acquisition, Y.-Y.W. and W.-H.C. All authors have read and agreed to the published version of the manuscript. Institutional Review Board Statement Not applicable. Informed Consent Statement Not applicable. Data Availability Statement Not applicable. Conflicts of Interest The authors declare no conflict of interest. Figure 1 Research workflow. Figure 2 Research framework. Figure 3 Emergence of each type of intervention program. Figure 4 Countries/regions engaged in academic research. Figure 5 Citation analysis of source titles cited. Figure 6 Co-citation analysis of cited authors. Figure 7 Bibliographic coupling of countries. Figure 8 Co-occurrence of authors' keywords. ijerph-20-03840-t001_Table 1 Table 1 Descriptive analysis (distribution of the total number of articles by year). Year N Percentage 2014 3 2.9% 2015 2 1.9% 2016 4 3.8% 2017 6 5.8% 2018 13 12.5% 2019 11 10.6% 2020 27 26% 2021 38 36.5% Total 104 100% ijerph-20-03840-t002_Table 2 Table 2 Ten research topics for the LDA analysis. Research Topics N Percentage 1 Age group (children, adolescents, college students, adults) 90 30.61% 2 Mental state (well-being, boredom, loneliness, fear of missing out, mental disorders, inattention) 58 19.73% 3 Usage behavior problems (dependence, attachment, gaming, social media) 51 17.35% 4 Living conditions (stress, learning, society, sleep, family, bullying) 45 15.31% 5 Physical problems (obesity, bone problems, posture) 11 3.74% 6 Supervision and management system 11 3.74% 7 Personality factors (emotional imbalance) 11 3.74% 8 Gender 8 2.72% 9 Work 5 1.70% 10 COVID-19 4 1.36% ijerph-20-03840-t003_Table 3 Table 3 Research subjects. Subject N Percentage Students (children, adolescents, college students) 59 56.7% General public 34 32.7% Parents 6 5.77% General workers (scholars, farmers, craftsmen, merchants) 4 3.85% Patients with mental disorders 1 0.96% ijerph-20-03840-t004_Table 4 Table 4 Intervention programs, definitions, frequencies, and percentages. Intervention Definition N Percentage Psychological intervention Smartphone addiction is related to depression and suicidality and addicts desire a sense of security by using their smartphones 48 26.97% Social support Smartphone addicts require support from peers or the surrounding environment 27 15.17% Lifestyle intervention Restrictions on smartphone usage in daily life 25 14.04% Technological intervention The usage of mobile phones is related to the development of apps 19 10.67% Family intervention Smartphone addicts increase family interactions through restrictions and influence placed upon by family members 18 10.11% Medical intervention Treatment associating smartphone addiction with psychological and physical problems 14 7.87% Educational intervention Smartphone addiction and psychosocial education courses 12 6.74% Exercise intervention Focus on exercise and reduce the temptation to use phones 8 4.49% Mindfulness intervention Enhancing self-belief and facilitating social adjustment 5 2.8% Meditation intervention Smartphone addiction and intervention through meditation 2 1.12% ijerph-20-03840-t005_Table 5 Table 5 Authors and total citations. Ranking Author Total Citations Ranking Author Total Citations 1 J. D. Elhai 80 6 K. Demirci 34 2 J. Billieux 62 7 O. Lopez-Fernandez 28 3 M. Kwon 40 7 D. Kardefelt-Winther 28 4 K. S. Young 36 9 A. J. A. M. van Deursen 27 5 D. J. Kuss 35 10 I. Leung 26 ijerph-20-03840-t006_Table 6 Table 6 Countries and total citations. Ranking Country Total Citations Ranking Country Total Citations 1 China 645 6 Israel 77 2 South Korea 304 7 Australia 71 3 Taiwan 193 8 Singapore 54 4 USA 105 9 Spain 42 5 UK 80 9 Austria 42 ijerph-20-03840-t007_Table 7 Table 7 Occurrence of keywords. Ranking Keyword Occurrence Ranking Keyword Occurrence 1 Smartphone addiction 39 7 Depression 8 2 Problematic smartphone use 23 8 Anxiety 8 3 Smartphone 17 8 Mental health 8 4 Adolescents 16 8 Intervention 8 5 Social media 9 9 College students 7 Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34770 Endocrinology/Diabetes/Metabolism Internal Medicine Oncology Malignant Hypercalcemia Induced by the Ectopic Production of Intact Parathyroid Hormone (PTH) Muacevic Alexander Adler John R Neves Ana 1 Mendona Ins 2 Cunha Marques Jos Alberto 1 Costa Jos 3 Almeida Jorge S 41 1 Internal Medicine, Centro Hospitalar Universitrio de So Joo, Porto, PRT 2 Intensive Care Medicine, Centro Hospitalar Universitrio de So Joo, Porto, PRT 3 Internal Medicine, Hospital Terras do Infante, Lagos, PRT 4 Medicine, Faculdade de Medicina da Universidade do Porto, Porto, PRT Ana Neves [email protected] 8 2 2023 2 2023 15 2 e347708 2 2023 Copyright 2023, Neves et al. 2023 Neves et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Malignant hypercalcemia is a common finding in patients with advanced cancer, involving mechanisms like tumor secretion of parathyroid hormone (PTH)-related protein, osteolytic metastases, and tumor production of calcitriol. Although rare, hypercalcemia induced by ectopic tumoral secretion of PTH can be an additional mechanism. Here we present an 84-year-old male patient who was admitted to the hospital with a non-productive cough, anorexia, and a single episode of small-volume hemoptysis. He was diagnosed with stage T4N3M1c left lung small cell carcinoma, and laboratory tests were remarkable for elevated ionized calcium as well as elevated serum intact PTH. A parathyroid 99mTc sestamibi scan showed no changes, suggesting ectopic production of PTH. Being a rare event, malignant hypercalcemia from intact PTH ectopic production should be considered in these patients. small cell lung cancer intact parathyroid hormone ectopic malignant hyperparathyroidism ectopic pth production malignant hypercalcemia The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Malignant hypercalcemia is relatively common in a wide range of cancers, from solid tumors to malignant hematologic tumors. This event may occur due to mechanisms like the presence of osteolytic metastases with local release of cytokines, tumor production of calcitriol, and tumor secretion of parathyroid hormone-related protein (PTH-rP), which is a humoral factor synthesized and secreted by tumor cells that exert similar biochemical changes as those observed in primary hyperparathyroidism . However, there are some reports of non-parathyroid tumors producing intact parathyroid hormone (PTH) [3-9].Herein, we report a case of hypercalcemia withhyperparathyroidism from ectopic production of intact PTH. Case presentation An 84-year-old male patient was admitted to the hospital with a non-productive cough and anorexia for one month, as well as constipation for three days and a single episode of small-volume hemoptysis. He was hemodynamically stable and had no nausea or vomiting, polyuria, weight loss, night sweats, dyspnea, palpitations, or chest pain. This patient had smoked for six pack-years and had no drinking history. He had no family history of cancer. Prior medical history included heart failure with preserved left ejection fraction, essential arterial hypertension (treated with amlodipine, bisoprolol, and perindopril), dyslipidemia (treated with atorvastatin and ezetimibe), obstructive sleep apnea syndrome (under nocturnal continuous positive airway pressure therapy), and rheumatic polymyalgia (treated with deflazacort). A thoracic and abdominal CT angiography showed a left lung mass on the hilum with invasion of the pulmonary artery and vein as well as the lingula bronchus, with no evidence of active bleeding . Figure 1 Thoracic CT scan showing a pulmonary mass invading the left pulmonary artery and vein Multiple adenopathies were also described on the mediastinum, as well as two hepatic nodules suggesting secondary lesions. There were also lytic lesions in the pelvis, sacrum, and in multiple lumbar and dorsal vertebrae . Figure 2 Thoracic CT scan showing vertebral lytic lesions Laboratory tests were remarkable for an elevated ionized calcium value of 4.02 mEq/L (reference range: 2.26-2.64 mEq/L) and serum phosphorous of 2.7 mg/dL (reference range: 2.7-4.5 mg/dL)without renal failure (Table 1). His electrocardiogram was unremarkable. He received fluid therapy, diuretics, and zoledronic acid, with a subsequent decrease in calcium serum levels. Table 1 Laboratory data Variable Reference Range On admission Hemoglobin (g/dL) 13-18 13.4 Leucocytes (x109/L) 4-11 4.73 Platelets (x109/L) 150-400 127 Alanine aminotransferase (U/L) 10-37 46 Aspartate aminotransferase (U/L) 10-37 21 Gamma-glutamyltransferase (U/L) 10-49 60 Alkaline phosphatase (U/L) 30-120 107 Total bilirubin (mg/dL) <1.20 0.7 Direct bilirubin (mg/dL) <0.4 0.14 Albumin (g/dL) 38-51 35 Sodium (mmol/L) 135-147 137 Potassium (mmol/L) 3.5-5.1 4.2 Ionized Calcium (mmol/L) 2.26-2.64 4.02 Magnesium (mmol/L 1.55-2.05 1.33 Phosphorus (mg/dL) 2.7-4.5 2.7 Urea nitrogen (mg/dL) 10-50 57 Creatinine (mg/dL) 0.67-1.17 0.98 Glucose (mg/dL) 75-110 106 Lactate dehydrogenase (U/L) 135-225 705 Parathyroid hormone (pg/mL) 10-65 117 Vitamin D (ng/mL) >20 24 Urinary calcium /24h (mmol/L) 5-15 9.1 In order to study the etiology of this hypercalcemia, serum PTH measurement was made showing a level of 117pg/mL (reference range: 10-65 pg/mL), suggesting primary hyperparathyroidism. PTH-rP measurement was not available at our laboratory. The 24-hour urinary calcium excretion and serum vitamin D were within the normal range. A parotid standard technetium (99mTc) sestamibi scan showed no changes on the parathyroid glands, suggesting ectopic production of intact PTH as an additional mechanism to hypercalcemia. A lung biopsy was performed, and histology showed a small cell lung cancer with the perinuclear expression of CK8/l8 and strong expression of synaptophysin and thyroid transcription factor 1 (TTF-1). This tumor was classified as stage T4N3M1c (staged by CT scan) . Palliative chemotherapy was initiated withetoposide and carboplatin with progressive lowering of serum ionized calciumlevels. Discussion The ectopic expression of hormones by cancer cells has been recognized as a cause of many paraneoplastic disorders, including Cushing syndrome, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), and hypercalcemia . Malignant hypercalcemia is most frequently associated with the production of PTH-rP. However, some reports show ectopic production of intact PTH by non-parathyroid tumors. These involve small cell carcinoma of the lung , squamous cell carcinoma , ovarian carcinoma , thymoma , neuroectodermal tumor , papillary thyroid carcinoma , bladder carcinoma , rhabdomyosarcoma ,pancreatic cancer , and lymphoma . The mechanism underlying these non-suppressible high serum PTH levels are not clearly known. Suggested mechanisms include calcium-independent PTH secretion, altered calcium set-point that need higher serum calcium to suppress PTH secretion, and decreased PTH clearance . However, concomitant primary hyperparathyroidism should be considered in these situations . In a study of ectopic PTH production in a patient with ovarian carcinoma and hypercalcemia, genomic analysis of tumor DNA suggested the possibility of the existence of DNA amplification and rearrangements uncovering an enhancer sequence or deleting a suppressor sequence to account for high PTH mRNA expression, leading to PTH overexpression . This way, the development of hypercalcemia with high intact serum PTH levels in a patient with malignancy may suggest new changes of the PTH gene or activation of suppressor/enhancement genes in these cells . In our patient, the presence of osteolytic lesions as well as a neoplastic process (through PTH-rP) could explain the hypercalcemia. However, PTH serum levels were elevated, supporting some contribution of intact production of PTH regardless of serum calcium levels. The 24-hour urinary calcium excretion as well as vitamin D levels should be evaluated in these patients. In the present case, vitamin D levels and 24-hour urinary calcium excretion were within normal limits. A parathyroid99mTc sestamibi scan showed no changes, supporting the possibility of ectopic production of intact PTH by the tumor. Fluid therapy, diuretics, and zoledronic acid will only lower the serum calcium temporarily. To treat hypercalcemia due to ectopic production of PTH, its underlying cause should be addressed through the reduction of the tumoral activity such as chemo or radiotherapy, surgery removal, or other directed therapies . For our patient, we decided to start palliative chemotherapy, which had a calcium-lowering effect. Conclusions Hypercalcemia is a common complication of malignancy caused by heterogenous groups of tumor-derived factors that disrupt normal calcium homeostasis. Even if it is a rare finding, intact PTH ectopic production should be suspected in patients with a known malignancy along with elevated serum calcium and PTH without abnormally active parathyroid glands. Prompt therapy should be administered in order to reduce tumoral activity and prevent life-threatening features of hypercalcemia. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 Mechanisms and treatment of hypercalcemia of malignancy Curr Opin Endocrinol Diabetes Obes Clines GA 339 346 18 2011 21897221 2 Hypercalcemia of malignancy: a study of clinical features and relationships among circulating levels of calcium, parathyroid hormone and parathyroid hormone-related peptide J Med Assoc Thail Sriussadaporn S Phoojaroenchanachai M Ploybutr S 663 671 90 2007 3 A thymoma as a cause of true ectopic hyperparathyroidism J Clin Endocrinol Metab Rizzoli R Pache JC Didierjean L Burger A Bonjour JP 912 915 79 1994 8077382 4 Recurrent hypercalcemia due to ectopic production of parathyroid hormone-related protein and intact parathyroid hormone in a single patient with multiple malignancies Endocr Pract Eid W Wheeler TM Sharma MD 125 128 10 2004 15256329 5 Hypercalcemia and ectopic secretion of parathyroid hormone by an ovarian carcinoma with rearrangement of the gene for parathyroid hormone N Engl J Med Nussbaum SR Gaz RD Arnold A 1324 1328 323 1990 2215618 6 Production of parathyroid hormone by a malignant nonparathyroid tumor in a hypercalcemic patient J Clin Endocrinol Metab Strewler GJ Budayr AA Clark OH Nissenson RA 1373 1375 76 1993 7684395 7 Hypercalcemia caused by ectopic production of parathyroid hormone in a patient with papillary adenocarcinoma of the thyroid gland J Clin Endocrinol Metab Iguchi H Miyagi C Tomita K Kawauchi S Nozuka Y Tsuneyoshi M Wakasugi H 2653 2657 83 1998 9709927 8 Ectopic parathyroid hormone syndrome. Occurrence in a case undifferentiated lymphoma with bone marrow involvement Arch Intern Med Goldman JW Becker FO 1290 1291 138 1978 677991 9 Absence of parathyroid hormone messenger RNA in nonparathyroid tumors associated with hypercalcemia N Engl J Med Simpson EL Mundy GR D'Souza SM Ibbotson KJ Bockman R Jacobs JW 325 330 309 1983 6866067 10 The IASLC lung cancer staging project: proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer J Thorac Oncol Goldstraw P Chansky K Crowley J 39 51 11 2016 00017-9 26762738 11 Paraneoplastic syndromes in lung cancer and their management Ann Transl Med Anwar A Jafri F Ashraf S Jafri MA Fanucchi M 359 7 2019 31516905 12 Ectopic production of parathyroid hormone by small cell lung cancer in a patient with hypercalcemia J Clin Endocrinol Metab Yoshimoto K Yamasaki R Sakai H 976 981 68 1989 2541161 13 Ectopic production of intact parathyroid hormone by a squamous cell lung carcinoma in vivo and in vitro J Clin Endocrinol Metab Nielsen PK Rasmussen AK Feldt-Rasmussen U Brandt M Christensen L Olgaard K 3793 3796 81 1996 8855839 14 Parathyroid hormone expression in a patient with metastatic nasopharyngeal rhabdomyosarcoma and hypercalcemia Endocrine Wong K Tsuda S Mukai R Sumida K Arakaki R 83 86 27 2005 16077176 15 Hypercalcemia of malignancy due to ectopic transactivation of the parathyroid hormone gene J Clin Endocrinol Metab VanHouten JN Yu N Rimm D Dotto J Arnold A Wysolmerski JJ Udelsman R 580 583 91 2006 16263810 16 An excess of CYP24A1, lack of CaSR, and a novel lncRNA near the PTH gene characterize an Ectopic PTH-producing tumor J Endocr Soc Uchida K Tanaka Y Ichikawa H 691 711 1 2017 29264523 17 Malignant hypercalcemia Curr Med Chem Basso U Maruzzo M Roma A Camozzi V Luisetto G Lumachi F 3462 3467 18 2011 21756237 18 Tumor hypercalcemia and "ectopic hyperparathyroidism" Medicine (Baltimore) Skrabanek P McPartlin J Powell D 262 282 59 1980 6993843 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34768 Internal Medicine Pathology Oncology The Value of a Negative Pleural Fluid Cytology and Biopsy in Diagnosing Malignant Pulmonary Lesions Muacevic Alexander Adler John R Egbuchiem Henry C 1 Onyechi Nkemputaife P 1 Sakamuri Laxmi P 1 1 Internal Medicine, University Hospitals Geauga Medical Center, Cleveland, USA Henry C. Egbuchiem [email protected] 8 2 2023 2 2023 15 2 e347688 2 2023 Copyright 2023, Egbuchiem et al. 2023 Egbuchiem et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Over 2 million patients developed lung cancer in 2018, and lung malignancy is responsible for an estimated 1.8 million deaths worldwide. Lung cancer diagnosis usually occurs after suspicious symptoms or incidental radiologic findings on chest imaging when the cancer is probably in an advanced stage. Therefore, initial evaluation, diagnosis, staging, and prompt treatment of lung cancer are required to improve pulmonary malignancies' morbidity and mortality rate. Unfortunately, the size of the tumor, the time of imaging, the quality and quantity of pleural fluid, and pleural biopsy all contribute to diagnostic difficulties in evaluating a lung lesion, leaving even the most astute clinician occasionally perplexed. We discuss a case of a female with lung cancer whose diagnosis was challenging because of a negative pleural biopsy, despite initial radiographic imaging suggesting a lung lesion. pleural fluid cytology nodule cytology pleural fluid pleural biopsy lung cancer The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Lung cancer is a leading cause of mortality worldwide . In the US, in 2020, lung cancer was described as the leading cause of cancer-related deaths . It is believed that over 200,000 new lung cancer cases are diagnosed yearly, with approximately over 150,000 deaths occurring annually from pulmonary cancer-related malignancy. More interestingly, despite advances in screening, diagnosis, and treatment, lung cancer's overall five-year survival rate remains low at 18% . Histopathologic tissue testing and radiologic imaging are required to evaluate pulmonary lesions . What happens when there is a discordance in the results of radiologic images and tissue histopathology? We discuss a case of a female who had a positive radiologic image for a lung lesion and a negative pleural biopsy. Case presentation The patient was a 61-year-old, obese, African American female with a past medical history significant for Behet's disease (on daily prednisone), superior vena cava syndrome, chronic obstructive pulmonary disease (on 3 liters home oxygen), unprovoked pulmonary embolism (on apixaban), gastrointestinal bleeding secondary to duodenal arteriovenous malformation, and history of lung nodules with mediastinal lymphadenopathy. She presented to the hospital because of intermittent chest pain and worsening shortness of breath for two days. Vital signs showed a temperature of 98 Fahrenheit, heart rate of 70 beats per minute, blood pressure of 120/85 mmHg, respiratory rate of 20 cycles per minute, and oxygen saturation of 90% on 5 liters via nasal cannula. On physical examination, she appeared to have mild respiratory distress, evidenced by the use of accessory muscles of respiration. She was alert and oriented (x3), with no motor or sensory deficit. Good air entry bilaterally with diffused rhonchi was noted, with no wheezes. She had first and second heart sounds only, with no murmurs or gallops. The rate and rhythm were regular. Soft abdomen, non-tender/distended, and no organomegaly were noted. Extremities showed no cyanosis/clubbing or edema on both lower extremities, and pedal pulses were intact. Her labs on presentation were significant for white blood cells at 20.4, hemoglobin at 6.2, hematocrit at 22.4, and platelets at 305. The metabolic panel was remarkable for elevated alkaline phosphatase at 325, negative coronavirus disease 2019 (COVID-19) test, brain natriuretic peptide at 37, and negative serial troponins. EKG showed normal sinus rhythm with no ST segment changes. CT scan showed no evidence of current embolism, with a stable right upper quadrant lung nodule with slightly increased bilateral hilar lymphadenopathy . There was also the presence of chronic superior vena cava occlusion with increased numbers of chest wall collateral and bony wall edema with some osseous changes. Of note, these changes were similar to her previous CT findings three months ago. Figure 1 Computed tomographic image showing a 14 mm right upper lung nodule and increased bilateral hilar lymphadenopathy. Her social history was significant for tobacco use, with 40 pack years. A positron emission tomography (PET) scan showed multiple foci in the hip. The initial evaluation was for possible acquired pneumonia, and she received antibiotics for several days without any improvement. She then had video-assisted thoracoscopic surgery (VATS) with pleural biopsy to investigate mediastinal lymphadenopathy. The biopsy was negative for malignant cells, and she failed to extubate twice following the procedure and subsequently became dependent on ventilatory support with a tracheostomy. While in the intensive care unit, she developed anasarca that was minimally responsive to diuretics. A duplex ultrasound showed a new left upper extremity and cephalic vein deep venous thrombosis. A diagnosis of sarcoidosis was considered, given the patient's race, history of behavioral changes, bilateral hilar lymphadenopathy, osteolytic bone lesions, and a negative initial pleural biopsy ruling out malignancy. However, extensive rheumatological workup, including anti-nuclear antibodies, rheumatoid factor, creatinine kinase, antineutrophil cytoplasmic antibodies, perinuclear antineutrophil cytoplasmic antibodies, angiotensin-converting enzymes level, and autoantibodies, was unremarkable. Brain MRI showed multiple nonspecific lesions in the calvarium and skull base. Serum and urine electrophoresis both showed unremarkable results. A repeat PET CT scan was nondiagnostic as it showed decreased metabolic activity. Also, a further workup for atypical infections such as tuberculosis (TB), viral, HIV, and fungal was unremarkable. Repeat chest CT showed loculated pleural effusion in the left lung , and a chest tube was subsequently inserted. Pleural fluid analysis showed a transudative pattern, and pleural fluid cytology was negative for malignancy. Figure 2 Computed tomography image showing left-loculated pleural effusion (large arrow) and right-sided pleural effusion (thin arrow). The possibility of lymph node biopsy was discussed and initially deferred, given her risk of bleeding. The patient underwent endobronchial ultrasound (EBUS) with bronchoalveolar lavage (BAL) and left lower paratracheal lymph node 4L biopsy. Rapid on-site evaluation (ROSE) preliminary cytology was suggestive of malignancy. The test showed adenocarcinoma of the lung with thyroid transcription factor 1 (TTF-1), napsin A, and cytokeratin (CK-7) stains positive, supporting a malignancy diagnosis. Discussion There are two significant forms of lung cancer: small-cell lung cancerand non-small cell lung cancer. Non-small cell lung cancer (adenocarcinoma, squamous cell carcinoma, and large cell carcinoma) accounts for 80% of all lung cancers . The definitive diagnosis of lung cancer is tissue histopathology . Studies show that pleural fluid cytology after the first thoracocentesis has 60% sensitivity in diagnosing lung cancer. This value increases to 75% when repeated . Hence, it is not advisable to depend solely on the absence of malignant cells in pleural cytology/biopsy for lung cancer diagnosis. In patients with imaging evidence of lesions suspicious of lung cancer, invasive tests at the location of the lesions are beneficial in staging and establishing a diagnosis . As seen in our case, it is possible to get a negative result of pleural biopsy in patients with pulmonary malignancy. It is speculated that about two-thirds of lung cancers have negative pleural cytological evaluation according to Purandare et al. Their research also showed that sizeable pleural fluid is suggestive of a malignant pulmonary lesion in the absence of a positive cytologic pleural fluid. However, when a pleural fluid cytology test is negative in a suspected case of malignant pleural effusion, there are several options for further investigations, such as image-guided cutting needle biopsy, closed pleural biopsy, medical thoracoscopy, video-assisted thoracic surgery, and thoracotomy . Therefore, a strong index of suspicion is required to help the clinician look for other avenues to ensure that the appropriate diagnosis is reached, irrespective of the distractors present. For example, as seen in our case presentation, we considered other possible etiology for the worsened dyspnea present in our patient. Her gender, race, and radiographic evidence of bilateral lymphadenopathy made us consider sarcoidosis as a top differential diagnosis, which was promptly discarded after further workup. Also, infectious causes like TB, fungal, viral, or atypical bugs as etiology for the dyspnea were entertained, all of which we ruled out upon further evaluation. Even though we did not initially have a histologic diagnosis supporting our suspicion of lung malignancy, we could not find any other possible explanation for the patient's shortness of breath. Also, the approach utilized for obtaining tissue biopsy could be a factor in the test's outcome. For example, most mediastinal and central lesions are best evaluated with bronchoscopy, while more minor and peripheral lesions are best approached with a transthoracic needle for aspiration . In our case presentation, the initial procedure with video-assisted thoracoscopic surgery and pleural biopsy was unremarkable and revealed no evidence of malignancy. However, when we utilized a different approach (endobronchial ultrasound with bronchoalveolar lavash) more suitable for centrally located lesions, it showed evidence of adenocarcinomatous lung malignancy. Conclusions Although pleural fluid cytology/biopsy remains present in various algorithms utilized in diagnosing a lung malignancy, its low sensitivity and the preponderance of false negative results should make clinicians apprehensive. Therefore, in patients with a suspicious lung lesion and a negative pleural biopsy, further evaluation is promptly required to avoid missing or delaying the diagnosis of pulmonary malignancy. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 Lung cancer Lancet Thai AA Solomon BJ Sequist LV Gainor JF Heist RS 535 554 398 2021 34273294 2 Centers for Disease Control and Prevention. An update on cancer deaths in the United States Control and Prevention, Division of Cancer Prevention and Control 2022 3 Cancer statistics, 2018 CA Cancer J Clin Siegel RL Miller KD Jemal A 7 30 68 2018 29313949 4 Current and future development in lung cancer diagnosis Int J Mol Sci Nooreldeen R Bach H 8661 22 2021 34445366 5 Establishing the diagnosis of lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines Chest Rivera MP Mehta AC Wahidi MM 0 65 143 2013 6 Comparison of needle biopsy with cytologic analysis for the evaluation of pleural effusion: analysis of 414 cases Mayo Clin Proc Prakash UB Reiman HM 158 164 60 1985 3974296 7 Imaging of lung cancer: implications on staging and management Indian J Radiol Imaging Purandare NC Rangarajan V 109 120 25 2015 25969634 8 Closed pleural biopsy is still useful in the evaluation of malignant pleural effusion J Lab Physicians Bhattacharya S Bairagya TD Das A Mandal A Das SK 35 38 4 2012 22923920 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.35920 Cardiology General Surgery Infectious Disease Pacemaker Pocket Infection After Splenectomy Muacevic Alexander Adler John R Barik Ramachandra Sr. 1 Deb Pranjit 1 Kumar Abhinav 1 Mahapatra Rudrapratap 2 1 Cardiology, All India Institute of Medical Sciences, Bhubaneswar, IND 2 Cardiothoracic Surgery, All India Institute of Medical Sciences, Bhubaneswar, IND Pranjit Deb [email protected] 9 3 2023 3 2023 15 3 e359207 3 2023 Copyright 2023, Barik et al. 2023 Barik et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from A post-splenectomy patient suffers from frequent infections due to capsulated bacteria like Streptococcus pneumoniae, Hemophilus influenzae, and Neisseria meningitidis despite vaccination because of a lack of memory B lymphocytes. Pacemaker implantation after splenectomy is less common. Our patient underwent splenectomy for splenic rupture after a road traffic accident. He developed a complete heart block after seven years, during which a dual-chamber pacemaker was implanted. However, he was operated on seven times to treat the complication related to that pacemaker over a period of one year because of various reasons, which have been shared in this case report. The clinical translation of this interesting observation is that, though the pacemaker implantation procedure is a well-established procedure, the procedural outcome is influenced by patient factors like the absence of a spleen, procedural factors like septic measures, and device factors like the reuse of an already-used pacemaker or leads. pneumococcal vaccine reuse of pacemaker abandoned leads pacemaker pocket infection splenectomy The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Pacemaker pocket infection or infective endocarditis due to vegetation over the pacemaker leads has several causes, like patient factors, procedural technique, and the type of pacemaker and its leads. When it occurs, it is associated with high treatment costs, prolonged hospital stays, frequent outpatient visits, morbidity, and in a few cases, may even result in death , which adds to the cost . Asplenia or post-splenectomy status causes significant bloodstream infection by capsulated bacteria due to the absence of memory B cells . Pacemaker pocket infection, especially after splenectomy, is less common. We came across a patient who had undergone a splenectomy for a spleen rupture in a road traffic accident in 2014. This patient underwent dual chamber pacemaker implantation after seven years to treat complete heart failure due to sick sinus syndrome. However, the pacemaker pocket had repeated infections, most probably due to impaired immunity because of its post-splenectomy status. The case report is very interesting because the patient was operated on seven times over a period of one year for a pacemaker pocket infection. Case presentation A 56-year-old man presented with a permanent pacemaker pocket infection in the right pectoral area for a month. The detailed case history with respect to the timeline is mentioned in Table 1. Table 1 Timeline of the case PPI: permanentpacemakerimplantation; DDD: dual chamber pacemaker; SJ Medical: St. Jude Medical; AIIMS: All India Institute of Medical Sciences Time Place/hospital Event/Procedure Additional history 2014 Tata Main Hospital, Jamshedpur Splenectomy for splenic rupture after a road traffic accident. The pneumococcal vaccine was given twice after the splenectomy. 30/12/2021 Brahmananda Narayana Multispeciality Hospital, Jamshedpur PPI (DDD, SJ Medical) from the left pectoral area. Complete heart block. 14/01/2022 Brahmananda Narayana Multispeciality Hospital, Jamshedpur The pacemaker pocket in the left pectoral area developed signs of infection. Organism not known. 23/02/2022 Meditrina Super Speciality Hospitals, Jamshedpur The pacemaker and one pacemaker lead could be explanted, but the pectoral pocket was discharging pus. This may be due to abandoned lead without capping the cut end in the pacemaker pocket. 01/03/2022 Meditrina Super Speciality Hospitals, Jamshedpur PPI on the right pectoral area (DDD, SJ medical). The pacemaker implantation was performed on the right pectoral area to treat the complete heart block even though the pocket on the left pectoral had a chronic infection. 08/07/2022 Meditrina Super Speciality Hospitals. Jamshedpur The second attempt to remove the abandoned lead failed, and the left side pocket continued to discharge pus. The patient was given several oral or injectable antibiotics, empirically. 10/10/2022 AIIMS, Bhubaneswar Right pocket infection reported. The patient was prescribed oral antibiotics empirically as he was not ready for admission during the same visit. 21/01/2023 AIIMS, Bhubaneswar Right side pacemaker explanted with both leads. Leads were screwing type, and straight stylet support was taken to unscrew. 28/01/2023 AIIMS, Bhubaneswar The left side abandoned lead was explanted with pocket debridement with support from the cardiac surgeon. Electric cautery was used for hemostasis. A left antecubital venogram revealed a left subclavian vein occlusion. 02/02/203 AIIMS, Bhubaneswar PPI (DDD, SJ Medical performed) from the right pectoral area near the previous scar. The right subclavian vein was partially occluded. 13/02/2023 AIIMS, Bhubaneswar The patient was discharged successfully. By this time, the patient had been operated on seven times over a period of one year. History revealed that he had a road traffic accident nine years ago when he sustained a splenic rupture, for which an exploratory laparotomy with splenectomy was done. After a period of seven years after the splenectomy, he developed a complete heart block, for which a permanent pacemaker (dual chamber pacemaker (DDD), St. Jude Medical (SJ Medical)) was implanted in the left pectoral fossa on December 31, 2021. On January 14, 2022, a pacemaker pocket infection was diagnosed, for which the pulse generator and atrial lead were explanted, but the ventricular lead could not be explanted, and the pocket was closed. On March 1, 2022, the sterilised left-sided pacemaker with two new leads (DDD and SJ medical) was implanted in the right pectoral region. In view of reinfection and continuous pus discharge from the left-sided pacemaker site, it was re-explored but failed to be extracted. On October 20, 2022, he reported to us with a right-sided pacemaker pocket infection but refused to get admitted on that visit. He was given oral levofloxacin in combination with ampicillin and sulbactam, and it was suggested that he visit again at the earliest possible time for the proper treatment of the pacemaker pocket infection. On January 20, 2023, he was admitted with a frank pus-discharging pacemaker pocket on the right side, a pulse generator protruding from the old skin incision site, and a discharging sinus tract formation on the left-sided wound. At the time of admission, he was fully conscious, cooperative, coherent, and afebrile, with a heart rate of 77 beats per minute. His blood pressure was 132/80 mm Hg, oxygen saturation (SpO2) was 98% in room air, there was no lymphadenopathy, and his left-sided pacemaker pocket was tender, swollen, and erythematous, suggesting cellulitis. His other systemic physical examination was grossly within normal limits except for a midline scar in the abdomen, suggestive of a previous history of splenectomy. A complete hemogram and liver and kidney function tests were grossly within the normal range. A chest x-ray of a normal lung field with the right-side pectoral pocket pacemaker and two leads connected to it and one left pectoral abandoned ventricular lead was taken . Figure 1 Chest x-ray Chest x-ray (posterior-anterior (PA) view) shows an abandoned left-side lead and two leads from the right-sided infected pacemaker pocket. Echocardiography showed good biventricular function and no signs of infective endocarditis. With temporary pacemaker support through the right femoral approach, a right-sided pacemaker, and both the leads and the pocket closed, keeping the drain in situ. On January 28, 2023, while he was on temporary pacemaker support under general anaesthesia, the left-sided pocket was re-explored with the support of a cardiothoracic and vascular (CTVS) surgeon, and abandoned lead extraction and wound debridement were performed. A drain was left in place. We used intravenous tranexamic acid throughout the procedures. His left antecubital venogram showed left subclavian vein occlusion. The pus samples that were sent from both infected wounds were sterile. As the patient requested a DDD pacemaker only and not epicardial pacing, on February 2, 2023, a permanent pacemaker (DDD, SJ Medical) was implanted in the right pre-pectoral area, near the previous scar. After 21 days of hospitalisation, the patient was successfully discharged, giving us a unique experience . The microscopic examination of urine showed plenty of pus cells, and the culture of urine yielded E. coli, which was resistant to most of the routinely used antibiotics except amikacin. Figure 2 Anterior chest wall The anterior chest wall shows two healed pacemaker implantation sites on the right side and one healed pacemaker site on the left side. Discussion Pacemaker pocket infection is defined as the presence of local signs of inflammation at the site of the pacemaker pocket . It may be associated with vegetation over the implanted pacemaker leads and heart valves, pulmonary thromboembolism, and other systemic infections due to bacteremia. By the time a patient goes to another hospital for proper care, the pacemaker is usually out of pocket, as in our case. The rate of pocket infection is significantly higher after reimplantation procedures . Nearly 15% of the patients with pacemaker pocket infections may have systemic infections. Risk factors for pacemaker pocket infection can be divided into three categories: patient-related, procedure-related, and device-related. Some of these are modifiable factors. Identification of modifiable risk factors is important because that may help to take preventive measures to reduce the risk of recurrent infections. Our patient had three apparent risk factors, namely post-splenectomy status, an abandoned pacemaker lead in the left pectoral pocket, and the reuse of a sterilised pacemaker (Table 1). Recurrent infection of the pacemaker pocket, as in our case, has not been reported earlier. It may be due to the repeated use of several empiric antibiotic regimens one after another that our patient did not grow bacteria on a blood or pus culture from the infected pocket, or the organism may be atypical. Our patient received the pneumococcal vaccination twice. In our case, the infection related to the abandoned lead on the left and the reuse of a sterilised pacemaker could have been prevented to reduce recurring infection . Chronic kidney disease, diabetes mellitus, chronic obstructive pulmonary disease, corticosteroid use, a history of previous device infection, malignancy, heart failure, pre-procedural infection in the body, anticoagulant or antiplatelet use, and skin disorders are important patient-related risk factors. The procedure-related factors are lack of proper hand washing, an inadequate infection control programme in the hospital, no standardised sterilisation protocol, pocket hematoma, poor hemostasis due to the lack of all the layers being stitched systematically, early lead repositioning, and inexperienced operators . The device-related factors are few but have a significant impact on the incidence rate of pacemaker pocket infections. The abdominal pocket site, a heavier device, a greater number of leads (including epicardial leads), and the reuse of sterile pacemakers or leads significantly increase pacemaker pocket infection and infective endocarditis, as in our case . Cultures from pocket sites, lead tips, and blood samples may become positive in 60 to 70% of the patients, but these were negative in our case because of repeated use of empirical antibiotics or because the patient had an atypical bacterial infection . As our patient had undergone splenectomy earlier, the multiple blood cultures or pus from both the pacemaker site were sent for aerobic, anaerobic, and fungal cultures, but none had growth of any organism. The reasons for repeated pacemaker infections in our case may be related to the post-splenectomy status, the re-use of an explanted pacemaker, abandoned leads without capping the cut end of them in the pacemaker packet, and the treatment of the patient in multiple centres. However, we feel the post-splenectomy status is the main reason for repeated infections. Even though there is no evidence of encapsulated bacterial growth in the blood or pus culture in our case, the repeated use of antibiotics can be explained. As we notice in everyday practice, all the risk factors except the splenectomy are usual risk factors, and they do not pose great challenges, i.e., seven operations by different experts over a period of one year. Conclusions Multiple factors that can lead to recurrent pacemaker pocket infections are patient-related, device-related, or procedure-related. A recurring pacemaker pocket infection in a post-splenectomy patient has not been reported earlier in this report. The other risk factors for recurrent pacemaker pocket infection in our case are things like abandoned leads on the left side, the reuse of a sterile pacemaker, and referrals for pocket infection to other centres. The latter risk factors usually do not pose great challenges, as in our case, where the patient needed seven surgeries over a period of one year, which makes this pacemaker pocket infection so interesting. The absence of bacterial growth in our case can be explained by the previous pneumococcal vaccination and partial treatment with several regimens of empirical antibiotics. The author is extremely thankful to the cardiology staff, cardiothoracic staff, intensive care unit staff, and anaesthesia team for their continuous and valuable support. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 Incidence, management patterns, and outcomes of cardiovascular implantable electronic device-related retrospective registry-based analysis J Indian Coll Cardiol Goel PK Rajput P Sahu AK 156 12 20221 2 Cardiac implantable electronic device infections: who is at greatest risk? 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Int J Mol Sci Int J Mol Sci ijms International Journal of Molecular Sciences 1422-0067 MDPI 10.3390/ijms24054301 ijms-24-04301 Editorial Aberrations of DNA Repair Pathways in Prostate Cancer The State of the Art Boussios Stergios 1234* Sheriff Matin 5 1 Department of Medical Oncology, Medway NHS Foundation Trust, Windmill Road, Gillingham ME7 5NY, UK 2 Faculty of Life Sciences & Medicine, School of Cancer & Pharmaceutical Sciences, King's College London, London SE1 9RT, UK 3 Kent Medway Medical School, University of Kent, Canterbury CT2 7LX, UK 4 AELIA Organization, 57001 Thessaloniki, Greece 5 Department of Urology, Medway NHS Foundation Trust, Windmill Road, Gillingham ME7 5NY, UK * Correspondence: [email protected] or [email protected] or [email protected] or [email protected] 21 2 2023 3 2023 24 5 430122 1 2023 13 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). This research received no external funding. pmcProstate cancer (PC) is the second most commonly diagnosed cancer in males worldwide and the fifth most common cause of cancer-related death in men . The incidence of metastatic PC has increased as has the incidence of localized PC, which is correlated with a variety of genetic, hereditary and environmental factors, including older age, family history of PC and African ethnicity. This Special Issue focused on but was not only limited to the state of the art in the aberrations of DNA damage repair (DDR) pathways in PC, given that large-scale sequencing efforts have resulted in a better understanding of the genomic landscape of PC. Synthetic lethality represents the therapeutic strategy of the "BRCAness" molecular signature, demonstrating the shared phenotype between sporadic and familial cancers with BRCA1 and BRCA2 mutations . This is based on the evidence that tumors with a deficiency in additional genes implicated in homologous recombination may also respond to treatment in a similar manner as BRCA2-mutated tumors. Proteins involved in homologous recombination repair include CDK12, ATM, FANCD2, RAD51C, CHEK2, PALB2, BRIP1 and HDAC2. Consequently, alterations in DDR genes, particularly in those involved in homologous recombination repair, are predictors of a response to poly (ADP-ribose) polymerase (PARP) inhibition. Whilst carriers of germline mutations in BRCA1 and BRCA2 genes are known to have a lifetime risk of ovarian cancer of 35-60% and 12-25%, respectively, it has more recently been established that germline or somatic aberrations in the DDR genes are present in 19% of cases of primary PC and in approximately 23% of metastatic castration-resistant PC cases . The incidence of germline BRCA1 and BRCA2 gene mutations in newly diagnosed PC is 1.2-2%. BRCA1 and BRCA2 gene carriers can lead to an increase in the risk of developing PC that is around 8-fold, respectively . Within this context apart from breast and ovarian cancer several PARP inhibitors have been investigated in metastatic castration-resistant PC patients . The PARP inhibitors currently approved by the US Food and Drug Administration (FDA) for the treatment of metastatic castration-resistant PC are olaparib, rucaparib and niraparib . Differences exist in their metabolism; olaparib and rucaparib are metabolized by cytochrome P450 enzymes, whilst niraparib is metabolized by carboxylesterase-catalyzed amide hydrolysis. The synthetic lethality mechanism of action may have a protective effect against severe PARP inhibitor toxicity . The treatment of PC has rapidly changed. Namely, androgen receptor (AR) signaling inhibitors downregulate DDR gene expression and increase DNA damage, maximizing the efficacy of PC to PARP inhibitors. Androgen deprivation therapy (ADT) formulates a status of "BRCAness" when PARP and AR signaling are concurrently inhibited. As such, PARP inhibitors may be effective even beyond DDR mutated PC . Furthermore, given that micro-vessel density represents a predictor of metastasis, targeting angiogenesis is an area of ongoing research . The majority of PC cases are diagnosed and treated with localized disease; nevertheless, some patients have metastatic PC, either at presentation or following localized disease . From a therapeutic point of view, those with high-risk non-metastatic PC receive ADT for 3 years, which may be combined with radiotherapy. Recently, it has been reported that abiraterone alone or in combination with enzalutamide with ADT led to significantly higher rates of metastasis-free survival versus ADT alone . There is robust evidence indicating that AR activates the DDR pathways, which provides a rationale for the use of ADT with stereotactic ablative radiotherapy for hormone-sensitive oligometastatic PC . Biomarkers play an important role in the selection of patients that may benefit from a particular type of treatment. Within this context, microRNAs, AR variants, bone metabolism, and neuroendocrine and metabolite biomarkers are promising candidates, which are crucial to identify in the era of the precision medicine . Teng PC et al. demonstrated a rigorous bioinformatic pipeline using publicly available platforms and databases to develop a DDR-based panel that could aid with PC prognostication . The study suggested that a four-gene panel consisting of EXO1, DNTT, NEIL3 and EME2 is a promising DDR-derived biomarker that should be further investigated. Depending on the cellular context, autophagy could play either a detrimental or a protective role in PC survival. There is ongoing research on autophagy modulation in vitro and on whether it may potentially serve as a biomarker. This can open up new therapeutic avenues in PC therapy and may also optimize the prognostic stratification of patients . The somatostatin, cortistatin and somatostatin receptor system is an additional source of prognostic biomarkers and therapeutic targets for the subset of endocrine-related cancers . This system inhibits multiple processes including hormone secretion, as well as cell proliferation, migration and invasion. Saez-Martinez P et al. reported that the treatment with somatostatin and cortistatin peptides may reduce proliferation, migration and colony formation only in androgen-independent PC cells (22Rv1 and PC-3 cells), but not in normal prostate and androgen-dependent PC cells. This supports the idea of the potential and specific antitumor capacity of these peptides in the most aggressive castration-resistant PC . Proteomic technologies, such as mass spectrometry and protein array analysis, have advanced the dissection of the underlying molecular signaling events and the proteomic characterization of several cancers, including PC . Zhong et al. compiled a comprehensive imaging resource to complement high-throughput proteomic and genomic data . Therefore, there now exists a large number of shared data resources with excellent potential for reuse in both biomedical and computational studies. N-Myc is not significantly expressed in adult tissues; nevertheless, it was reported to be amplified and overexpressed in neuroendocrine PC tumors. The alteration and deregulation of N-Myc induced tumor proliferation and progression, resulting in a low survival rate in neuroendocrine PC patients . The Myc protein represents a "slippery as an eel" target, and this is the reason for the indirect pharmacological approaches that target its transcription, translation or degradation . 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]) OR (attritio*[Title/Abstract])) OR (dropou*[Title/Abstract])) OR (success[Title/Abstract])) OR (graduat*[Title/Abstract])) OR (Absent*[Title/Abstract])) OR (leave*[Title/Abstract])) OR (Academic Failur*[Title/Abstract])) OR (Academic Performanc*[Title/Abstract]) 956,191 #3 #1 OR #2 957,001 #4 "students, nursing"[MeSH Terms] 28,963 #5 (((((Nursing student*[Title/Abstract]) OR (undergraduate nurs*[Title/Abstract])) OR (nursing education*[Title/Abstract])) OR (Nursing teach*[Title/Abstract])) OR (nurs* students[Title/Abstract])) OR (baccalaureate nurs*[Title/Abstract]) 57,132 #6 #4 OR #5 66,342 #7 #3 AND #6 9749 #8 ((((((((("Australia"[MeSH Terms]) OR (western Australia[MeSH Terms])) OR ("south Australia"[MeSH Terms])) OR ("Queensland"[MeSH Terms])) OR (new south wales[MeSH Terms])) OR ("Victoria"[MeSH Terms])) OR (((((((Australia*[Title/Abstract]) OR (New South Wales[Title/Abstract])) OR (Queensland[Title/Abstract])) OR (Sydney[Title/Abstract])) OR (Victoria[Title/Abstract])) OR (Melbourne[Title/Abstract])) OR (Canberra[Title/Abstract]))) OR ("Northern Territory"[MeSH Terms])) OR ("Tasmania"[MeSH Terms])) OR ("Australian capital territory"[MeSH Terms]) 239,339 #9 (((((((Australia*[Title/Abstract]) OR (New South Wales[Title/Abstract])) OR (Queensland[Title/Abstract])) OR (Sydney[Title/Abstract])) OR (Victoria[Title/Abstract])) OR (Melbourne[Title/Abstract])) OR (Canberra[Title/Abstract])) OR (Darwin[Title/Abstract]) 190,187 #10 # 8 OR #9 243,027 #11 #7 AND #10 634 #12 (((((((Barrier*[Title/Abstract]) OR (facilitator*[Title/Abstract])) OR (experienc*[Title/Abstract])) OR (difficult*[Title/Abstract])) OR (challenge*[Title/Abstract])) OR (hindrance*[Title/Abstract])) OR (influencing factor*[Title/Abstract])) OR (obstacle*[Title/Abstract]) 3,050,957 #13 #11 AND #12 377 #14 Filters applied: from 5 July 2017 to 5 September 2022. 115 Web of Science #1 ((((TS = (retentio*)) OR TS = (attritio*)) OR TS = (dropou*)) OR TS = (Academic Failur*)) OR TS = (Academic Performanc*)Indexes = SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, ESCI, CCR-EXPANDED, IC Timespan = All years 512,055 #2 (((((TS = (Nursing student*)) OR TS = (undergraduate nurs*)) OR TS = (nursing education*)) OR TS = (Nursing teach*)) OR TS = (nurs* student*)) OR TS = (baccalaureate nurs*)Indexes = SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, ESCI, CCR-EXPANDED, IC Timespan = All years 98,159 #3 #2 AND #1 4410 #4 ((((((((TS = (Australia*)) OR TS = (western Australia)) OR TS = (south Australia)) OR TS = (Queensland)) OR TS = (New South Wales)) OR TS = (Victoria)) OR TS = (Northern Territory)) OR TS = (Australian capital territory)) OR TS = (Tasmania)Indexes = SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, ESCI, CCR-EXPANDED, IC Timespan = All years 444,904 #5 #4 AND #3 335 #6 (((((TS = (Barrier*)) OR TS = (facilitator*)) OR TS = (difficult*)) OR TS = (challenge*)) OR TS = (influencing factor*)) OR TS = (obstacle*)Indexes = SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, ESCI, CCR-EXPANDED, IC Timespan = All years 4,760,403 #7 #5 AND #6 153 #8 ((((TS = (rural)) OR TS = (remote)) OR TS = (regional)) OR TS = (Indigenou*)) OR TS = (Aborigina*) 1,381,276 #9 #7 AND #8Indexes = SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, ESCI, CCR-EXPANDED, IC Timespan = 5 July 2017-5 September 2022 26 EBSCOhost: Medline + Cumulative Index to Nursing and Allied Health Literature (CINAHL) + Education Research Complete + ERIC Education Resources Information Center + PsycoINFO #1 TI retentio* OR AB retentio* OR TI attritio* OR AB attritio* OR TI dropou* OR AB dropou* OR TI Academic Failur* AND AB Academic Failur* OR TI Academic Performanc* OR AB Academic Performanc*Expanders Apply related words; Apply equivalent subjects 415,746 #2 TI Nurs* student* OR AB Nurs* student* OR TI undergraduate nurs* AND AB undergraduate nurs* OR TI baccalaureate nurs* OR AB baccalaureate nurs* OR TI Nursing teach* OR AB Nursing teach* OR TI nursing education* OR AB nursing education*Expanders Apply related words; Apply equivalent subjects 141,017 #3 #2 AND #1 5424 #4 TI Australia* OR AB Australia* OR TI Queensland OR AB Queensland OR TI New South Wales OR AB New South Wales OR TI Victoria OR AB Victoria OR TI Northern Territory OR AB Northern Territory OR TI Tasmania OR AB TasmaniaExpanders Apply related words; Apply equivalent subjects 365,620 #5 #4 AND #3 305 #6 TI Barrier* OR AB Barrier* OR TI difficult* OR AB difficult* OR TI challenge* OR AB challenge* OR TI obstacle* OR AB obstacle* OR TI influencing factor* OR AB influencing factor* OR TI facilitator* OR AB facilitator*Expanders Apply related words; Apply equivalent subjects 3,286,013 #7 #6 AND #5 Limiters Published Date: 5 July 2017-5 September 2022;(MEDLINE: 15; CINAHL: 19; PsycInfo: 8; PsycoINFO: 2 and ERIC: 2) 46 A+ Education #1 [All Fields: retentio* OR All Fields: attritio* OR All Fields: dropout* OR All Fields: academic] AND [All Fields: failur* OR All Fields: academic] AND All Fields: performanc* AND [All Fields: nurs* OR All Fields: undergraduate] AND [All Fields: nurs* OR All Fields: baccalaureate] AND [All Fields: nurs* OR All Fields: nursing] AND [All Fields: teach* OR All Fields: nursing] AND All Fields: education* AND [All Fields: barrier* OR All Fields: facilitator* OR All Fields: difficult* OR All Fields: challenge* OR All Fields: influencing] AND [All Fields: factor* OR All Fields: obstacl*] 1 The JBI EBP database + Journals@Ovid #1 retentio*.mp. [mp = ti, ab, tx, ct, hw, sw] 344,439 #2 attritio*.mp. [mp = ti, ab, tx, ct, hw, sw] 77,970 #3 dropou*.mp. [mp = ti, ab, tx, ct, hw, sw] 79,758 #4 Academic Failur*.mp. [mp = ti, ab, tx, ct, hw, sw] 2105 #5 Academic Performanc*.mp. [mp = ti, ab, tx, ct, hw, sw] 18,807 #6 #1 or #2 or #3 or #4 or #5 487,411 #7 Nursing student*.mp. [mp = ti, ab, tx, ct, hw, sw] 36,438 #8 undergraduate nurs*.mp. [mp = ti, ab, tx, ct, hw, sw] 7194 #9 nurs* students.mp. [mp = ti, ab, tx, ct, hw, sw] 34,276 #10 baccalaureate nurs*.mp. [mp = ti, ab, tx, ct, hw, sw] 5785 #11 #7 or #8 or #9 or #10 40,672 #12 Australia*.mp. [mp = ti, ab, tx, ct, hw, sw] 489,887 #13 Queensland.mp. [mp = ti, ab, tx, ct, hw, sw] 43,620 #14 new south wales.mp. [mp = ti, ab, tx, ct, hw, sw] 41,612 #15 Victoria.mp. [mp = ti, ab, tx, ct, hw, sw] 95,353 #16 Northern Territory.mp. [mp = ti, ab, tx, ct, hw, sw] 5489 #17 Tasmania.mp. [mp = ti, ab, tx, ct, hw, sw] 8324 #18 #12 or #13 or #14 or #15 or #16 or #17 533,303 #19 #6 and #11 and #18 1289 #20 Barrier*.mp. [mp = ti, ab, tx, ct, hw, sw] 634,922 #21 facilitator*.mp. [mp = ti, ab, tx, ct, hw, sw] 72,329 #22 difficult*.mp. [mp = ti, ab, tx, ct, hw, sw] 2,250,234 #23 challenge*.mp. [mp = ti, ab, tx, ct, hw, sw] 1,297,134 #24 influencing factor*.mp. [mp = ti, ab, tx, ct, hw, sw] 17,553 #25 obstacle*.mp. [mp = ti, ab, tx, ct, hw, sw] 143,085 #26 #20 or #21 or #22 or #23 or #24 or #25 3,240,786 #27 #19 and #26 1195 #28 rural.mp. [mp = ti, ab, tx, ct, hw, sw] 228,094 #29 remote.mp. [mp = ti, ab, tx, ct, hw, sw] 162,065 #30 regional.mp. [mp = ti, ab, tx, ct, hw, sw] 610,200 #31 Indigenou*.mp. [mp = ti, ab, tx, ct, hw, sw] 51,286 #32 #28 or #29 or #30 or #31 931,358 #33 #27 and #32 494 #34 limit #33 to last 5 years 202 Figure 1 PRISMA flow diagram for search results. ijerph-20-03983-t001_Table 1 Table 1 Characteristics of the included studies. First Author, Year Context and Settings Study Design and Data Source Participants (n) Study Objective Related to This Systematic Review Influencing Factors and Barriers to Retention Retention Rate/Intention Hays, C., 2022 A regional university in Queensland, Australia Qualitative descriptive study, interviews Undergraduate nursing students (n = 9) Explore the learning experiences of studying at a university campus located in a remote town Physical stress felt because of other competing priorities Ability to engage with study Experiences of face-to-face tutorials and recorded or videoconference lectures (technical difficulties and casually employed staff prioritizing their full-time positions at the hospital) Forming mentor-mentee relationships difficulties Lack of support from partners, family, friends, and the wider community Lack of financial support N/A Walker, S. B., 2021 A regional university in Queensland Australia A descriptive exploratory study design, electronic questionnaire Undergraduate nursing students (n = 121) Identify the personal qualities the students bring to and need for work integrated learning success Six personal qualities: confidence, commitment to learning, compassion, effective communication skills, enthusiasm to succeed, and self-motivation. N/A Middleton, R., 2021 A regional university with five satellite campuses and a main campus across New South Wales, Australia A prospective cross-sectional study, university belonging questionnaire Pre-registration nursing students enrolled in the undergraduate nursing program (n = 201) Evaluate students' intention to complete the pre-registration undergraduate nursing program following the initiatives for retention intervention Extra personal support 84% of the participants plan to continue and finish their study. Glew, P. J., 2019 A large multi-campus program in Australia A correlational design, administrative data First-, third-year undergraduate nursing students (n = 4472) Examine support uptake and the demographic characteristics of nursing students who sought support, and the relationships between demographic characteristics with undergraduate student retention Students who sought Professional Communication Academic Literacy (PCAL) support were more likely to continue to remain enrolled (72.4% versus 95.2%, p < 0.001). Predictors of continuing, high academic performance nursing students: non-school leavers, female, Australian-born, domestic students, not first-in-family to attend university, classified to have residential addresses in high socio-economic status (SES) areas and those who sought Professional Communication Academic Literacy (PCAL) support. 72.4 % for non-support consult students and 95.2% for support consult students Elmir, R., 2019 A large nursing school in New South Wales, Australia A descriptive qualitative design, interviews First year undergraduate nursing students who repeating one or more units (n = 9) Explore nursing students' experiences of repeating at least one unit Lack of academic writing confidence Many competing demands that affected their studies Working hours and family duties Academic support and resources (peer support) Motivational support from family members Fortitude and resilience (accomplish dream) N/A Henschke, K., 2017 A regional university at south-east Queensland A phenomenological study, in-depth interviews Indigenous Bachelor of Nursing students (n = 4) Explore insight strategies to improve retention, attrition and completion rates. Misperceptions: Preparedness (knowledge limitations) and similarities (family demands and commitments, financial restraints, knowledge limitations, lack of study skills and time management) Feeling different: Cultural well-being and indigenous identity Internal conflict: Lack of engagement, cultural or community responsibility and conflict N/A Note: N/A: not applicable. ijerph-20-03983-t002_Table 2 Table 2 Methodological quality assessment of included studies. First Author, Year Item 1 Item 2 Item 3 Item 4 Item 5 Item 6 Item 7 Item 8 Item 9 Item 10 Hays, C., 2022 Yes Yes Yes Yes Yes Yes Unclear Yes Yes Yes Walker, S. B., 2021 Unclear Unclear Unclear Yes Yes Unclear Unclear Yes Yes Yes Middleton, R., 2021 Yes Yes NA No Yes Unclear Yes Yes Glew, P. J., 2019 Yes Yes NA No Yes Unclear No Yes Elmir, R., 2019 Yes Yes Yes Yes Yes Unclear Unclear Unclear Yes Yes Henschke, K., 2017 Yes Yes Yes Yes Yes Unclear Unclear Unclear Yes Yes Note: NA: Not applicable; the JBI analytical cross-sectional studies critical appraisal tool (Item 1 to 8: "1. Were the criteria for inclusion in the sample clearly defined?" "2. Were the study subjects and the setting described in detail?" "3. Was the exposure measured in a valid and reliable way?" "4. Were objective, standard criteria used for measurement of the condition?" "5. Were confounding factors identified?" "6. Were strategies to deal with confounding factors stated?" "7. Were the outcomes measured in a valid and reliable way?" "8. Was appropriate statistical analysis used?") was used for the quantitative studies and the JBI qualitative research critical appraisal tool (Item 1 to 10: "1. Is there congruity between the stated philosophical perspective and the research methodology?" "2. Is there congruity between the research methodology and the research question or objectives?" "3. Is there congruity between the research methodology and the methods used to collect data?" "4. Is there congruity between the research methodology and the representation and analysis of data?" "5. Is there congruity between the research methodology and the interpretation of results?" "6. Is there a statement locating the researcher culturally or theoretically?" "7. Is the influence of the researcher on the research, and , addressed?" "8. Are participants, and their voices, adequately represented?" "9. Is the research ethical according to current criteria or, for recent studies, and is there evidence of ethical approval by an appropriate body?" "10. Do the conclusions drawn in the research report flow from the analysis, or interpretation, of the data?") was used for qualitative studies accessed on 15 June 2022). 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s and papers written in languages other than English were excluded. Additional articles were uncovered by checking the reference lists of the articles that were already examined. The specific question addressed was, "What are the possible applications of KT for masticatory myofascial pain dysfunction?". 3. Kinesio Taping 3.1. Background of Kinesio Taping Dr. Kenzo Kase, a Japanese chiropractor and acupuncturist, created Kinesio taping (KT) in 1973 to support the musculoskeletal system without excessive immobilization . Initially, the objective was to minimize swelling by regulating edema, supporting soft tissues, protecting joints, and reducing inflammation-caused heat . The main objective was to extend the benefits of manual therapy from the clinic to daily life at home and in other settings. After the Japanese athletics team used KT in the 1988 Olympics in Seoul, it attracted worldwide recognition and was imported to the US, where it gained popularity . MMPS, subacromial syndrome, hemiplegic shoulder, lymphedema, tendinitis, lateral epicondylitis, patellofemoral pain syndrome, and knee osteoarthritis are treated by KT . Previous research demonstrated post mandibular fracture surgery; KT reduced post-surgery swelling in the first two days . Despite its novelty as a tape method, few studies have examined it. Effectiveness in treating MPS. The lack of data makes it hard to tell how different types of KT work on MMPS. 3.2. Characters of Kinesio Taping Kinesio is woven cotton and elastic tape used to manage movement and accomplish functional goals. Kinesio Tape's elastic fibers might be cotton or polyester. Tape is applied to the paper backing using an acrylic adhesive and 10-15% stretching . In Kinesio Taping, this strain is called "paper off tension". This tape's heat-sensitive acrylic adhesive and cotton-wrapped elastic core lessen the risk of latex allergy in children. The non-medicinal tape is water-resistant and may remain effective for 3 to 5 days. Waved designs may alternate proprioception and somatosensory inputs. The elastic tape may be easily trimmed to fit any body alignment . Kinesio Tape may stretch to 120-150% of its original length without stretching. 3.3. Types of Kinesio Taping For humans, there are four Kinesio Tape varieties and two for animals. Clinicians pick tape based on the patient's purpose and skin condition. Classic or Performance+ Tape is suggested for beginners. KT varies in size and form . Types of KT and its features and tape selection based on types of applications are mentioned in Table 1. 4. Mechanism of Action of Kinesio Taping The skin is the body's largest sensory organ and a key conduit for eliciting the appropriate motor responses. The required therapeutic motor impact can be achieved by applying the KT to certain skin sensory receptors . So, it alleviates discomfort, decreases swelling and inflammation, enhances or suppresses motor function in the muscles, stimulates proprioception, and promotes lymphatic drainage. When placed on the skin with minimal strain, KT raises the region under the skin and soft tissue to increase subcutaneous space, stimulate blood and lymph fluid circulation, expedite tissue recovery and channel fluid flow away from and into the damaged area to speed the recovery of wounded tissue. Varying the application and tension of the tape influence the body's natural healing processes . Pain and abnormal sensations are minimized, muscles are supported, subcutaneous lymphatic fluid and blood are emptied, and joint derangement is repaired. This product lifts skin, improves space between muscles and skin, and reduces pressure. Reduced pressure diminishes subcutaneous pain receptor activation, allowing pain-free movement . Previous research showed the effect of tape on blood circulation to confirm that regular compression and decompression of the lymphatic system boosted flow and circulation . Negative-pressure pumping directs fluid from the superficial to deeper levels of the one-way lymphatic system beneath the skin . Muscle contraction and relaxation help create negative pressure. Intercellular junction shutters close as edema increases the interstitial pressure in the lymphatic system. Muscular contraction and relaxation, massage, and compression clothing may vary the pressure in each area. Lymph and interstitial fluid recirculation reduce swelling and pain. Lymph edema drains lesions and promotes tissue repair, improving circulation . Taping may affect proprioception, placebo effect, and biomechanics. Patients with patellofemoral pain syndrome may benefit from further KT . Gate control theory may explain KT's pain-management benefits. Touch A-fiber diameter and conduction velocity are higher than pain C-fibers. Mildly touching afferent skin receptors may activate glial spinal cells. The spinal cord blocks pain conduction to the brain . Although KT does not replace the need for exercise, it is recommended as an adjunctive strategy for the short term in the treatment of pain . Therefore, the KT tape is not to be used as the sole form of treatment, but rather as an alternative or complementary treatment when an immediate and short-duration effect by application is desired. Pairing with other methods and tools is recommended including manual therapy, muscle strengthening, electrothermal, and phototherapy . Kinesio taping may be the best treatment option for patients with myofascial pain syndrome, but more high-quality RCTs are needed to determine this at post-intervention and follow-up stages. Schematic diagrams represent the effects of KT application for MMPS in Figure 2. 5. Clinical Application of Kinesio Taping for Myofascial Pain Syndrome KT, when used in conjunction with other therapy modalities, may provide additional advantages such as enhanced proprioceptive feedback and enhanced joint stabilization. To be able to recommend KT to a patient, a practitioner has to be aware of the patient's previous medical history, the nature of the patient's occupation or activity, as well as the biomechanics of the injury, and the duration of the damage. A complete physical examination will include inspection, palpation, and active and passive ranges of motion (ROM), as well as the identification of the MTrPs. There have been a number of investigations on the effectiveness of KT for the management of myofascial pain syndrome in TMJ patients. According to a systematic review and meta-analysis, the kinesiology tape had a significant effect on the masseter muscles, with tremendous pain relief assessed with VAS after using the tape for one week in comparison to other interventions occlusal splint, compressions to deactivate MTrPs, and counseling are some of the treatment options in people who suffered from temporomandibular disorders (TMDs). The inverse variance approach was used throughout the process of doing the meta-analysis. The mean value that was displayed on the visual analog scale was regarded to be the intervention effect measure. measure. The experimental group had 1.4 points of pain intensity decrease in VAS, with a p-value = 0.013. The conclusions of the research were, however, restricted due to the low number of studies and the inherent biases in those investigations . The efficacy of KT for treating temporomandibular joint (TMJ) problems were studied in a single-blind, randomized, controlled experiment undertaken by Coskun Benlidayi and colleagues . Patients with TMDs were divided into two groups, one for the trial and the other as a control. Fourteen participants in the study got KT in addition to counseling and jaw exercises, whereas another fourteen participants in the control group received just therapy and exercise alone. Before beginning therapy, the first and sixth weeks measured the efficiency of the patient's chewing, as well as the patient's self-reported functional limitations. The biobehavioral questionnaire was completed twice, once at the beginning and again at the end of the study. Active mouth opening increased more in the treatment group compared to the control group. A substantial improvement in the visual analog scale (VAS) for TMJ, masticatory efficiency of mastication, and functional restriction was seen in the experimental group but not in the control group. The study showed that the experimental group's subjective treatment effectiveness was greater than that of the controls. The experimental group had substantial decreases in pain (p = 0.001), sadness (p = 0.006), and disability ratings (p = 0.01), but not the control group. To sum it up, when it comes to TMDs, KT is more beneficial than counseling and exercise by itself (or even in combination) . Patients with latent MTrPs in the sternocleidomastoid muscle (SCM) were taped using Kinesio taping to see how that affected their myofascial discomfort and temporomandibular joint range of motion. A total of 42 individuals between the ages of 20 and 30 took part in the study (male 17, female 25). One group received KT, and the other received a placebo. The SCM was Kinesio-taped three times a week for two weeks. The amount of discomfort felt while pressing on a tight band or nodule was recorded and analyzed. VAS and pressure pain threshold (PPT) was used to assess the degree of discomfort. The temporomandibular joint's range of motion was assessed. Each participant's temporomandibular joint range of motion, VAS, and degree of discomfort were evaluated post-treatment. It was discovered that pain in the SCM muscle was relieved after Kinesio taping was applied to subjects with latent MTrps and restriction of the ROM of the TMJ. This was demonstrated by the fact that the VAS score and PPT significantly (p < 0.01 and p < 0.05, respectively) decreased. The TMJ's ROM has significantly increased (p < 0.05). These findings showed that Kinesio taping reduced pain in latent MTrPs that was brought on by overexerting the SCM muscle, and that the ROM of the TMJ also changed as overexerting the SCM muscle decreased. The control group, on the other hand, exhibited no change between the times of the taping and before. Significant differences in VAS and PPT scores as well as TMJ ROM were found when comparing the groups (p < 0.05). Hence it was concluded KT could be used to treat latent MTrPs . Another illustration of this is a comparative study carried out showed that, after treatment, there was not a substantial difference discovered between the two categories with respect to values on the VAS or measurements of mouth opening; however, the values achieved for the pain threshold for the temporal muscle were higher in the Kinesio group. It was an easy-to-apply non-invasive procedure that did not stop regular oral activities, in addition to minimizing the amount of discomfort experienced . Ristow and associates examined the efficacy of KT on postoperative edema, discomfort, and trismus in 26 patients with open reduction and internal fixation of mandibular fractures. Within the first two days after surgery, the administration of KT using the lymphatic approach had the ability, according to this research, to cut the occurrence of edema and reduce turgidity by at least 60%. However, there was no discernible impact on the amount of pain relief experienced . Another research that aimed to elucidate the impact of KT on third-molar surgery-related postoperative morbidity, found that KT decreased edema, trismus, and discomfort, which ultimately resulted in a lower morbidity rate after surgery . The researchers drew attention not only to the positive outcomes that may be achieved with KT but also to the fact that it is risk-free and requires just a little expenditure. Kijak and their team examined patients suffering from temporomandibular problems to see if the KT approach and the deactivation of trigger points might successfully eliminate pain without using pharmaceuticals. The research was carried out on a total of sixty patients with an age range of 18 to 35 years. The participants were randomly split into groups of two, each consisting of thirty individuals. KT has been applied actively to the members of Group KT (there were 15 males and 15 women in this group). Physiotherapy was performed on Group MTrP, which included the ischemic compression approach for the release of trigger points. There was a total of 16 females and 14 males in this group. The results show that MTrP inactivation and the KT technique had significant therapeutic analgesic effects throughout pain-related functional abnormalities of the muscles involved in mastication. After utilizing the KT strategy, which increased the analgesic effect in patients with dysfunction, the researchers noticed that the treatment positively impacted the patients. There was no discernible effect of either the patient's gender or age on the therapy outcomes. In addition, they concluded that there is a need for the development of algorithms for diagnosing and treating oral facial pain, as well as how dentists and physiotherapists contribute to the process . Previous studies prospectively compared the early results of Kinesio tape (KT) to those of corticosteroid injection (CSI) and the rest-and-medication group (RMG) for the treatment of lateral epicondylitis. Nirschl scores were used to categorize patients, and the VAS, QDASH, and the Turkish adaptation of the Patient-Related Elbow Evaluation were used for further evaluation (PREE-T). All groups showed statistically significant gains by the end of the second week. The functional scores for those in the RMG and CSI groups decreased slightly from week to week, and only KT remained effective throughout the entire study. At week four, the average QDASH score for the KT group was 18.1 (4.5-35), the VAS score was 2 (1-3), the VAS score for resisted wrist extension was 4 (2-4), and the Nirschl score was 2 (1-3). It was found that the KT group performed better than the RMG in all four of these measures, p = 0.035, p = 0.035, p = 0.029, and p = 0.035, respectively . The effectiveness of trapezius-muscle kinesio taping (KT) in addition to TPI (TPI of 1 mL of 20 mg betamethasone dipropionate combined with 3 mL of 2% lidocaine and 1 mL of saline solution) for the treatment of MPS was investigated in a separate study. Fifty patients diagnosed with MPS were divided into two groups of 25 individuals using a random number generator. Group 1 TPI plus KT; TPI plus sham KT in Group 2. At pretreatment, one, and three months posttreatment, patients filled out a VAS and a Neck Disability Index (NDI). VAS and NDI scores at 3 months were significantly lower in Group 1 versus Group 2 (p < 0.05). Treatment with TPI and KT on the trapezius muscle for MPS has shown promise in halting the chronic process, preventing recurrence, and breaking the pain cycle. Due to its limited role in the long-term management of MPS, MTrP injection runs the risk of creating dependence in patients when used as the primary therapy. The combined therapy appears to generate a more influential outcome in the long run, than monotherapy, in alleviating pain and reforming functional amelioration in the management of MPS . The results of KT and dry needling (DN) for the treatment of trapezius muscle myofascial pain syndrome were compared in another recent study. A blinded evaluator took readings on a Visual Analog Scale (VAS), Pressure Pain Threshold (PPT), Neck Disability Index (NDI), and Global Perceived Effect Scale (GPES) at the beginning and end of the second week. The pain, disability, and global effects of MPS treatment are significantly better for those who undergo KT and DN as opposed to those who do not (p < 0.001 for all). Supplementing an exercise regimen with DN or KT applications improved outcomes for patients with MPS. Comparative effectiveness between DN and KT was not observed . Among adult patients with cervical dystonia (CD), the application of KT after botulinum toxin (BoNT) injection did not affect the severity of dystonia but did improve quality of life (p < 0.05, p = 0.03). The Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), comprising Torticollis severity, Disability, and Pain scales, was used to quantify the severity of CD. The Craniocervical Dystonia Questionnaire was used to assess the quality of life (CDQ4) . However, we need more studies looking into the impact of KT before and after BoNT injection in MMPS. Despite extensive research, KT has only recently been used in the maxillofacial region. Additionally, little is known about the potential impact on MMPS. KT has not been proven to be an effective stand-alone treatment for MMPS, but the studies we've highlighted in this review suggest it may be useful as an adjunct to conventional care. To be accepted as a viable independent treatment option, KT must be thoroughly explored in future studies, especially randomized clinical trials. 6. Limitations and Research Gap KT has only recently been used in the maxillofacial region, and there haven't been many studies published on this topic; it is still relatively new in the field of dentistry. Furthermore, not much is known about how KT can affect the TMJ and masticatory muscles. In addition, the current research has numerous flaws because, despite the fact that the sample size was sufficient for a statistical analysis that successfully identified significance in comparisons, it's more reasonable to back the findings of this research with trials with a larger sample size. Some researchers did not include a placebo group. The usefulness of KT, if any, should be clarified via placebo-controlled research with more significant sample numbers independent of the placebo effect. So, more studies are required in this field that should strive to use KT over other methods of intervention in the maxillofacial region. In addition, there is a specific limitation in using KT under the circumstances like open wounds, deep vein thrombosis, allergy, fragile skin, and active malignant sites. Self-application of tape, however, can be challenging due to a lack of familiarity with the taping procedure, the need to use both hands, the placement of the MTrP, and a lack of knowledge of anatomy or biomechanics. As a result, the vast majority of people can't tape independently. 7. Conclusions Treatment of MMPS may be challenging due to its complex pathology and underlying peripheral and central neural mechanisms, particularly during the chronic phase. The inability to recognize trigger points, a lack of experience with the taping technique, and a lack of knowledge of anatomy or biomechanics are some other obstacles to self-taping. From a variety of treatment options (such as manual therapies, massage, electrophysical agents, medical care, electrotherapy, cold spray/stretching, ischaemic compression, and acupuncture), the choice of kinesiology taping remains up to the individual practitioner and clinic policy. Healthcare professionals may, however, continue to view kinesiology taping as a practical therapeutic non-pharmacological approach for MMPS management in light of the current evidence. It allows for a significant reduction in edema and discomfort without endangering the patient's metabolism or digestive system, is simple to perform, affordable, and less traumatic. Finally, studies included in this review demonstrated that, despite its limitations, KT can be considered an adjunctive therapeutic tool to standard therapy for the treatment of MMPS and has not been shown to be a valid independent treatment option. It's still unclear whether Kinesio taping is more effective in the long run than other treatments. Future studies are necessary to confirm the effectiveness of KT techniques and applications, particularly randomized clinical trials, to establish KT as a reliable independent treatment option. Author Contributions Conceptualization, A.S.A.; methodology, S.P.; software, A.S.A.; validation, S.P. and A.S.A.; formal analysis, S.P.; investigation, S.P.; resources, S.P. and A.S.A.; data curation, S.P.; writing original draft preparation, S.P.; writing review and editing, S.P. and A.S.A.; visualization, A.S.A.; supervision, A.S.A.; project administration, A.S.A. All authors have read and agreed to the published version of the manuscript. Institutional Review Board Statement Not applicable. Informed Consent Statement Not applicable. Data Availability Statement Not applicable. Conflicts of Interest The authors declare no conflict of interest. Figure 1 These two images demonstrated how KT is applied to soft tissue and its mechanism. The lesion site, such as a taut band or bruise, may have bleeding, pressure, and lymph fluid build-up which will then cause pain before taping. The fluid drainage is aided by the space-lifting mechanism after taping as shown. The muscles' ability to move will then be enhanced as the pressure and inflammatory factors are decreased . Figure 2 Effects of Kinesio taping on masticatory myofascial pain syndrome. CNS central nervous system; KT Kinesio taping. ijerph-20-03872-t001_Table 1 Table 1 Types and Features of Kinesio taping. S. No. Types of Kinesio Taping Features Reference 1. KinesioTex Classic Universal and best option since it can be used in any situation and is most suited for healthy skin. 2. KinesioTex Performance+ Polyester and cotton blends are excellent for delicate skin when more significant tape tensions are needed. 3. KinesioTex Gold For low-tension applications and uses a specific distribution of glue accessible exclusively to qualified specialists that provide high adhesion without needing an enormous surface area. 4. KinesioTex Gold Light Touch Plus used for short-term treatments and is often used on youngsters and the elderly with sensitive skin. 5. Kinesio Equine It can be applied straight to horsehair and has a flavor that animals would not eat. 6. Kinesio Canine For dogs, it works nicely with their hair. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
Int J Environ Res Public Health Int J Environ Res Public Health ijerph International Journal of Environmental Research and Public Health 1661-7827 1660-4601 MDPI 10.3390/ijerph20054367 ijerph-20-04367 Correction Correction: Martinez-Valverde et al. Health Needs Assessment: Chronic Kidney Disease Secondary to Type 2 Diabetes Mellitus in a Population without Social Security, Mexico 2016-2032. Int. J. Environ. Res. Public Health 2022, 19, 9010 Martinez-Valverde Silvia 1 Zepeda-Tello Rodrigo 2 Castro-Rios Angelica 3* Toledano-Toledano Filiberto 4 Reyes-Morales Hortensia 5 Rodriguez-Matias Adrian 6 Duran-Arenas Juan Luis Gerardo 7 1 Centro de Estudios Economicos y Sociales en Salud, Hospital Infantil de Mexico Federico Gomez, Instituto Nacional de Salud, Mexico City 06720, Mexico 2 Direccion de Prestaciones Economicas y Sociales, Instituto Mexicano del Seguro Social, Mexico City 06600, Mexico 3 Unidad de Investigacion en Epidemiologia Clinica, Hospital de Pediatria, Centro Medico Nacional SXXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico 4 Unidad de Investigacion en Medicina Basada en Evidencias, Hospital Infantil de Mexico Federico Gomez, Instituto Nacional de Salud, Mexico City 06720, Mexico 5 Centro de Investigacion en Sistemas de Salud, Instituto Nacional de Salud Publica, Cuernavaca 62100, Mexico 6 Servicio de Nefrologia, Hospital Angeles Metropolitano, Mexico City 06760, Mexico 7 Departamento de Salud Publica, Facultad de Medicina, Universidad Autonoma de Mexico, Mexico City 04510, Mexico * Correspondence: [email protected] 28 2 2023 3 2023 28 2 2023 20 5 436708 10 2022 11 10 2022 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). pmcError in Table In the original publication , there was a mistake in Table 3 as published. Table 3 has five sections, the fourth is "Progression to CKD" and the fifth is "Distribution". 1. Please modify the text of the fourth section, instead of "Progression to CKD" change to "Progression to CKD (cases)". 2. In the last "Distribution" section, the last column was duplicated. It should be deleted (the one that starts at 62.7%). 3. Then, all columns of the "Distribution" section should be shifted one place to the right to coincide with the year titles "2025 to 2032". 4. Unify format, the lines of the two upper sections do not have horizonal lines, while the two lower sections do". The corrected Table 3 appears below. The authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated. ijerph-20-04367-t003_Table 3 Table 3 Health needs assessment of CKD secondary to T2 DM in patients without social security in Mexico (20-79 years of age). Health Needs a/2016 b/2017 b/2018 b/2019 b/2020 b/2021 b/2022 b/2023 b/2024 Diabetes population without social security 5,449,204 5,703,343 5,963,455 6,229,519 6,501,512 6,779,409 7,063,191 7,352,844 7,648,353 Cases of chronic kidney disease secondary to T2 DM Normoalbuminuria 4,026,612 4,124,684 4,225,015 4,327,494 4,432,015 4,538,472 4,646,773 4,756,831 4,868,561 Microalbuminuria 578,720 626,333 672,847 718,388 763,074 807,011 850,296 893,015 935,250 Macroalbuminuria 118,084 133,416 149,127 165,159 181,460 197,987 214,704 231,581 248,592 End-stage renal 28,750 31,562 34,415 37,307 40,236 43,199 46,194 49,216 52,264 Deaths associated with CV risk. 697,039 787,347 882,051 981,171 1,084,727 1,192,739 1,305,225 1,422,201 1,543,686 Distribution Normoalbuminuria 74% 72.3% 70.8% 69.5% 68.2% 66.9% 65.8% 64.7% 63.7% Microalbuminuria 10.6% 11.0% 11.3% 11.5% 11.7% 11.9% 12.0% 12.1% 12.2% Macroalbuminuria 2.2% 2.3% 2.5% 2.7% 2.8% 2.9% 3.0% 3.1% 3.3% End-stage renal 0.53% 0.55% 0.58% 0.60% 0.62% 0.64% 0.65% 0.67% 0.68% Deaths 12.8% 13.8% 14.8% 15.8% 16.7% 17.6% 18.5% 19.3% 20.2% Progression to CKD (cases) b/2025 b/ 2026 b/ 2027 b/ 2028 b/ 2029 b/ 2030 b/ 2031 b/ 2032 Cohort of DM T2 7,949,693 8,256,841 8,569,754 8,888,350 9,212,529 9,542,175 9,877,143 10,217,299 Normoalbuminuria 4,981,876 5,096,690 5,212,900 5,330,372 5,448,955 5,568,490 5,688,796 5,809,707 Microalbuminuria 977,072 1,018,546 1,059,731 1,100,681 1,141,441 1,182,050 1,222,543 1,262,945 Macroalbuminuria 265,716 282,938 300,243 317,622 335,065 352,566 370,121 387,724 End-stage renal disease 55,335 58,425 61,533 64,657 67,795 70,945 74,108 77,280 Deaths associated with CV risk 1,669,695 1,800,243 1,935,346 2,075,018 2,219,273 2,368,122 2,521,576 2,679,643 Distribution Normoalbuminuria 62.7% 61.7% 60.8% 60.0% 59.1% 58.4% 57.6% 56.9% Microalbuminuria 12.29% 12.34% 12.37% 12.38% 12.39% 12.39% 12.38% 12.40% Macroalbuminuria 3.34% 3.43% 3.50% 3.57% 3.64% 3.69% 3.75% 3.79% End-stage renal disease 0.70% 0.71% 0.72% 0.73% 0.74% 0.74% 0.75% 0.76% Deaths 21.00% 21.80% 22.58% 23.35% 24.09% 24.82% 25.53% 26.23% Source: Authors' estimates. a/ Health Needs Assessment = T2 DM cases in 2016 that progressed to CKD; b/ T2 DM cases (2017...2032) = Prevalence of T2 DM(2016) + k<=iIncidence of T2 DM for year i. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. Reference 1. Martinez-Valverde S. Zepeda-Tello R. Castro-Rios A. Toledano-Toledano F. Reyes-Morales H. Rodriguez-Matias A. Duran-Arenas J.L.G. Health Needs Assessment: Chronic Kidney Disease Secondary to Type 2 Diabetes Mellitus in a Population without Social Security, Mexico 2016-2032 Int. J. Environ. Res. Public Health 2022 19 9010 10.3390/ijerph19159010 35897379 |
Int J Mol Sci Int J Mol Sci ijms International Journal of Molecular Sciences 1422-0067 MDPI 10.3390/ijms24054343 ijms-24-04343 Editorial Liposomes: The Brave Old World Matos Carla M. FP-I3ID (Instituto de Investigacao, Inovacao e Desenvolvimento Fernando Pessoa), FP-BHS (Biomedical and Health Sciences), Universidade Fernando Pessoa, Praca 9 de Abril, 349, 4249-004 Porto, Portugal; [email protected] 22 2 2023 3 2023 24 5 434328 11 2022 03 2 2023 (c) 2023 by the author. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). This research received no external funding. pmcLiposomes have been known of for about 60 years, since they were discovered by A. Bangham in the mid-1960s in a serendipitously brilliant finding . The observation that adding a negative stain to dry phospholipids, when testing the institute's new electron microscope, leads to the formation of a milky suspension, which was revealed to be composed of self-enclosed lipid bodies (liposomes). Immediately, their potential use in diverse research fields was perceived, and diverse areas of liposome use rapidly started to develop: as models for cellular membranes and drug-membrane interactions , as drug delivery and drug targeting tools , as microreactors for compartmentalizing reactional media , or in the development of chromatographic methods, used as the stationary phase . One of the most interesting areas is using liposomes as site-specific drug delivery systems, improving the bioavailability and minimizing the systemic side effects; or for the topical administration of drugs, improving penetration through the skin . A first drawback in the use of liposomes as drug delivery systems was their detection and capture by the body's resticuloendothelial system (RES), namely the liver and the spleen. To avoid such a fate, PEG (polyethyleneglycol) is added to the outer layer as a way to disguise the lipid membrane (Stealth liposomes) and avoid RES. Other specific ligands can also be used to target specific delivery sites, as monoclonal antibodies (immunoliposomes) or antigens. This Special Issue had the purpose to gather a collection of articles that highlight some recent liposome applications, such as the development of stealth liposomes to aim for the placenta, the use of liposomes as vaccine adjuvants, the development of prodrugs to increase liposome encapsulation and specific targeting, the development of theranostic (therapeutics and diagnostics) liposomes, and the use of elastic and ultradeformable liposomes for topical use. One of the populations that can benefit from the use of drugs delivered in liposomes is pregnant women. However, to date, there are not enough studies on the pharmacokinetics and placental disposition of liposomes in this population. Fliedel et al. presented a study with PEGylated liposomes and their uptake by the human placenta, using an in vitro model of human trophoblast cell line (BeWo cells) and an ex vivo model of suspended human villous placental explants for their study. Cationic liposomes exhibited a significant higher internalization compared to the neutral ones and exhibited an endocytosis mechanism of internalization via pathways implicating dynamin. These data highlight the key role of the liposome's lipid composition and the possibility to modulate their internalization in the placenta by adjusting their design. Zimmermann et al. presented a work designed in the context of the recent SARS-CoV-2 pandemic, which was disruptive to the habits and planning of current societies. In the context of the development of new viral vaccines, against viruses such as SARS-CoV-1 and H5N1 influenza, among others, these authors suggest the use of liposomal vaccine adjuvant CAF(r) 09b. This system induces a type I interferon response and can be used as a pan-viral prophylaxis prior to the development and approval of specific vaccines. Intranasal administration of these liposomes to mice showed an improved immunological defense response to the Influenza virus if administered prior to infection. Kobanenko et al. studied the drug colchicine (antimitotic and anti-inflammatory), frequently used as an acute gout flare treatment, in the form of a pro-drug (phospholipid-allocolchicinoid) as a way to incorporate the drug in the liposome bilayer and increase its encapsulation. As the complex does not have a pharmacological activity, but can be metabolized by hydrolysis to the active drug by means of the enzyme phospholipase A2, which exists in increased amounts in places where inflammatory processes are developing, this association constitutes an ingenious way of using the pro-drug concept to release the active ingredient colchicine in the site of action, increasing its selectivity and targeting. The use of liposomes further increases the passive targeting to inflammation or tumor sites. Analytical techniques for the characterization of liposomes are also highlighted in this issue. Skupin-Mrugalska et al. used AF4 (asymmetric field-flow fractionation) associated with MALLS (multi-angle laser light scattering) to elucidate the release mechanism of zinc phthalocyanine, a photosensitizing agent for photodynamic cancer therapy, from theranostic liposomes. In this study, liposomes had a dual function: first, as drug carriers, as the photosensitizing agent is usually a highly lipophilic compound, but that can easily incorporated in the liposome membrane; second, liposomes were used as an acceptor for the drug, to study the transference kinetics and the release mechanism to biological sinks, such as red blood cells. Souto and co-workers presented a review on the use of elastic and ultradeformable liposomes on transdermal delivery. The transdermal route is challenging, since the skin is a protection organ, built-up in order for protection and preventing the passage of exogenous molecules. The topical administration is intended to convey a local effect, and transdermal applications are employed to gain a systemic effect, avoiding the first-pass metabolism. Ultradeformable carriers (such as elastic liposomes) seem to be much more capable of permeating the skin, going deep enough to be absorbed by systemic circulation. The modification of the liposome composition can lead to a superior capability to enhance the transdermal drug delivery in comparison to conventional liposomes. Highly deformable liposomes, composed of a lipid mixed with some type of surface activator, were introduced, and are known as "elastic vesicles". In that context, new vesicles, such as transfersomes, niosomes, ethosomes, and cerasomes, have been described. Institutional Review Board Statement Not applicable. Informed Consent Statement Not applicable. Data Availability Statement Not applicable. Conflicts of Interest The author declares no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Bangham A.D. Standish M.M. Weissmann G. The action of steroids and streptolysin S on the permeability of phospholipid structures to cations J. Mol. Biol. 1965 13 253 259 10.1016/S0022-2836(65)80094-8 5859040 2. Esteves F. Moutinho C. Matos C. Correlation between octanol/water and liposome/water distribution coefficients and drug absorption of a set of pharmacologically active compounds J. Liposome Res. 2013 23 83 93 10.3109/08982104.2012.742539 23464986 3. Matos C. Lobao P. Non-Steroidal Anti-Inflammatory Drugs Loaded Liposomes for Topical Treatment of Inflammatory and Degenerative Conditions Curr. Med. Chem. 2020 27 3809 3829 10.2174/0929867326666190227233321 30827226 4. Matos C. Chaimovich H. Lima J.L.F.C. Cuccovia I.M. Reis S. Effect of liposomes on the rate of alkaline hydrolysis of indomethacin and acemetacin J. Pharm. Sci. 2001 90 298 309 10.1002/1520-6017(200103)90:3<298::AID-JPS5>3.0.CO;2-1 11170023 5. Hou X. Lou X. Guo Q. Tang L. Shan W. Development of an immobilized liposome chromatography method for screening and characterizing a-glucosidase-binding compounds J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2020 1148 122097 10.1016/j.jchromb.2020.122097 6. Fliedel L. Alhareth K. Seguin J. El-Khashab M. Chissey A. Mignet N. Fournier T. Andrieux K. Influence of Liposomes' and Lipoplexes' Physicochemical Characteristics on Their Uptake Rate and Mechanisms by the Placenta Int. J. Mol. Sci. 2022 23 6299 10.3390/ijms23116299 35682978 7. Zimmermann J. Schmidt S.T. Trebbien R. Cox R.J. Zhou F. Follmann F. Pedersen G.K. Christensen D. A Novel Prophylaxis Strategy Using Liposomal Vaccine Adjuvant CAF09b Protects against Influenza Virus Disease Int. J. Mol. Sci. 2022 23 1850 10.3390/ijms23031850 35163772 8. Kobanenko M.K. Tretiakova D.S. Shchegravina E.S. Antipova N.V. Boldyrev I.A. Fedorov A.Y. Vodovozova E.L. Onishchenko N.R. Liposomal Formulation of a PLA2-Sensitive Phospholipid-Allocolchicinoid Conjugate: Stability and Activity Studies In Vitro Int. J. Mol. Sci. 2022 23 1034 10.3390/ijms23031034 35162957 9. Skupin-Mrugalska P. Elvang P.A. Brandl M. Application of Asymmetrical Flow Field-Flow Fractionation for Characterizing the Size and Drug Release Kinetics of Theranostic Lipid Nanovesicles Int. J. Mol. Sci. 2021 22 10456 10.3390/ijms221910456 34638795 10. Souto E.B. Macedo A.S. Dias-Ferreira J. Cano A. Zielinska A. Matos C.M. Elastic and Ultradeformable Liposomes for Transdermal Delivery of Active Pharmaceutical Ingredients (APIs) Int. J. Mol. Sci. 2021 22 9743 10.3390/ijms22189743 34575907 |
Int J Mol Sci Int J Mol Sci ijms International Journal of Molecular Sciences 1422-0067 MDPI 10.3390/ijms24054337 ijms-24-04337 Editorial Editorial of Special Issue "The Role of Vitamin D in Human Health and Diseases 2.0" Silvagno Francesca * Bergandi Loredana * Department of Oncology, University of Torino, Via Santena 5 bis, 10126 Torino, Italy * Correspondence: [email protected] (F.S.); [email protected] (L.B.) 22 2 2023 3 2023 24 5 433719 2 2023 20 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). pmcVitamin D performs a differentiating, metabolic and anti-inflammatory function, through genomic, non-genomic and mitochondrial mechanisms of action. In fact, vitamin D not only controls the transcription of thousands of genes and is involved in the modulation of calcium fluxes, but it also influences cellular metabolism and the maintenance of specific nuclear programs. Due to its broad spectrum of action, and because of the large number of target tissues, the deficiency of vitamin D and the molecular defects of its signaling pathway, such as VDR polymorphism or epigenetic silencing, can be involved in many pathologies. In this Special Issue, many scientists have contributed to elucidating the role of vitamin D in health and disease. Eight research articles and a compendium of nine reviews are published, covering different aspects of the activity of vitamin D and its defective signaling or low levels associated with many pathological conditions. Among diseases, the impact of vitamin D deficiency and supplementation in COVID-19 remains a hot topic, as revealed in the previous Special Issue "The role of vitamin D in human health and diseases" and confirmed in this collection. Here, in addition to a systematic review discussing the evidence of beneficial effects of vitamin D supplementation in COVID-19 patients , two additional studies focused on the implications of vitamin D deficiency in the COVID-19-related acute kidney injury (AKI), which is one of the most common extrapulmonary manifestations of this infectious disease. The review from Hsieh et al. highlighted the cross-relationship between vitamin D deficiency and AKI, reporting the evidence of their mutual causality and the molecular mechanisms triggered by SARS-CoV-2 infection in inducing both dysfunctions . Similarly, a narrative review from Liao et al. explored the potential role of vitamin D in preventing AKI in COVID-19 patients, but with a focus on the urokinase-type plasminogen activator/soluble urokinase-type plasminogen activator receptor (uPA/suPAR) pathway and its possible relationship with vitamin D in patients with COVID-19-related AKI . Moreover, the role of vitamin D deficiency in COVID-19 was analyzed by interrogating genetic and biological databases. Genome-wide association studies were explored by enrichment analyses of the pathways, in search of gene-disease associations. Although the study reported the absence of a common genetic background between vitamin D deficiency and COVID-19, it supported the possibility that a vitamin D deficiency causes comorbid conditions linked to a higher risk of developing severe COVID-19 disease . Furthermore, one study investigated the relationship between vitamin D deficiency in pregnant women and the severity of COVID-19 infection. Low vitamin D levels were detected in symptomatic, but not asymptomatic, COVID-19 patients, and vitamin D deficiency was described as an independent predictor of severe COVID-19, supporting the recommendation of vitamin D supplementation during pregnancy to avoid worse COVID-19 outcomes . The effect of vitamin D in pregnancy was considered in two other studies of this collection. A systematic review examined the associations between maternal vitamin D levels and offspring neuropsychiatric and psychiatric outcomes, finding a positive association for attention-deficit/hyperactivity disorder and schizophrenia . Moreover, a research article investigated the role of chorionic somatomammotropin hormone (CSH) in the regulation of calcium, phosphate and vitamin D utilization in late gestation of sheep. This study provided a model of the hormonal regulation of mineral transport during pregnancy from which further understanding in mammalian species can be achieved . Among the signaling pathways analyzed in this collection, the antioxidant and anti-inflammatory properties of vitamin D were largely investigated, and several studies revealed the central role of vitamin D in inflammatory diseases, such as COVID-19, diabetes, AKI, liver and kidney disease. The anti-inflammatory effects of vitamin D were explored in the adipose tissue of obese mice fed a high-fat diet , in T cell immunity and in the analysis of inflammatory markers in healthy Saudi males . All studies demonstrated that the treatment with vitamin D significantly reduced the level of pro-inflammatory cytokines, measured in serum or in activated T cells . Interesting experimental work carried out on obese mice revealed that the beneficial effects of the hormone were detected as decreased levels of pro-inflammatory cytokines, attenuated obesity-induced adipose hypertrophy and macrophage recruitment, and were related to increased AMPK activity and suppressed NF-kB phosphorylation . Vitamin D deficiency correlates with the severity of many pathologies, for example, in Type 1 diabetes, as reported by a systematic review , and in chronic kidney disease and kidney transplant . The reduced levels of vitamin D also correlate with chronic liver disease and have a predictive role in complications and the progression of advanced disease . A combination of poor vitamin D status and dysbiosis may contribute to the progression of cardiometabolic diseases, as can be inferred from the accurate review that presents the relationship among vitamin D, microbiota and cardiometabolic diseases, with a focus on metabolic syndrome . Among the causes of variability in vitamin D signaling, single nucleotide polymorphisms (SNPs) are to be mentioned. Indeed, SNPs can influence the expression and/or functions of the VDR and of other genes in the vitamin D metabolic pathways, and may justify interindividual differences in responsiveness to the hormone. One study of this Special Issue explored five SNPs in the VDR gene in order to unravel the role of genetic polymorphisms on VDR expression in periodontal fibroblasts during simulated orthodontic compressive force . Genetic polymorphisms were also investigated in the systematic review by Jaroenlapnopparat et al. , which revealed the association between the variations of several genes in the vitamin D metabolic pathway and the occurrence, severity and response to the treatment of non-alcoholic fatty liver disease (NAFLD). These findings support the notion that the vitamin D signaling pathway may play a significant role in the pathogenesis of NAFLD, in agreement with the reported beneficial effects of vitamin D supplementation described in the published review by Ravaioli et al. . Finally, the effects of vitamin D supplementation were investigated in inflammatory diseases and in metabolism . The latter was analyzed in a randomized crossover study carried out in post-menopausal women. The findings of this trial revealed an influence of diurnal rhythm on the plasma metabolome, while vitamin D supplementation appeared to have little influence on fluctuations in the plasma metabolome. As a whole, this Special Issue contains an interesting combination of research articles and reviews that present novel data on the effects of vitamin D in many pathologies, such as COVID-19 and diabetes, and in kidney, liver and cardiometabolic disease. The anti-inflammatory properties of vitamin D are the "fil rouge" in the heterogeneous spectrum of beneficial effects of the hormone described in this collection, which discusses current knowledge of the impact of vitamin D deficiency and supplementation in a variety of diseases. Author Contributions F.S. and L.B. wrote and edited the manuscript. All authors have read and agreed to the published version of the manuscript. Conflicts of Interest The authors declare no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Solis A.F. Salas A.A. Bartolome M.J.L. Ballestin S.S. The Effects of Vitamin D Supplementation in COVID-19 Patients: A Systematic Review Int. J. Mol. Sci. 2022 23 12424 10.3390/ijms232012424 36293279 2. Hsieh M.-C. Hsiao P.-J. Liao M.-T. Hou Y.-C. Chang Y.-C. Chiang W.-F. Wu K.-L. Chan J.-S. Lu K.-C. The Role of Vitamin D in SARS-CoV-2 Infection and Acute Kidney Injury Int. J. Mol. Sci. 2022 23 7368 10.3390/ijms23137368 35806377 3. Liao T.-H. Wu H.-C. Liao M.-T. Hu W.-C. Tsai K.-W. Lin C.-C. Lu K.-C. The Perspective of Vitamin D on SuPAR-Related AKI in COVID-19 Int. J. Mol. Sci. 2022 23 10725 10.3390/ijms231810725 36142634 4. Alcala-Santiago A. Rodriguez-Barranco M. Rava M. Jimenez-Sousa M.A. Gil A. Sanchez M.J. Molina-Montes E. Vitamin D Deficiency and COVID-19: A Biological Database Study on Pathways and Gene-Disease Associations Int. J. Mol. Sci. 2022 23 14256 10.3390/ijms232214256 36430729 5. Vasquez-Procopio J. Torres-Torres J. Borboa-Olivares H. Sosa S.E.Y. Martinez-Portilla R.J. Solis-Paredes M. Tolentino-Dolores M.-C. Helguera-Repetto A.C. Marrufo-Gallegos K.C. Missirlis F. Association between 25-OH Vitamin D Deficiency and COVID-19 Severity in Pregnant Women Int. J. Mol. Sci. 2022 23 15188 10.3390/ijms232315188 36499537 6. Upadhyaya S. Stahlberg T. Silwal S. Arrhenius B. Sourander A. Maternal Vitamin D Levels during Pregnancy and Offspring Psychiatric Outcomes: A Systematic Review Int. J. Mol. Sci. 2023 24 63 10.3390/ijms24010063 7. Stenhouse C. Halloran K.M. Tanner A.R. Suva L.J. Rozance P.J. Anthony R.V. Bazer F.W. Uptake of Phosphate, Calcium, and Vitamin D by the Pregnant Uterus of Sheep in Late Gestation: Regulation by Chorionic Somatomammotropin Hormone Int. J. Mol. Sci. 2022 23 7795 10.3390/ijms23147795 35887141 8. Chang E. Effects of Vitamin D Supplementation on Adipose Tissue Inflammation and NF-KB/AMPK Activation in Obese Mice Fed a High-Fat Diet Int. J. Mol. Sci. 2022 23 10915 10.3390/ijms231810915 36142842 9. Peruzzu D. Dupuis M.L. Pierdominici M. Fecchi K. Gagliardi M.C. Ortona E. Pagano M.T. Anti-Inflammatory Effects of 1,25(OH)2D/Calcitriol in T Cell Immunity: Does Sex Make a Difference? Int. J. Mol. Sci. 2022 23 9164 10.3390/ijms23169164 36012424 10. AlGhamdi S.A. Enaibsi N.N. Alsufiani H.M. Alshaibi H.F. Khoja S.O. Carlberg C. A Single Oral Vitamin D3 Bolus Reduces Inflammatory Markers in Healthy Saudi Males Int. J. Mol. Sci. 2022 23 11992 10.3390/ijms231911992 36233290 11. Yu J. Sharma P. Girgis C.M. Gunton J.E. Vitamin D and Beta Cells in Type 1 Diabetes: A Systematic Review Int. J. Mol. Sci. 2022 23 14434 10.3390/ijms232214434 36430915 12. Zappulo F. Cappuccilli M. Cingolani A. Scrivo A. Chiocchini A.L.C. Nunzio M.D. Donadei C. Napoli M. Tondolo F. Cianciolo G. Vitamin D and the Kidney: Two Players, One Console Int. J. Mol. Sci. 2022 23 9135 10.3390/ijms23169135 36012412 13. Ravaioli F. Pivetti A. Di Marco L. Chrysanthi C. Frassanito G. Pambianco M. Sicuro C. Gualandi N. Guasconi T. Pecchini M. Role of Vitamin D in Liver Disease and Complications of Advanced Chronic Liver Disease Int. J. Mol. Sci. 2022 23 9016 10.3390/ijms23169016 36012285 14. Sukik A. Alalwani J. Ganji V. Vitamin D, Gut Microbiota, and Cardiometabolic Diseases-A Possible Three-Way Axis Int. J. Mol. Sci. 2023 24 940 10.3390/ijms24020940 36674452 15. Kuchler E.C. Schroder A. Spanier G. Thedei G. Carvalho Ribeiro de Oliveira M.B. de Menezes-Oliveira M.A.H. Proff P. Kirschneck C. Influence of Single-Nucleotide Polymorphisms on Vitamin D Receptor Expression in Periodontal Ligament Fibroblasts as a Response to Orthodontic Compression Int. J. Mol. Sci. 2022 23 15948 10.3390/ijms232415948 36555589 16. Jaroenlapnopparat A. Suppakitjanusant P. Ponvilawan B. Charoenngam N. Vitamin D-Related Genetic Variations and Nonalcoholic Fatty Liver Disease: A Systematic Review Int. J. Mol. Sci. 2022 23 9122 10.3390/ijms23169122 36012386 17. Espersen R. Correia B.S.B. Rejnmark L. Bertram H.C. The Diurnal Blood Metabolome and Effects of Vitamin D Supplementation: A Randomised Crossover Trial in Postmenopausal Women Int. J. Mol. Sci. 2022 23 9748 10.3390/ijms23179748 36077145 |
Int J Environ Res Public Health Int J Environ Res Public Health ijerph International Journal of Environmental Research and Public Health 1661-7827 1660-4601 MDPI 10.3390/ijerph20053914 ijerph-20-03914 Viewpoint COVID-19 and SARS-CoV-2 Vaccines: A Cameo Role for Headache Martelletti Paolo Esposito Maria Academic Editor Department of Clinical and Molecular Medicine, Sapienza University, 00189 Roma, Italy; [email protected] 22 2 2023 3 2023 20 5 391403 1 2023 11 2 2023 20 2 2023 (c) 2023 by the author. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). Headache is a very frequent symptom in COVID-19 and SARS-CoV-2 vaccination. Many studies have emphasized its clinical diagnostic and prognostic importance on the one hand, as in many cases these aspects have been completely ignored. It is therefore opportune to go back over these lines of research in order to gather what usefulness the headache symptom may or may not represent for the clinician dealing with COVID-19 or performing or following up on the clinical course following vaccination for SARS-CoV-2. The clinical evaluation of headache in COVID-19 is not fundamental in the diagnostic and prognostic process of the emergency departments; however, the risk of severe adverse events, although very rare, must be taken into account by the clinicians. For subjects presenting with severe, drug-resistant, and delayed-onset post-vaccination headache, it could represent a possible sign of central venous thrombosis or other thrombotic complications. Thus, a re-reading of the role of headache in COVID-19 and SARS-CoV-2 vaccination seems clinically useful. headache migraine SARS-CoV-2 COVID-19 vaccines cerebral venous thrombosis thrombotic complications This research received no external funding. pmc1. Introduction Three years after the outbreak of the COVID-19 pandemic, we can pinpoint that vaccination campaigns for SARS-CoV-2 together with stringent public policies have helped to contain the pandemic, which up to the time of writing, has caused 651 million cases of COVID-19 and 6.7 million deaths, and has resulted in the administration of 13 billion doses of vaccine . Certainly, new outbreaks and/or possible pandemic resurgences may still develop, as seems to be the case in the country of origin of the pandemic, despite showing very low official figures of COVID-19 (62,723 cases and 7 deaths) in the November 2022 China Centre of Diseases Control report . The importance of variants of concern (VOC) now sees the Omicron form with its six variants expanding , and this may imply an increase in transmissibility, virulence, and change in clinical features. Consequently, the health alert levels of prevention, diagnosis, therapy, and vaccination still need to be maintained. In this context, this paper will present a description of the role of a very frequent COVID-19 symptom, which is observed in about one quarter of affected individuals: headache . What follows will be a description of the clinical diagnostic and prognostic aspects of headache regarding COVID-19 disease and also its role in vaccinated individuals. 2. COVID-19 and Headache The consideration of headache as a clinically relevant symptom of COVID-19, as well as a possible sign of mild adverse events in the immediate post-vaccinal phase or as a serious warning sign for serious adverse events due to vaccination, has been the subject of clinical reports and systematic reviews, including the persistence in long COVID headache . Regarding the last point, the current recommendation is to assign a final value to headache in multisystem COVID-19 and in mild SARS-CoV-2 infection. Additionally, given that SARS-CoV-2 carries a high incidence of ageusia and anosmia, other clinical symptoms such as headache could be scaled up in priority in terms of diagnostic importance. This is what a copious amount of literature has largely reported in all clinical areas involved with SARS-CoV-2 infection. Indeed, as far as headache in COVID-19 is concerned, it is surprising to see retrospectively both how much has been published and what has been published, even though the scientific community was going through a period of great uncertainty due to a lack of knowledge and consequently a great surrounding scientific fervor. At the time of writing, a search on PubMed using the MeSH term "COVID-19" generates about 327,000 results; if we then add the term "headache", we get about 3000 results about 0.9% as many results. The number of results can be few if we refer to a multi-system disease that is a clinical mutant and with a trend toward the reduction of secondary transmission and immune evasion. Furthermore, this non-extensive scientific interest within the torrent of scientific publications during the pandemic raises some questions . The clinical use of the headache symptom in the clinical/therapeutic course has always been of modest usefulness in emergency departments, intensive care units, as well as low and medium settings, such as the wards of the internal and emergency medicine departments, as it does not represent a main alert sign for the risk of death, even though it has previously been observed in 1684 out of 3044 hospitalized patients . Therefore, it can now be affirmed that any doubts about the relevance of research on COVID-19-related headache, apart from the transient clinical worsening observed with primary headaches, especially migraine without aura, can be definitively dismissed . 3. SARS-CoV-2 Vaccines and Headache A recent meta-analysis on the occurrence of headache as an AE after vaccination for SARS-CoV-2 showed that headache is the third most common AE associated with SARS-CoV-2 vaccination, occurring in 22% of individuals after the first vaccination dose and 29% of individuals after the second dose over a 7-day period; these rates are higher when compared with those who received placebo (10-12%) and to population studies showing a 6-17% probability of individuals having a headache on the previous day . There were no significant variations in the frequency of headache observed with the different vaccine types. In about one-third of cases, the features of this resolving headache are like those of migraine with pulsating quality, phono, and photophobia, while exacerbation with physical activity is more frequent (40-60% of cases). The onset is mostly within the first 24 h, and many patients have been on some form of medication to treat the headache, with acetylsalicylic acid considered to be the most efficacious . If we then consider the impact on migraine of vaccinations, a recent study showed that out of 841 migraine patients who filled out an online questionnaire, 66.47% and 60.15% of patients experienced a migraine(-like) attack that occurred within 1 h to 7 days of their first and second vaccination, respectively . It is, however, important to note that 57.60% of these patients reported these attacks to be more severe (50.62% of patients), longer lasting (52.80%), or resistant (49.69%) than their other case of migraine attacks. The type of causation between the two events (specific/inflammatory or non-specific/triggering) has not yet been clarified, although the immediate temporal relationship is clear . Conversely the risk of serious AE is inherent in post-vaccination headaches with delayed presentation (+-7 days), which may represent a red flag for secondary headaches due to cerebral venous thrombosis (CVT) and other thrombotic complications . The symptomatology starts about 7 days after vaccination; the headache lacks its typical characteristics and is progressively worse, unresponsive to common analgesics, and insidious, especially in migraine sufferers who underestimate the difference compared to their usual migraine crises, resulting in delayed consultation, and potentially leading to a late-onset CVT diagnosis. 4. Conclusions Vaccination for SARS-CoV-2 has played a key role in the pandemic in reducing viral aggressiveness and the subsequent clinical manifestations of COVID-19. The emergence of SARS-CoV-2 VOC with an increased tropism for the upper respiratory tract has favored a reversal of its life-threatening risk. In the light of the scientific evidence accumulated during these last three years of the pandemic, it can be affirmed that headache has not had either a diagnostic or a prognostic role in COVID-19; however, it may be present for a long time in the consortium of symptoms of long-COVID. Of considerable importance, on the other hand, is delayed headache after vaccination for SARS-CoV-2, which may underlie an elevated risk of CVT and/or other thrombotic complications and should therefore be carefully looked for in the case of post-vaccination headache occurring around seven days after vaccination. However, early post-vaccination headache does not pose any level of risk, other than that in subjects already suffering from migraine of triggering an attack that is more severe, longer, and refractory to common acute treatment than usual . Among children and adolescents infected by SARS-CoV-2, a high rate of asymptomatic carriage has been observed , and the safety of current COVID-19 vaccines has remained acceptable . Thus, in terms of considering an overall framework for the headache during COVID-19, or immediately after vaccination for SARS-CoV-2 in both migraine and non-migraine subjects, the role of headache contextualized in a broader holistic view of medicine can rightly be described as a cameo. However, the attention that needs to be paid to the rare forms of late post-vaccination thrombotic risks is quite different . Institutional Review Board Statement Not applicable. Informed Consent Statement Not applicable. Conflicts of Interest The author discloses no financial or non-financial interests that are directly or indirectly related to the work submitted for publication. The author has no relevant affiliation or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants, patents received or pending, or royalties. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Coronavirus Diseases Pandemic Available online: (accessed on 31 December 2022) 2. Reported Cases and Deaths of National Notifiable Infectious Diseases China, November 2022 China CDC Wkly. 2023 5 23 24 10.46234/ccdcw2022.234 36777471 3. 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Int J Mol Sci Int J Mol Sci ijms International Journal of Molecular Sciences 1422-0067 MDPI 10.3390/ijms24054355 ijms-24-04355 Editorial Photosynthesis 2.0 Cazzaniga Stefano Ballottari Matteo * Department of Biotechnology, University of Verona, 37134 Verona, Italy * Correspondence: [email protected] 22 2 2023 3 2023 24 5 435530 11 2022 09 1 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). This research received no external funding. pmcPhotosynthesis is a process that provides the continuous income of energy needed to sustain life on our planet. The main group of photosynthetic organisms uses water as an electron donor generating oxygen in the process. Many life forms depend upon oxygenic photosynthetic organisms to generate chemical energy from light, to extract oxygen from water, and to regulate CO2 concentrations in the atmosphere. During the last decade, several advancements have been made surrounding the fundamental molecular mechanisms at the base of photosynthesis; the study of structures of PSII, PSI complexes, and antenna proteins; how they interact and are organized inside the thylakoid membrane; and how they respond to different light regimes and to excess light stress. However, there are still several gaps in our understanding of the photosynthetic processes that need to be filled by advanced and multidisciplinary research efforts. An understanding of the mechanisms, constrains, and limitations of photosynthesis will allow for the design and testing of a synthetic biology approach that could improve the efficiency of light conversion toward Photosynthesis 2.0, with enhanced carbon fixation and biomass/biomolecule production. This understanding could help to fill the gap between actual photosynthetic productivity and the need to manage the forecasted increase in the global population. With limited agricultural land and increasing human population, it is essential to enhance productivity, and increasing the photosynthesis yield of plant and algae offers the highest potential for trying to solve these critical issues. This Special Issue aims to add to this effort by trying to provide new insight on different aspects of the photosynthesis. The papers presented in this Special Issue are studied and described below:(i) a new fluorescence technique to determine the aggregation state and quenching capacity of antenna protein applied to a new microalgal strain; (ii) a pigment composition and photosynthetic response in a poplar cultivar with increased anthocyanin content; (iii) the role of the TOR kinase in regulating photosynthesis and photomorphogenesis in plant; (iv) the change in photosynthetic apparatus and photosynthetic yield in wheat regarding pathogen infection. PSII and PSI are the complexes responsible for trapping light energy and converting it in chemical energy. The two photosystems have a similar organization being composed by a core complex surrounded by an array of antennae . While antenna proteins increase the light-harvesting efficiency in low-light conditions, too many excitations are transferred to the photochemistry in excessive light conditions and the electron transport chain becomes saturated, increasing reactive oxygen species formation and photoinhibition . Non-photochemical quenching (NPQ) dissipates the excess light energy absorbed by photosystems as heat in order to decrease the amount of excited chlorophylls . NPQ is a complex mechanism, not completely elucidated, that involves LHCII antenna aggregation . Crepin and co-workers describe a new approach using fluorescence correlation spectroscopy (FCS) to study the in vitro clustering of plant LHCII antennas in a surfactant solution. This technique allows the LHCII oligomerization state and their fluorescence properties to be simultaneously estimated in very small volumes and can help to provide new details on the molecular mechanisms of LHCII aggregation and contribute to their quenching. The same technique was used to study the aggregation state of antenna particles, isolated from alveolate alga Chromera velia , which involved comparing their sizes and fluorescence intensities with the monomeric and trimeric antennas from higher plants. The C. velia antenna complexes, called Chromera Light Harvesting (CLH), arecloser to LHC from dinoflagellate and diatoms, but with unique features such as red-shifted antenna proteins accumulated in red light. Little information was available on the organization of the LHC in this species and FCS was able to distinguish between antennae in the monomeric state and the trimeric state. CLH antennae resulted in monomeric state and these monomers were found in a more quenched state than plant trimeric LHCII. These data were also confirmed by biochemical analysis. The FCS technique, described in these two papers, could help to obtain data in the organization and quenching capacity of the photosynthetic complexes of different species. Poplar is a fast-growing tree species and an important source of raw materials with a high economic value. This species is used as a model for research on the physiological and molecular mechanisms of trees. Wang and co-workers characterized a Populus deltoides cultivar (ZHP) that constitutively accumulates a higher amount of anthocyanins, given that the leaves have a darker reddish color. The higher anthocyanin content in the ZHP reduces the light-harvesting capacity, resulting in a decrease in photosynthetic efficiency. The target of rapamycin (TOR) kinase is a central component of nutrient sensing in all eukaryotic organisms and it is also fundamental for plant development . TOR activity modulates many cellular and metabolic processes, including nutrient assimilation and transport, cell division and expansion, and plant development . Compared to the case of mammalians or yeasts, the understanding of plant and algal TOR is still limited. Song and co-workers highlighted the role of TOR on regulating photosynthesis and, in particular, on sensing the nutrients produced by photosynthesis, as well as regulating light absorption and chloroplast development. Authors described TOR cascade signaling in photomorphogenesis in the plant transition from dark to light. They also described the role of this kinase in chloroplast biogenesis and maturation, as well as the biosynthetic pathway of chlorophylls. Photosynthesis is very sensitive to abiotic stress . Drought, high or low temperatures, and excess irradiances may lead to a rapid decline in photosynthetic efficiency . Indeed, photosynthesis could be used as an early sensing tool to detect these types of stresses. In addition, photosynthesis changes in response to biotic stress in relation to various insects and pathogens . Yang and co-workers described the photosynthetic changes in wheat in response to fungal pathogens . Available literature data were integrated to highlight the photosynthetic changes in the early and late stages of pathogen infection. Photosynthetic changes during the early stage of infection are positively correlated with the resistance ability of plants, while changes in the late stage result from the resistance response itself. This correlation can also be attributed to ROS accumulation, a signaling molecules can be used to activate protective responses. Photosynthesis can thus be a useful indicator for interactions between hosts and pathogens. Author Contributions Conceptualization, M.B. and S.C.; writing original draft preparation, S.C.; writing review and editing, M.B. All authors have read and agreed to the published version of the manuscript. Institutional Review Board Statement Not applicable. Informed Consent Statement Not applicable. Data Availability Statement Not applicable. Conflicts of Interest The authors declare no conflict of interest. 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Front Pediatr Front Pediatr Front. Pediatr. Frontiers in Pediatrics 2296-2360 Frontiers Media S.A. 10.3389/fped.2023.1073090 Pediatrics Case Report Case report: Transcatheter arterial embolization in a newborn with cervical rapidly involuting congenital hemangioma and Kasabach-Merritt phenomenon Peng Ying-Hsuan 1 2 Lin Ming-Chih 3 Liu Wei-Li 4 Jan Sheng-Ling 3 5 * 1 Department of Pediatrics, Chung Shan Medical University Hospital, Taichung, Taiwan 2 Department of Pediatrics, School of Medicine, Chung Shan Medical University, Taichung, Taiwan 3 Department of Pediatrics, Children's Medical Center, Taichung Veterans General Hospital, Taichung, Taiwan 4 Department of Pediatrics, Dalin Tzu Chi Hospital, Chiayi, Taiwan 5 Department of Pediatrics, School of Medicine, National Yang-Ming University and Kaohsiung Medical University, Hsinchu and Kaohsiung, Taiwan Edited by: Tomasz Szczepanski, Medical University of Silesia, Poland Reviewed by: Toshio Harumatsu, Kagoshima, Japan Ahmed Hafez Mousa, Batterjee Medical College, Saudi Arabia * Correspondence: Sheng-Ling Jan [email protected] Specialty Section: This article was submitted to Pediatric Hematology and Hematological Malignancies, a section of the journal Frontiers in Pediatrics 24 2 2023 2023 11 107309018 10 2022 06 2 2023 (c) 2023 Peng, Lin, Liu and Jan. 2023 Peng, Lin, Liu and Jan This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Congenital hemangiomas (CHs) are rare vascular tumors and do not exhibit progressive postnatal growth. The incidence is less than 3% of all hemangiomas. Most CHs have a favorable prognosis; however, the Kasabach-Merritt phenomenon (KMP) is a rare but life-threatening complication in CHs that requires aggressive treatment. Medical treatments with corticosteroids and interferon have been suggested. Surgical resection can be considered for the treatment of complicated CHs in medically resistant lesions. Vascular embolization could be an alternative method if surgery is not considered feasible. Herein, we report a case of a 9-day-old newborn who underwent arterial embolization for a CH with KMP, combined with sirolimus treatment, and the outcome was favorable. The hemangioma completely regressed by 3 months and rapidly involuting congenital hemangioma (RICH) was diagnosed. Our successful experience with treating RICH associated with KMP revealed that RICH can have potentially serious complications although they usually resolve rapidly after birth without treatment. Surgical resection is considered to be the standard method for the treatment of medically resistant vascular tumors, but it is difficult to perform during the active phase of KMP due to acute bleeding and severe coagulopathy. Arterial embolization is feasible and can be used as an alternative to surgical resection, even in small babies. congenital hemangioma Kasabach-Merritt phenomenon coagulopathy transarterial embolization infants pmcCase report The patient was a male newborn from the first pregnancy of a clinically healthy woman. He was born at 38 + 6 weeks of gestational age by normal spontaneous delivery, weighing 2,890 g. His mother received regular prenatal examinations revealing no specific abnormality. There was a large, firm, immovable oval mass approximately 6 cm x 5 cm x 2 cm in diameter behind his left ear, with a vibrating surface on palpation, suggesting a possible fast-flowing vascular tumor. The lesion was purple in color and had a telangiectatic appearance with a central depression and pale margins . He was initially treated with propranolol combined with simple occlusive dressings containing epinephrine; however, the hemangioma became engorged with massive bleeding from the sixth day of life. Laboratory data showed Kasabach-Merritt phenomenon (KMP) with thrombocytopenia (platelet of 17,000/mL), coagulopathy (international normalized ratio of prothrombin time was 2.04 and activated partial thromboplastin time was greater than 150 s), and hypofibrinogenemia (fibrinogen of 152.1 mg/dL). Magnetic resonance imaging (MRI) on the seventh day of life revealed a well-defined margin, T2 high-intensity signals, flow voids, a vascular-rich lesion with a central scar, no intracranial extension or involvement of adjacent tissues, and confirmed the presence of a hemangioma . Biopsy was not performed due to the risk of bleeding from an associated consumptive coagulopathy. After the diagnosis of Kasabach-Merritt phenomenon was made, propranolol was shifted to sirolimus 0.8 mg/m2 twice daily. Platelet was transfused for thrombocytopenia. Fresh frozen plasma and cryoprecipitate were given due to coagulopathy. However, the active bleeding persisted. Thrombocytopenia and coagulopathy cannot be corrected under medical treatment. Platelet decreased to 14,000/mL. Hemoglobin dropped from 14 to 7.4 mg/dL. Pediatric surgeon was consulted for the possibility of surgery, but he hesitated because of the higher risk during the acute phase of KMP. Therefore, transcatheter arterial embolization was performed at 9 days of age and 3.05 kg weight. Selective left common carotid arteriography demonstrated a clear boundary, uniform parenchymal staining mass with a single large feeder artery from the internal carotid artery . A 4F delivery catheter (Amplatzer Judkins Right catheter, Abbott Medical, MN, United States) was advanced over a 0.018'' Terumo guide wire into the feeding artery of the mass lesion. A total of three Cook Embolization Coils, two 3 mm x 4 cm, one 3 mm x 5 cm, and one 3/2 mm x 2 cm Cook Tornado Embolization Microcoil (Cook Medical, Bloomington, IN, United States), were selected for embolization of the feeding artery. Repeat arteriography showed no obvious residual shunt after embolization . After transcatheter embolization, the bleeding stopped. Moreover, there was no transcatheter complications noted including renal impairment or femoral vascular damage. Laboratory data revealed neither thrombocytopenia nor coagulopathy 1 week later. No more blood transfusion was needed. Due to stable condition, he was discharged from the hospital on day 18 . At 3 months, the hemangioma had almost completely regressed, leaving a halo-shaped telangiectatic scar , and then sirolimus was shifted to propranolol. He received regular follow-up at outpatient department. The scar became lighter and lighter gradually without hemangioma recurred. Propranolol was tapered and discontinued 6 months later. Eventually, rapidly involuting congenital hemangioma (RICH) was diagnosed and cured successfully by transcatheter arterial embolization. Medical treatment do not require in a long time. Figure 1 (A) A purple, telangiectatic, centrally depressed mass with pale margins was found behind the left ear at birth. (B) The mass shrank 2 weeks after arterial embolization. (C) The mass had almost completely resolved by 3 months of age, leaving a telangiectatic scar with halo margins. Figure 2 (A) Magnetic resonance imaging showed a well-defined margin, vascular-rich lesion with a central scar. (B) Selected left common arteriography demonstrated a clear boundary, uniform staining mass with a feeder artery from the internal carotid artery to the mass without collateral artery to adjacent organs (arrow). (C) Repeat arteriography after arterial embolization using multiple coils shows no residual shunt (arrow). Discussion Infantile hemangiomas (IHs) with strawberry-like bright red and ridged appearance are common, occurring in 1%-2% of newborns (1). Typical IHs rapidly grow 1 year after birth, followed by slow complete involution in subsequent years. Congenital hemangiomas (CHs) are often clinically and histopathologically distinguishable from IHs. CHs are rare, accounting for less than 3% of all hemangiomas (2). CHs are fully developed at birth and do not proliferate further (3). The diagnosis of CHs is based on the combination of clinical, histological, and imaging features and is confirmed by subsequent changes of the tumor. CHs are usually diagnosed as high-flow parenchymal, violaceous, and telangiectatic masses. CHs are mainly classified into two types: RICH and non-involuting congenital hemangioma (NICH). RICH and NICH share many similarities in appearance, location, size, sex distribution, and imaging studies, but both have different regressive changes and overlapping histological appearances. RICH, the most common type of CH, tends to have accelerated regression after birth, so lesions usually resolve completely by 6-14 months, leaving atrophic skin. NICH does not resolve, defined as no change in size or color by 6 months, usually requiring surgical excision (4). CHs, especially RICHs, can look very much like Kaposiform hemangioendothelioma (KHE), particularly in the neonatal period and should be carefully differentiated (5). KHE is a rare vascular tumor of infancy that presents as a locally infiltrating subcutaneous violaceous mass. Spontaneous involution is very rare in KHE and usually requires multimodal treatment. KMP, a severe, life-threatening consumptive coagulopathy with profound thrombocytopenia and hypofibrinogenemia with elevated coagulation activation markers, is a common complication of KHE and occasionally occurs in CHs. KMP is currently thought to occur in approximately 42%-71% of KHE and less than 10% of CHs (3, 6, 7). A comparison of the two common infantile vascular tumors associated with KMP is shown in Table 1 (3-6, 8). Table 1 Comparison of two common infantile vascular tumors associated with KMP (3-6, 8). RICH KHE Incidence <3-6/10,000 (4) <1/10,000 (6) Sex distribution Female = male (4) Slight male predominance (6) Clinical presentation Location Head/neck = extremities Extremities > trunk or head/neck, 12% extracutaneous Size 1-15 cm 0.9-7 cm Appearance Raised, round or ovoid, violaceous tumor, covered with telangiectases, surrounding pale rim, central ulcer/scar Slightly raised, erythematous papule, plaque, or nodule to an indurated, purple, and firm tumor Complications Occasional; ulceration with bleeding, compression of vital structures, congestive heart failure Common; local invasive features, compression of vital structures, lymphedema KMP Occasional, less than 10% (3) Frequent, about 42%-71% (6) Diagnostic modalities Ultrasonography Echogenic, well-defined vascular parenchymal mass with fast-flow, occasional venous lakes/ectasia Heterogeneous echogenicity, ill-defined vascular mass with infiltrative pattern, rare venous lakes/ectasia MRI Well-defined margins, T2 hyperintense masses with high-flow vessels, flow voids, and without adjacent destruction Ill-defined margins, multiplanar, diffuse enhancement, T1 isointensity relative to adjacent muscle, T2 hyperintensity, occasional flow voids Angiography Clear boundary, uniform staining, distributed on one side of the normal artery, usually 1-4 feeder arteries, and the diameter is proportional to the tumor size Obscure boundary, uneven staining, surrounding the normal artery, fine and multifeeder arteries, and the diameter is not proportional to the tumor size Biopsy Circumscribed small lobules of capillaries lined by endothelial cells and surrounded by fibrous tissue, absent staining for the lymphatic markers and glucose transporter-1 (GLUT-1) Coalescing nodules of spindled endothelial cells, slit-like or crescentic vessels containing hemosiderin, positive staining for the lymphatic markers, negative for glucose transporter-1 (GLUT-1) Treatment and prognosis Treatment Most (about 90%) do not require therapy and propranolol is ineffective. corticosteroids, interferon-a, surgical resection Propranolol, corticosteroids, vincristine, sirolimus, interferon-a, surgical resection. Needs combination therapy if with KMP Embolization Feasible technique to embolize for larger and fewer feeding vessels Challenging technique to embolize for fine and multifeeding vessels Prognosis Most fully regress by 12 months, mortality is rare (6) Rare spontaneous involution, most progressive enlargement, 30% mortality (6) KHE, kaposiform hemangioendothelioma; KMP, Kasabach-Merritt phenomenon; MRI, magnetic resonance imaging; RICH, rapidly involuting congenital hemangioma. Since most RICHs usually resolve rapidly after birth, most affected cases do not require treatment and only need to be kept in observation. However, RICH can have potentially serious complications, such as ulceration with bleeding, vital organ compression, KMP, and congestive heart failure. Treatment of complicated RICH includes assessment of hemodynamic status, wound care, pharmacologic therapy, and surgery or embolization. Compared to IHs, propranolol treatment is now known to be ineffective for CHs (9). Corticosteroid and interferon alfa-2a are used for some dangerous lesions (3). Surgical resection is indicated for persistent ulceration and bleeding, sepsis, hemodynamic instability, or high-output cardiac failure in medically resistant cases. RICH complicated by KMP can be mild and transient, but there have also been reports of RICH complicated by severe and life-threatening KMP, including our case (3). As the mortality rate of KMP is as high as 8%-24% (10), accurate diagnosis of KMP and prompt treatment are very important. Due to the rarity of cases of RICHs complicated with KMP (11), there are currently no standard treatment guidelines for RICH complicated with KMP. Treatment is based primarily on expert opinion as well as treatment experience with a small number of KMP case reports and case series (12, 13). Supportive treatment should be provided first to prevent the patient's condition from getting worse, followed by curative therapy for the underlying vascular tumor. Fresh frozen plasma or cryoprecipitate is used to correct coagulopathy. Platelets are reserved for active bleeding during or before surgery because it will exacerbate mass bleeding and the trapping of platelets in the tumor (6, 13). Surgical resection is considered to be the standard method for the treatment of vascular tumors, but it is difficult to perform during the active phase of KMP due to acute bleeding and severe coagulopathy. Instead, technical difficulty is not the main limitation of transcatheter arterial embolization nowadays. It is very straightforward for experienced pediatric interventional cardiologists and radiologists. Advantages of arterial embolization include lower risk of anesthesia, smaller wound, and shorter recovery time. We should still pay attention to avoid transcatheter complications such as contrast allergy, renal impairment, thrombus formation, or vascular injury during the procedure. In our case, embolization was initially performed because surgery was considered too risky. On the other hand, pharmacologic therapy takes too long to correct coagulopathy with active bleeding. Therefore, transcatheter arterial embolization may be a feasible therapy for the treatment of RICH complicated by KMP, because RICH is characterized by larger and fewer feeder vessels. In contrast, in neonates and young infants with KHE, access to very small and numerous feeder arteries remains technically more difficult (6, 8). In this case, a 9-day-old neonate with RICH underwent arterial embolization in combination with sirolimus for a rare but life-threatening complication of KMP with good outcomes. Our successful experience with treating RICH associated with KMP revealed that RICH can have potentially serious complications although they usually resolve rapidly after birth without treatment. Surgical resection is considered to be the standard method for the treatment of medically resistant vascular tumors, but it is difficult to perform during the active phase of KMP due to acute bleeding and severe coagulopathy. Arterial embolization is feasible and can be used as an alternative to surgical resection, even in small babies. Acknowledgments The language of this study was edited by American Journal Experts (AJE) groups. Data availability statement The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author. Ethics statement Written informed consent was obtained from the individual(s), and minor(s)' legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article. Author contributions Y-HP and W-LL: data collection, data analysis, interpretation, and writing. M-CL and S-LJ: study design, interpretation, writing, and reviewing. All authors contributed to the article and approved the submitted version. Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher's note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. References 1. Pratt AG . Birthmarks in infants. Arch Dermatol. (1953) 67 (3 ):302-5. 10.1001/archderm.1953.01540030065006 2. North PE Waner M Mizeracki A Mihm MC Jr . GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas. Hum Pathol. 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Rapidly involuting congenital haemangioma associated with transient thrombocytopenia and coagulopathy: a case series. Br J Dermatol. (2008) 158 (6 ):1363-70. 10.1111/j.1365-2133.2008.08546.x 18410425 8. Tan X Liu Z Zhou S Chen K Zhang M Xia J Analysis of angiographic characteristics of kaposiform hemangioendothelioma and investigation of the value of transcatheter arterial embolization therapy. Transl Pediatr. (2021) 10 (12 ):3194-201. 10.21037/tp-21-486 35070833 9. Saint-Jean M Leaute-Labreze C Mazereeuw-Hautier J Bodak N Hamel-Teillac D Kupfer-Bessaguet I Groupe de recherche clinique en dermatologie pediatrique [Propranolol for treatment of ulcerated infantile hemangiomas]. J Am Acad Dermatol. (2011) 64 (5 ):827-32. 10.1016/j.jaad.2010.12.040 21353332 10. Ryan C Price V John P Mahant S Baruchel S Brandao L Kasabach-Merritt phenomenon: a single centre experience. Eur J Haematol. (2010) 84 (2 ):97-104. 10.1111/j.1600-0609.2009.01370.x 19889011 11. Hsiao CH Tsao PN Hsieh WS Chou HC . 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Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34771 Endocrinology/Diabetes/Metabolism Urology Therapeutics Testicular Regression Syndrome: Two Case Studies Muacevic Alexander Adler John R Elazizi Lamiaa 1 Elazime Zineb 1 Lahmamssi Fatima-Zahra 1 Salhi Houda 1 Elouahabi Hanan 1 1 Department of Endocrinology, Diabetology, Metabolic Diseases and Nutrition, Hassan II University Hospital Center, Fez, MAR Lamiaa Elazizi [email protected] 8 2 2023 2 2023 15 2 e347718 2 2023 Copyright (c) 2023, Elazizi et al. 2023 Elazizi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Testicular agenesis, also called testicular regression syndrome (TRS), is a rare disease. It is defined by the complete absence of testicular tissue associated with a 46,XY karyotype. The phenotype is variable depending on when gonadal regression occurs in utero. Several etiologies have been identified. Here, we report two cases of TRS with an initial diagnosis of cryptorchidism and bilateral impalpable testes. The hormonal assessment showed an undetectable anti-Mullerian hormone (AMH) level and high gonadotropins. Also, radiological exploration did not show the testicles in a normal position, which was confirmed by a negative laparoscopy, establishing the diagnosis of TRS. Androgen replacement therapy along with psychological support to the patient is recommended is such cases. laparoscopy karyotype amh testicular agenesis testicular regression The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Bilateral testicular agenesis or bilateral congenital anorchia (BCA) is defined as the absence of partial or complete testicular tissue in the presence of a 46,XY karyotype, and is part of testicular regression syndrome (TRS) . Its incidence is estimated to be 0.5-1 in 20,000 men . Diagnosis is based on clinical findings, endocrine investigations, cytogenetic analysis, and sometimes surgical exploration. Unfortunately, androgen replacement therapy and prosthetic implantation are the only available therapies for these patients. Herein, we report two cases of bilateral testicular regression syndrome. Case presentation Case 1 A 24-year-old male with a history of treated pleural tuberculosis was followed up from the age of five years for a suspicion of cryptorchidism discovered through the observation of a micropenis with non-palpable testes during a physical examination. The patient was not seen again until he was 15 years old, when he was examined due to delayed puberty. The patient had been treated for micropenis (three monthly testosterone enanthate IM injections at a dose of 100 mg/m2). The clinical examination found the patient in a good general condition, with depressed mood, without dysmorphia, and without macroscelia. His weight was 46.5 kg, with a body mass index of 16.08 kg/m2, and height was 1.70 m. The penile length was 7.5 cm (-1.5 SD). Pubic hair was classified as Tanner stage IV, and axillary hair was present. Gynecomastia or spontaneous or induced galactorrhea was not present. Absence of palpable testes in both the intrascrotal and inguinal regions was found. The karyotype was normal (46,XY) and the SRY gene was normal. His hormonal assessment showed objectively high gonadotropin levels with follicle stimulating hormone (FSH) at 73.9 mIU/mL (normal value, or NV, 1.27-19.26), luteinizing hormone (LH) at 15.37 mIU/mL (NV, 1-7), and an undetectable testosterone level, leading to the conclusion of hypergonadotropic hypogonadism. A human chorionic gonadotropin (HCG) test came out negative, and the anti-Mullerian hormone (AMH) level was found to be very low. Abdominopelvic and scrotal ultrasounds did not show the testicles in a normal position, which was confirmed by a negative laparoscopy . This confirmed the diagnosis of TRS. Regarding the therapeutic procedure, hormone replacement therapy was initiated (250 mg of testosterone enanthate IM every three weeks) and psychological support was offered before sending him for scrotoplasty. Figure 1 A transverse ultrasound image, in a ventral view through penis and bursae (arrows) Case 2 A 36-year-old male had consulted with the urology department (Hassan II University Hospital) at the age of 17 for suspicion of cryptorchidism and was then admitted to our endocrinology department for additional treatment. The clinical examination found the patient in a good general condition, with depressed mood and without dysmorphism. His weight was 81 kg, height 160 cm and body mass index 31.50 kg/m2. His facial hair was well-developed. The examination also showed pubic hair at stage V and a 9-cm penis (-1 SD) with a small empty, pleated scrotal bursa. The patient's hormonal assessment revealed high gonadotropin levels with FSH at 54.1 mIU/mL (NV, 1.27-19.26) and LH at 23.9 mIU/mL (NV, 1-7), and his testosterone levels were undetectable, leading to the conclusion of hypogonadotropic hypogonadism. Cytogenetic examination revealed a 46,XY karyotype. Karyotyping confirmed the patient to be a 46,XY male with no evidence of mosaicism in the blood cells. PCR amplification of the SRY gene indicated that the patient's SRY gene was normal. The AMH assay showed a level of <0.01 ng/mL (3.1-5.3), and the HCG test was not performed. The abdominopelvic computed tomography did not reveal the presence of intra-abdominal testicles or any other detectable anomaly. A laparoscopy was subsequently performed and returned negative. In view of these tests, the diagnosis was determined to be that of testicular regression syndrome. Psychological care was first indicated for our patient, and he was then sent for plastic surgery to benefit from a bilateral mastectomy and testicular prosthesis. To address the patient's hormonal levels, he was put on hormone replacement therapy with testosterone enanthate. Discussion The true prevalence of TRS remains unknown. It is estimated to affect 0.5-1 in 20,000 male births and occurs in 1 out of 177 cases of cryptorchidism . Testicular agenesis is a congenital malformation characterised by the absence of testicles due to abnormalities at the start of embryogenesis . Indeed, the foetal testicle must be present during the first 12 weeks of pregnancy for the normal development of male genitalia . Thus, the presence of a normal male phenotype suggests that gonadal regression occurred late in the foetal life, beyond the 12th-14th gestational weeks. Furthermore, rudimentary testicular syndrome develops between the 14th and 20th weeks of pregnancy while anorchia develops after 20 weeks . This is characterised by the internal and external differentiation of the genitalia without the presence of gonadal tissue. This was the case with the two patients in this case study. In both situations, the foetal testicle was functional, ensuring fairly sufficient production of androgen for normal differentiation of the male genital tract and external genitalia through the action of AMH and testosterone. On the other hand, early testicular regression before eight weeks of pregnancy would be due to a female phenotype, and between 8 and 12 weeks would be due to intermediate phenotypes characterised by sexual ambiguity. These forms present the clinician with the problem of sex assignment. Although the aetiology of testicular agenesis is not fully understood, several hypotheses have been invoked to explain this phenomenon. Some have thought that testicular atrophy results from vascular thrombosis or from testicular torsion in the foetal or perinatal period given the demonstration of macrophages loaded with hemosiderin on the surgical specimens . Furthermore, a combination of a micropenis and an anomaly in the development of the sexual ducts is often present, suggesting the prior presence of an intrinsic alteration of the testicular tissue before its regression. Finally, the description of similar cases in consanguineous families and the association with other congenital malformations suggest a genetic aetiology with autosomal recessive transmission or environmental factors . Indeed, heterozygous mutations of testicular differentiation genes such as WT1, SOX9 and DMRT1 have been described in cases of testicular agenesis in humans. Other genes involved in the development or descent of the gonads (SRY, INSL3 or LGR8) have been suggested, but, to our knowledge, no mutations at these levels have been documented to date . Our observations show that the growth and development of children with testicular agenesis before puberty are normal. Timed androgen replacement therapy leads to a pubertal growth spurt with normal secondary sex characteristics and normal bone maturation. A delay in treatment initiation after normal puberty bone age leads to the development of eunuchoid body proportions. Biologically, the AMH level can be used as a marker for the presence of testicular tissue. Extremely low or undetectable AMH levels with an absence of the plasma testosterone response to stimulation by HCG can indicate TRS. Misra et al. reported a higher specificity and positive predictive value of AMH compared to the HCG test for diagnosis . The levels of gonadotropins, FSH and LH are found to be high. The combination of undetectable AMH levels and high gonadotropins during puberty is very likely in the diagnosis of TRS. However, an HCG stimulation test is necessary in prepubertal children, whose gonadotropin levels are not high, to eliminate the rare cases of persistence of Muller's ducts, or dosage errors. In the first patient, we noted perfect concordance between the AMH results and the HCG stimulation test. In the second patient, for whom the stimulation test was not performed, laparoscopic exploration was indicated, which subsequently confirmed the diagnosis. Ultrasound and magnetic resonance imaging may sometimes fail to show testicular tissue . Diagnostic confirmation can only be provided by laparoscopic exploration, the use of which remains controversial . When it is carried out, it can confirm the absence of gonads, as was the case for our patients, or the presence of rudimentary testicles. It can also confirm the existence of a normal arrangement of the spermatic pedicle and the vas deferens, testifying to normal migration of the testicle that was destroyed late in the foetal life . Given the negligible risk of malignant degeneration of the testicular tissue, which is only found in 10% of explorations, and without germ cells on the surgical specimens, some authors suggest that laparoscopic exploration is not systematic . However, other authors reported the presence of germ cells in 11% of cases and seminiferous tubules in 0 to 40%, with viability in 0 to 16% of cases. This raises fears of a potential risk of malignant degeneration, thus justifying laparoscopic exploration. We also believe that laparoscopy should always be indicated, which was carried out in our first patient, to be able to conclude the status of the gonads definitively, thus obviating other investigations. Patient management requires a multidisciplinary team approach. Androgen replacement therapy is recommended at the time of puberty. The presence of a micropenis, as in our patients, requires androgen therapy to be initiated as soon as possible to avoid further burdening their psychological experience in adolescence and adulthood. Indeed, psychological evaluation and advice from the parents at diagnosis are necessary. Implantation of a testicular prosthesis can be envisaged for psycho-social and aesthetic reasons but should be carried out before the start of replacement treatment. This technique carries possible complications, such as inflammation or perforation of the skin. Finally, psychological support should be offered to patients and their families. Conclusions Testicular regression syndrome is a rare condition that is defined by the complete absence of testicular tissue in a patient with a normal male karyotype. The phenotype is variable depending on when gonadal regression occurs in utero. Its aetiology is still debated but its familial occurrence is an argument to suggest a genetic aetiology. The diagnostic approach of this entity requires paraclinical investigations or even laparoscopy. The therapeutic possibilities are currently limited to androgen replacement therapy that could be combined with the implantation of a prosthesis. It is necessary to initially give psychological support to the parents and then to the patient himself, thus improving the experience of the pathology. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 The vanishing testis Lancet Abeyaratne WA Aherne WA Scott JE 822 824 294 1969 2 Natural history of testicular regression syndrome and consequences for clinical management J Pediatr Urol Hegarty PK Mushtaq I Sebire NJ 206 208 3 2007 18947736 3 Undescended testis - current trends and guidelines: a review of the literature Arch Med Sci Niedzielski JK Oszukowska E Slowikowska-Hilczer J 667 677 12 2016 27279862 4 Congenital bilateral anorchia in childhood: a clinical, endocrine and therapeutic evaluation of twenty-one cases Clin Endocrinol (Oxf) Aynsley-Green A Zachmann M Illig R Rampini S Prader A 381 391 5 1976 786507 5 46,XY disorders of sex development (DSD) Clin Endocrinol (Oxf) Mendonca BB Domenice S Arnhold IJ Costa EM 173 187 70 2009 18811725 6 Bilateral anorchia in infancy: occurence of micropenis and the effect of testosterone treatment J Pediatr Zenaty D Dijoud F Morel Y 687 691 149 2006 17095345 7 Familial functional anorchism: a review of etiology and management J Urol Connors MH Styne DM 1049 1051 133 1985 3999209 8 Vanishing testes: a literature review J Clin Res Pediatr Endocrinol Pirgon O Dundar BN 116 120 4 2012 22985611 9 An analysis of the genetic factors involved in testicular descent in a cohort of 14 male patients with anorchia J Clin Endocrinol Metab Vinci G Anjot MN Trivin C Lottmann H Brauner R McElreavey K 6282 6285 89 2004 15579790 10 Measurement of Mullerian inhibiting substance facilitates management of boys with microphallus and cryptorchidism J Clin Endocrinol Metab Misra M MacLaughlin DT Donahoe PK Lee MM 3598 3602 87 2002 12161481 11 The limited role of imaging techniques in managing children with undescended testes J Urol Hrebinko RL Bellinger MF 458 460 150 1993 8100860 12 Comparison of ultrasonographic and laparoscopic findings in adult nonpalpable testes cases Eur Urol Pekkafali MZ Sahin C Ilbey YO Albayrak S Yildirim S Basekim C 124 127 44 2003 12814687 13 Laparoscopic surgery for undescended testicles. (Article in French) Arch Pediatr Stefaniu M Lefebure B Liard-Zmuda A Bachy B 315 318 11 2004 15051089 14 Laparoscopic management of impalpable testis in children, new classification, lessons learned, and rare anomalies J Laparoendosc Adv Surg Tech A Hassan ME Mustafawi A 265 269 20 2010 20059389 15 Congenital bilateral anorchia: clinical, hormonal and imaging study in 12 cases Andrologia De Rosa M Lupoli G Mennitti M Zarrilli S Mirone V Lombardi G 281 285 28 1996 8893097 |
Int J Mol Sci Int J Mol Sci ijms International Journal of Molecular Sciences 1422-0067 MDPI 10.3390/ijms24054744 ijms-24-04744 Editorial Autophagy in Cell Survival and Death Yang Jinsung Kim Wanil Kim Deok Ryong * Department of Biochemistry and Convergence Medical Science, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju 52727, Republic of Korea * Correspondence: [email protected]; Tel.: +82-55-772-8054 01 3 2023 3 2023 24 5 474421 2 2023 27 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). National Research Foundation of Korea (NRF)2022K1A3A1A18079735 Korean Government (MSIT)2020R1A2C2011416 2022R1A2C1092943 Institute of Health Sciences of Gyeongsang National UniversityIHS GNU-2022-01 Gyeongsang National UniversityThis work was supported by a National Research Foundation of Korea (NRF) grant, funded by the Korean Government (MSIT) (2020R1A2C2011416, 2022R1A2C1092943). This work was supported under the framework of the international cooperation program managed by the National Research Foundation of Korea (2022K1A3A1A18079735). This research was supported by a grant from the Institute of Health Sciences of Gyeongsang National University, IHS GNU-2022-01. This work was supported by funding from the research promotion program, Gyeongsang National University, 2022. pmcAutophagy is a degradative process to remove damaged or unnecessary cellular components, and it has been implicated in many biological processes during cell survival and death . Several factors, such as the availability of nutrients and growth factors, intracellular metabolic situations, and other environmental stressors, could determine the cell fate between survival and death, as shown in Figure 1. Under these conditions, autophagy plays a multifunctional role in cell fate determination. It can promote cell growth under starvation by providing nutrients necessary for survival through the degradation of self-components. Additionally, autophagy can induce cell death under specific conditions, including prolonged starvation and stress, by activating the apoptotic process. The context-dependent activation of autophagy is critical for deciding cell fate. To date, the molecular mechanism of induction of autophagy is relatively well-established, but the mechanisms interacting with autophagy are not fully understood. This Special Issue focuses on the link between autophagy and various biological functions. Biagioni et al. suggested that the autophagoproteasome is suppressed within the ischemic penumbra . The ischemic penumbra is a region in the brain between the dying part caused by ischemic stroke and the salvageable part that still receives blood supply. The overexpression of HSP70 is a well-established biochemical marker of the penumbra area. The region's autophagy-related proteins, including LC3, increase to keep the system cleared. Indeed, P20S colocalized with LC3 within autophagoproteasome vacuoles, and these proteins were massively degraded within the penumbra area. This study provides a molecular and spatial understanding of the ischemic penumbra. Lin et al. showed that fatty acid binding protein 6 (FABP6) regulates cell cycle progression and autophagy in bladder cancer (BC) cells . Knockdown of FABP6 inhibited BC cell growth via regulation of cell-cycle-related protein expressions. It also caused a severe decrease in nuclear receptor PPARs/RXRa and activation of NF-kB signaling. Moreover, in the FABP6-deficient cells, the activated signaling of AKT and mTOR inhibited autophagy. As a result, FABP6 regulates the focal adhesive protein level in BC cells and decreases cancer cell migration. This study suggested that controlling FABP6 can be a novel strategy for the progression of BC cells. Jalouli et al. stressed the adverse effect of pyrethroid-based insecticides in developing rat ovaries . Allethrin is one of the most commonly utilized pyrethroids. In the paper, the authors intragastrically administered allethrin and assessed the consequences. Allethrin caused structural damage and oxidative stress in ovaries. It also inhibited the expression of PI3K/AKT/mTOR. Moreover, allethrin increased the expression of the autophagy marker, LC3, and proapoptotic marker, caspase-3. In conclusion, exposure to allethrin may cause significant damage to the female reproductive system via the structural and functional alterations in the ovary. Kim et al. showed that zinc deficiency activates autophagy in hippocampal neuronal cells . Zinc deficiency due to the zinc chelator, N, N, N', N'-tetrakis (2-pyridyl methyl) ethylenediamine (TPEN), in HT-22 cells promoted the lipidation of LC3 and its subsequent cytotoxicity. Additionally, TPEN treatment increased the expression of several autophagy-related genes and the phosphorylation of AMPK. Moreover, autophagy inhibition reversed TPEN-dependent cell survival. Therefore, this study demonstrated that neural cells are protected by zinc deficiency-induced autophagy. Jeon et al. researched the role of the cytoprotective function of L-serine in hippocampal neurons . Propionic acid (PPA) decreased cell viability and lysosomal activity in HT-22 cells. Moreover, PPA-induced lipid accumulation was reduced by L-serine. Colocalized lipid droplets and lysosomes were observed regardless of lysosomal activity. L-serine recovered dysfunctional lysosomes induced by PPA and decreased lipid accumulation. In conclusion, L-serine controls lipid metabolism by inducing the lysosomal activity in hippocampal neurons. Jung et al. proposed that chrysin, a flavonoid compound, induces both autophagy and apoptosis in human mucoepidermoid carcinoma (MC-3) cells . According to the results, chrysin treatment stimulated autophagy via the lipidation of LC3, expression of Beclin-1, and inhibition of the mTOR signal. This chrysin-induced autophagy significantly protected the cells from apoptosis triggered by chrysin via mitogen-activated protein kinases (ERK, JNK, and p38), suggesting that balance between autophagy and apoptosis is critical for maintaining cellular homeostasis and that chrysin has a potential anticancer effect in MC-3 cells. Lv et al. discussed the role of exogenous hydrogen sulfide (H2S) in regulating autophagy in diabetic-related diseases . H2S is a signal transducer in many biological functions, including antiapoptosis, antioxidative stress, blood vessel relaxation, blood pressure reduction, and the anti-inflammatory process. Indeed, H2S triggered autophagy via the Keap1 , AMPK/mTOR , PI3K/AKT1 , SIRT6/AMPK , Nrf2/ROS/AMPK , TGFb1/NF-kB/AKT , and BDNF/TrkB pathways in diabetes-related diseases. In conclusion, understanding the role of autophagy regulated by H2S may provide a potential therapeutic strategy for diabetes. Yang discussed autophagic regulation during the viral binding to cell surface receptors . A virus binds to its specific receptors to infect cells. Binding viral particles to their specific receptors on the host cells can regulate several intracellular signalings, including autophagy, during infection. This autophagy activation subsequently triggers the removal of pathogens via lysosomal degradation, but how viral binding to receptors on the cell surface induces autophagy is unclear. Many viruses use CD46, TLRs, and integrins as binding receptors. In the paper, the author summarized some details about how these interactions trigger and activate autophagy and what are determinants for either viral survival or eradication, although further studies are necessary to understand the effect of viral binding in regulating autophagy. Truzzi et al. suggested that wheat-germ spermidine (SPD) and clove eugenol (EUG) combination supplement (SUPPL) could reduce inflammatory parameters by activating autophagy in intestinal epithelial cells . SUPP ameliorated the inflammation induced by lipopolysaccharide through the activation of AMPK-dependent autophagy. Therefore, this study exhibits the impact of SUPPL on anti-inflammation by targeting autophagy. In conclusion, autophagy is a biological response that protects cells from internal or external stimuli and interacts with various cell signaling systems. This Special Issue discussed the role of autophagy in neurons, adipocytes, and the uterus. In addition, it discussed that various stimuli regulate the activity of autophagy. Autophagy can either save or kill cells depending on the cellular condition, but further studies could be necessary for assuring its detailed mechanisms in the future. These studies will shed light on understanding autophagy-dependent cell survival and death in different systems. We hope this Special Issue will be helpful to researchers who study autophagy. Author Contributions Conceptualization, J.Y. and D.R.K.; writing original draft preparation, J.Y.; writing review and editing, J.Y., W.K. and D.R.K.; supervision, D.R.K.; funding acquisition, J.Y. and D.R.K. All authors have read and agreed to the published version of the manuscript. Institutional Review Board Statement Not applicable. Informed Consent Statement Not applicable. Data Availability Statement Not applicable. Conflicts of Interest The authors declare no conflict of interest. Figure 1 Cell fate can be determined by autophagy regulators under many biological conditions. This figure was created with www.Biorender.com, accessed on 1 March 2023. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Jung S. Jeong H. Yu S.-W. Autophagy as a decisive process for cell death Exp. Mol. Med. 2020 52 921 930 10.1038/s12276-020-0455-4 32591647 2. Biagioni F. Mastroiacovo F. Lenzi P. Puglisi-Allegra S. Busceti C.L. Ryskalin L. Ferese R. Bucci D. Frati A. Nicoletti F. The Autophagy-Related Organelle Autophagoproteasome Is Suppressed within Ischemic Penumbra Int. J. Mol. Sci. 2021 22 10364 10.3390/ijms221910364 34638703 3. Lin C.-H. Chang H.-H. Lai C.-R. Wang H.-H. Tsai W.-C. Tsai Y.-L. Changchien C.-Y. Cheng Y.-C. Wu S.-T. Chen Y. Fatty Acid Binding Protein 6 Inhibition Decreases Cell Cycle Progression, Migration and Autophagy in Bladder Cancers Int. J. Mol. Sci. 2022 23 2154 10.3390/ijms23042154 35216267 4. Jalouli M. Mofti A. Elnakady Y.A. Nahdi S. Feriani A. Alrezaki A. Sebei K. Bizzarri M. Alwasel S. Harrath A.H. Allethrin Promotes Apoptosis and Autophagy Associated with the Oxidative Stress-Related PI3K/AKT/mTOR Signaling Pathway in Developing Rat Ovaries Int. J. Mol. Sci. 2022 23 6397 10.3390/ijms23126397 35742842 5. Kim S.-Y. Lee J.-H. Kim S.-A. Zinc Deficiency Induces Autophagy in HT-22 Mouse Hippocampal Neuronal Cell Line Int. J. Mol. Sci. 2022 23 8811 10.3390/ijms23158811 35955944 6. Jeon H. Kim Y.J. Hwang S.-K. Seo J. Mun J.Y. Restoration of Cathepsin D Level via L-Serine Attenuates PPA-Induced Lysosomal Dysfunction in Neuronal Cells Int. J. Mol. Sci. 2022 23 10613 10.3390/ijms231810613 36142514 7. Jung G.-H. Lee J.-H. Han S.-H. Woo J.-S. Choi E.-Y. Jeon S.-J. Han E.-J. Jung S.-H. Park Y.-S. Park B.-K. Chrysin Induces Apoptosis via the MAPK Pathway and Regulates ERK/mTOR-Mediated Autophagy in MC-3 Cells Int. J. Mol. Sci. 2022 23 15747 10.3390/ijms232415747 36555388 8. Lv S. Liu H. Wang H. Exogenous Hydrogen Sulfide Plays an Important Role by Regulating Autophagy in Diabetic-Related Diseases Int. J. Mol. Sci. 2021 22 6715 10.3390/ijms22136715 34201520 9. Xie L. Gu Y. Wen M. Zhao S. Wang W. Ma Y. Meng G. Han Y. Wang Y. Liu G. Hydrogen Sulfide Induces Keap1 S-sulfhydration and Suppresses Diabetes-Accelerated Atherosclerosis via Nrf2 Activation Diabetes 2016 65 3171 3184 10.2337/db16-0020 27335232 10. Wang H. Zhong P. Sun L. Exogenous hydrogen sulfide mitigates NLRP3 inflammasome-mediated inflammation through promoting autophagy via the AMPK-mTOR pathway Biol. Open 2019 8 bio043653 10.1242/bio.043653 31315822 11. Xiao T. Luo J. Wu Z. Li F. Zeng O. Yang J. Effects of hydrogen sulfide on myocardial fibrosis and PI3K/AKT1-regulated autophagy in diabetic rats Mol. Med. Rep. 2016 13 1765 1773 10.3892/mmr.2015.4689 26676365 12. Li Y. Liu M. Song X. Zheng X. Yi J. Liu D. Wang S. Chu C. Yang J. Exogenous Hydrogen Sulfide Ameliorates Diabetic Myocardial Fibrosis by Inhibiting Cell Aging Through SIRT6/AMPK Autophagy Front. Pharmacol. 2020 11 1150 10.3389/fphar.2020.01150 32903815 13. Liu J. Wu J. Sun A. Sun Y. Yu X. Liu N. Dong S. Yang F. Zhang L. Zhong X. Hydrogen sulfide decreases high glucose/palmitate-induced autophagy in endothelial cells by the Nrf2-ROS-AMPK signaling pathway Cell Biosci. 2016 6 33 10.1186/s13578-016-0099-1 27222705 14. Lu M. Li H. Liu W. Zhang X. Li L. Zhou H. Curcumin attenuates renal interstitial fibrosis by regulating autophagy and retaining mitochondrial function in unilateral ureteral obstruction rats Basic Clin. Pharmacol. Toxicol. 2021 128 594 604 10.1111/bcpt.13550 33354908 15. Liu H.Y. Wei H.J. Wu L. Liu S.M. Tang Y.Y. Zou W. Wang C.Y. Zhang P. Tang X.Q. BDNF-TrkB pathway mediates antidepressant-like roles of H(2) S in diabetic rats via promoting hippocampal autophagy Clin. Exp. Pharmacol. Physiol. 2020 47 302 312 10.1111/1440-1681.13201 31660632 16. Yang J. Viruses Binding to Host Receptors Interacts with Autophagy Int. J. Mol. Sci. 2023 24 3423 10.3390/ijms24043423 36834833 17. Truzzi F. Whittaker A. D'Amen E. Valerii M.C. Abduazizova V. Spisni E. Dinelli G. Spermidine-Eugenol Supplement Preserved Inflammation-Challenged Intestinal Cells by Stimulating Autophagy Int. J. Mol. Sci. 2023 24 4131 10.3390/ijms24044131 36835540 |
bioRxiv BIORXIV bioRxiv Cold Spring Harbor Laboratory 36909573 10.1101/2023.02.25.530000 preprint 1 Article Rapid resistance profiling of SARS-CoV-2 protease inhibitors Moghadasi Seyed Arad 1 Biswas Rayhan G. 1 Harki Daniel A. 1 Harris Reuben S. 12 1 University of Minnesota, Minneapolis, Minnesota, USA, 55455 2 Howard Hughes Medical Institute, University of Texas Health San Antonio, San Antonio, Texas, USA, 78229 Correspondence: [email protected] and [email protected] 27 2 2023 2023.02.25.530000 This work is licensed under a Creative Commons Attribution 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. nihpp-2023.02.25.530000.pdf Resistance to nirmatrelvir (Paxlovid) has been shown by multiple groups and may already exist in clinical SARS-CoV-2 isolates. Here a panel of SARS-CoV-2 main protease (Mpro) variants and a robust cell-based assay are used to compare the resistance profiles of nirmatrelvir, ensitrelvir, and FB2001. The results reveal distinct resistance mechanisms ("fingerprints") and indicate that these next-generation drugs have the potential to be effective against nirmatrelvir-resistant variants and vice versa. pmcAntiviral drugs are necessary to combat SARS-CoV-2/COVID-19, particularly with waning interest in the repeated vaccination boosts necessary to keep-up with virus evolution. The main protease (Mpro) of SARS-CoV-2 is essential for virus replication and, accordingly, a proven therapeutic target as evidenced by Paxlovid . However, as for drugs developed to treat other viruses1 and for first-generation SARS-CoV-2 vaccines, there is a high probability that variants will emerge that resist nirmatrelvir. Indeed, a flurry of recent studies has described a variety of candidate nirmatrelvir-resistance mutations2-9. Thus, considerable urgency exists to develop next-generation Mpro inhibitors with different resistance mechanisms and, in parallel, robust systems to rapidly assess the potential impact of candidate resistance mutations. Ensitrelvir (Xocova) and FB2001 are being evaluated in clinical trials, and the former drug also recently received EUA in Japan10,11 . We recently developed a gain-of-signal system for facile quantification of Mpro inhibition12, and subsequently used it together with an structure-guided approach to characterize candidate ensitrelvir-resistance mutations2. Here, an expanded panel of Mpro single and double mutants based on recent studies by our group and others2-9 is leveraged to determine resistance profiles of these two drugs, as well as FB2001, a potential next-generation therapy . Several single amino acid substitution variants including T21I, L50F, P252L, and T304I show minimal resistance to nirmatrelvir, ensitrelvir, or FB2001. Selective resistance to ensitrelvir is conferred by M49I and M49L, whereas selective resistance to nirmatrelvir is caused by A173V (highlighted in gray in Table 1). DP168 elicits similar resistance to all inhibitors, and synergistic resistance to nirmatrelvir when combined with A173V. S144A and L167F show the greatest resistance to ensitrelvir, intermediate resistance to nirmatrelvir, and lower resistance toward FB2001. In contrast to E166A and L50F/E166A, which cause a similar broad-spectrum resistance, E166V and L50F/E166V elicit very high resistance to nirmatrelvir, intermediate resistance to ensitrelvir, and substantially lower resistance to FB2001. In addition to providing a method to rapidly profile candidate resistance mutations in living cells, our gain-of-signal assay also provides a quantitative metric for Mpro functionality12 (Methods). This system is based on the fact that overexpression of wildtype SARS-CoV-2 Mpro results in the cleavage of multiple substrates in cells13,14 including at least one required for RNA Polymerase II-dependent gene expression12. Therefore, expression of the Src-Mpro-Tat-Luc reporter itself is rapidly shut down following transfection and can only be recovered by chemical or genetic inhibition of Mpro. Thus, genetic mutations effectively phenocopy the chemical dose-responsiveness of the system, with some variations showing wildtype Mpro activity (background luminescence) and others compromising activity weakly or strongly depending on the nature of the mutation (low to high luminescence). For example, in comparison to wildtype Mpro, catalytic mutants such as C145A yields 100-fold higher luminescence2,12. The Mpro variant constructs used here display a range of luminescence levels in the absence of drug indicative of near-normal Mpro activity (notably, M49I and M49L), weakly compromised Mpro activity (notably, A173V), and strongly compromised Mpro activity (notably, E166V) . These results suggest that several variants can confer at least partial drug resistance with little loss in Mpro functionality (and accordingly high viral fitness), whereas others such as E166V require suppressor mutations such as L50F to restore Mpro function to a level that enables virus replication (evidenced by recent resistance studies with pathogenic SARS-CoV-2 in culture and in vivo in animal models3,5). Regardless of the details of each molecular mechanism, the results here demonstrate that nirmatrelvir, ensitrelvir, and FB2001 have distinct resistance profiles and that the latter inhibitors (with appropriate formulations) may be effective in patients suffering from Paxlovid rebound15 or bona fide resistance2. FB2001 may additionally have a higher resistance barrier given that no fully functional single Mpro variants tested to-date confer a strong resistance to this compound. Importantly, the gain-of-signal live cell assay recapitulates recent findings using replication competent viruses and provides a safe and rapid method for assessing resistance. As the SARS-CoV-2 variant pool deepens, this assay and variant panel can be expanded in lock-step to provide early resistance "fingerprints" of candidate next-generation Mpro inhibitors. Such an early profiling strategy has the potential to minimize the risks of developing drugs prone to cross-resistance and, importantly, to help identify inhibitors with the highest barriers to resistance. Supplementary Material Supplement 1 Acknowledgments This work was supported by National Institute of Allergy and Infectious Disease grant U19-AI171954. RSH is an Investigator of the Howard Hughes Medical Institute, a CPRIT Scholar, and the Ewing Halsell President's Council Distinguished Chair at University of Texas Health San Antonio. Figure 1. Resistance profiles of nirmatrelvir, ensitrelvir, and FB2001. (A) Co-crystal structures of SARS-CoV-2 Mpro in complex with nirmatrelvir (PDB:7SI9), ensitrelvir (PDB:7VU6), or FB2001 (PDB:6LZE). Labeled residues are interrogated in panel B. (B) Fold-change in IC50 relative to WT for the indicated mutants using the live cell gain-of-signal assay in 293T cells. Table 1. IC50 values of nirmatrelvir, ensitrelvir, and FB2001 against Mpro resistance variants. Mpro variant IC50 [nM] (Fold-change relative to WT) Nirmatrelvir Ensitrelvir FB2001 WT 29.4 (1.0) 35.9 (1.0) 27.2 (1.0) T21I 36.0 (1.2) 16.3 (0.5) 34.0 (1.3) M49I 23.0 (0.8) 338 (9.4) 29.8 (1.1) M49L 27.1 (0.9) 769 (21.4) 10.7 (0.4) L50F 58.4 (2.0) 21.0 (0.6) 33.2 (1.2) S144A 236 (8.0) 623 (17.3) 74.7 (2.7) E166A 622 (21.2) 126 (35.2) 355 (13.1) E166V >10000 (>300) 2800 (77.9) 645 (23.7) L167F 282 (9.6) 728 (20.3) 115 (4.2) DP168 243 (8.3) 193 (5.4) 184 (6.8) A173V 460 (15.8) 45.9 (1.3) 45.7 (1.7) P252L 76.9 (2.6) 28.8 (0.8) 38.9 (1.4) T304I 40.7 (1.4) 19.0 (0.5) 10.5 (0.4) L50F/E166A 793 (27) 1040 (28.8) 355 (13) L50F/E166V >10000 (>300) 751 (20.9) 185 (6.8) DP168/A173V 1630 (55.4) 122 (3.4) 166 (6.1) Clear examples of single amino acid substitution mutations conferring selective resistance to nirmatrelvir and ensitrelvir are highlighted in gray; similar mutations have yet to be found for FB2001. The relative values in brackets are reflected in the heatmap in Figure 1B. References 1 Majerova T. & Konvalinka J. Viral proteases as therapeutic targets. Mol Aspects Med 88 , 101159 (2022). 10.1016/j.mam.2022.101159 36459838 2 Moghadasi S. A. Transmissible SARS-CoV-2 variants with resistance to clinical protease inhibitors. Sci Adv in press (2023). 10.1101/2022.08.07.503099 3 Zhou Y. Nirmatrelvir-resistant SARS-CoV-2 variants with high fitness in an infectious cell culture system. Sci Adv 8 , eadd7197 (2022). 10.1126/sciadv.add7197 36542720 4 Iketani S. Functional map of SARS-CoV-2 3CL protease reveals tolerant and immutable sites. Cell Host Microbe 30 , 1354-1362 e1356 (2022). 10.1016/j.chom.2022.08.003 36029764 5 Iketani S. Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir. Nature 613 , 558-564 (2023). 10.1038/s41586-022-05514-2 36351451 6 Jochmans D. 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Discovery of S-217622, a noncovalent oral SARS-CoV-2 3CL protease inhibitor clinical candidate for treating COVID-19. Journal of medicinal chemistry 65 , 6499-6512 (2022). 10.1021/acs.jmedchem.2c00117 35352927 12 Moghadasi S. A. Gain-of-signal assays for probing inhibition of SARS-CoV-2 M(pro)/3CL(pro) in living cells. mBio 13 , e0078422 (2022). 10.1128/mbio.00784-22 35471084 13 Meyers J. M. The proximal proteome of 17 SARS-CoV-2 proteins links to disrupted antiviral signaling and host translation. PLoS Pathog 17 , e1009412 (2021). 10.1371/journal.ppat.1009412 34597346 14 Gordon D. E. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 583 , 459-468 (2020). 10.1038/s41586-020-2286-9 32353859 15 Anderson A. S. , Caubel P. , Rusnak J. M. & Investigators E.-H. T. Nirmatrelvir-ritonavir and viral load rebound in Covid-19. N Engl J Med 387 , 1047-1049 (2022). 10.1056/NEJMc2205944 36069818 |
bioRxiv BIORXIV bioRxiv Cold Spring Harbor Laboratory 36909631 10.1101/2023.02.28.530429 preprint 2 Article BrainLine: An Open Pipeline for Connectivity Analysis of Heterogeneous Whole-Brain Fluorescence Volumes Athey Thomas L. *12 Wright Matthew A. 3 Pavlovic Marija 4 Chandrashekhar Vikram 1 Deisseroth Karl 4567 Miller Michael I. 1289 Vogelstein Joshua T. 1289 1 Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA 2 Institute of Computational Medicine, Johns Hopkins University, Baltimore, MD, USA 3 Department of Psychiatry, Weill Cornell Medicine, New York, NY, USA 4 Department of Bioengineering, Stanford University, Stanford, CA, USA 5 CNC Program, Stanford University, Stanford, CA, USA 6 Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA 7 Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA 8 Center for Imaging Science, Johns Hopkins University, Baltimore, MD, USA 9 Kavli Neuroscience Discovery Institute, Johns Hopkins University, Baltimore, MD, USA * [email protected] 01 3 2023 2023.02.28.530429 This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, and only so long as attribution is given to the creator. The license allows for commercial use. nihpp-2023.02.28.530429.pdf Whole-brain fluorescence images require several stages of computational processing to fully reveal the neuron morphology and connectivity information they contain. However, these computational tools are rarely part of an integrated pipeline. Here we present BrainLine, an open-source pipeline that interfaces with existing software to provide registration, axon segmentation, soma detection, visualization and analysis of results. By implementing a feedback based training paradigm with BrainLine, we were able to use a single learning algorithm to accurately process a diverse set of whole-brain images generated by light-sheet microscopy. BrainLine is available as part of our Python package brainlit: pmcWhole-brain image volumes at the micron scale are helping scientists characterize neuron-level morphology and connectivity, and discover new neuronal subtypes. These volumes require intense computational processing to uncover the rich neuronal information they contain. Currently, however, image acquisition is outstripping the availability and throughput of analysis pipelines. The steps in analyzing these images include registration, axon segmentation, soma detection, visualization and analysis of results. Several tools exist for these individual steps, but are rarely all part of an integrated pipeline and able to facilitate cloud-based collaboration . Further, many existing machine learning based tools are highly tuned to their training data and perform poorly when they encounter out-of-distribution artifacts or signal levels . To address these challenges, we present BrainLine, an open-source, fully-integrated pipeline that performs registration, axon segmentation, soma detection, visualization, and analysis on whole-brain fluorescence volumes . BrainLine combines state-of-the-art, already available open-source tools such as CloudReg and ilastik with brainlit, our Python package developed here. The BrainLine pipeline uses generalizable machine learning training schemes that adapt to out-of-distribution samples and facilitates cloud-based collaboration across institutions. To share and interact with data across multiple institutions, BrainLine uses Amazon S3 to store data in precomputed format, so it can be viewed using Neuroglancer . Specifically, we use CloudReg for file conversion of the stitched image, and for image registration to the Allen atlas . For axon segmentation and soma detection, we sought to leverage recent machine learning advances but experienced two major constraints. First, as generating ground truth image annotations is labor intensive, we wanted the approach to be effective on a small amount of training data. Second, images were provided to us in a sequential manner, and new samples would sometimes have unique artifacts or different levels of image quality . We therefore sought a learning algorithm that could be quickly retrained on new data. Many learning algorithms assume that all training and testing data come from the same distribution and fail when this is not the case . However, using our closed-loop training paradigm with ilastik , we were able to use a single ilastik project for all samples, only occasionally adding training data when difficult samples arose. We used an ilastik pixel classification workflow for both axon segmentation and soma detection, but in the latter case we applied a size threshold to the connected components following segmentation. In both cases, the training approach was the same. For each new whole-brain volume, we identified a set of subvolumes (993 voxels for axons, 493 for somas) across a variety of brain regions, and annotated only a few slices (three for axons, five for somas) in each subvolume for our validation set. This strategy is similar to that employed in Friedmann et al. . If our model could not achieve a satisfactory f-score on this validation dataset, we would annotate more subvolumes from the sample and add them to the training set until satisfactory performance was achieved. We observed that this heterogeneous training procedure (i.e. training on multiple brain samples) often improved performance on other samples as well. In an experiment where we controlled the number of subvolumes used for training, this approach was at least as good as a homogeneous approach, where all training subvolumes came from a single brain sample . The pipeline can display the axon segmentation and soma detection results in a variety of ways, including brain-region-based bar charts accompanied by statistical tests (Fig. 1a.i), 2D plots with the atlas borders (Fig. 1a.ii), and 3D visualizations using brainrender (Fig. 1a.iii) . Since every experimental design is unique, we designed our pipeline in a modular way, so investigators can pick and choose which components they want to incorporate in their own analyses. We also leverage existing software and file formats to facilitate interoperability . BrainLine enables accelerated analysis of brain-wide connectivity through parallel programming, the use of cloud-compliant file formats, and a machine learning training scheme that generalizes across brain samples. As a result, BrainLine alleviates the need for investigators to build custom analysis pipelines from scratch, helping them characterize the morphology and connectivity profiles of neurons, and discover new neuronal subtypes. BrainLine is available as a set of thoroughly documented notebooks and scripts in our Python package brainlit: Acknowledgements This work is supported by NIH Grants RF1MH121539, U19AG033655, and RO1AG066184-01, NSF grants 2031985, 2014862 and the CAREER award. M.W. is supported by NIMH Grant K08MH113039. K.D. is supported by NIMH, NIDA, the NIH BRAIN Initiative, the Integrated Circuit Cracking NeuroNex Technology Hub funded by the National Science Foundation, the NOMIS Foundation, the Else Kroner Fresenius Foundation, the Gatsby Foundation and the AE Foundation. Figure 1: BrainLine allows for efficient processing of heterogeneous whole brain fluorescence volumes. a BrainLine combines CloudReg , ilastik and our package, brainlit, to produce results in both quantitative (a.i) and visual (a.ii-a.iii) formats. b Example images with fluorescently labeled axon projections and arrows pointing to regions with (green) and without (red) labeled axons. c Intensity histograms of 20x20x20 voxel subvolumes located at the arrows in b. d Comparison between axon segmentation performance after training on subvolumes from different samples (heterogeneous) or the same sample (homogeneous). e Example images with fluorescently labeled cell bodies and arrows pointing to regions with (green) and without (red) labeled cell bodies. f Intensity histograms of 20x20x20 voxel subvolumes located at the arrows in e. g Comparison between soma detection performance after training on subvolumes from different brain samples (heterogeneous) or a single brain sample (homogeneous). Conflict of Interest Statement M.I.M. owns a significant share of Anatomy Works with the arrangement being managed by Johns Hopkins University in accordance with its conflict of interest policies. V.C. owns a significant share of Neurosimplicity, LLC, which is a medical device and technology company focusing on medical image processing. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. References and Notes Neuroglancer. URL Berg Stuart , Kutra Dominik , Kroeger Thorben , Straehle Christoph N , Kausler Bernhard X , Haubold Carsten , Schiegg Martin , Ales Janez , Beier Thorsten , Rudy Markus , Ilastik: interactive machine learning for (bio) image analysis. Nature methods, 16 (12 ):1226-1232, 2019.31570887 Chandrashekhar Vikram , Tward Daniel J , Crowley Devin , Crow Ailey K , Wright Matthew A , Hsueh Brian Y , Gore Felicity , Machado Timothy A , Branch Audrey , Rosenblum Jared S , Cloudreg: automatic terabyte-scale cross-modal brain volume registration. Nature methods, 18 (8 ):845-846, 2021.34253927 Claudi Federico , Tyson Adam L , Petrucco Luigi , Margrie Troy W , Portugues Ruben , and Branco Tiago . Visualizing anatomically registered data with brainrender. Elife, 10 :e65751, 2021.33739286 Friedmann Drew , Pun Albert , Adams Eliza L , Lui Jan H , Kebschull Justus M , Grutzner Sophie M , Castagnola Caitlin , Tessier-Lavigne Marc , and Luo Liqun . Mapping mesoscale axonal projections in the mouse brain using a 3d convolutional network. Proceedings of the National Academy of Sciences, 117 (20 ):11068-11075, 2020. Geisa Ali , Mehta Ronak , Hayden S Helm Jayanta Dey , Eaton Eric , Dick Jeffery , Priebe Carey E , and Vogelstein Joshua T . Towards a theory of out-of-distribution learning. arXiv preprint arXiv:2109.14501, 2021. Pisano Thomas J , Dhanerawala Zahra M , Kislin Mikhail , Bakshinskaya Dariya , Engel Esteban A , Hansen Ethan J , Hoag Austin T , Lee Junuk , de Oude Nina L , Venkataraju Kannan Umadevi , Homologous organization of cerebellar pathways to sensory, motor, and associative forebrain. Cell reports, 36 (12 ):109721, 2021.34551311 Quinonero-Candela Joaquin , Sugiyama Masashi , Schwaighofer Anton , and Lawrence Neil D . Dataset shift in machine learning. MIT Press, Boston, 2008. 1 Tyson Adam L and Margrie Troy W . Mesoscale microscopy and image analysis tools for understanding the brain. Progress in Biophysics and Molecular Biology, 168 :81-93, 2022.34216639 Wang Quanxin , Ding Song-Lin , Li Yang , Royall Josh , Feng David , Lesnar Phil , Graddis Nile , Naeemi Maitham , Facer Benjamin , Ho Anh , The allen mouse brain common coordinate framework: a 3d reference atlas. Cell, 181 (4 ):936-953, 2020.32386544 |
Res Sq ResearchSquare Research Square American Journal Experts 36909637 10.21203/rs.3.rs-2574215/v1 10.21203/rs.3.rs-2574215 preprint 1 Article Bumetanide Exposure Association with Alzheimer's Disease Risk Graber-Naidich Anna Stanford University Lee Justin Stanford University Younes Kyan Stanford University Greicius Michael D. Stanford University Le Guen Yann Stanford University He Zihuai Stanford University Authors' contributions AGN and JL performed the analyses. AGN, JL, KY wrote the main manuscript. YLG and ZH supervised the analysis. All authors interpreted statistical analyses and reviewed the manuscript. AGN, JL, KY contributed equally to this work. YLG and ZH contributed equally to this work. [email protected] 28 2 2023 rs.3.rs-2574215 This work is licensed under a Creative Commons Attribution 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. nihpp-rs2574215v1.pdf Background: To investigate whether exposure history to two common loop diuretics affects the risk of developing Alzheimer's disease (AD) after accounting for socioeconomic status and congestive heart failure. Methods: Individuals exposed to bumetanide or furosemide were identified in the Stanford University electronic health record using the deidentified Observational Medical Outcomes Partnership platform. We matched the AD case cohort to a control cohort (1:20 case:control) on gender, race, ethnicity, hypertension and controlled for variables that could potentially be collinear with bumetanide exposure and/or AD diagnosis. Among individuals older than 65 years, 5,839 AD cases and 116,103 matched controls were included. A total of 1,759 patients (54 cases, 1,705 controls) were exposed to bumetanide. Results: After adjusting for socioeconomic status and other confounders, bumetanide exposure was significantly associated with reduced AD risk (odds ratio = 0.50; 95% confidence interval, 0.37-0.68; p = 9.9x10-6), while the most common loop diuretics, furosemide, was not associated with AD risk. Conclusion: Our study replicates in an independent sample that history of bumetanide exposure is associated with reduced risk of AD and emphasizes that this association is not confounded by difference in socioeconomic status, which was an important caveat given the cost difference between bumetanide and furosemide. Alzheimer's disease bumetanide electronic health record informatics furosemide pmcIntroduction Medical systems generate massive amounts of Electronic Health Record (EHR) data and researchers have analyzed these data to derive new insights and improve healthcare1,2. Stanford University has established a novel and secure data platform: Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). Alzheimer's disease (AD) is well-suited for analysis with OMOP given its multifaceted complexity, prevalence, and the multitude of small size studies that claim benefit for certain interventions. AD is a neurodegenerative disorder of uncertain cause and pathogenesis. In the United States, as many as 1 in 9 people (10.7%) older than 65 have AD3. Recently, repurposing bumetanide as an AD medication was proposed based on data that showed bumetanide "reversed" APOE genotype-dependent transcriptomic signatures in mouse and cell culture models.4 This finding was investigated in two EHR-based cohorts demonstrating that in individuals over 65 years of age, bumetanide exposure was associated with lower AD prevalence4. This finding warrants further validation as bumetanide is more expensive than the commonly prescribed loop diuretic (furosemide) and thus potential socioeconomic status (SES) confounding such as insurance coverage needs to be investigated. Both furosemide and bumetanide are indicated, and often interchangeably used, for patients with hypertension, congestive heart failure (CHF), and kidney disease. In this study, using Stanford's EHR data, we sought to replicate the bumetanide findings in an independent dataset accounting for SES, hypertension, and CHF. A total of 1,759 patients (54 cases, 1,705 controls) were exposed to bumetanide during any of their visits (Table 1). For the full matched cohort, the bumetanide prevalence among AD cases was 0.92% compared to 1.47% in the controls. The unadjusted odds ratio (OR) for AD diagnosis among bumetanide exposed was 0.63 (95% CI, 0.48-0.82; p = 7.6x10-4, Table 2). We had some missingness in our data for the SES variables - insurance information was available for 94.0% of cases and 84.5% of controls. In addition, for the zip code data informing the median income component, we focused on patients from California, and due to deidentification reasons the data were only available for 76.8% of cases and 74.1% of controls. Since SES estimates were not easily imputable from our data, a sensitivity analysis was performed as a complete case analysis. In this sensitivity analysis we restricted the cohort to patients with complete insurance and median income data (N=77,688) and repeated the unadjusted analysis prior to fitting a multivariable model adjusted for CHF, insurance, and median income. In the complete case restricted cohort, 45/4238 (1.06%) AD cases and 1,321/7,3450 (1.8%) matched controls were exposed to bumetanide. The unadjusted OR remained similar to the one in our primary analysis (OR=0.59; 95% CI, 0.43-0.79; p = 4.5x10-4, Table 2). After adjusting for CHF, insurance, and median income the estimated OR for AD diagnosis among bumetanide exposed was 0.50 (95% CI, 0.37-0.68; p = 9.9x10-6, Table 2). For the full matched cohort, the furosemide prevalence among AD cases was 18.8% compared to 17.2% in the controls. The unadjusted OR for AD diagnosis among furosemide exposed was 1.11 (95% CI, 1.03-1.18; p = .003, Table 2); however, this effect was not replicated when adjusting for CHF. Most clinical trials in AD suffer from an inherent shortfall regarding primary prevention as they do not give insights on whether a compound reduces the incidence of AD since medications are tested after disease onset. Studying EHR using OMOP allows us to derive insight on possible primary prevention of AD5. In an independent dataset, our results replicate the original study that found a protective effect of Bumetanide exposure on AD risk4. We further investigated whether this effect is generalizable to the more commonly used and less expensive medication in the same class and adjusted for potential confounding variables such as SES and CHF. In our study, despite their similar indications and mechanism of action, only bumetanide exposure associated with reduced future AD diagnosis. Notably, both bumetanide and furosemide seem to penetrate the blood brain barrier6-9. Potential explanations for these results include unique effects of bumetanide on the APOE genotype-dependent transcriptomic signature,4 bumetanide being a more potent medication than furosemide with a dose ratio of 1:40 mg, or potential protective molecular modulation of neuronal transmembrane chloride gradients by blocking NKCC1 in the central nervous system.10 A mechanism that led to its proposed investigations to treat autism,11 schizophrenia,12 and epilepsy12,13. Our OMOP EHR dataset analysis demonstrated potential association between past bumetanide exposure and AD onset. This effect remained significant even after correcting for SES and CHF indicating that the results are not driven by differences in SES or severity of cardiac disease. These results should be treated cautiously since they are based on retrospective data. Bumetanide is a potent loop diuretic which, if given in excessive amounts, can lead to a profound diuresis with water and electrolyte depletion which is particularly problematic in the elderly population. Additionally, insurance and income were modeled through proxies available in OMOP and may not fully account for difference in SES. Last, additional functional studies are warranted to investigate the biological mechanism through which bumetanide exposure is associated with reduced AD risk. The current findings do not support the use of bumetanide for the prevention or treatment of AD. There is a need for prospective, randomized, double-blinded, placebo-controlled clinical trials to confirm the findings in patients without comorbidities and determine the lowest effective dose that may reduce the risk of AD without causing intolerable side effects. Given the lack of effect of furosemide and its similar side effect profile, one could also consider using it as an active placebo to increase the efficacy of double blinding. Methods Stanford's deidentified OMOP instance hosts multi-factor and multi-modal data, including Stanford's structured clinical data, clinical notes, meta-data on clinical notes, extracted concepts from clinical notes using Natural Language Processing and other approaches, and radiological images. Participants or their caregivers provided written informed consent for their data to be stored in OMOP. The current study protocol was granted an exemption by the Stanford University institutional review board because the analyses were carried out on deidentified data; therefore, additional informed consent was not required. All experimental protocols were approved by were approved by the Stanford University institutional review board. We have curated the OMOP data for 656,683 patients over age 65 at their last known visit. We focused on 5,872 patients with AD defined by ICD9 and ICD10 codes (ICD10: G30.1, G30.8, G30.9 and ICD9:331.0). We matched individual AD patients with up to 20 controls on age and exact match of sex, race, ethnicity, and hypertension with the R package optmatch14. We excluded 937 matched controls that had an age difference greater than 5 years and 373 matched controls that belonged to strata that had fewer than 15 controls per case resulting in 5,839 AD cases and 116,103 matched controls (Table 1). Statistical analysis We scanned the data using the medication orders or medical history variable tables to identify those who had been exposed to bumetanide. We included any type of exposure to the drug, specifically oral or IV exposures for any duration of time. Additionally, as post-hoc sensitivity analyses, we controlled for variables that could potentially be collinear with bumetanide exposure and/or AD diagnosis including diagnosis of CHF (defined by the ICD10 of I11, I13, I50), insurance type, and median income (defined by the patient's recorded zipcode, derived from publicly available data form the United States Census Bureau)5 and explored the relationship of AD with the other commonly used loop diuretic, furosemide. We calculated the prevalence of exposure to bumetanide in cases compared to the non-AD control group using a kh2 test. Statistical analyses were performed using R (version 3.6.3). Funding This research was supported by NIH/NIA award AG066206 (ZH), AG066515 (ZH, KY, MDG), and the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie (grant agreement No. 890650, YLG). Availability of data and materials This research used data or services provided by STARR, "STAnford medicine Research data Repository," a clinical data warehouse containing live Epic data from Stanford Health Care (SHC), the Stanford Children's Hospital (SCH), the University Healthcare Alliance (UHA) and Packard Children's Health Alliance (PCHA) clinics and other auxiliary data from Hospital applications such as radiology PACS. STARR platform is developed and operated by Stanford Medicine Research IT team and is made possible by Stanford School of Medicine Research Office. Abbreviations AD Alzheimer's Disease EHR Electronic Health Record CDM Common Data Model OHDSI Observational Health Data Sciences and Informatics OMOP Observational Medical Outcomes Partnership Table 1. Demographics of participants by diagnosis status. Each AD patient was matched with up to 20 controls on age and exact match of sex, race, ethnicity, and hypertension. AD Case Matched Control SMD n 5,839 116,103 Age at last visit (median [IQR]) 84.00 [79.00, 88.00] 83.00 [79.00, 87.00] 0.058 Gender = MALE (%) 2256 (38.6) 45134 (38.9) 0.005 Race (%) 0.013 White 3636 (62.3) 72719 (62.6) Asian 835 (14.3) 16633 (14.3) Black or African American 262 (4.5) 4961 (4.3) Native Hawaiian or Other Pacific Islander 38 (0.7) 700 (0.6) American Indian or Alaska Native 4 (0.1) 80 (0.1) Patient Refused 65 (1.1) 1271 (1.1) Other 755 (12.9) 14869 (12.8) Unknown 205 (3.5) 4100 (3.5) No matching concept 39 (0.7) 770 (0.7) Ethnicity (%) 0.001 Not Hispanic or Latino 5022 (86.0) 99824 (86.0) Hispanic or Latino 437 (7.5) 8717 (7.5) No matching concept 380 (6.5) 7562 (6.5) Hypertension (%) 3667 (62.8) 72663 (62.6) 0.004 Congestive heart failure (%) 414 (7.1) 5627 (4.8) 0.095 Table 2. Odds ratio for AD diagnosis among bumetanide and furosemide exposed participants. Individuals were over the age of 65 years, and odds ratio were adjusted for age, sex, race, ethnicity, hypertension and with and without adjusting CHF and SES (insurance, and median income). AD: Alzheimer's Disease, CHF: Congestive Heart Failure, SES: Socioeconomic Status. OR: Odds Ratio. Analysis OR (95% CI) p-value Unadjusted matched cohort bumetanide exposure 0.63 (0.48, 0.82) 7.6x10-4 CHF adjusted matched cohort bumetanide exposure 0.52 (0.39, 0.68) 3.1x10-6 Unadjusted matched cohort furosemide exposure 1.11 (1.03, 1.18) .003 CHF adjusted matched cohort furosemide exposure 1.02 (0.94, 1.09) .70 Unadjusted complete case cohort bumetanide exposure 0.59 (0.43, 0.79) 4.5x10-4 CHF adjusted complete case cohort bumetanide exposure 0.49 (0.36, 0.67) 5.0x10-6 CHF, SES adjusted complete case cohort bumetanide exposure 0.50 (0.37, 0.68) 9.9x10-6 Ethics approval and consent to participate Participants or their caregivers provided written informed consent for their data to be stored in OMOP. The current study protocol was granted an exemption by the Stanford University institutional review board because the analyses were carried out on deidentified data; therefore, additional informed consent was not required. All methods were carried out in accordance with relevant guidelines and regulations. All experimental protocols were approved by were approved by the Stanford University institutional review board. Consent for publication Not applicable. Competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. References 1. Shah NH , Milstein A , Bagley PhD SC . Making Machine Learning Models Clinically Useful. JAMA. United States; 2019;322 :1351-1352.31393527 2. Rajkomar A , Dean J , Kohane I . Machine Learning in Medicine. The New England journal of medicine. United States; 2019;380 :1347-1358.30943338 3. 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Int J Mol Sci Int J Mol Sci ijms International Journal of Molecular Sciences 1422-0067 MDPI 10.3390/ijms24054892 ijms-24-04892 Editorial Editorial of Special Issue "Materials for Energy Applications 2.0" Kim Sun-Jae 12 1 Department of Nanotechnology and Advanced Materials Engineering, Sejong University, 209, Neungdong-ro, Gwangjin-gu, Seoul 05006, Republic of Korea; [email protected] 2 Metal-organic Compounds Materials Research Center, Sejong University, 209, Neung dong-ro, Gwangjin-gu, Seoul 05006, Republic of Korea 03 3 2023 3 2023 24 5 489224 2 2023 28 2 2023 (c) 2023 by the author. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). pmcEnergy is a key factor in determining the growth of human society. The production of energy and the storing of energy for a later usage is an important action in this current scenario. In recent years, many technologies involve energy storage and conversion applications. Among these, secondary batteries (Li-ion and Na-ion), supercapacitors, solar cells, electrochemical water splitting, photoelectric water splitting, and photocatalytic are most frequently concerned in these prompt technologies. In this Issue, a theoretical and experimental analysis of materials for sustainable and clean energy technologies is outlined. The construction of materials is an important factor in determining the performance of energy storage and conversion devices. Naveenkumar et al. reported on carbon-coated hetero-structured ZnS-FeS2 anode materials for lithium-ion batteries. The bimetal sulfide-based anode delivers a better lithium-ion battery performance than single metal sulfide. Here, heterostructure nanoarrays offer a number of advantages, such as abundant electroactive sites for redox reactions, a larger electrode-electrolyte contact surface, a shorter electrolyte diffusion path, and fascinating synergistic effects between the heterointerface. However, the achieved performance of the heterostructure is not satisfactory in Lithium-ion batteries. Moreover, the bimetal sulfide was coated with carbon using the hydrothermal method, which boosts the electrical conductivity and results in a good structural flexibility. The carbon coating and nature of carbon that exists on the surface of hetero-structured ZnS-FeS2 was identified from the Raman spectrum. The initial discharge capacity of the ZnS-FeS2@C composite delivered a capacity of 1481 mAh g-1 at 0.1 A g-1. It exhibited a capacity of 821 mAh g-1 at a current density of 1 A g-1 after the 500th cycle. This result has clearly exposed the importance of the construction of a heterostructure followed by carbon coating techniques in lithium-ion battery applications. JH kim et al. fabricated a sterilized rayon-activated carbon fiber (RACF) as an electrode material for electric double-layer capacitor applications. RACFs were prepared by the steam activation method. The effect of various time intervals of steam-activated RACFs was investigated in this study. The XRD data revealed the formation of typical isotropic carbon materials. The results showed that as the activation time increased, the structure of the pores in the RACF changed from being rich in micropores to mesopores. Even though the activation yield was high at about 28-37%, the pores in the RACF were very good, with a specific surface area of 1990-2150 m2/g and a mesopore fraction of 20.5-31.1% as the activation time increased. Particularly, the specific capacitance of RACF-70 was found to be higher than that of YP-50F at current densities of 2 and 50 mA/cm2 by about 26% and 150%, to 103.6 and 85.8 F/g, respectively. Additionally, RACFs had a low IR-drop, low charge transfer resistance, and low Warburg impedance. Finally, the RACF made by activating it with steam had better pore properties and an electrochemical performance than YP-50F. It also had the potential to function as a better electrode material for EDLC. The results of this study should make it easier to use an RACF as an effective performance-enhancing electrode material for the EDLC, which is cheap and environmentally friendly. Dun Wu et al. reported on the low-cost effective fabrication of nitrogen-doped carbon Fe2O3/carbon nanosheet nanocomposite by the laser ablation method. By including a photothermal agent of nano-magnetite into the polyimide precursor, a flat and dense Fe3O4-PI hybrid film with a good near-infrared light absorption may be created after thermal curing. It can be turned into composite electrodes of carbon nanosheets coated with nitrogen-doped Fe3O4 nanoparticles when scanned with a 1064 nm laser beam. The composite electrode provides an exceptional overpotential of 247 mV at a current density of 10 mA cm2 in 1M KOH due to the management of the electronic configurations of Fe-O sites in anti-spinel Fe3O4 with doped N atoms. The intriguing help of Fe3O4 octahedral Fe sites is thought to aid water dissociation via bi-molecule Volmer reaction pathways. Our established fabrication technique not only provides new insights into the simple synthesis of affordable Fe-based electrocatalysts for hydrogen production but it may also be used to develop electrode materials for energy storage and conversion applications. KH Chung et al. reported on the H2 production phenomenon of bismuth ferrite catalyst using liquid phase plasma. The solo-gel method was employed to prepare the bismuth ferrite catalyst. The phase and purity of the catalyst was confirmed by XRD data. The polygonal morphology was revealed by SEM and TEM images. The bandgap energy of bismuth ferrite was around 2.0 eV; it suggests that it is a good candidate for a photo-catalytic reaction in the visible region. The light absorption behavior of bismuth ferrite was well extended in the visible region. It can absorb both UV and visible light produced from the liquid phase plasma. The order of HER is bismuth ferrate > Ni/TiO2 > TiO2. The hydrogen evolution rate of bismuth ferrite in 10% methanol solution was higher than distilled water. Further, bismuth ferrate shows good catalytic behavior in the visible light region; it performs well as a feature in clean hydrogen production applications. Metal-based electrodes have good electrochemical catalytic activity for the conversion of pollutant organic moiety to useful products. Hong Lu et al. reported on the electroreduction of CO2 into ethanol using copper as a catalyst. In this work, the copper metal catalyst was prepared by the electrodeposition method using monoethanolamine as a regulating agent on the surface of a fluorinated tin oxide plate. The spectroscopic investigations showed that the concentration ratio of localized Cu+ and Cu0 on copper electrodes was monitored from 1.24/1 to 1.54/1 by tweaking with the help of monoethanolamine. The faradic efficiencies of ethanol and C2 are 48% and 77%, respectively, at a voltage of -0.6 V versus a reversible hydrogen electrode. The presence of Cu+ and Cu0 in an electrode could stabilize the formation of *CO intermediate. The intermediate could significantly involve the formation of the C-C bond towards the production of ethanol. This result exhibits the successful fabrication of electrocatalyst and their selectivity of CO2 reduction reactions. We looked at how well hematite (a-Fe2O3) precipitation catalysts worked with methane (CH4) and found that they worked very well and stayed stable below 500 degC. This study compared the structural state of hematite nanoparticles (NPs) that were formed in water from the precursor ferric chloride hexahydrate using NaOH or NH4OH as a precipitant at pH 11, and then heating up to 500 degC to oxidize CH4 at low concentrations (5% by volume in air). The decreasing conversion (%) of CH4 values over time was discussed in terms of how goethite and hydrohematites NP precursors change into magnetite and how the structure of calcined hydrohematites changes. After goethite loses its water, the water and vacancies that were built into it change into hydrohematite, which is different from a-Fe2O3. The surface area SBET of protohematite-based Fe2O3 NH-70 precipitate was 53 m2/g greater than that of goethite-based precipitate. Hydrohematites with water and voids in their structure oxidized methane more efficiently. Designing and developing catalysts with benign, low-cost, and efficient photocatalytic activity is one of the most pressing challenges in environmental remediation. Metal-organic frameworks (MOFs) are used as a template precursor to the synthesis of a variety of functional materials using various treatment approaches that result in order structures with a large surface area, regulated pore texture, and a high carbon content. Using a facile MOF-based solvothermal self-assembly approach, Maniyazagan et al. successfully produced a flower-like indium oxide (In2O3-MF) catalyst. Morphology and structural research indicate that the In2O3-MF photocatalyst has a flower-like structure. In the presence of NaBH4 and visible light, the catalytic performance of In2O3-MF, In2O3-MR, and In2O3-MD catalysts for the reduction of 4-NP and MB degradation was analyzed. As electron-hole pairs, reactive oxygen species (ROS) such as superoxide radicals and hydroxyl ions are responsible for the photocatalytic degradation of organic pollutants. The photocatalytic reduction and degradation reactions of 4-NP and MB, accompanied by the generation of charge carriers by UV-light irradiation of a flower-like In2O3-MF photocatalyst surface, resulted in valence bond stimulation, electron transfer to the conduction band (CB), and the formation of an equal number of holes in the valence band. These photoexcited charge carriers created superoxide radicals and hydroxyl ions upon contact with dissolved oxygen (O2) and water molecules (H2O) in 4-NP and MB. Using In2O3-MF as a catalyst, they were able to reduce 4-NP by 99.32 percent in 20 minutes and MB by 99.2 percent in three minutes. After five consecutive cycles of catalytic tests, the conversion rates of catalytic 4-NP and MB remained above 95 and 96 percent, indicating that the In2O3-MF catalyst has an excellent catalytic performance and a high reutilization rate. The most recent developments in hydrogen storage technology utilizing nanosized complex hydrides were detailed . Methods for enhancing thermodynamics and accelerating sluggish kinetics have been summarized. Thermodynamic destabilization, cation and anion substitution, the eutectic formation approach, doping and additives, selecting the appropriate scaffold and electron tuning, and the now-famous nanoconfinement are all examples. The primary benefits and long-lasting drawbacks of employing such strategies were discussed in light of real-world examples found in the literature. The effective re-hydrogenation behavior of the reported nanocomposites lends support to the discussed mechanistic insights. Moreover, the author says that, among the improvement pillars presented before, the electronic synergy direction is not yet fully explored and is an area where substantial advances can be foreseen based on recent developments. To achieve the long-term goal of energy storage, known as the sustainable hydrogen economy, researchers from both the theoretical and experimental spheres will collaborate. Perovskite solar cells (PSCs) have demonstrated competitive power conversion efficiencies with the potential for a higher performance, but their stability and nonradiative recombination of carriers are still limited. To address these issues, this Special Issue introduces inverted PSCs and discusses and summarizes the latest research of inverted hybrid PSCs . First, the architecture and working principle of inverted PSCs are presented. Then, the materials regarding inverted PSCs, including charge transport materials and perovskite films, are discussed. In the end, the challenges of inverted PSCs and the strategies for improving the performance are discussed. As another way to solve the issues mentioned above, quantum dots (QDs) materials are considered promising materials for the high performance of PSCs . This article showed QDs as additives in electron transport layers (ETLs), hole transport layers (HTLs), and perovskite films, and directly analyzed electron transport materials (ETMs), hole transport materials (HTMs), light-absorbing layers, and luminescent downshifting materials. Particularly, this Special Issue summarizes the role of QDs in PSCs and analyzes the perspectives and related issues. As the global energy demands continue to rise, academia and industry are on a mission to discover renewable and innovative energy sources. Photovoltaic materials are promising candidates for clean and renewable energy technology applications. Due to the tunability of their structures and the local displacement of their B-site atoms within the original structure of these materials, pyrochlore oxides with the formula A2B2O7 (A2B2O6O') have emerged as potential multiferroic materials. In addition to possessing the proper properties for use in TE devices, pyrochlore oxides are also effective photon absorbers. Zeesham et al. studied the optical, electronic, and thermoelectric properties of the pyrochlore oxides La2Tm2O7 (Tm = Hf, Zr) using first-principles-based DFT calculations. Using the FP-LAPW technique, the ground-state properties of pyrochlore oxides were investigated to gain insight into their potential applications in thermoelectric devices and solar cells. Growing scientific interest in pyrochlore oxides as potential materials for renewable energy applications was the driving force behind this investigation. This family of complex materials is fascinating for applications in photovoltaic and thermoelectric devices due to their high energy conversion efficiency, which is dependent on their high absorption capacity and figure of merit. Due to the relatively wide band gaps and structural stability of La2Tm2O7 (Tm = Hf, Zr), these materials are promising candidates for UV photovoltaic devices. On the basis of the investigated structural properties and the ground state energy, we have determined that La2Hf2O7 is more stable than La2ZrO7. La2Hf2O7 and La2ZrO7 are direct bandgap materials with 4.45 and 4.40 eV, respectively, as shown by their energy band structures. By analyzing the TDOS spectra, it was determined that these pyrochlore oxides are nonmagnetic compounds. On the basis of e2 (o), they can conclude that these pyrochlore oxides absorb UV photons efficiently. In this Special Issue entitled "Materials in Energy applications 2.0" under the physical chemistry of chemical physics in the International Journal of Molecular Sciences, our aim was successfully achieved for this topic. Acknowledgments This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Ministry of Science, ICT, and Future Planning []. This research was also supported by the Korea Basic Science Institute (National research Facilities and Equipment Center) grant funded by the Ministry of Education. [2022R1A6C101A774]. Conflicts of Interest The author declares no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Naveenkumar P. Maniyazagan M. Kang N. Yang H.-W. Kang W.-S. Kim S.-J. Carbon-Coated ZnS-FeS2 Heterostructure as an Anode Material for Lithium-Ion Battery Applications Int. J. Mol. Sci. 2022 23 13945 10.3390/ijms232213945 36430422 2. Kim J.-H. Jung S.-C. Lee H.-M. Kim B.-J. Comparison of pore structures of cellulose-based activated carbon fibers and their applications for electrode materials Int. J. Sci. 2022 23 3680 10.3390/ijms23073680 35409039 3. Wu D. Zhao J. Cheng J. Liu C. Wang Q. Laser Shock Fabrication of Nitrogen Doped Inverse Spinel Fe3O4/Carbon Nanosheet Film Electrodes towards Hydrogen Evolution Reactions in Alkaline Media Int. J. Mol. Sci. 2022 23 7477 10.3390/ijms23137477 35806484 4. Chung K.-H. Jung H.-H. Kim S.-J. Park Y.-K. Kim S.-C. Jung S.-C. Hydrogen Production through Catalytic Water Splitting Using Liquid-Phase Plasma over Bismuth Ferrite Catalyst Int. J. Mol. Sci. 2021 22 13591 10.3390/ijms222413591 34948387 5. Lu H. Wang G. Zhou Y. Wotango A.S. Wu J. Meng Q. Li P. Concentration Optimization of Localized Cu0 and Cu+ on Cu-Based Electrodes for Improving Electrochemical Generation of Ethanol from Carbon Dioxide Int. J. Mol. Sci. 2022 23 9373 10.3390/ijms23169373 36012626 6. Valaskova M. Lestinsky P. Matejova L. Klemencova K. Ritz M. Schimpf C. Motylenko M. Rafaja D. Belik J. Hematites Precipitated in Alkaline Precursors: Comparison of Structural and Textural Properties for Methane Oxidation Int. J. Mol. Sci. 2022 23 8163 10.3390/ijms23158163 35897740 7. Munisamy M. Yang H.-W. Perumal N. Kang N. Kang W.S. Kim S.-J. A Flower-like In2O3 Catalyst Derived via Metal-Organic Frameworks for Photocatalytic Applications Int. J. Mol. Sci. 2022 23 4398 10.3390/ijms23084398 35457216 8. Comanescu C. Paving the Way to the Fuel of the Future Nanostructured Complex Hydrides Int. J. Mol. Sci. 2023 24 143 10.3390/ijms24010143 36613588 9. Yang J. Luo X. Zhou Y. Li Y. Qiu Q. Xie T. Recent Advances in Inverted Perovskite Solar Cells: Designing and Fabrication Int. J. Mol. Sci. 2022 23 11792 10.3390/ijms231911792 36233093 10. Zhou Y. Yang J. Luo X. Li Y. Qiu Q. Xie T. Selection, Preparation and Application of Quantum Dots in Perovskite Solar Cells Int. J. Mol. Sci. 2022 23 9482 10.3390/ijms23169482 36012746 11. Abbas Z. Hussain S. Muhammad S. Siddeeg S.M. Jung J. A First-Principles Investigation on the Structural, Optoelectronic, and Thermoelectric Properties of Pyrochlore Oxides (La0Tm2O7 (Tm = Hf, Zr)) for Energy Applications Int. J. Mol. Sci. 2022 23 15266 10.3390/ijms232315266 36499593 |
Int J Mol Sci Int J Mol Sci ijms International Journal of Molecular Sciences 1422-0067 MDPI 10.3390/ijms24054999 ijms-24-04999 Editorial New Insights into Cardiac Ion Channel Regulation 2.0 Delisle Brian P. 1 Aromolaran Ademuyiwa S. 23* 1 Department of Physiology, 741 S Limestone Street BBSRB B353, Lexington, KY 40536, USA 2 Department of Surgery, Division of Cardiothoracic Surgery, Nora Eccles Harrison Cardiovascular Research and Training Institute, Salt Lake City, UT 84112, USA 3 Department of Biomedical Engineering, Nutrition and Integrative Physiology, Biochemistry and Molecular Medicine Program, University of Utah School of Medicine, Salt Lake City, UT 84112, USA * Correspondence: [email protected]; Tel.: +1-(801)-581-3095 05 3 2023 3 2023 24 5 499919 2 2023 21 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). National Institutes of HealthR01HL147044 R01HL153042 R01HL141343 Nora Eccles Treadwell Foundation AwardThis work was supported by the National Institutes of Health (R01HL147044 to A.S.A.; R01HL153042 and R01HL141343 to B.P.D.) and the Nora Eccles Treadwell Foundation Award (to A.S.A.). pmcSudden cardiac death (SCD) and arrhythmias represent a global public health problem, accounting for 15-20% of all deaths . The past 30 years have seen improvements in cardiovascular (CV) care that have decreased the risk for SCD, but there is still much to be learned about the numerous and complex mechanisms that cause SCD. Evidence from both clinical and animal studies have shown that the pathological remodeling of major cardiac ionic channels contributes prominently to arrhythmias/SCD and further highlights a key role for ion channel biophysical properties and the normal sinus rhythm. The Special Issue New Insights into Cardiac Ion Channel Regulation 2.0 presents a series of articles that provide new and important mechanistic insights into ion channel biophysics, which are expected to help guide future studies that continue to decrease the risk for SCD. The Special Issue opens with a research article by Chowdhury and colleagues which is based on the premise that dietary obesity elevates the risk for CV disease, particularly the incidence for life-threatening arrhythmias that increases propensity for SCD in patients. Although it is known that obesity and its associated pathologies (including diabetes and insulin resistance) contribute to the prevalence of ventricular arrhythmias, more work is required to understand the mechanism(s) by which obesity elevates the risk for CV disease. One reason more work is needed is because the pathophysiology of obesity is complex, involving individual and multiple combinations of pathological cellular remodeling that ultimately provides triggers and substrates for the initiation and maintenance of arrhythmias. In obesity, the heart responds to metabolic stress through the marked accumulation of adipose tissue, leading to cardiac lipotoxicity (or the abnormal accumulation of free fatty acids in the heart) , which likely plays a critical role in the pathological remodeling of ventricular electrical activity, leading to delayed repolarization and the prolongation of heart-rate-corrected QT intervals, and also predisposes patients to life-threatening polymorphic ventricular tachycardia such as torsades de pointes. Thus, understanding the cellular proarrhythmic mechanisms of lipotoxicity is likely to provide novel and additional insights into obesity-related arrhythmias. Chowdhury and colleagues tested the hypothesis that obesity-related lipotoxicity induced profound adverse ventricular electrical activity via chronic elevations of proinflammatory cytokines. In the study, using a combination of approaches (including electrophysiology, biochemical, and in silico), the authors revealed that the proinflammatory cytokine, interleukin (IL)-6, promotes arrhythmogenesis and severely blunts the densities of the rapid (IKr) and slow (IKs) components of the delayed rectifier K current, and therefore may contribute to lipotoxicity-induced QTc prolongation and vulnerability to life-threatening arrhythmias. Importantly, these findings suggest the intriguing potential for anti-IL-6 trans-signaling therapy for the prevention of life-threatening ventricular arrhythmias in obese patients. The potential of the IL-6 trans-signaling pathway as a promising therapeutic target has also been demonstrated in a Duchenne muscular dystrophy mouse model . The clinical significance of IL-6 trans-signaling therapy is further highlighted by the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS). In this trial, Ridker et al. demonstrated that although canakinumab, a human therapeutic monoclonal antibody targeting IL-1b, significantly reduces major adverse cardiovascular events, participants remained at an increased risk for recurring cardiovascular events, particularly those with the highest pathological levels of IL-6. Thus, specific IL-6 trans-signaling modulators have the potential to enhance the efficacy and even exceed the beneficial effects of anti-inflammatory drugs that are currently used in clinical trials. Further studies addressing the molecular and functional basis of cytokine-related arrhythmogenesis are starting to emerge and further research is warranted. The upstroke or initial phase of the cardiac action potential is controlled by the influx of Na currents (INa) through voltage-gated Na channels, specifically Nav1.5, which is encoded by the SCN5A gene. Another research article by Marcos Rubio-Alarcon and colleagues builds on their earlier work on the transcriptional regulation of major atrial ion channels , and provides evidence for how the zinc finger homeobox 3 (Zfhx3) transcription factor may regulate the functional expression of NaV1.5 channels. The authors provide compelling evidence for the multiple effects of Zfhx3 on the functional expression of SCN5A that leads to a severe depression of peak INa density. These effects include acting as a repressor on the SCN5A promoter, preventing the Tbx5-dependent facilitation of INa density, and increasing the expression of Nedd4-2. This elegant study highlights the complex relationships between ion channel dysfunction, pathological cardiac electrical excitability, and the increased risk for arrhythmias (particularly atrial fibrillation). Additionally, Daimi and colleagues provide a timely review of the molecular events that underlie the functional regulation of the SCN5A/NaV1.5 channel, and discuss how channel protein dysfunction may cause cardiac channelopathies and promote associated arrhythmias. The modulation of NaV1.5 channel gating by the neurotoxin veratridine (VTD) is the focus of the research article by Gulsevin and colleagues . An important implication of their findings is that VTD binds to a site close to the cytoplasmic mouth of the channel pore, which may therefore play an important role in the VTD-dependent allosteric inactivation of the NaV1.5 channel. Together, these articles highlight the pathophysiology of SCN5A/NaV1.5 and identify new opportunities in the development of novel anti-arrhythmia therapies. The research article by Wei Hu and colleagues is a comprehensive and rigorous electrophysiological and computational evaluation of the biophysical properties (including gating kinetics and sensitivity to ionic and organic inhibitors) of the hyperpolarization-activated nonselective cation current (If). The study reveals novel biophysical insights into the regulation of the If channel, which are likely to be informative in the development of efficient and clinically relevant approaches that regulate cardiac automaticity. Finally, the article by Aromolaran and colleagues describes a novel mechanism involving the mTOR complex 1 (mTORC1, protein translation pathway) modulation of atrial myocyte electrical activity . The authors demonstrate a potential role for the overactivation of mTORC1 activity in the progression of atrial arrhythmogenesis (shortened action potential duration, increased IKr current density, and gating defects), due to lipotoxicity or high-fat diet feeding. An important demonstration from this study is that this occurred through a targeted effect on hERG1b protein translation, but was independent of on-going transcription. In light of the findings of Marcos Rubio-Alarcon and colleagues, and a recent study from Dr. Gail Robertson's laboratory that elegantly presented evidence for the co-translational association and regulation of NaV1.5 and hERG transcripts, it is tempting to speculate about the cellular mediators that prevent the transcription and/or translation of SCN5A/NaV1.5 protein channel subunits, or promote hERG1b protein expression, which may limit pathological atrial arrhythmogenesis and decrease the risk for supraventricular arrhythmias. Whether and how such reciprocal regulation of NaV1.5/hERG channel protein subunits may occur in metabolic obesity, a prominent contributor to the prevalence of arrhythmias warrants further investigation. In summary, the articles published in the Special Issue New Insights into Cardiac Ion Channel Regulation 2.0 continue the discussion on, and provide new information about, the complex modulation of cardiac ion channels that impact the electrical activity of the heart. Advancing research that explores inherited and acquired channelopathies will advance the arrhythmia field in ways that provide new opportunities for the development of novel therapies that reduce the risk for SCD and improve the quality of life for people living with heart disease. Author Contributions A.S.A. and B.P.D. planned the editorial. A.S.A. drafted the editorial. B.P.D. reviewed and edited the manuscript. All authors contributed significantly to this work, and then finalized and approved it for publication. All authors have read and agreed to the published version of the manuscript. Institutional Review Board Statement Not Applicable. Informed Consent Statement Not Applicable. Data Availability Statement All the relevant data are included within the paper itself. Conflicts of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Hayashi M. Shimizu W. Albert C.M. The Spectrum of Epidemiology Underlying Sudden Cardiac Death Circ. Res. 2015 116 1887 1906 10.1161/CIRCRESAHA.116.304521 26044246 2. Srinivasan N.T. Schilling R.J. Sudden Cardiac Death and Arrhythmias Arrhythm. Electrophysiol. Rev. 2018 7 111 117 10.15420/aer.2018:15:2 29967683 3. Wende A.R. Abel E.D. Lipotoxicity in the heart Biochim. Biophys. Acta 2010 1801 311 319 10.1016/j.bbalip.2009.09.023 19818871 4. Chowdhury M.K.H. Martinez-Mateu L. Do J. Aromolaran K.A. Saiz J. Aromolaran A.S. Macrophage-Dependent Interleukin-6-Production and Inhibition of I(K) Contributes to Acquired QT Prolongation in Lipotoxic Guinea Pig Heart Int. J. Mol. Sci. 2021 22 11249 10.3390/ijms222011249 34681909 5. Conceicao M. Forcina L. Wiklander O.P.B. Gupta D. Nordin J.Z. Vrellaku B. McClorey G. Mager I. Gorgens A. Lundin P. Engineered extracellular vesicle decoy receptor-mediated modulation of the IL6 trans-signalling pathway in muscle Biomaterials 2021 266 120435 10.1016/j.biomaterials.2020.120435 33049461 6. Ridker P.M. MacFadyen J.G. Thuren T. Libby P. Residual inflammatory risk associated with interleukin-18 and interleukin-6 after successful interleukin-1beta inhibition with canakinumab: Further rationale for the development of targeted anti-cytokine therapies for the treatment of atherothrombosis Eur. Heart J. 2020 41 2153 2163 10.1093/eurheartj/ehz542 31504417 7. Rubio-Alarcon M. Camara-Checa A. Dago M. Crespo-Garcia T. Nieto-Marin P. Marin M. Merino J.L. Toquero J. Salguero-Bodes R. Tamargo J. Zfhx3 Transcription Factor Represses the Expression of SCN5A Gene and Decreases Sodium Current Density (I(Na)) Int. J. Mol. Sci. 2021 22 13031 10.3390/ijms222313031 34884836 8. Perez-Hernandez M. Matamoros M. Barana A. Amoros I. Gomez R. Nunez M. Sacristan S. Pinto A. Fernandez-Aviles F. Tamargo J. Pitx2c increases in atrial myocytes from chronic atrial fibrillation patients enhancing IKs and decreasing ICa, L. Cardiovasc. Res. 2016 109 431 441 10.1093/cvr/cvv280 26714926 9. Daimi H. Lozano-Velasco E. Aranega A. Franco D. Genomic and Non-Genomic Regulatory Mechanisms of the Cardiac Sodium Channel in Cardiac Arrhythmias Int. J. Mol. Sci. 2022 23 1381 10.3390/ijms23031381 35163304 10. Gulsevin A. Glazer A.M. Shields T. Kroncke B.M. Roden D.M. Meiler J. Veratridine Can Bind to a Site at the Mouth of the Channel Pore at Human Cardiac Sodium Channel Na(V)1.5 Int. J. Mol. Sci. 2022 23 2225 10.3390/ijms23042225 35216338 11. Hu W. Clark R.B. Giles W.R. Kondo C. Zhang H. Frequency-Dependent Properties of the Hyperpolarization-Activated Cation Current, I(f), in Adult Mouse Heart Primary Pacemaker Myocytes Int. J. Mol. Sci. 2022 23 4299 10.3390/ijms23084299 35457119 12. Aromolaran K.A. Do J. Bernardi J. Aromolaran A.S. mTOR Modulation of IKr through hERG1b-Dependent Mechanisms in Lipotoxic Heart Int. J. Mol. Sci. 2022 23 8061 10.3390/ijms23158061 35897638 13. Eichel C.A. Rios-Perez E.B. Liu F. Jameson M.B. Jones D.K. Knickelbine J.J. Robertson G.A. A microtranslatome coordinately regulates sodium and potassium currents in the human heart Elife 2019 8 e52654 10.7554/eLife.52654 31670657 |
Chinese formulation-based medicinal food has been widely used in clinical trials, but its safety is not well studied. In this research, the edible safety assessment of Balanced Health Care Dan a formulation containing traditional edible ingredients that were initially formulated to reduce side effects for lung cancer patients was studied in mice based on biochemical and gut microbial analyses. The experimental mice were subcutaneously loaded with lung tumor A549 cells and then administrated with Balanced Health Care Dan (200 mg/kg or 400 mg/kg b.w. in gavage feeding) for 4 weeks. The body weight, blood parameters, and pathogenic phenotype in tissues were examined. No toxicological symptom was found in experimental mice compared with the normal control. Comprehensive analyses were also conducted to evaluate intestinal microbiota that are associated with many diseases. Balanced Health Care Dan modified the gut microbiota structure in a positive way. In conclusion, the Chinese formulation-based medicinal food has shown no toxicological effect in mice within 4 weeks of feeding experiment and has the potential to be used in clinical trials. Chinese formulation-based medicinal food has been widely used in clinical trials, but its safety is not well studied. The current research evaluated a medicinal food for cancer patients using biochemical and gut microbial analyses to support the use of such a formula. cancer medicinal food safety evaluation toxicological assessment source-schema-version-number2.0 cover-dateMarch 2023 details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.2.6 mode:remove_FC converted:10.03.2023 Dong, F. , Zhao, C. , He, X. , Dong, Y. , Liu, H. , Yao, P. , & Xu, W. (2023). Safety evaluation of Balanced Health Care Dan A medicinal formulation containing traditional edible ingredients in lung tumor-loaded mice. Food Science & Nutrition, 11 , 1544-1552. 10.1002/fsn3.3195 pmc1 INTRODUCTION Chinese formulation-based medicinal food has made great progress in clinical uses. There are increasing varieties of traditional Chinese formulations used in cancer treatment, but the safety of these formulations has not been systematically evaluated. Tumors are seriously threatening human life and health, leading to increased mortality and morbidity worldwide (Ferlay et al., 2021; Siegel et al., 2019). Among all diseases, cancer has the second highest death rate, only next to cardiovascular and cerebrovascular diseases (Siegel et al., 2018; Zhang et al., 2021). Lung cancer is a malignant tumor characterized by a rapid proliferation rate, less survivability, and high mortality. Lung cancer has the highest mortality rate among all cancers (Su et al., 2021). Surgery, radiotherapy, and chemotherapy are the most common clinical treatment strategies (Couzin-Frankel, 2013; Ma et al., 2019). These treatments have greatly improved the prognosis of lung cancer patients, but also have brought about many side effects (Wang et al., 2020, 2021). These side effects greatly reduce the quality of life of the patients during treatment. Traditional medicinal food (TMF) offers a promising option to reduce the side effects during cancer treatment (Luo et al., 2019; Zhang et al., 2022). "Balanced Health Care Dan" is a formula that is designed to improve patient's quality of life, and decrease chemotherapy-induced adverse effects. Although most of the TMFs are botanical and have been traditionally considered to be nontoxic, the ingredients of TMF are generally complex with certain substances that might cause additive toxicities (Lin et al., 2018; Zhang & Yuan, 2012). Therefore, edible safety evaluation and clinical studies of TMFs are equally important. Animal-based toxicity evaluation is necessary before the clinical application of these TMFs added to the diet of cancer patients (Shen et al., 2014; Wang, 2015). The current research focuses on the edible safety evaluation of "Balanced Health Care Dan," which can be considered a model for traditional formula-based medicinal food. 2 MATERIALS AND METHODS 2.1 Animals and cells Totally, 72 BALB/C Nude mice (36 males and 36 females) of 5-week-old with an average body weight of 40-60 g were purchased from Vital River Laboratory Animal Technology Co., Ltd. The animal room was maintained at 23 +- 2degC, with relative humidity of 50 +- 5%. A 12 h light/dark cycle was provided by automated fluorescent illumination. All mice were provided with their diet and water ad libitum. The animal studies were approved by the Animal Care and Use Committee at China Agricultural University and all experiments were performed in accordance with relevant guidelines and regulations (Approval Number: AW02110202-4). A549 lung cancer cells (ATCC) were cultured in a carbon dioxide cell incubator at 37degC. The medium was Dulbecco's modified Eagle medium basal medium, complemented with 10% fetal bovine serum and 100 U/ml penicillin and streptomycin. The cells were digested with 0.25% trypsin and passaged on alternate days. 2.2 Traditional formula ingredients The Balanced Health Care Dan was prepared using the following ingredients: Dangshen, Astragalus membranaceus, Atractylodes macrocephala, white lentil, Ligusticum chuanxiong, bezoar, musk, Rhodiola, Platycodon grandiflorum, mulberry bark, licorice, Poria cocos, wood incense, Sichuan pepper, aloes, polygonatum, purple Ganoderma lucidum, Hedyotis diffusa, Dendrobii Officmalis Caulis, pollen, and honey. Each ingredient was washed, dried, disinfected, and ground into very fine powder. The powder was then mixed with condensed honey followed by pellet making for serving. Currently, the formulation is in the application for patent protection (Application No. CN20180374829.6). 2.3 Mouse lung cancer tumor modeling Each mouse was subcutaneously inoculated with A549 cells (5 x 106 cells/mouse) on the right back. The animals were used for the experiment when the average tumor volume of the group reached over 100 mm3. The successful model mice were randomly divided into groups as follows: Control model mice were gavaged with sterile water, while low-dose group and high-dose groups of mice were gavaged with 200 or 400 mg/kg of Balanced Health Care Dan solution for 4 weeks, respectively. The doses used were physiologically relevant to that administered to humans. The treatment was carried out in six consecutive days per week. The daily body weight of the mice was recorded. 2.4 Blood biochemistry At the end of the experiment, mice were fasted for 12 h before blood collection. Blood samples were collected from the inner canthus under anesthesia. The serum samples were analyzed for alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin (ALB), creatinine (CREA), urea, triglycerides (TG), and cholesterol (CHO) as previously reported (He et al., 2020). 2.5 Pathology examination The fresh tissues of the tumor, liver, kidney, spleen, and lung of mice were fixed with 4% paraformaldehyde for 24-48 h. The tissues were dehydrated, waxed, embedded, and sliced. Subsequent HE staining was performed and then examined microscopically by a professional staff. 2.6 Fecal metagenomic analysis The intestinal contents of mice were collected in sterilized tubes and frozen at -80degC. DNA was then extracted from the intestinal contents according to the instructions in the kit (FDA6512, Beijing Ford Press Technology Co., LTD). The 16S rDNA sequencing and data analysis were performed as reported (He et al., 2020; Xu et al., 2020). Briefly, The V3-V4 region of the 16S rDNA was amplified by PCR with specific primers linked to the barcode. Thermal cycling consisted of initial denaturation at 98degC for 1 min, followed by 30 cycles of denaturation at 98degC for 10 s, annealing at 50degC for 30 s, and elongation at 72degC for 30 s. Finally, 72degC for 5 min. Sequencing libraries were generated using TruSeq(r) DNA PCR-Free Sample Preparation Kit (Illumina) following the manufacturer's recommendations, and index codes were added. The library quality was assessed on the [email protected] Fluorometer (Thermo Scientific) and Agilent Bioanalyzer 2100 system. At last, the library was sequenced on an Illumina NovaSeq platform. After data filtering, UPARSE software (uparsev7.0.1001) was used to cluster valid data into Operational Taxonomic Units. Mothur method and SILVA138 )'s SSUrRNA database were used for species annotation analysis. Qiime software (Version 1.9.1) was used to analyze diversity. R software (Version 2.15.3) was used for PCA analysis. LEfSe software was used for LEfSe analysis, and the filter value of LDA Score was 4 by default (Segata et al., 2011). 2.7 Statistical analysis The experimental data were presented as mean value +- standard deviation, and the data were analyzed by GraphPad Prism 8. A one-way analysis of variance (ANOVA) was applied with Dunnet-1 post hoc analysis. Differences between values were considered statistically significant at *p < .05, and extremely significant at **p < .01. 3 RESULTS AND DISCUSSION 3.1 Tumor incidence A total of 72 mice (36 female and 36 male mice) were used in this experiment, among which 54 mice (27 males and 27 females) were successfully loaded with tumors that met the requirement and were included in the follow-up experiment. The 54 mice were randomly divided into six groups (3 male groups and 3 female groups; 9 mice/group) following a computerized randomization scheme based on body weight. Four weeks treatment with Balanced Health Care Dan did not significantly affect the body weight of these mice . FIGURE 1 Body weight of male and female mice during treatment. (a) Male mice; (b) female mice. CK, control group; Low, low-dose group; High, high-dose group 3.2 Analysis of clinical appearance During the 4-week experiment, no treatment-related adverse effects in the clinical appearance of the animals were observed. The body weight of male and female mice in the experimental groups was comparable with that of the control group on day 7, day 14, day 21, and at the end of the experiment. Balanced Health Care Dan slightly increased body weight nonsignificantly, demonstrating that the formula did not exhibit any acute toxicity effects on the animals' growth and development (Hamaguchi et al., 2019). 3.3 Analysis of hematology Hematology index is an important indicator in safety evaluation (Rosa et al., 2018). Serum biochemical profile derangement can reflect nutrient metabolism abnormality (Ca Llens & Bartges, 2015; Gwinn et al., 2020; Paiano et al., 2019), as damaged tissues or organs modify the serum parameters. We detected blood biochemical indexes including ALB, ALP, ALT, AST, CREA, Urea, CHO, and TG at day 28 . These indicators can reflect liver, kidney function, and lipid metabolism. Liver and kidney are important target organs of many toxins, which can alter relevant indicators after intragastric administration (Calle-Toro et al., 2020; Ursell et al., 2012). As the important indexes of liver and kidney function, the values of ALP, ALT, AST, and Urea were not significantly different between groups. In female groups, the mean values of ALB and CREA were slightly lower in low-dose and high-dose groups, respectively, compared with control. However, these differences were within the normal range, which possibly resulted from individual differences between mice. Such differences were not seen in male mice. FIGURE 2 Blood biochemistry of male and female mice during treatment. (a) Male mice; (b) female mice FIGURE 3 Lipid profile of male and female mice during treatment. (a) Male mice; (b) female mice. CHO, cholesterol; TG, total triglycerides The lipid profile reflects basic metabolism of the body. CHO and TG are the common indicators for lipid metabolism. In the female group, the mean value of TG in the low-dose group reduced slightly compared with that of the control group indicating the treatment might have a hypolipidemic effect. Since this beneficial effect was not shown in the high-dose group, we think the difference was more likely attributed to the background variability and sporadic deviation. 3.4 Analysis of pathology in organs A complete gross necropsy and microscopic anatomic pathological analysis of organs were conducted on all animals after the 4-week feeding study. The liver, kidney, lung, and spleen showed no pathological lesions (data not shown) in the low-dose or high-dose groups. From the pathological point of view, Balanced Health Care Dan does not have any toxic or adverse effects. 3.5 Analysis of microbiota Intestinal flora is known as the "second fingerprint" of the body (Duffy et al., 2015; Ursell et al., 2012), which has an enormous impact on the nutrition and health status of the host. Diet directly affects the balance of intestinal microbiota. For edible safety evaluation, analyzing the changes in intestinal microbiota can directly reflect the effects of tested materials on body health (Barko et al., 2017). Therefore, the evaluation of intestinal microbiota is an important part of edible safety evaluation. Thus, in this study, the intestinal contents were used to evaluate the effects of Balanced Health Care Dan. Based on metagenomic sequencing, in both male and female mice, the relative abundance of intestinal microbiota changed after TMF treatment . Principal coordinates analysis showed significant changes in the intestinal microbiota of male mice in the TMF-treated group compared with the control group, while the effect of TMF on the intestinal microbiota of female mice was relatively small . The Shannon index was used to measure species diversity (Nielsen, 2021). From Figure 4e,f, TMF treatment significantly altered the structure and composition of intestinal microbiota in both male and female mice. FIGURE 4 The overall level of intestinal flora change. (a, b) The overall level of intestinal flora changed; (c) OUT analysis of each dose group in male mice; (d) OUT analysis of each dose group in female mice; (e) principal coordinate analysis of male mouse samples; (f) principal component analysis of female mouse samples From the analysis of the genus level, the most predominant 10 genera were identified . According to the species annotation and abundance information of all samples at the genus level, correlation heatmap was applied to represent the top 35 genera . Compared with the control group, Bacteroides, Ralstonia, Bilophila, Muribaculum, Prevotellaceae, Alistipes, and Anaerotruncus all showed significant changes in the TMF treatment groups . The results showed that there were different effects on the mice by gender. For example, in male mice groups as shown in Figure 6a,b, Deterribacteres, Deferribacteraceae, Deferribacterales, and Deferribacteres increased significantly compared with the control group. Bacteroides acidifaciens and Proteobacteria decreased significantly. In addition, the proportion of Firmicutes to Bacteroidetes did not change significantly. While in the female mice groups as shown in Figure 6c,d, Muribaculaceae, Blautia, Bacteroides caccae, Clostridia, Firmicutes, Lachnospiraceae Bacterium, Lachnospiraceae, Oscillibacter, Lachnospirales, Oscillospirales, and Osillospiraceae increased significantly. Mucispirillum, Deferribacteraceae, Deferribacterales, Deferribacteres, Bacteroides, Alistipes Bacteroidaceae, Bacteroides acidifaciens, Bacteroidales, Bacteroidota, Bacteroidia, and Rikenellaceae significantly decreased. In addition, the proportion of Firmicutes to Bacteroidetes increased significantly. In order to further confirm the gender difference in the effects of TMF, functional predictive analysis was performed. As shown in Figure 7a, there was no difference in the top 10 functions between male and female mice although the function of the top 35 varied by gender . FIGURE 5 Changes in the level of intestinal flora. (a) Top 10 dominant bacteria analysis; (b) top 35 dominant bacteria thermogram analysis; (c) abundance distribution box map between groups FIGURE 6 LEfSe analysis in mice (a) and (b) Male mice; (c) and (d) female mice. FIGURE 7 Function prediction analysis. (a) Relative abundance analysis of top 10 function annotation; (b) cluster analysis of relative abundance of top 35 function; (c) functional notes of Venn diagram; (d) function annotation of petal diagram There was more Bacteroides in the gut of colorectal cancer patient, which indirectly proved that the decrease in Bacteroides had a positive effect on the body's resistance to cancer (Garrett, 2019). Proteobacteria have been found to dominate the intestinal microbiota in acute and chronic inflammation caused by infectious pathogens or protozoan parasites, and the same phenomenon has been found in colorectal cancer associated with enteritis in animal and human experiments (Da et al., 2020). Balanced Health Care Dan significantly reduced Proteobacteria, indicating that Balanced Health Care Dan could help improve body health. The abundance of Muribaculaceae was negatively correlated with proinflammatory factors (Chung et al., 2020), and the increasing abundance of Muribaculaceae in the study indicated that it could protect intestinal health. The abundance of Lachnospiraceae was increased in the TMF treatment groups. As a potentially beneficial bacterium, Lachnospiraceae participates in the metabolism of a variety of carbohydrates, among which acetic acid, the fermentation product, is the main source of energy for the host (Vacca et al., 2020). In contrast to the control groups, the proportion of Firmicutes to Bacteroidetes in male mice groups did not change but significantly increased in female mice group, suggesting that after high-dose treatment, female mice were more likely to absorb heat to maintain body weight (John & Mullin, 2016; Zhao et al., 2021). Therefore, to a certain extent, Balanced Health Care Dan improved the intestinal microbiota of mice and then might increase body immunity. This effect was more obvious in male mice. Therefore, from the point of view of intestinal health, Balanced Health Care Dan is not potentially harmful to the body. It needs to be noted that there are huge differences in gut microbiota between human and animal models, which are caused by species-specific differences, evidenced by host-microbial interactions, environment, diet, and genetic responses (Nguyen et al., 2015). Further clinical trial is still necessary for accurate risk assessment. 4 CONCLUSION In a 4-week animal feeding test, we evaluated edible safety of a traditional formula-based medicinal food called Balanced Health Care Dan by examining behavior performance, body weight, relevant blood parameters, pathological phenotype, and intestinal microbiota in lung tumor-loaded mice. We found no treatment-related adverse effects in this short-term toxicity evaluation experiment. This research provides a new strategy for the edible safety evaluation of TMFs which have the potential to be used for cancer patients. CONFLICT OF INTEREST The authors declare no conflict of interest in this study. ACKNOWLEDGMENT None. DATA AVAILABILITY STATEMENT The datasets used and/or analyzed during this study are available from the corresponding author upon reasonable request. |
Int J Mol Sci Int J Mol Sci ijms International Journal of Molecular Sciences 1422-0067 MDPI 10.3390/ijms24055063 ijms-24-05063 Editorial Molecular Pathology, Diagnostics and Therapeutics: A Story of Success in 2022 Bustin Stephen A. Medical Technology Research Centre, Anglia Ruskin University, Chelmsford CM1 1SQ, UK; [email protected] 06 3 2023 3 2023 24 5 506324 2 2023 6 3 2023 (c) 2023 by the author. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). pmc1. Introduction Molecular pathology, diagnostics and therapeutics are three closely related topics of critical importance in medical research and clinical practice. Understanding the biology of diseases at the molecular level by identifying molecular and pathway alterations is important for several reasons: It can facilitate earlier and more accurate diagnoses of diseases, which are key to initiating appropriate treatments at the right time as well as reducing healthcare costs. It enables the development of new drugs and the design of more effective therapies, including the development of treatments that are tailored to the individual patient's genetic makeup. It is useful for disease prevention by identifying individuals at risk of developing certain conditions, thus encouraging early targeted interventions and lifestyle changes. This field has transitioned into an extensive range of molecular and cell methodologies and techniques in the clinical arena that analyse an equally wide range of samples and diseases. A vast amount of complex data is generated and results in a taxing bioinformatic, bioanalytic and statistical workload. The molecular pathology, diagnostics and therapeutics section of the International Journal of Molecular Science (IJMS) aims to provide a go-to home for high quality, innovative and definitive publications in this critical area of health research. 2. Review of 2022 The significance of this field is reflected in the important contribution made by the molecular pathology, diagnostics and therapeutics section to the IJMS. This section includes contributions from basic research all the way to clinical and forensic applications and is especially open to studies that challenge existing concepts. It accounted for 14.4% of papers published in the journal during 2022, with the number of publications increasing to 2356 out of 4995 submissions (47%), resulting in 1.5 million downloads. Papers published in 2020/21 were cited nearly 15,000 times, with the most cited publications in the areas of cardiovascular diseases, cancer/tumour treatment, neurodegenerative diseases, endocrine diseases, and COVID-19-related research. Of these, 163 papers (6.9%) were cited more than five times and 20 of those more than 10 times. Consequently, papers published in this section have contributed to the steady rise of the journal's impact factor, which currently stands at 6.208. This increase in quality and quantity is nurtured by the increased number of specialist editorial board and topical advisory panel members and is sustained by the many expert reviewers, whose comments and contributions are an essential part of this rise. Together this helps to ensure that the research presented in our section is of high quality, that methods are clearly described, results are fully reported and that the conclusions drawn are supported by the data. As a consequence, our section and the journal as a whole are respected by the scientific community and that the research is widely cited. Further to this topic, I would like to remind potential authors of the importance of method and data transparency, as both are critical components for evaluating the significance of reported results and any conclusions. For example, quantitative PCR (qPCR) and reverse transcription (RT)-qPCR are widely used technologies in this field, not least evidenced by the huge number of recent publications relating to SARS-CoV-2. Yet as an editor it continues to surprise me how little technical detail is generally included with the first submisssions of manuscripts and how inadequately results are presented. It is as though many authors either regard this technology as so common and standardised that no detail is required, or they have no understanding of its complexity of the various components such as RNA quality, PCR efficiency, primer specificity or significance of fold-changes in biomarker expression levels. I would urge authors to consult an earlier editorial describing the essential criteria that should accompany any submission to IJMS . The same requirement for transparency is obviously important for any technique used in a published paper. The percentage of primary research articles has increased to 60.1% in 2022, up from 52.2% in 2021. This is probably a reflection of the increasing impact factor of the journal, which encourages more researchers to trust it with their latest and most important research results and, in turn, fuels a virtuous circle of increased quality resulting in further increases in the impact factor. Conversely, this increase has led to a decrease in the number of review articles (36.6% from 45.9% in 2021). Clearly there is a need to strike a balance, since review articles tend to attract more citations and increase the scholarly impact of the journal. Nevertheless, as an editor I find it promising and exciting that so many authors choose our section for the dissemination of their precious data. There has been an increasing emphasis on Special Issues, to which publications are invited by guest editors and panel members, with a consistent review process ensuring high quality as well as topicality. In 2022 there were 547 Special Issues launches, compared with 368 in 2021. Indeed, the vast majority of papers in 2022 were published as parts of Special Issues. Nevertheless, the rise in the impact factor and the corresponding increase in our reputation saw an increasing number of regular submissions to the journal. I anticipate that this trend will continue for three reasons: (i) the IJMS impact factor is higher than that of competitor journals, (ii) the steady increase in its impact factor is not mirrored by those journals and (iii) their article processing charges are higher. The open access format combined with reasonable processing charges are two important reasons for the success of the journal. Papers can be accessed by anyone with an internet connection, regardless of their location or affiliation, thus can reach a much wider audience. Combined with a rapid processing workflow, this makes research published in our section available to the scientific community as well as the public sooner, making our contributions more topical and relevant to current news cycles. The increased visibility and accessibility also help articles being cited more frequently, so adding to their impact and influence. It follows, then, that the logistics of manuscript handling should be as clear, smooth, and rapid as possible as every author likes their manuscript to be reviewed and processed in as short a time frame as possible. IJMS in general and this section in particular have clear policies and guidelines on how to prepare and submit manuscripts, for ethical behaviour, and for the peer review process. The molecular pathology, diagnostics, and therapeutics section of the IJMS performs well, with a first decision provided to authors 16 days after submission and the median processing time being 36 days. This is remarkably swift, given that each manuscript is subject to strict peer review and considering the 16% increase in submissions since 2020. Feedback surveys indicate that authors appreciate our fast publication times, and the editors will strive to maintain this benefit for the future, whilst obviously ensuring that the section maintains the high paper quality. Amongst the top 15 countries publishing in this section, most continue to come from Europe (including Russia) at 41.5%, slightly down on the 45% recorded in 2021. Contributions from Asia (24.2% vs. 23.4%) and North America (13.7% vs. 14.8%) are roughly the same and the appearance of contributions from Australia (1.9%) is welcome. Within those groupings, there has been a sizeable increase in manuscripts submitted from China (+5.1%) and decrease from South Korea (-4.4%). An analysis of author origin in the pathology category of the Web of Science reveals that of the top three countries, only China has a similar number of submissions to our journal (10.9% vs. 8.6%). The USA (41.3% vs. 12% and the UK (6.2% vs. 2%) are under-represented. I also note that there are few submissions from India, which is home to 3.5% of submissions on the Web of Science. In contrast, the journal is rather popular with researchers from Japan (5.3% vs. 7.3%), Germany (4.8% vs. 6.6%) and, especially, Italy (4.1% vs. 13.6%). Clearly there is work to be done to encourage authors in countries such as India, South Africa and South America to consider IJMS as a destination for their research outputs. Author origin and online readership are closely aligned, suggesting a good cooperative relationship with the section. The readership extends way beyond the top contributor nations, though, with 26% of the online readership from countries with fewer than 2% views. Editorial board and topical advisory panel members are composed of experts in molecular pathology, diagnostics, therapeutics, and related field. Their understanding of, and indeed personal contribution to current research developments are important safeguards that allow unbiased and professional evaluation of the quality of the manuscripts submitted to the section. It is also important to note that the name of the academic editor accepting a manuscript after full peer review becomes associated with the published paper. This enhances the rigorous and unprejudiced review procedure, promotes maximum transparency for authors and readers alike, and provides a measure of responsibility if subsequent uncertainties arise. Board and advisory panel members play an essential role in ensuring that published manuscripts are of the highest quality, report innovative research results and are published with transparent methods and appropriate statistical analyses. They are from a wide range of countries, with most concentrated in two countries, Italy and the USA. Clearly one aim for next year must be to recruit more academic editors from a wider range of countries, especially China. 3. Outlook for 2023 With awareness of the current pandemic fading, it is essential to maintain the spotlight on the importance of molecular pathology and diagnostics as critical components of any country's public health infrastructure and their role in opening new therapeutic pathways. Hence, the focus in 2023 will be to make our section an even better platform for authors and guest editors of Special Issues to publish relevant, influential, and conclusive research results. Ultimately, the basis of journal's reputation is the quality of its primary research papers; it is enhanced by the publication of authoritative reviews that become influential in shaping the debate surrounding public health. Our aim must be to continue to provide a first-class publication experience to authors and encourage the submission of leading-edge research papers as well as of forward-looking and open-minded profiles of current work and future goals. Conflicts of Interest The author declares no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. Reference 1. Bustin S. Transparency of reporting in molecular diagnostics Int. J. Mol. Sci. 2013 14 15878 15884 10.3390/ijms140815878 23903047 |
Int J Mol Sci Int J Mol Sci ijms International Journal of Molecular Sciences 1422-0067 MDPI 10.3390/ijms24054642 ijms-24-04642 Editorial Vitamin D and Vitamin D-Binding Protein in Health and Disease Delrue Charlotte 1 Speeckaert Marijn M. 2* 1 Department of Nephrology, Ghent University Hospital, 9000 Ghent, Belgium 2 Research Foundation-Flanders (FWO), 1000 Brussels, Belgium * Correspondence: [email protected]; Tel.: +32-9-332-4509 28 2 2023 3 2023 24 5 464229 1 2023 23 2 2023 27 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). pmcVitamin D is a fat-soluble secosteroid that exists in two forms: vitamin D2 and vitamin D3 . While plants and fungi produce vitamin D2 from ergosterol , human skin produces vitamin D3 from 7-dehydrocholesterol (7-DHC) when exposed to UVB radiation from the sun . The UV photons trigger a photochemical reaction that converts 7-DHC into previtamin D3, which then becomes vitamin D3 via a series of thermal isomerizations . Vitamin D3 is transported to the liver and converted by CYP2R1 to 25-hydroxyvitamin D3 [25(OH)D3], the major circulating form of vitamin D3 . Finally, 25(OH)D3 is converted to its active form, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], in the kidneys via CYP27B1 . The primary function of 1,25(OH)2D3 is to maintain normal calcium levels and bone development by regulating phospho-calcium metabolism. Additionally, because vitamin D receptors (VDRs) have been discovered in numerous tissues (prostate, brain, breast, pancreas, colon, and immune cells), vitamin D can also provide non-skeletal actions. 1,25(OH)2D3 can play a role in the immune function and regulation of cell proliferation and differentiation in a variety of cell lineages (lymphocytes, endothelial cells, osteoblasts, and keratinocytes). Vitamin D can modify the risk of cardiometabolic outcomes, including hypertension, cardiovascular disease, and diabetes mellitus. Although the regulatory role of vitamin D in many biological processes is well documented, there is insufficient evidence to support the therapeutic use of vitamin D supplementation for the prevention or treatment of immunoinflammatory, infectious, or hyperproliferative diseases. 1,25(OH)2D3 exerts most of its functions via nuclear VDR, which forms a heterodimer with the retinoid X receptor (RXR). VDR/RXR in turn binds to vitamin D response elements (VDRE) in target genes and regulates gene transcription. The VDR pathway interacts with other intracellular signaling pathways to exert its biological effects . In some cases, 1,25(OH)2D3 exerts its influence without affecting gene expression or protein synthesis . Vitamin D and its metabolites are generally transported from the site of production to target tissues. Mainly responsible for this transport is the vitamin-D-binding protein (DBP) or group-specific component (Gc-globulin), which binds 85% of the circulating 25(OH)D3 and 1,25(OH)2D3. It has a high binding affinity for vitamin D and its metabolites, which contributes to the maintenance of adequate vitamin D levels in the blood. On the other hand, albumin has a low binding affinity for vitamin D but also contributes to vitamin D transport, especially at low DBP levels. The relative proportion of vitamin D bound to DBP and albumin may affect the bioavailability of vitamin D, with vitamin D bound to DBP being more bioavailable than that bound to albumin. Understanding the role of these two carriers in vitamin D transport and regulation is critical for a better understanding of vitamin D metabolism and for developing effective strategies to treat vitamin D deficiency and related diseases. Aside from its sterol-binding capacity, DBP has been shown to possess antioxidant and anti-inflammatory properties, without binding to vitamin D, that likely contribute to its role in disease prevention and treatment. DBP has been found to regulate immune function and play a role in the removal of toxins and pathogens from the bloodstream. DBP is also involved in the regulation of calcium metabolism, which is critical for maintaining healthy bones, and may have anti-cancer properties in the form of the vitamin-D-binding protein macrophage-activating factor (DBP-MAF) . Seven interesting manuscripts (three original articles and four review articles) were included in the Special Issue titled "Vitamin D and Vitamin D-Binding Protein in Health and Disease". In the first paper, Xu et al. investigated how 1,25(OH)2D3 can affect the regenerative ability of intestinal stem cells. A novel approach was used to deliver regionally high concentrations of 1,25(OH)2D3 only to the inflamed intestine. Throughout the epithelial regeneration process, a pulse-and-chase method using 5-bromo-2'-deoxyuridine (BrdU) labeling was used to track Lgr5+ stem cells. Macrophages engineered to synthesize high levels of 1,25(OH)2D3 de novo specifically migrated into the inflamed intestine and supported the regenerative capacity of intestinal stem cells by hosting CD11b+Gr1+ macrophages. The results of this study may contribute to the development of a promising therapy to accelerate the repair of the intestinal epithelium in patients with inflammatory bowel disease (IBD). The second paper addressed the free-hormone hypothesis for vitamin D in psoriasis patients. In a retrospective cross-sectional study involving 40 bionaive patients with mild-to-severe plaque psoriasis, total 25(OH)D3 serum levels appeared to be a reliable indicator of vitamin D status, as they correlated well with free 25(OH)D3 serum levels. No associations were found between any of the vitamin D metabolites and psoriatic disease severity. Despite potential confounding variables, such as age, sex, and body weight, DBP serum levels were higher in patients who self-reported having arthropathy than in those who did not. DBP may be a brand-new indicator of inflammation in psoriasis, particularly psoriatic arthritis. As mentioned in the introduction, DBP performs a number of other roles in addition to binding to vitamin D, including therapeutic properties against tumors after conversion to DBP-MAF. Dolgova et al. evaluated the benefit of the DBP-MAF-related factor (DBP-MAF-RF) in a Lewis carcinoma model under two clinical conditions: untreated tumor lesions and tumor resorption after "Karanahan" (derived from Sanskrit "killing the source") therapy. The results of the study suggest that the primary requirement for the manifestation of the antitumor effect of DBP-MAF-RF is the inhibition of the suppressor effect of tumor-associated stroma (myeloid-derived suppressor cells, regulatory T lymphocytes). The anti-inflammatory effect of DBP-MAF-RF supports tumor progression and immune surveillance defense when the tumor has an active protective humoral background. The pro-inflammatory tumor reactive effects of DBP-MAF-RF become more pronounced when the tumor loses the suppressive humoral background. The results of this study demonstrate that DBP-MAF-RF, when used properly in conjunction with the "Karanahan" strategy, may enhance the antitumor immune response elicited by "Karanahan" therapy. As discussed in two reviews in this Special Issue, diabetes mellitus, renal dysfunction, and heart failure act synergistically. Diabetes mellitus and its complications have been associated with vitamin D deficiency, although the major question remains whether vitamin D deficiency is a cause or merely a consequence of diabetic kidney disease (DKD). The possible renal protective role of vitamin D in the development of DKD and the reversal of pre-existing renal damage is not known, although vitamin D has been shown to play a critical role in the development of DKD in numerous animal and human studies. More extensive, protracted, randomized, controlled human studies are needed to determine how vitamin D and its analogues may affect mortality, end-stage kidney disease (ESKD) progression, the development of DKD, and the decline in estimated glomerular filtration rate (eGFR) . In another article, Chan et al. provided a systematic review of the association between vitamin D and various ocular diseases. In addition to the association with diabetic retinopathy, vitamin D was also associated with myopia, age-related macular degeneration, and dry eye syndrome. Evidence for an association with other ocular diseases such as glaucoma, thyroid disease, and retinoblastoma is still sparse. Although vitamin D has been associated with several disease-related processes, the causes of these diseases are complex, and knowledge of their underlying mechanisms remains limited. Vitamin D not only has an impact on the homeostasis of mineral metabolism, but also has anti-inflammatory and antioxidant properties. It influences the process of anti-angiogenesis by modulating various aspects of the cell cycle, such as cell division, proliferation, and apoptosis. Ocular tissues contain the vitamin D receptor (VDR) and vitamin-D-regulating enzymes, and research has shown that these tissues can activate and regulate vitamin D, indicating the importance of vitamin D in maintaining eye health. Finally, Papagni et al. studied the antifungal effect of vitamin D. Due to its relationship with oxidative balance, vitamin D inhibits the replication of Mycobacterium tuberculosis in vitro and has shown promise for the treatment of tuberculosis. Further clinical studies are needed to evaluate the efficacy of the drug in vivo, rule out confounding factors, and ultimately determine the dosages and delivery systems best suited for the treatment and prophylaxis of tuberculosis. It is important to investigate the potential benefits of combining vitamin D with other vitamins, such as vitamin A, which has antifungal activity in vitro. On the other hand, it would be advisable to measure vitamin D levels in both patients with active tuberculosis and those at risk, and to administer vitamin D, at least to achieve adequate levels, based on evidence of its efficacy in vitro and taking into account its low incidence of side effects, even at high doses, and its low cost. In summary, this Special Issue on vitamin D and its binding proteins showcases a promising role in monitoring, preventing, and treating a variety of human diseases, including IBD, psoriasis, tuberculosis, diabetic nephropathy and retinopathy, and cancer. However, more research is needed to fully understand the mechanisms by which vitamin D affects these diseases and to determine the optimal vitamin D levels needed to prevent and treat disease. Future studies will also explore the potential use of DBP as a biomarker for disease and as a therapeutic target. The discovery of the unique role of vitamin D and its binding protein in human health has the potential to lead to new and innovative treatments for a variety of diseases, making it an exciting and rapidly evolving area of research. Author Contributions Conceptualization, C.D. and M.M.S.; writing original draft preparation, C.D. and M.M.S.; writing review and editing, C.D. and M.M.S. All authors have read and agreed to the published version of the manuscript. Institutional Review Board Statement Not applicable. Informed Consent Statement Not applicable. Data Availability Statement Not applicable. Conflicts of Interest The authors declare no conflict of interest. Figure 1 Vitamin D exerts its biological effects through the vitamin D receptor (VDR). 1,25(OH)2D3 can quickly diffuse through cell membranes and bind to VDR. VDR forms heterodimers with the retinoid X receptor (RXR) after binding to the ligand, moving into the nucleus where it binds to vitamin D response elements (VDREs) to regulate gene transcription. The VDR also controls the transcription of genes by interacting with other nuclear receptors. The functions of vitamin D include growth and bone mineralization, immune function regulation, insulin secretion regulation, cell proliferation control, cell differentiation stimulation, apoptosis induction, phosphor-calcium homeostasis regulation, and muscle calcium transport regulation. Figure 2 An overview of vitamin-D-binding protein's various physiological roles, including the binding of vitamin D metabolites, the binding of fatty acids, the transport of endotoxins, neutrophil chemotaxis, the influence on T cell response, actin scavenging, and the influence of vitamin-D-binding protein-macrophage activating factor (DBP-MAF) on bone metabolism and cancer. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Bikle D.D. Vitamin D and the Skin: Physiology and Pathophysiology Rev. Endocr. Metab. Disord. 2012 13 3 19 10.1007/s11154-011-9194-0 21845365 2. Japelt R.B. Jakobsen J. Vitamin D in Plants: A Review of Occurrence, Analysis, and Biosynthesis Front. Plant Sci. 2013 4 136 10.3389/fpls.2013.00136 23717318 3. Bikle D. Christakos S. New Aspects of Vitamin D Metabolism and Action Addressing the Skin as Source and Target Nat. Rev. Endocrinol. 2020 16 234 252 10.1038/s41574-019-0312-5 32029884 4. Tian X.Q. Holick M.F. Catalyzed Thermal Isomerization between Previtamin D3 and Vitamin D3 via Beta-Cyclodextrin Complexation J. Biol. Chem. 1995 270 8706 8711 10.1074/jbc.270.15.8706 7721775 5. Bhattacharyya M.H. DeLuca H.F. Subcellular Location of Rat Liver Calciferol-25-Hydroxylase Arch. Biochem. 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Speeckaert R. Delanghe J.R. Speeckaert M.M. The Role of Vitamin D in Diabetic Nephropathy: A Translational Approach Int. J. Mol. Sci. 2022 23 807 10.3390/ijms23020807 35054991 15. Chan H.-N. Zhang X.-J. Ling X.-T. Bui C.H.-T. Wang Y.-M. Ip P. Chu W.-K. Chen L.-J. Tham C.C. Yam J.C. Vitamin D and Ocular Diseases: A Systematic Review IJMS 2022 23 4226 10.3390/ijms23084226 35457041 16. Papagni R. Pellegrino C. Di Gennaro F. Patti G. Ricciardi A. Novara R. Cotugno S. Musso M. Guido G. Ronga L. Impact of Vitamin D in Prophylaxis and Treatment in Tuberculosis Patients IJMS 2022 23 3860 10.3390/ijms23073860 35409219 |
Int J Mol Sci Int J Mol Sci ijms International Journal of Molecular Sciences 1422-0067 MDPI 10.3390/ijms24054385 ijms-24-04385 Editorial PD-L1, a Master Regulator of Immunity 2.0 Kochan Grazyna Oncoimmunology Group, Navarrabiomed, Fundacion Miguel Servet-Complejo Hospitalario de Navarra-UPNA-IdISNA, 31008 Pamplona, Spain; [email protected] 23 2 2023 3 2023 24 5 438529 11 2022 09 1 2023 (c) 2023 by the author. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). pmcSince the introduction of the first anticancer treatments at the beginning of the 20th century, many different chemotherapeutics have been developed . The use of all these treatments has increased the overall survival of cancer patients. However, long-term survival (over five years) has, in general terms, been very low. A significant improvement in survival was achieved after the introduction of therapies targeted towards specific tumour mutations. Despite their fewer side effects and higher efficacies, the development of drug resistance is a major drawback . The identification of immune checkpoint molecules on the surface of immune and cancer cells led to the development of therapies that greatly improved the overall survival of patients with numerous tumours. These highly promising results led to rapid progress in the development of different therapeutics blocking the immune checkpoints . These novel immunotherapy treatments significantly extended overall survival and progression-free survival in treated individuals. However, a large group of patients still do not respond to these immunotherapies. The identification of all factors affecting therapy success is key. This entails the unveiling of the molecular mechanisms of intracellular signalling of these immune checkpoint molecules in health and disease. Different monoclonal antibodies targeting CTLA-4, PD-1, and LAG-3 are already applied in human therapy , and some of the most-used are monoclonal antibodies that block interactions between PD-L1 and PD-1 . PD-L1 is of special interest as its presence on the cancer cell surface was demonstrated early on to be associated with the clinical success of immune checkpoint blockades . In fact, the application of pembrolizumab (humanised IgG4 anti-PD-1 by Merck) is conditioned by the presence of PD-L1 on the surface of cancer cells. PD-L1 is a type I transmembrane protein of the B7 family of co-stimulatory and co-inhibitory molecules that play a central role in regulating systemic tolerance . Its natural receptor, PD-1, is expressed on the surface of activated T, B, and NK cells . PD-L1 engagement with PD-1 regulates the degree of activation of effector immune cells . However, cancer cells up-regulate PD-L1 to avoid T cell attack . In addition, PD-L1 confers survival advantages to the cancer cell by counteracting apoptosis mediated by interferons and many other pro-inflammatory mediators . PD-L1 expression in cancer cells is currently used as a biomarker of response. However, we have to remember that PD-L1 expression on the cell surface is dynamic. Moreover, the histochemical determination of PD-L1 presence on the tumour cells in histopathological analyses can vary depending on the reagents used for analysis, sample preparation (fixation), or tumour fragment representation in a sample . Additionally, it has been shown that immune responses triggered by immunotherapy treatments depend not only on PD-L1 expression levels on cancer cells' surface, but also on the surface of myeloid compartment cells . We have to be aware that myeloid cells are key regulators of T cell responses as well. It has also been previously shown that the degree of PD-L1 surface expression on myeloid cells can be associated with clinical responses to treatment. Therefore, a "PD-L1-negative tumour" can still respond to a PD-L1/PD-1 blockade by acting over the myeloid compartment . Indeed, this molecule is also present as a soluble form in plasma from patients, where it likely plays a regulatory role as well. Based on the "knowns and unknowns", PD-L1 is a very attractive subject for research and a therapeutic target still undergoing exploitation. Following on from all clinical observations and basic investigations, more and more information is being gathered on the role of PD-L1. The current issue tries to contribute knowledge of PD-L1 in different tumours and autoimmune diseases, but also in physiological conditions. Until now, the majority of research has been centred mainly in the field of oncology. However, in the current issue we have some examples of the importance of PD-L1 expression and function in other aspects of human health. It is important to characterize PD-L1 expression and its role in different cancers and diseases, but also in physiological conditions. Gathering all this information together will help us to find analogies and similarities between cancers and other disorders. Only systematically filling the gaps in knowledge of the molecular mechanisms of action and the status quo of PD-L1 expression in health and disease will help us develop personalised treatments, not only for cancer, but also for other inflammatory disorders. Conflicts of Interest The author declare there is no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. De Vita V.T. Jr. Chu E. A history of cancer chemotherapy Cancer Res. 2008 68 8643 8653 10.1158/0008-5472.CAN-07-6611 18974103 2. Min H.Y. Lee H.Y. Molecular targeted therapy for anticancer treatment Exp. Mol. Med. 2022 54 1670 1694 10.1038/s12276-022-00864-3 36224343 3. Brahmer J.R. Tykodi S.S. Chow L.Q. Hwu W.J. Topalian S.L. Hwu P. Drake C.G. Camacho L.H. Kauh J. Odunsi K. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer N. Engl. J. Med. 2012 366 2455 2465 10.1056/NEJMoa1200694 22658128 4. Topalian S.L. Hodi F.S. Brahmer J.R. Gettinger S.N. Smith D.C. McDermott D.F. Powderly J.D. Carvajal R.D. Sosman J.A. Atkins M.B. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer N. Engl. J. Med. 2012 366 2443 2454 10.1056/NEJMoa1200690 22658127 5. Chocarro L. Blanco E. Arasanz H. Fernandez-Rubio L. Bocanegra A. Echaide M. Garnica M. Ramos P. Fernandez-Hinojal G. Vera R. Clinical landscape of LAG-3-targeted therapy Immuno-Oncol. Technol. 2022 14 100079 10.1016/j.iotech.2022.100079 6. Arasanz H. Gato-Canas M. Zuazo M. Ibanez-Vea M. Breckpot K. Kochan G. Escors D. PD1 signal transduction pathways in T cells Oncotarget 2017 8 51936 51945 10.18632/oncotarget.17232 28881701 7. Escors D. Gato-Canas M. Zuazo M. Arasanz H. Garcia-Granda M.J. Vera R. Kochan G. The intracellular signalosome of PD-L1 in cancer cells Signal Transduct. Target. Ther. 2018 3 26 10.1038/s41392-018-0022-9 30275987 8. Topalian S.L. Drake C.G. Pardoll D.M. Immune checkpoint blockade: A common denominator approach to cancer therapy Cancer Cell 2015 27 450 461 10.1016/j.ccell.2015.03.001 25858804 9. Grigg C. Rizvi N.A. PD-L1 biomarker testing for non-small cell lung cancer: Truth or fiction? J. Immunother. Cancer 2016 4 48 10.1186/s40425-016-0153-x 27532023 10. Karwacz K. 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Int J Mol Sci Int J Mol Sci ijms International Journal of Molecular Sciences 1422-0067 MDPI 10.3390/ijms24055038 ijms-24-05038 Editorial Genetic Variation in Transcription Factor Binding Sites Santpere Gabriel Neurogenomics Group, Research Programme on Biomedical Informatics (GRIB), Hospital del Mar Medical Research Institute (IMIM), MELIS, Universitat Pompeu Fabra, 08003 Barcelona, Spain; [email protected] 06 3 2023 3 2023 24 5 503810 2 2023 16 2 2023 (c) 2023 by the author. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). Instituto de Salud Carlos III (Spain) and the European Social FundMS20/00064 Agencia Estatal de Investigacion, AEI, SpainPID2019-104700GA-I00/AEI/10.13039/501100011033 NIHR01HG010898-01 G.S. is supported by grant MS20/00064 from the Instituto de Salud Carlos III (Spain) and the European Social Fund, as well as grant PID2019-104700GA-I00/AEI/10.13039/501100011033, funded by the Agencia Estatal de Investigacion, AEI, Spain. G.S. is also supported by the NIH grant R01HG010898-01. pmcThe interaction between transcription factors (TFs) and DNA is the core process that determines the state of a cell's transcriptome. Changes in TF binding can have consequences for normal cellular development as well as function and can also be the substrate for molecular evolution. Comparing TF-DNA binding across cells, tissues, and organisms, as well as across individuals, conditions, states, and developmental trajectories, is fundamental to assessing the impact of the gene regulatory networks' (GRNs) dynamics on normal cellular function, disease, and evolution. There are many observed mechanisms by which a given TF-DNA binding event can be altered. For example, at the TF level, variations in the concentration, subcellular localization, and post-translational modifications of TFs and their cofactors can all help to explain such differences. At the DNA level, changes in chromatin status (e.g., histone modifications and DNA methylation) and sequence variations that alter the preferred motifs of TFs or DNA shape may be determinants of GRN variation. Indeed, a large body of evidence links genetic mutations that specifically disrupt binding sites not only to the expected differences in TF binding and gene expression but also to the allelic imbalance in chromatin accessibility. This latter observation applies to both segregating sites within populations and substitutions between species , and further illustrates the bidirectional relationships between TF binding and chromatin accessibility that play a role in, as well as determine, target gene expression differences. Not surprisingly, TFBS-disrupting variants are particularly enriched at GWAS loci and represent the best candidates with which to explain the functional consequences of evolutionarily relevant genomic regions . In this Special Issue, entitled "The Role of Genetic Variation in Transcription Factor Binding Sites in Evolution and Disease", we aim to present and promote research on these aspects, which cut across a wide range of research areas. Degtyareva et al. review the history of regulatory SNPs that modify TFBS and discuss the range of available methods that can be used to dissect the specific TFs affected by genetic variants, such as EMSA, ChIP-seq, and pull-down assays . To extend this type of analysis genome-wide, with the aim of prioritizing causal GWAS variants, the authors discuss the capabilities of current state-of-the art functional genomics methods, such as eQTL mapping, massive parallel reporter assays, and ChIP-seq, as they apply to the determination of allele-specific expression, regulation, and TF binding. Finally, the review provides illustrative examples of disease-associated variants from GWAS where TFs with allele-specific binding have been identified . Another practical example of using allelic asymmetries in gene expression and chromatin state to identify regulatory SNPs is provided by Korbolina et al. In their study, the authors leverage RNA-seq and H3K4me3 ChIP-seq data from human pulmonary arterial endothelial cells to identify such allelic asymmetries, a catalogue that is subsequently refined with existing eQTL and GWAS data . Tseng et al. complement this by reviewing aspects of the mechanisms that influence TF binding, including histone modifications, DNA methylation, and chromatin conformation, as well as providing several instances of disease risk alleles that affect the interplay between specific TFs and chromatin status . The experimental determination of TF binding sites is an essential step as it reveals a variety of nuances in motif preference that often misalign with in silico predictions. In de Martin et al., the authors focus on the complexities of TF binding to DNA of the basic helix-loop-helix (bHLH) TFs, and how motif preference is determined by a combination of factors, including spatiotemporally regulated co-factor interactions, post-translational modifications, and chromatin status . Members of the bHLH family are also the subject of Yoshikawa et al., who review the evolutionary history of the regulatory elements associated with the recombination-activating genes Rag1 and Rag2, which mediate the recombination process that confers variability to T cell receptors and immunoglobulin genes, as well as their bHLH regulators . TFs can also operate on regulatory regions encoded in the genomes of DNA viruses. For example, hosts' TFs initiate and coordinate the viral cycle of the JC polyomavirus (JCPyV), the causative agent of a demyelinating disease called progressive multifocal leukoencephalopathy (PML). Wilczek et al. present their work on the structural variation affecting the JCPyV regulatory region and how this affects host TF binding. Their study found that JCPyV rearrangements resulting in more TFBS of TFs enhancing viral replication are more common in PML than in non-PML samples . Finally, Wang et al. introduce the topic of gene clusters regulated by few TFs and the grammar of their components. In particular, the authors review the complexity and interactions of pathway-specific TFs involved in the regulation of biosynthetic gene clusters in two model fungal organisms . Taken together, this Special Issue illustrates a wide range of molecular mechanisms that generate variation in TF function in different organisms. It also reflects the importance of combining computational modeling and prediction with the experimental determination of TFBS. I hope that this Special Issue will contribute to drawing more attention and research to variation in TF-DNA interactions in the context of evolution and disease. Conflicts of Interest The author declares no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Kasowski M. Grubert F. Heffelfinger C. Hariharan M. Asabere A. Waszak S.M. Habegger L. Rozowsky J. Shi M. Urban A.E. Variation in Transcription Factor Binding among Humans Science 2010 328 232 235 10.1126/science.1183621 20299548 2. Atak Z.K. Taskiran I.I. Demeulemeester J. Flerin C. Mauduit D. Minnoye L. Hulselmans G. Christiaens V. Ghanem G.-E. Wouters J. Interpretation of allele-specific chromatin accessibility using cell state-aware deep learning Genome Res. 2021 31 1082 1096 10.1101/gr.260851.120 33832990 3. Maurano M.T. Haugen E. Sandstrom R. Vierstra J. Shafer A. Kaul R. Stamatoyannopoulos J.A. Large-scale identification of sequence variants influencing human transcription factor occupancy in vivo Nat. Genet. 2015 47 1393 1401 10.1038/ng.3432 26502339 4. Starr A.L. Gokhman D. Fraser H.B. Accounting for cis-regulatory constraint prioritizes genes likely to affect species-specific traits Genome Biol. 2023 24 11 10.1186/s13059-023-02846-8 36658652 5. Yan J. Qiu Y. dos Santos A.M.R. Yin Y. Li Y.E. Vinckier N. Nariai N. Benaglio P. Raman A. Li X. Systematic analysis of binding of transcription factors to noncoding variants Nature 2021 591 147 151 10.1038/s41586-021-03211-0 33505025 6. Whalen S. Inoue F. Ryu H. Fair T. Markenscoff-Papadimitriou E. Keough K. Kircher M. Martin B. Alvarado B. Elor O. Machine learning dissection of human accelerated regions in primate neurodevelopment Neuron 2023 in press 10.1016/j.neuron.2022.12.026 36640767 7. Degtyareva A. Antontseva E. Merkulova T. Regulatory SNPs: Altered Transcription Factor Binding Sites Implicated in Complex Traits and Diseases Int. J. Mol. Sci. 2021 22 6454 10.3390/ijms22126454 34208629 8. Korbolina E.E. Bryzgalov L.O. Ustrokhanova D.Z. Postovalov S.N. Poverin D.V. Damarov I.S. Merkulova T.I. A Panel of rSNPs Demonstrating Allelic Asymmetry in Both ChIP-seq and RNA-seq Data and the Search for Their Phenotypic Outcomes through Analysis of DEGs Int. J. Mol. Sci. 2021 22 7240 10.3390/ijms22147240 34298860 9. Tseng C.-C. Wong M.-C. Liao W.-T. Chen C.-J. Lee S.-C. Yen J.-H. Chang S.-J. Genetic Variants in Transcription Factor Binding Sites in Humans: Triggered by Natural Selection and Triggers of Diseases Int. J. Mol. Sci. 2021 22 4187 10.3390/ijms22084187 33919522 10. de Martin X. Sodaei R. Santpere G. Mechanisms of Binding Specificity among bHLH Transcription Factors Int. J. Mol. Sci. 2021 22 9150 10.3390/ijms22179150 34502060 11. Yoshikawa G. Miyazaki K. Ogata H. Miyazaki M. The Evolution of Rag Gene Enhancers and Transcription Factor E and Id Proteins in the Adaptive Immune System Int. J. Mol. Sci. 2021 22 5888 10.3390/ijms22115888 34072618 12. Wilczek M.P. Pike A.M.C. Craig S.E. Maginnis M.S. King B.L. Rearrangement in the Hypervariable Region of JC Polyomavirus Genomes Isolated from Patient Samples and Impact on Transcription Factor-Binding Sites and Disease Outcomes Int. J. Mol. Sci. 2022 23 5699 10.3390/ijms23105699 35628509 13. Wang W. Yu Y. Keller N.P. Wang P. Presence, Mode of Action, and Application of Pathway Specific Transcription Factors in Aspergillus Biosynthetic Gene Clusters Int. J. Mol. Sci. 2021 22 8709 10.3390/ijms22168709 34445420 |
Int J Mol Sci Int J Mol Sci ijms International Journal of Molecular Sciences 1422-0067 MDPI 10.3390/ijms24054457 ijms-24-04457 Editorial Proteomics and Its Applications in Cancers Naryzhny Stanislav 12 Hoheisel Jorg D. Academic Editor 1 Institute of Biomedical Chemistry, Pogodinskaya, 10, 119121 Moscow, Russia; [email protected] 2 Petersburg Institute of Nuclear Physics (PNPI) of National Research Center "Kurchatov Institute", 188300 Gatchina, Russia 24 2 2023 3 2023 24 5 445714 2 2023 20 2 2023 (c) 2023 by the author. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). pmcCancer is a system malignant transformation that covers a wide group of diseases and can affect any organ of the human body. Cancer is one of the leading causes of mortality worldwide. The specific feature of cancer is a cellular reorganization that causes rapid, uncontrolled proliferation. Just a single abnormal cell can produce a tumor . The tumor may penetrate surrounding tissues and migrate to other organs, i.e., metastasize. Proteomics can generate detailed information on the situation with the human proteome during this malignant transformation. For example, it unravels key information, which can contribute to the search for clinically applicable biomarkers and therapeutic targets. Proteomics can give answers not only about the number and abundance of proteins but also about their involvement in metabolic pathways, interactions, post-translational modifications (PTMs), and synthesis and degradation. Many other features of proteomics can be used in the study of cancer as well. Together with other omics studies, proteomics is providing extensive data related to molecular mechanisms of cancer. Based on extensive data generated by proteomics methods, cancer databases have been organized . Our Special Issue (SI) was conceived to facilitate the publication of the latest papers in the field of cancer proteomics. A collection of seven articles presented in this SI offers very different examples of the most recent proteomics advances in the study of cancer. The review paper of Arias-Hidalgo et al. is about single-cell proteomics (SCP) analysis . SCP is used in many biomedical aspects, including cancer immunotherapy or biomarkers. Here, to study proteins as accurately as possible, advanced approaches in SCP are needed. Sample preparation is critical, as it influences the reliability of liquid chromatography-mass spectrometry (LC-MS) analysis. The review describes several methods that facilitate the processing of samples at the nanoscale and allows the quantitative determination of more than a thousand proteins in individual cells. The interesting proteomics application in cancer vaccine development was presented by Lokhov et al. . Recently, a new proteomics platform that enables the production of antigen compositions called "antigenic essences" has been developed. This approach has been used to produce cancer vaccines. Here, to guarantee similarity, the antigenic essence is accurately controlled by peptide mass spectrometry. Therefore, the proteomics platform has a high potential to improve the currently used cancer vaccines. In their paper, Lokhov et al. draw the attention of the science community to this innovative platform. Together with a summary of the approach and a list of cancer vaccines appropriate to be upgraded, this paper provides the main issues of the vaccine update using antigenic essences. The article by Cheng Ma et al. concerns anti-cancer medication . Complex changes in glycosylation and protein levels underlie the various effects of the antitumor drug 2-deoxy-D-glucose (2DG) on cancer cells. 2DG inhibits the growth and survival of cancer cells by interfering with the ATP produced during D-glucose metabolism. In addition, 2DG inhibits protein glycosylation in vivo by competing with D-mannose, leading to endoplasmic reticulum (ER) stress responses in cancer cells. Using the HT29 colorectal cancer cell line as a model system, Cheng Ma et al. characterized 2DG-induced changes in N-glycosylation. 2DG treatment also functionally disrupted the global cellular proteome, as evidenced by significant activation of proteins involved in protein folding, endoplasmic reticulum, mitochondrial function, cellular respiration, oxidative phosphorylation, and translation. Taken together, these results reveal the complex changes in the cancer proteome that underlie the various effects of 2DG on cancer cells and may provide important clues to the development of therapeutics targeting protein glycosylation. This new information may provide clues to therapeutic developments targeting protein glycosylation. There are a couple of papers in the SI that are in a rather different proteomics area a functional role of a single protein in connection to the whole proteome . Michalak et al. investigate the role of galectin-4 (Gal4) in colorectal cancer (CRC) . To explore its function in CRC, Michalak et al. have established a CRC cell line with the possibility of Gal4 expression regulation. Using this model in combination with proteomics and phosphoproteomics analyses, they have screened the intracellular changes induced by Gal4 expression. They have identified and quantified 3083 proteins and 2071 phosphosites. They found that the top candidates that were modulated by Gal4 are PURB, MAPKAPK3, BTF3 and BCAR1, while the prime candidates with altered phosphorylation included ZBTB7A, FOXK1, PURB and CK2beta. The data presented by Torres et al. show that haptoglobin (HP) can be considered a new member of the inducible damage-associated molecular patterns (DAMPs) with an important role in vitro dendritic cells (DC) activation for cancer immunotherapy . DAMPs are conserved endogenous factors that can act as "danger signals" and induce an inflammatory response . The data of Torres et al. support the idea that HP induces a specific proteomics profile and a mature-associated phenotype on generated primary human monocyte-derived DC. It allows us to consider HP as a DAMP molecule. This information could be used in developing new ex vivo manipulation of DC for therapeutic purposes, not only treatment of the cancer, but also autoimmune and neurodegenerative diseases. The review paper of Tutanov and Tamkovich is about the combining effects of circulating DNA and proteins . Circulating DNA is already used as a valuable tool in translational medicine. However, the association of this DNA with different proteins was not analyzed so far, despite considerable evidence that this association might impact circulation and the biological role of DNA. Tutanov and Tamkovich have collected and analyzed the current information about circulating DNA's origins and forms of circulation, known biological effects, and the clinical potential of circulating tumor DNA-protein complexes. Finally, the paper "Construction of 2DE Patterns of Plasma Proteins: Aspect of Potential Tumor Markers" is focused on the classical aspects of cancer proteomics a search for clinically applicable biomarkers and new therapeutic targets. The use of tumor markers aids in cancer treatment prognosis and recurrence. There is also hope that they might be useful in screening tests for the early detection of cancer. Here, the finding of ideal tumor markers, which should be sensitive, specific, and reliable, is an acute issue. Human plasma analysis is one of the most popular assays in clinics. Plasma proteomics can be useful to follow any changes in the human body, including cancer. Here, the availability of reliable control of proteoform patterns is a very important issue. Altogether, this SI presents two very interesting reviews and five research papers covering a wide scientific area, in which cancer proteomics is involved. As a guest editor, I would like to thank all contributors, peer reviewers, editors, and MDPI s publishing team for their efforts. I also hope that this SI will be of interest to the scientific community. Conflicts of Interest The author declares no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Upadhyay A. Cancer: An unknown territory; rethinking before going ahead Genes Dis. 2021 8 655 661 10.1016/j.gendis.2020.09.002 34291136 2. Kwon Y.W. Jo H.-S. Bae S. Seo Y. Song P. Song M. Yoon J.H. Application of Proteomics in Cancer: Recent Trends and Approaches for Biomarkers Discovery Front. Med. 2021 8 747333 10.3389/fmed.2021.747333 34631760 3. Arias-Hidalgo C. Juanes-Velasco P. Landeira-Vinuela A. Garcia-Vaquero M.L. Montalvillo E. Gongora R. Hernandez A.-P. Fuentes M. Single-Cell Proteomics: The Critical Role of Nanotechnology Int. J. Mol. Sci. 2022 23 6707 10.3390/ijms23126707 35743151 4. Lokhov P.G. Lichtenberg S. Balashova E.E. Changing Landscape of Cancer Vaccines-Novel Proteomics Platform for New Antigen Compositions Int. J. Mol. Sci. 2022 23 4401 10.3390/ijms23084401 35457221 5. Ma C. Tsai H.-Y. Zhang Q. Senavirathna L. Li L. Chin L.-S. Chen R. Pan S. An Integrated Proteomic and Glycoproteomic Investigation Reveals Alterations in the N-Glycoproteomic Network Induced by 2-Deoxy-D-Glucose in Colorectal Cancer Cells Int. J. Mol. Sci. 2022 23 8251 10.3390/ijms23158251 35897829 6. Michalak M. Golde V. Helm D. Kaltner H. Gebert J. Kopitz J. Combining Recombinase-Mediated Cassette Exchange Strategy with Quantitative Proteomic and Phosphoproteomic Analyses to Inspect Intracellular Functions of the Tumor Suppressor Galectin-4 in Colorectal Cancer Cells Int. J. Mol. Sci. 2022 23 6414 10.3390/ijms23126414 35742860 7. Torres A. Vivanco S. Lavin F. Pereda C. Chernobrovkin A. Gleisner A. Alcota M. Larrondo M. Lopez M.N. Salazar-Onfray F. Haptoglobin Induces a Specific Proteomic Profile and a Mature-Associated Phenotype on Primary Human Monocyte-Derived Dendritic Cells Int. J. Mol. Sci. 2022 23 6882 10.3390/ijms23136882 35805888 8. Krysko D.V. Garg A.D. Kaczmarek A. Krysko O. Agostinis P. Vandenabeele P. Immunogenic cell death and DAMPs in cancer therapy Nat. Rev. Cancer 2012 12 860 875 10.1038/nrc3380 23151605 9. Tutanov O. Tamkovich S. The Influence of Proteins on Fate and Biological Role of Circulating DNA Int. J. Mol. Sci. 2022 23 7224 10.3390/ijms23137224 35806228 10. Naryzhny S. Ronzhina N. Zorina E. Kabachenko F. Klopov N. Zgoda V. Construction of 2DE Patterns of Plasma Proteins: Aspect of Potential Tumor Markers Int. J. Mol. Sci. 2022 23 11113 10.3390/ijms231911113 36232415 |
J Clin Med J Clin Med jcm Journal of Clinical Medicine 2077-0383 MDPI 10.3390/jcm12051819 jcm-12-01819 Case Report Takayasu Arteritis Coexisting with Cutaneous Leishmaniasis Zhao Mutong 1 Liu Ying 1 Hu Zhihai 2 Sun Juan 1 Yang Zhou 1 Wei Li 1 Xu Zigang 1 Ma Lin 1* von den Driesch Peter Academic Editor 1 Department of Dermatology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China 2 Department of Medical Imaging, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China * Correspondence: [email protected]; Tel.: +86-13601305676 24 2 2023 3 2023 12 5 181910 1 2023 09 2 2023 15 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). Takayasu arteritis (TA) is a rare large-vessel vasculitis that can result in significant morbidity and mortality. The coexistence of TA with leishmaniasis infection has not been reported previously. Case description: An 8-year-old girl presented with recurrent skin nodules that heal spontaneously for four years. Her skin biopsy revealed granulomatous inflammation with Leishmania amastigotes identified in the histocyte cytoplasm and the extracellular space. The diagnosis of cutaneous leishmaniasis was made and intralesional sodium antimony gluconate was started. One month later, she experienced dry coughs and fever. The CT angiography of the carotid arteries showed dilation in the right common carotid artery and thickening of artery walls with elevated acute phase reactants. The diagnosis of Takayasu arteritis (TA) was made. Reviewing her chest CT before treatment, a soft-tissue density mass was identified in the right carotid artery region, suggesting a pre-existing aneurysm. The patient was treated with surgical resection of the aneurysm with systemic corticosteroids and immunosuppressants. Her skin nodules resolved with scars after the second cycle of antimony while a new aneurysm arose due to a lack of control of TA. Conclusions: This case highlights that benign as the natural course is for cutaneous leishmaniasis, fatal comorbidities can occur as a consequence of chronic inflammation, and can be aggravated by the treatment. leishmaniasis antimony Takayasu arteritis inflammation infection the Capital's Funds for Health Improvement and ResearchCFH2020-2-7121 This research was funded by the Capital's Funds for Health Improvement and Research, grant number CFH2020-2-7121. pmc1. Introduction Leishmaniases are a group of diseases caused by protozoan parasites from more than 20 Leishmania species. It was estimated that 700,000 to 1 million new cases occur annually worldwide . Leishmania parasites are transmitted through the bites of infected female phlebotomine sandflies during a blood meal, allowing the transmission of promastigotes which reside in the midgut of the sandfly vector. Reservoirs include humans, dogs, leopards, hyenas, rodents, bats, and baboons. There are three forms of leishmaniases the visceral, the cutaneous, and the mucocutaneous, with the cutaneous variant being the benign form. Cutaneous leishmaniasis is a neglected tropical disease that affects people worldwide. Because of the enhanced opportunity for exposure and possibility of not having a fully developed immune system, children may be more susceptible to infection than adults. Takayasu arteritis (TA) is a form of granulomatous large-vessel arteritis with an ethnic predisposition in patients of Asian and Indian descent. TA significantly increases morbidity and mortality , with a 5-year mortality of up to 1.9%. While the pathogenesis of TA remains to be elucidated, infections of tuberculosis, chlamydia pneumoniae, mycoplasma, and Mycobacterium were suggested to be associated with an increased risk for TA . We herein report a case of Takayasu arteritis coexisting with leishmaniasis infection, with disease relapse during antimony treatment. This case highlights that benign as the disease course is for cutaneous leishmaniasis, it is important to be alerted of fatal inflammatory comorbidities as inflammation always chaperones infection. 2. Case Description An 8-year-old child presented with recurrent skin nodules that heal spontaneously with atrophic scars for four years . She was not responsive to topical steroids, nor to systemic treatments of cephalosporins and itraconazole. A short residence on a cargo ship that imports timber from West Africa (The Republic of Cameroon), which has been identified as an endemic region for leishmaniasis, was reported. No prior history of fever or weight loss was reported. Physical examination was notable for disfiguring painless erythematous papules and nodules with overlying hyperkeratotic scales . Vital signs were normal. Her skin biopsy revealed granulomatous inflammation with Leishmania amastigotes identified in the histocyte cytoplasm and the extracellular space . Bone marrow aspiration was unremarkable and no evidence of anemia, hepatomegaly, or splenomegaly was present, which ruled out visceral leishmaniasis. The diagnosis of cutaneous leishmaniasis was made and intralesional sodium antimony gluconate (20 mg/kg daily for six consecutive days) was started with rapid improvement of the skin lesions. One month later, she experienced dry coughs, tachypnea, and recurrent fever. The vital signs were T 99.1 to 101.5 F, HR 123-138 bpm, BP 113-135/64-86, RR 17-26, and SpO2 100% on room air. Chest CT revealed a soft-tissue mass in the neck next to the thyroid with color Doppler ultrasonography showing aneurysm formation with swirling blood flow. The intima media thickness (IMT) was measured to be: left carotid artery 0.28 cm, right carotid artery 0.16 cm. A CT angiography was requested, which confirmed the diagnosis of an aneurysm with a dilation of the right common carotid artery . Wall thickening of the carotid arteries was noticed. ESR (80-140 mm/h, normal range: 0-20 mm/h) and CRP (11-190 mg/L, normal range: <8 mg/L) were significantly elevated. Based on the 2008 European League Against Rheumatism (EULAR) criteria for childhood TA , the diagnosis of Takayasu arteritis (TA) was made. Reviewing her chest CT before antimony administration, a soft-tissue density mass was identified in the right carotid artery region, suggesting a pre-existing aneurysm ; however, due to a lack of symptoms and low awareness of inflammatory comorbidities that may accompany chronic infectious diseases, this was overlooked. Other causes for aneurysms, including rheumatic disorders, hereditary connective tissue disorders (Marfan syndrome, Ehlers-Danlos syndromes, et al.), and other chronic infections associated with TA (syphilis, tuberculosis) were considered. Laboratory tests yielded the following: normal anti-nuclear antibodies, extractable nuclear antigens, complements, and antineutrophil cytoplasmic antibodies. Infectious screening tests for tuberculosis (tuberculin skin test and T-SPOT.TB) and syphilis (anti-TP-specific antibody) were negative. Genetic testing with Whole-Exome Sequencing (WES) was unremarkable. Considering that chronic infection might contribute to TA, and the close temporal association between antimony administration and the onset of TA relapse, the second cycle of antimony was postponed. A multidisciplinary consultation with rheumatologists, dermatologists, intensivists, and tropical disease specialists was held and the patient was subsequently treated with surgical resection of the aneurysm. Histopathology of the aneurysm showed histiocytic and lymphocytic infiltration which further confirmed the diagnosis of TA. A pulsed methylprednisolone course of 20 mg/kg for 3 days, followed by 2 mg/kg daily, was started with mycophenolate mofetil added concurrently at a dose of 250 mg 3 times daily. Inflammatory markers were normalized within two months. The second cycle of antimony treatment was administered while methylprednisolone was gradually tapered off. Unfortunately, at the six-month follow-up check, while clinically stable, worsening of disease was evident with CT angiography notable for a progressively increasing wall thickening of the left aortic artery when methylprednisolone was tapered to 16 mg daily. A total of 200 mg of infliximab and 7.5 mg of methotrexate weekly were added on. Subsequently, the patient received 200 mg of infliximab at weeks 0, 2, 6, and 8 with weekly methotrexate while gradually tapering off methylprednisolone. ESR and CRP were normal. At the one-year follow-up, her skin nodules completely resolved with scars and no TA-related symptoms were present. The patient refused to undergo further surveillance of inflammatory markers due to COVID lockdowns and has declined further TA treatment ever since. At the writing of this case report, the 18-month follow-up was completed with CT angiography notable for an aneurysm of the aortic arch . ESR (87 mm/h) and CRP (>180 mg/L) were significantly elevated. The patient is currently under evaluation and weighing her treatment options. 3. Discussion Our case described an 8-year-old leishmaniasis patient with a coexisting TA relapse during antimony treatment. Chronic infections are associated with a significantly higher risk of TA . Our case was the first TA case known to coexist with leishmaniasis infection. Persistent infection with pathogens and chronic antigenic stimulation can activate vascular DCs, leading to large-vessel arteritis. However, prior to antimony treatment, this arteritis appeared to be in remission with no symptoms and only mildly elevated acute phase reactants (CRP of 10 mg/L, normal range <8 mg/L; ESR of 12 mm/h, normal range 0-20 mm/h). Upon treatment with antimony, metabolic perturbations of the parasite, i.e., long-chain fatty acid b-oxidation contribute to enhanced drug and ROS-mediated parasite killing . Meanwhile, activation of the host immune system, including activation of macrophages, dendritic cells, T cells, and upregulation of proinflammatory cytokines contribute to clearance of infection . Both ROS metabolites and the activated immune system may then in turn mediate vascular inflammation, leading to the onset or relapse of large-vessel arteritis . The relapse of TA in the current patient was manifested by the increased size of the pre-existing aneurism, significantly elevated acute-phase reactants, and the recent onset of clinical symptoms. Treatment-associated inflammation exacerbation is best known in syphilis infection as the Jarisch-Herxheimer reaction. Cases have been reported on the presence of arteritis following syphilis treatment . However, due to the limited evidence, we were not able to conclude on a causal relationship. Nonetheless, it is important to be alerted to the coexistence of fatal inflammatory comorbidities and infection, as inflammation always chaperones infection. Close monitoring should be implemented before and during treatment. Treatment of TA during ongoing infection can be challenging. While clearance of leishmaniasis infection depends on the pro-inflammatory M1 macrophage polarization, mediators including cytokines such as TNF-a, IL-1b, IL-6, IL-12, and NO that kill the parasites also potently mediate tissue injury, culminating in possible aggravation of TA . Meanwhile, inhibition of pro-inflammatory cytokines may facilitate parasite survival . While TNF-alpha inhibition can be used as second-line treatment in case of relapsing disease , using TNF-alpha inhibition in the current patient was debated among the multidisciplinary team as a growing body of evidence suggested that greater risk for leishmaniasis can be associated with TNF-a inhibition . Interestingly, this increase varies markedly between the different inhibitors currently in use with antibodies (e.g., infliximab and adalimumab) associated with approximately eight-fold odds of opportunistic leishmaniasis as opposed to etanercept . This might be explained by the differences in the mode of action of different compounds. The anti-TNF antibodies bind to both the soluble and the transmembrane form of TNF, whereas etanercept targets mainly soluble TNF and interacts with the transmembrane form with reduced avidity. This can be beneficial for anti-leishmanial immunity, as transmembrane TNF but not soluble TNF is essential to control leishmaniasis infection . In addition, the complement or antibody-dependent cellular cytotoxicity mediated by antibodies can induce apoptosis of pathogen-containing macrophages, thus leading to reactivation of latent infection . While etanercept might be preferable in TA with leishmaniasis infection as a comorbidity, our patient chose to use infliximab due to the lower frequency of drug administration and traveling expenses. Considering the satisfactory efficacy of the first antimony treatment cycle, infliximab was added on and TA was controlled with no sign of leishmaniasis reactivation. The long-term prognosis of TA can vary significantly. Ishikawa used a prognostic stratification system based on the presence of complications and the clinical course. In a group of patients who had major complications together with a progressive course, the 15-year survival rate was only 43% . In contrast, for patients with no major complications, the 15-year survival rate was 96.4%. Similarly, in a more recent study by Mirouse, progressive disease course at diagnosis and complications of thoracic aorta involvement and retinopathy were independently associated with death and complication-free survival in the multivariate analysis . With a progressive disease course complicated by the presence of an aortic arch aneurysm, the prognosis of the current patient is bleak. 4. Conclusions TA and leishmaniasis are both rare diseases. Our case was the first TA case known to coexist with leishmaniasis infection. Cutaneous leishmaniasis, which is regarded as benign, can have fatal comorbidities due to the chaperoning inflammation, which can possibly be worsened by antileishmanial treatments. Close monitoring should be implemented for leishmaniasis patients at baseline and during treatment. Author Contributions Conceptualization and draft preparation, M.Z. and Y.L.; resources, Z.H.; writing review and editing, J.S., L.W. and Z.Y.; supervision, L.M. and Z.X.; funding acquisition, L.M. All authors have read and agreed to the published version of the manuscript. Institutional Review Board Statement Not applicable. Informed Consent Statement Written informed consent has been obtained from the patient's guardian to publish this paper. Data Availability Statement Not applicable. Conflicts of Interest The authors declare no conflict of interest. Figure 1 Disfiguring painless erythematous papules and nodules with overlying hyperkeratotic scales on the face of the patient. Figure 2 (A) Low-magnification HE staining showing a mixed infiltration of lymphocytes and histiocytes. (B) HE staining showing Leishmania amastigotes (arrow, x400 magnification). (C) Giemsa staining showing Leishmania amastigotes (arrow, x400 magnification). Figure 3 (A) Coronal plane of CT angiography showing dilation of the carotid arteries. (B) Transverse plane of CT angiography showing dilation (yellow arrow) and wall thickening (green arrows) of carotid arteries. (C) Chest CT before antimony treatment showing a pre-existing soft-tissue mass at the right common carotid artery region (arrow). Figure 4 Histopathology of the aneurysm showing histiocytic and lymphocytic infiltration with multinucleate giant cells (blue arrows), x200 magnification. Figure 5 CT angiography of showing pseudoaneurysm of the aortic arch. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Leishmaniasis Available online: (accessed on 10 January 2023) 2. Mirouse A. Biard L. Comarmond C. Lambert M. Mekinian A. Ferfar Y. Kahn J.E. Benhamou Y. Chiche L. Koskas F. Overall survival and mortality risk factors in Takayasu's arteritis: A multicenter study of 318 patients J. Autoimmun. 2019 96 35 39 10.1016/j.jaut.2018.08.001 30122419 3. Pedreira A.L.S. Santiago M.B. Association between Takayasu arteritis and latent or active Mycobacterium tuberculosis infection: A systematic review Clin. Rheumatol. 2020 39 1019 1026 10.1007/s10067-019-04818-5 31729680 4. Ozen S. Pistorio A. Iusan S.M. Bakkaloglu A. Herlin T. Brik R. Buoncompagni A. Lazar C. Bilge I. Uziel Y. EULAR/PRINTO/PRES criteria for Henoch-Schonlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: Final classification criteria Ann. Rheum. Dis. 2010 69 798 806 10.1136/ard.2009.116657 20413568 5. Pugh D. Karabayas M. Basu N. Cid M.C. Goel R. 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s/titles were screened by three different authors. Only English-language works were admitted. After initial valuation, we excluded reviews or cross-sectional studies and case reports about items beyond the scope of our eligibility criteria represented by angiomyxoma of the genital tract in women. We also excluded a case of superficial angiomyxoma and studies evaluating data from children, males, or pregnant women due to hormonal interference for tumour growth during pregnancy . 3. Results We conducted a review of case reports of the last 10 years on aggressive vulvar angiomyxoma in non-pregnant women. Twenty-five studies were selected regarding thirty-three cases of aggressive angiomyxoma . The median age of the patients was 39. One case of an 89-year-old woman, despite the patient's age, was not typical. Almost all women complained of the onset of a growing soft, tender mass on the pelvic region without pain or other urinary symptoms (97%). No inguinal lymph nodes were detectable in any of the cases. In just one report, there was an absence of a palpable mass, and diagnosis was achieved only by ultrasound detection of a detached echogenic mass of the pelvic cavity (3%). The principal symptom was a feeling of pelvic fullness (100%). Two patients complained of dysuria (6%), one declared an excess of pruritus (3%), one reported dyspareunia (3%), one reported difficulty urinating (3%), and one noted blood loss from ulceration (3%). Primary angiomyxoma was described in twenty-five women (75%); the other eight patients were affected by recurrent lesions after a period between 1 and 20 years after primary excision (24%). The treatment choice in all cases was surgery with wide margins. After excision, five women received hormonal therapy for three or more months represented by GnRH-analogue (15%); others followed only clinical and radiological periodic controls (85%). 4. Discussion Aggressive angiomyxoma (AAM) is a rare mesenchymal tumour described for the first time in 1983 by Steeper and Rosai as a slow-growing neoplasm with a high local recurrence rate but benign behaviour with poor ability to give distant metastasis . It was classified as ''Tumours of uncertain differentiation'' in the latest WHO classification . Generally, angiomyxomas are categorised either as superficial or AAM. Superficial angiomyxoma, also known as cutaneous myxoma, looks like a polypoid cutaneous mass arising from the superficial tissues. This lesion is observed predominantly in middle-aged male adults and may occur in the setting of the Carney complex . The pathogenetic basis is still uncertain, but a translocation at chromosome 12 has been detected in the 12q15 region, which causes an aberrant expression of the high-mobility group protein isoform I-C (HMGI-C) involved in DNA transcription . Differential diagnosis includes angiomyoblastoma, myxoid neurofibroma, myxoma, spindle cell lipoma, myxoid liposarcoma, leiomyosarcoma, and botryoid rhabdo-myosarcoma . Evidence suggests that AAM affects almost exclusively the genital, perineal, and pelvic regions in women of reproductive age. The epidemiological and immunohistochemical characteristics of AAM seem to be related to a hormonal correlation . Immunohistochemical investigation shows positivity for estrogen receptor (ER), progesterone receptor (PR), desmin, smooth muscle actin, and vimentin; some tumours are also CD34-positive . Furthermore, AAM seems to grow in size in pregnant women due to the positivity of progesterone receptors . Hormonal correlation suggests gonadotrophin-releasing hormone (GnRH) agonist or antihormonal therapy (tamoxifen) as emerging therapies, either as an adjuvant approach for residual mass or before surgery to minimize tumour size, and may increase the chance of complete excision . However, adverse effects of long-term use of the GnRH agonist (e.g., menopausal symptoms and bone loss) and tumour regrowth after drug discontinuation do not confirm it as a definitive choice of treatment . An alternative hormone therapy in postmenopausal women is the oral administration of aromatase inhibitors . Finally, angiographic embolization or even chemoembolization has been described; however, alternative blood vessels could provide vascularization of the neoplasm . Wide surgical excision with tumour-free margins remains the preferred approach, but it requires long-term follow-up because of the high frequency of recurrence of AAM. The recurrence rate of AAM after surgery is between 36 and 72%, and it can occur at the same site as the initial resection . The radiological study of neoplasm is significant to determine the actual extension of the tumour; it is also useful for surgical planning and recurrence monitoring. Indeed, it is usually slow-growing and locally infiltrative, extending insidiously into adjacent soft tissues but rarely invading pelvic organs. The infiltrative behaviour and the absence of a well-defined capsule make complete removal difficult and contribute to the high rate of tumour recurrence . MRI with contrast enhancement by gadolinium is the best radiological option for diagnosis, especially on T2-weighted images, which show the lesion as hyperintense relative to muscle . The prognosis is excellent, and metastasis is rarely described in the literature, thanks to the low mitotic index . Despite the potential effect of medical therapies , in our patient, we opted for immediate surgery considering her discomfort and blood loss. A subsequent radicalization surgery was necessary because of the positivity of tumour tissue in the surgical resection margins, which confirmed the local infiltrative trend of AAM. Considering the absence of consensus on the role of radical surgery for this type of tumour, we explained to the patient the risks and benefits of a subsequent radicalization surgery vs. medical management in case of positivity for tumour tissue in the surgical resection margins, and the patient accepted the surgical option. The strength of our work is the description of a rare but insidious tumour that affects women of reproductive age. The knowledge of AAM's behaviour may guide the surgeon to carry out scrupulous radicalization to prevent local recurrences. Moreover, we realized an extensive review of the literature of the last ten years to analyse which is the best management strategy for this condition. The main limitation of this study is the heterogeneity of management of this condition regarding medical therapy vs. long-term observation after surgery. Further research on this topic is needed. 5. Conclusions Aggressive angiomyxoma is a very rare neoplasm, and its incidence is predominant among women of reproductive age. The infiltrative behaviour and the high risk of local recurrence make it insidious. Wide surgical excision is the gold standard for treatment, succeeded by either clinical or radiological (ultrasound or MRI) follow-up. However, hormonal therapy as a neo-adjuvant or adjuvant strategy may play a role in management. Acknowledgments The authors acknowledge the mentorship provided by Giuseppe Ettore, Department of Obstetrics and Gynaecology, Azienda di Rilievo Nazionale e di Alta Specializzazione (ARNAS) Garibaldi, Catania, Italy, throughout the preparation of this manuscript. Author Contributions F.A.G.: manuscript writing/editing; M.G.: conceptualization; C.E.: formal analysis; A.G.: data collection; E.R.: project administration; G.E.: coordinator of the study. All authors have read and agreed to the published version of the manuscript. Institutional Review Board Statement This study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board (or Ethics Committee) of Azienda di Rilievo Nazionale e di Alta Specializzazione (ARNAS) Garibaldi, Catania. Informed Consent Statement Informed consent was obtained from all subjects involved in the study. Data Availability Statement Data are contained within the article. Conflicts of Interest The authors declare that they have no conflict of interest. Figure 1 Angiomyxoma of the left labium. Figure 2 Note the admixture of thin and thick-walled vessels of varying calibre within a sparse cellular stroma. Figure 3 Tumour cells with scanty cytoplasm and bland nuclear features are widely separated by a sparse cellular stroma. Figure 4 Radicalization three months after primary surgery. Figure 5 Vulva after radicalization surgery. Figure 6 Prisma flow chart. jcm-12-01726-t001_Table 1 Table 1 Review of literature of the last 10 years. Author, Year Clinical Aspects History Symptoms Site Treatment Follow-up Aguilar-Frasco et al., 2018 39 yrs; bulky, soft, and mobile bilobulated tumour with dimensions of 28.1 x 10.4 cm R After 1 year Tumour Right labium majus Surgical excision GnRH-analogue therapy > 3 months Brzezinska et al., 2018 47 yrs; bulky, soft, and mobile tumour with dimensions of 4.3 x 3.6 cm P Tumour Right labium majus Surgical excision Observation Zamani et al., 2021 28 yrs; bulky, soft pedunculated tumour with dimensions of 20 x 15 x 10 cm. R After 2 years Tumour Vulva and pubis Surgical excision GnRH-analogue therapy for 3 months Xie et al., 2019 22 yrs; bulky, soft, pedunculated, and ulcerated tumour with dimensions of 30 cm x 20 cm P Tumour, pruritus Left vulva Surgical excision Observation Muskan et al., 2022 19 yrs; bulky, soft tumour with dimensions of 10 cm x 10 cm P Tumour Left vulva Surgical excision Observation Goyal et al., 2022 40 yrs; bulky, soft pedunculated and ulcerated tumour 8 x 8 cm P Tumour, serosanguinous discharge from the ulceration Left labium majus Surgical excision GnRH-analogue therapy for 3 months Zhao et al., 2018 (1) 40 yrs; bulky, soft tumour (2) 38 yrs; bulky soft tumour with dimensions of 7.2 x 5.6 x 14.6 cm (3) 40 yrs; bulky, soft tumour with dimensions of 17.1 x 10.6 x 8.9 cm (4) 35 yrs; bulky, soft tumour with dimensions of 16.2 x 6.9 x 7.4 cm (5) 38 yrs; bulky, soft tumour (6) 45 yrs; bulky, soft tumour with dimensions of 12.3 x 8.8 x 6.3 cm (7) 34 yrs; bulky, soft tumour measuring 11 cm (1) P (2) R After 2 years (3) P (4) P (5) R After 3 years (6) P (7) P (1) Tumour (2) Tumour (3) Tumour (4) Tumour (5) Tumour (6) Tumour (7) Tumour (1) Left vulva (2) Right vulva (3) Left labium majus (4) Left labium majus (5) Left vulva (6) Left vulva (7) Left vulva (1) Surgical excision (2) Surgical excision (3) Surgical excision (4) Surgical excision (5) Surgical excision (6) Surgical excision (7) Surgical excision (1) Observation (2) Observation (3) Observation (4) GnRH-analogue therapy (5) Observation (6) Observation (7) Observation Fatusic et al., 2015 57 yrs; bulky, soft ulcerated tumour P Tumour Left vulva Surgical excision Observation Ribeiro et al., 2015 42 yrs; bulky, soft tumour P Tumour, difficulty in urinating Vulva Surgical excision Observation Tariq et al., 2014 40 yrs; bulky, soft tumour P Tumour, pain Lower-left pelvic-perineal and medial gluteal region Surgical excision Observation Narayama et al., 2016 49 yrs; bulky, soft tumour with dimensions of 15 x 9.5 x 9 cm P Tumour Left vulva Surgical excision Observation Amin et al., 2013 89 yrs; bulky, pedunculated tumour with dimensions of 12 x 7 x 6 cm P Tumour Left labium majus Surgical excision Observation R. Elkattah et al., 2013 38 yrs; bulky, soft tumour with dimensions of 12 x 6 x 4 cm P Tumour, dyspareunia Left labium majus Surgical excision Observation Zizi-Sermpetzoglou et al., 2015 47 yrs; bulky, soft tumour with dimensions of 25 x 20 x 6 cm P Tumour Right labium majus Surgical excision Reoperation 18 months later for recurrence Sengupta et al., 2014 34 yrs; bulky, soft tumour with dimensions of 5 x 4 cm R After 2 years Tumour Left labium majus Surgical excision Observation Narang et al., 2014 40 yrs; bulky, soft tumour with dimensions of 15 x 12 cm R After 16 months Tumour Perineum Surgical excision Observation Das et al., 2016 40 yrs; bulky, soft tumour with dimensions of 18 x 10 cm P Tumour Right labium majus Surgical excision Observation Schwartz et al., 2014 32 yrs; bulky, soft tumour with dimensions of 4 x 2.5 cm R A lot of recurrence during 16 years Tumour Left labium majus Surgical excision GnRH-analogue therapy for 5 years Huang et al., 2013 44 yrs; bulky, soft tumour with dimensions of 12 x 9 x 5 cm P Tumour Left vulva Surgical excision Observation Kiran et al., 2013 57 yrs; bulky, soft tumour with dimensions of 25 x 30 cm R After 20 years Tumour Left vulva Surgical excision Observation Lee et al., 2014 35 yrs; bulky, soft tumour with dimensions of 10 x 7 cm P Tumour Right labium majus Surgical excision Observation Choi et al., 2015 (1) 49 yrs; bulky, soft tumour with dimensions of 19 x 19 cm (2) 31 yrs; mixed echogenic mass of the pelvic cavity with dimensions of 18 x 15 x 8 cm (3) 36 yrs; bulky, soft tumour with dimensions of 15 x 10 x 6 cm (1) P (2) P (3) P (1) Tumour (2) Abdominal distension and lower abdominal swelling. (3) Tumour (1) Left labium majus (2) Pelvis (3) Left buttock (1) Surgical excision (2) Surgical excision (3) Surgical excision (1) Observation (2) Observation (3) Observation Lourenco et al., 2013 47 yrs; bulky, soft tumour with dimensions of 9 x 7 cm P Tumour Left labium majus Surgial excision Observation Foust-Wright et al., 2012 19 yrs; soft tumour measuring 3.4 cm P Tumour, dysuria Periurethral mass extending beyond the hymen Surgical excision Observation Ota et al., 2013 28 yrs; bulky, soft tumour with dimensions of 4.8 x 4 cm P Tumour, dysuria Left labium majus Surgical excision Observation Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
Int J Mol Sci Int J Mol Sci ijms International Journal of Molecular Sciences 1422-0067 MDPI 10.3390/ijms24054563 ijms-24-04563 Editorial Molecular Mechanisms of Adaptation to Hypoxia Rybnikova Elena 1* Lukyanova Ludmila 2 1 I.P. Pavlov Institute of Physiology RAS, St. Petersburg 199034, Russia 2 Institute of General Pathology and Pathophysiology, Moscow 125315, Russia * Correspondence: [email protected]; Tel.: +7-(911)954-15-96 26 2 2023 3 2023 24 5 456313 2 2023 21 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). Russian Science Foundation22-25-00781 E.A. Rybnikova is supported by the Russian Science Foundation, grant 22-25-00781. pmcOxygen is one of the most important elements, ensuring the vital activity of the body. It is a key component of aerobic energy metabolism and supplies cells with macroergic ATP molecules. Therefore, a lack of oxygen, hypoxia, can have serious negative consequences and is considered a pathogenic factor in many diseases. On the other hand, in evolution, living beings experienced hypoxia even at the stage of unicellular organisms and, as a result, have formed effective mechanisms of adaptation to it that are among the most phylogenetically ancient and, therefore, reliable. These mechanisms are triggered when the oxygen level decreases, and they provide multilevel physiological adjustments that allow the maintenance of vital activity in hypoxic conditions. Thus, on the one hand hypoxia is a negative factor that causes energy deficiency and oxidative stress, and on the other it is a factor that triggers adaptive reactions. The main question is how to draw the line between positive and damaging hypoxias. This is possible only with a detailed understanding of the events occurring at the molecular level during the development either of hypoxic damage or adaptive reactions. This Special Issue is aimed at integrating a number of notable recent achievements in this area of research to stimulate further progress towards understanding the boundary between hypoxia as a pathological and hypoxia as an adaptative factor, as well as identifying the molecular mechanisms mediating the mutual transformation of the proadaptive effects to the pathological ones. The most important questions in such studies concern the development of reliable physiological models to examine hypoxia-related cellular processes. Analyzing the relationship between aldosterone, the HIF-1 pathway and epithelial sodium channels in the kidney cortical collecting cells, Keppner and colleagues have experimentally proved that these cells can serve as such a model. In particular, using the mouse cortical collecting duct cell line mCCDcl1, which represents polarized epithelial cells, exhibiting both corticosterone dependent sodium transport, they have demonstrated that these cells responded to hypoxia by up-regulating the HIF-1 target genes, with HIF-1a, rather than HIF-2a, mediating this hypoxic response at the target gene level. In addition, these authors have revealed that mCCDcl1 cells can also be used to search for protective factors against kidney damage caused by hypoxia. Their findings have suggested that the newly identified protective transcription factor, namely estrogen-related receptor alpha (Esrra), can act as a cofactor of HIF-1, thereby contributing to the implementation of adaptive reactions triggered by HIF-1, at least in the mCCD cells. However, a question still remains as to whether Esrra is a universal cofactor of HIF-1, and whether a similar phenomenon can be observed in other cell lines and tissues, both in vitro and in vivo. In the paper by Nascimento-Filho and co-authors , a new method to culture cells at different oxygen levels using deoxidizing absorbers is presented. A feature of the method is the ability to not only maintain in cell cultures a low level of oxygen close to the physiological norm (physioxic level), but also to gradually reduce it even further (hypoxia modeling). The results demonstrated that the cultivation of cancer cells under hypoxia conditions led to the activation of the epithelial-mesenchymal transition, increasing the expression of HIF-1a. An exacerbation of the oncogenic pathway of PI3K was also revealed in comparison with tumor cells growing at atmospheric oxygen levels. At the same time, there was an increase in oxidative stress and superoxide levels, as well as an increase in cell cycle arrest. The cultivation of cancer cells under hypoxia conditions led to the accumulation of cancer stem cells, depending on time, thus, the hypoxic environment enhanced the oncogenic effect. The presented method of oxygenation during cell culture is cost-effective and can be easily implemented. The study of Suzuki and co-authors is also based on the successful experimental application of a three-dimensional (3D) in vitro model, associated with spontaneous O2 gradients. The conventional 2D and this original 3D model were used to create pathological hypoxic conditions in order to study the effect of hypoxia on transforming growth factor-b2 (TGFss2)-induced epithelial mesenchymal transition (EMT) of human retinal pigment epithelium (HRPE) cells, a process that makes a significant contribution to the pathogenesis of proliferative retinal diseases. The results obtained by Suzuki and colleagues indicate that TGF-b2-induced EMT of both 2D and 3D cultured HRPE cells was significantly modified by simulated pathological hypoxia. TGF-b2 and hypoxia synergistically but diversely induced EMT of the HRPE cells, judging by the fluctuations in HIF-1a and target genes mRNA expression, as well as mitochondrial metabolism. The effects also differed between the 2D and 3D cultures, indicating some variability during the spatial spreading of the cells. The authors hypothesized that this may be caused by possible upstream regulators requiring the generation of the 3D spheroids, but this question still needs further study. To date, the interest in the application of hypobaric hypoxia (HH), both natural or simulated in a pressure chamber, to study the processes of hypoxic adaptation and maladaptation has not faded. Thus, Arriaza and colleagues provided a comprehensive review of the accumulated literature relevant to the current classification of the HH modes, as well as of physiologic and pathologic responses of the organism to HH. It is important that the authors draw the reader's attention to the fact that HH cannot be equated with other types of hypoxia with a similar level of oxygen deficiency, including normobaric. Low pressure is also a contributing factor to the changes in the physiological processes enhancing the impact of the hypoxic factor itself. However, the focus of this review is hypoxic pulmonary vasoconstriction (HPV), representing one of the physiological compensation mechanisms in hypoxia, aimed at redistributing the blood to more ventilated areas of the lung. It is well-known that HPV overresponse can underline the pathogenesis of high-altitude pulmonary hypertension (HAPH). Analyzing the extensive literature on the mechanisms of HPV, Arriaza and co-authors indicated the role of elevated Zn2+ levels and oxidative stress in the development of HPV in different models of hypobaric hypoxia. This conclusion suggests possible therapeutic targets for the elimination of excessive HPV as a mechanism inducing the development of HAPH. An important factor that largely determines the level of translation of cell proteins in response to hypoxia are post-transcriptional processes, in particular the regulation of functional dynamics of RNA. Comparing the effects of acute and chronic hypoxia in monocytic THP-1 cell culture, Bauer and colleagues have described in detail the profiles of differential gene expression. At the level of de novo mRNA synthesis, only minor changes, pointing to the attenuation of hypoxia-induced transcription under chronic conditions, have been revealed. The data by Bauer and co-authors also indicated that most of the mRNAs are destabilized under hypoxia and, again, only slight changes between the effects of acute and chronic hypoxic conditions have been detected. Based on these findings, the authors have concluded that general adaptations during the course of hypoxia appear to be determined largely at a transcriptional level, but post-transcriptional mRNA destabilization also plays an important role, affording a reduction in the translation of mitochondrial proteins and, thus, modifying the mitochondria functioning under extended hypoxia. The study by Baranova and co-authors is focused on an oxygen-saving reaction such as a diving reflex, representing a complex adaptive physiological response, including changes in the cardiorespiratory function, erythropoiesis, peripheral vasoconstriction and the redistribution of the blood circulation. The molecular mechanisms of the diving reflex as an evolutionarily gained form of systemic adaptation to hypoxia have so far been understudied. The results reported by Baranova and colleagues in this Special Issue describe the polymorphisms of the a 1A adrenoceptor (ADRA1A) gene in humans, correlating with the most prominent adaptive reaction to diving hypoxia or high risks to develop lung hypertension. It is well-known that prenatal hypoxia is one of the most common pathologies of embryonic development, which has long-term negative health consequences throughout the subsequent life, including premature aging. Based on the analysis of the accumulated evidence, the review by Sutovska and co-authors aims to emphasize the role of prenatal hypoxia in the formation of hypertension in adulthood. The authors convincingly conclude that even short-term prenatal hypoxia significantly affects the mechanisms of regulation of the cardiovascular system, programming the development of hypertension in adulthood. This effect of the prenatal hypoxia depends on the critical period of pregnancy, sex and, probably, the time of day. Recently it has been hypothesized that ferroptosis might be a possible key injury mechanism in neonatal hypoxic-ischemic brain injury. This question is extensively reviewed for our Special Issue by Peeples and colleagues . Their review suggests that the attenuation of changes associated with ferroptosis after injury may be neuroprotective. In this respect, Peeples and colleagues discuss current unresolved relevant issues that need to be studied. One of the most negative roles of hypoxic signaling, in particular related to HIF-1, is its persistent hyperactivation in tumors, leading to increased malignancy, vascularization and resistance of the cancer cells to anticancer therapy. One of the most malignant types is an androgen-dependent triple-negative breast cancer, in which hypoxic signaling provides resistance to therapy aimed at androgen or androgen receptor signaling. Analyzing the accumulated data, Jinna and colleagues suggested that dual targeting of the hypoxia signaling pathway and androgen receptors may provide a promising strategy to decrease the resistance to therapy in patients with this disease. Along with the reports on the facts testifying to the pathogenic role of HIF-1 and its down-stream hypoxic signaling, convincing data on its positive effects continue to accumulate. In particular, Cirillo and co-authors have found a decrease in the expression of HIF-1a and its target genes in sarcopenia. The findings allow us to expect that pharmacological reactivation of HIF-1a could prevent and treat sarcopenia. Along with the pathological consequences of hypoxia, it is important to pay special attention to the protective effects of its moderate forms. Studies of such effects and the protective hypoxia regimes are important not only for fundamental research, but also with regard to the practical potential of using such regimes to improve health, as well as to increase body resistance to pathogenic factors. In this regard, interesting data have been published in our Special Issue by Luo and colleagues , demonstrating that the daily training of obese mice using moderate hypoxia (10% of O2) alleviated the pathogenic effects of a high fat diet. In particular, hypoxic training prevented bodyweight gain and development of insulin resistance, reversed the enlargement of white and brown adipocytes and protected liver function. A high fat diet downregulated the expression of genes required for lipolysis and thermogenesis, while these molecules were upregulated by hypoxia. The authors revealed that hypoxia, being a stress factor, significantly increased the serum levels of epinephrine, and then proved experimentally that the up-regulation of epinephrine represents a key factor mediating the observed therapeutic effect of hypoxia via the catecholamine-PKA-AMPK pathway. The findings reveal for the first time the therapeutic potential of hypoxic training in the treatment of obesity, nonalcoholic fatty liver disease and other metabolic disorders. In conclusion, the articles published in the Special Issue "Molecular Mechanisms of Adaptation to Hypoxia" make a significant contribution to the current knowledge on the mechanisms of hypoxia and our adaptation to it. However, there are still many topical issues left outside the scope of this Special Issue, which we hope to cover very soon in the next Special Issue: "Molecular Mechanisms of Adaptation to Hypoxia 2.0". Acknowledgments The authors are deeply grateful to Natalia Nalivaeva for her kind help in editing the English language of the manuscript. Data Availability Statement Not applicable. Conflicts of Interest The authors declare no conflict of interests. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Keppner A. Maric D. Orlando I.M.C. Falquet L. Hummler E. Hoogewijs D. Analysis of the Hypoxic Response in a Mouse Cortical Collecting Duct-Derived Cell Line Suggests That Esrra Is Partially Involved in Hif1a-Mediated Hypoxia-Inducible Gene Expression in mCCDcl1 Cells Int. J. Mol. Sci. 2022 23 7262 10.3390/ijms23137262 35806266 2. Nascimento-Filho C.H.V. Glinos A.T. Jang Y. Goloni-Bertollo E.M. Castilho R.M. Squarize C.H. From Tissue Physoxia to Cancer Hypoxia, Cost-Effective Methods to Study Tissue-Specific O2 Levels in Cellular Biology Int. J. Mol. Sci. 2022 23 5633 10.3390/ijms23105633 35628446 3. Suzuki S. Sato T. Watanabe M. Higashide M. Tsugeno Y. Umetsu A. Furuhashi M. Ida Y. Hikage F. Ohguro H. Hypoxia Differently Affects TGF-b2-Induced Epithelial Mesenchymal Transitions in the 2D and 3D Culture of the Human Retinal Pigment Epithelium Cells Int. J. Mol. Sci. 2022 23 5473 10.3390/ijms23105473 35628282 4. Arriaza K. Cuevas C. Pena E. Siques P. Brito J. Impact of Zinc on Oxidative Signaling Pathways in the Development of Pulmonary Vasoconstriction Induced by Hypobaric Hypoxia Int. J. Mol. Sci. 2022 23 6974 10.3390/ijms23136974 35805984 5. Bauer R. Meyer S.P. Kloss K.A. Guerrero Ruiz V.M. Reuscher S. Zhou Y. Fuhrmann D.C. Zarnack K. Schmid T. Brune B. Functional RNA Dynamics Are Progressively Governed by RNA Destabilization during the Adaptation to Chronic Hypoxia Int. J. Mol. Sci. 2022 23 5824 10.3390/ijms23105824 35628634 6. Baranova T. Podyacheva E. Zemlyanukhina T. Berlov D. Danilova M. Glotov O. Glotov A. Vascular Reactions of the Diving Reflex in Men and Women Carrying Different ADRA1A Genotypes Int. J. Mol. Sci. 2022 23 9433 10.3390/ijms23169433 36012699 7. Sutovska H. Babarikova K. Zeman M. Molcan L. Prenatal Hypoxia Affects Foetal Cardiovascular Regulatory Mechanisms in a Circadian-Dependent Manner: A Review Int. J. Mol. Sci. 2022 23 2885 10.3390/ijms23052885 35270026 8. Peeples E.S. Genaro-Mattos T.C. Ferroptosis: A Promising Therapeutic Target for Neonatal Hypoxic-Ischemic Brain Injury Int. J. Mol. Sci. 2022 23 7420 10.3390/ijms23137420 35806425 9. Jinna N. Rida P. Smart M. LaBarge M. Jovanovic-Talisman T. Natarajan R. Seewaldt V. Adaptation to Hypoxia May Promote Therapeutic Resistance to Androgen Receptor Inhibition in Triple-Negative Breast Cancer Int. J. Mol. Sci. 2022 23 8844 10.3390/ijms23168844 36012111 10. Cirillo F. Mangiavini L. La Rocca P. Piccoli M. Ghiroldi A. Rota P. Tarantino A. Canciani B. Coviello S. Messina C. Human Sarcopenic Myoblasts Can Be Rescued by Pharmacological Reactivation of HIF-1a Int. J. Mol. Sci. 2022 23 7114 10.3390/ijms23137114 35806119 11. Luo Y. Chen Q. Zou J. Fan J. Li Y. Luo Z. Chronic Intermittent Hypoxia Exposure Alternative to Exercise Alleviates High-Fat-Diet-Induced Obesity and Fatty Liver Int. J. Mol. Sci. 2022 23 5209 10.3390/ijms23095209 35563600 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34773 Neurology Pediatrics Infectious Disease A Case Report on CNS Hemophagocytic Lymphohistiocytosis in an Infant With Dengue Hemorrhagic Fever Muacevic Alexander Adler John R Arora Amodini 1 Verma Sarita 23 Khot Nikita 1 Chalipat Shiji 1 Agarkhedkar Sharad 1 Kiruthiga Kala Gnanasekaran 4 1 Pediatrics, Dr. D.Y. Patil Medical College, Pune, IND 2 Pediatric Oncology, KEM Hospital & Research Centre, Pune, IND 3 Pediatric Oncology, Dr. D.Y. Patil Medical College, Pune, IND 4 Histopathology, KEM Hospital & Research Centre, Pune, IND Nikita Khot [email protected] 8 2 2023 2 2023 15 2 e347738 2 2023 Copyright (c) 2023, Arora et al. 2023 Arora et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from India is an endemic country for dengue. The incidence of hemophagocytic lymphohistiocytosis (HLH) with dengue in children has been well-reported. However, central nervous system (CNS) HLH associated with dengue has not been described in the literature yet. We hereby report a novel case of CNS HLH triggered by dengue infection. An eight-month-old, well-grown male infant with uneventful antenatal, perinatal, and neonatal history was admitted with a history of febrile illness associated with cough, cold, vomiting, and loose motions and one episode of hematochezia and hepatosplenomegaly on examination. Investigations revealed bi-cytopenia, hyper-ferritinemia, deranged coagulation profile, liver function test, and hypo-fibrinogenemia. Dengue non-structural protein 1 ( NS1) antigen was positive. The child was given dexamethasone and continued supportive care with a diagnosis of dengue shock syndrome. The child showed an overall transient improvement, however, he had rebound fever followed by right focal convulsion on Day 9 of steroids. MRI brain revealed areas of diffusion-restricted embolic infarcts with diffuse leptomeningeal enhancement and mild cerebral edema, and CSF showed a total leukocyte count of 80 cells with 75% lymphocytic picture, histiocytes with hemophagocytosis, confirmatory of CNS HLH. Intrathecal methotrexate, hydrocortisone, and intravenous (IV) etoposide were started. However, the child succumbed to his illness. CNS involvement in dengue-triggered HLH needs to be suspected despite subtle neurological signs and aggressively managed following a multi-departmental approach to ensure the best clinical and neuro-developmental outcomes. cns involvement dengue with warning signs dengue fever/complications cns manifestations pediatric infectious disease neurology paediatrics hemophagocytic lymphohistiocytosis (hlh) dengue hemorrhagic fever (dhf) The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction The incidence of hemophagocytic lymphohistiocytosis (HLH) with dengue in children has been well-reported . India contributed 34 of 96 million apparent global dengue infections, a number which stands in stark contrast to the 12,484 reported cases from India to the WHO in the same year . Recently, dengue has been associated with hyper-inflammation and hyper-ferritinemia with or without HLH, an uncommon fatal syndrome. It is called primary HLH when caused by genetic mutations responsible for the production of T cells and natural killer (NK) cells. It can be secondary when triggered by malignant or non-malignant diseases like juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE), other autoimmune diseases, and infections like Epstein Barr Virus (EBV), human immunodeficiency virus (HIV), cytomegalovirus (CMV), tuberculosis (TB), dengue and possibly severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) . Timely administration of steroids has led to improved outcomes in HLH with dengue . The incidence of HLH with dengue in children has been well-reported . However, CNS HLH associated with dengue has not been described in the literature yet. We hereby report a novel case of CNS HLH in an infant triggered by dengue infection. Case presentation An eight-month-old, well-grown male infant with an uneventful antenatal, perinatal, and neonatal course was admitted with febrile illness associated with cough, cold, vomiting, and loose motions for 10 days and one episode of hematochezia a day before admission. Clinical examination revealed tachycardia (HR 174), hypotension (78/32 mmHg - at the 5th percentile), and delayed capillary refill time (4 seconds). On abdominal examination, there was hepato-splenomegaly. Neurologically, the child's consciousness was obtunded (the Alert/Voice/Pain/Unresponsive (AVPU) scale - Pain). The child was admitted to the pediatric intensive care Unit. After initial stabilization, fluid resuscitation and supportive treatment were started. Several crucial investigations were done, including a hemogram, which revealed a bi-cytopenic picture (Table 1). Liver function tests were grossly deranged with serum glutamic oxaloacetic transaminase - 18,261 IU/L, serum glutamic pyruvic transaminase - 7834 IU/L, and a deranged coagulation profile with international normalized ratio (INR) 4.11 was noted. Ferritin was more than 40,000 ng/ml, lactate dehydrogenase (LDH) was 9116 IU/L, fibrinogen was 75.6 mg/dl, and triglycerides were 278 mg/dl; most of these reports were strongly suggestive of HLH. He was dengue non-structural protein 1 (NS1) antigen-positive. Immunoglobulin M (IgM) and IgG were negative with a normal chest X-ray and 2-dimensional echocardiography. IV dexamethasone was started at 10 mg/m2 on the first day of admission itself, based on clinical and laboratory confirmation of dengue-triggered HLH. Table 1 Comparison of the serial investigations of the patient DAY Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10 Day 11 Day 12 Haemoglobin (g/dl) (Reference Range - 11.14-14.1g/dl) 7.7 11.2 9.8 8.8 9.8 12 8.5 7.9 5.4 11.8 10.8 9.5 Total Leukocyte Count ( per microliter) (Reference -11,000/microliter) 20500 14300 8600 9300 8700 13300 12600 11100 7100 9300 8200 3400 Differential leukocyte count (Neutrophil/Lymphocyte/Eosinophil) (%) Reference Range - Neutrophil (1500-8500/microliter), Lymphocytes (4000-10,000 /microliter), Eosinophils (50-700/microliter) 46/34/20 51/34 46/41 47/40 56/29 76/15 77/15/8 79/15 66/25 76/16 79/18 70/30 Platelets (per microliter) (Reference ,50,000-4,10,000/microliter) 44000 78000 61000 62000 82000 42000 90000 78000 32000 49000 40000 14000 Packed cell volume (%) (Reference Range -33.0-40.0%) 22.4 33.4 28.1 26 29.3 36.1 27.1 24.7 17 36.2 33.4 29.4 Aspartate transaminase (Units/Liter) (Reference Range 0-11 months-Not established, 1-13 years - 8 to 60 U/liter) 18261 8404 7132 3134 2067 1374 549 231 186 183 Alanine transaminase (Units/Liter) (Reference to 11 months-Not Established, 1-13 years - 8 to 60 U/Liter) 7834 4113 4266 2680 2294 1863 1236 698 625 512 Lactate dehydrogenase (Units/Liter) (Reference Range - 31 days to 11 months -180-435 U/Liter) 9116 4921 Ferritin (Nanogram/ml) (Reference Range - 21.81 to 274.66 ng/ml) >40000 37964 23169 8125 3324 As shown in Table 1, a repeat hemogram post 24 hours showed an improvement in the platelet count and general condition of the child. The child became afebrile after 48 hours of dexamethasone and the blood indices improved with rising platelet count and total leukocytes. Hence, steroids with other supportive treatments were continued. The serum ferritin improved to 8125 ng/ml on Day 6 of dexamethasone. The child was shifted out of the pediatric intensive care unit (PICU) after seven days of intensive support. On Day 9 of dexamethasone, the child had a rebound fever spike followed by right-sided focal convulsions and a right-sided focal neurological deficit with hemiparesis, facial nerve palsy, and altered sensorium. After initial stabilization, neuroimaging followed by a lumbar puncture was done. Cerebrospinal fluid examination showed histiocytes with hemophagocytosis confirming hemophagocytic histiocytosis (CNS HLH) along with absent cob-webs, proteins - 61.70 mg/dl, glucose - 64 mg/dl, red blood cells - absent, total leukocyte count - 80 cells, polymorphonuclear leukocytes - 5% and lymphocytes - 75%, macrophages - 20%, pleomorphic cells - 0, adenosine deaminase (ADA) - 8.21 IU/L . Magnetic resonance imaging (MRI) brain revealed areas of diffusion-restricted embolic infarcts with diffuse leptomeningeal enhancement and mild cerebral edema . Figure 1 Cerebrospinal fluid cytology The black arrow represents the nucleus of the macrophage/histiocyte. A. Pleocytosis of CSF; B. Macrophage engulfing a neutrophil (red arrow), Leishman stain; C. Macrophage engulfing a lymphocyte (red arrow), hematoxylin and eosin stain; D. Macrophage engulfing a lymphocyte (red arrow), Papanicolaou stain Figure 2 Magnetic resonance imaging (MRI) brain (diffusion restriction, T1, T2, Flair) (top to bottom) revealed areas of diffusion-restricted embolic infarcts with diffuse leptomeningeal enhancement and mild cerebral edema The child was given intrathecal methotrexate and hydrocortisone with IV etoposide as per the Hemophagocytic Lymphohistiocytosis 2004 protocol , however, the patient remained persistently febrile and the pancytopenia worsened despite granulocyte colony-stimulating factor (G-CSF) support. The child also deteriorated hemodynamically and neurologically and required mechanical ventilation. Despite all resuscitative measures, the child succumbed to his illness 72 hours post receiving intrathecal chemotherapy. Discussion Viral infections commonly trigger pathologies like HLH; however, the exact mechanisms of viral implication in the pathogenesis of HLH are unproven. Some studies postulate viruses, as potent modulators of the immune system, causing evasion of interference with the cytokine balance, immune recognition, and hindrance of apoptotic pathways. Some theories suggest abnormally proliferating as well as activated T-cells as possible causes of activation of macrophages and sub-normal destruction of phagocytes. Others postulated the role of perforin and natural killer (NK) cells. A deficiency of perforin can impair cellular defenses and reduced NK cell activity causes greater T-cell functioning and significant amounts of cytokine production (IFN-g, TNF-a, GM-CSF), causing persistent macrophage activation. These findings are commonly triggered by viral pathologies. Even though macrophages phagocytize infected leukocytes, they are not very effective in killing them. Active T cells along with plenty of activated macrophages significantly increase inflammatory cytokine production resulting in greater damage to bone marrow and tissues. The invariant natural killer T (iNKT) cells are also activated during acute phases of dengue; they are poly-functional and produce IFN-g and GM-CSF on stimulation. Detailed studies are required to clarify the pathogenesis of HLH and dengue. The most recent criteria for diagnosis of HLH include fever, splenomegaly, cytopenias, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis, decreased natural killer (NK) cell function, and elevated ferritin and elevated soluble interleukin-2 (IL-2) receptor levels. CNS involvement was not included in the criteria and can include seizures, focal deficits, meningismus, and altered levels of consciousness; and portends worse outcomes . Severe dengue infection complicated with HLH requires very prompt and aggressive treatment with steroids or intravenous immune globulin or chemotherapy . Many reports of secondary HLH triggered by dengue infection have been reported [6-8]; however, none of them had CNS HLH documented. We, for the first time, report on confirmed CNS HLH triggered by dengue infection in an eight-month-old infant. Our patient had all the laboratory markers confirmatory to HLH at presentation as per HLH 2004 protocol; hence, was immediately treated with steroids within 24 hours. The child showed significant transient responses like improvement in Glasgow Coma Scale decreasing inflammatory markers and rising blood indices; however, the acute unpredictable neurological worsening in this infant emphasizes the need of suspecting CNS involvement in dengue-triggered secondary HLH because it warrants specific intrathecal chemotherapy. Genetic evaluation could not be performed, hence the possibility of congenital HLH being precipitated with dengue infection always remains. Though primary HLH always remains a differential, the treatment in the acute scenario is the same. Whether CSF examination in all patients with HLH is warranted and needs to be addressed with subsequent studies on a larger population. Conclusions Hemophagocytic lymphohistiocytosis has proven to be a potentially lethal pathology with multisystemic manifestations, especially in developing countries like India. However, CNS involvement secondary to HLH is an infrequent finding. To differentiate HLH from the underlying disease mechanism or overt septicemia is imperative and taxing owing to high mortality and morbidity. Steroids alone are insufficient for treating CNS HLH. Dengue hemorrhagic fever has been a strongly and commonly documented trigger, A diagnosis of HLH should be considered in every sick child presenting with bi-cytopenia and hyperferritinemia. If there is CNS HLH in the form of aseptic meningitis or the frank morphological presence of macrophages and hemophagocytes in the CSF, aggressive treatment with intrathecal methotrexate and intrathecal steroids should be initiated immediately. The addition of systemic etoposide with cyclosporine in patients not improving despite steroids can prove to be potentially life-saving. A take-home message on the basis of a single novel experience is the importance of CSF screening in relevant scenarios (subtle neurological symptoms) for the timely diagnosis and treatment of CNS involvement in dengue-triggered HLH. We highlight the importance of a multi-departmental approach with pediatric intensivists working in close proximity with pediatric neurologists, hemato-oncologists, histopathologists, and microbiologists to devise a comprehensive plan of action with a focus on the best clinical and neuro-developmental outcomes. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 Incidence and risk factors for developing dengue-associated hemophagocytic lymphohistiocytosis in Puerto Rico, 2008 - 2013 PLoS Negl Trop Dis Ellis EM Sharp TM Perez-Padilla J 0 10 2016 2 Economic and disease burden of dengue illness in India Am J Trop Med Hyg Shepard DS Halasa YA Tyagi BK 1235 1242 91 2014 25294616 3 Hyperferritinaemia in dengue virus infected patients is associated with immune activation and coagulation disturbances PLoS Negl Trop Dis van de Weg CA Huits RM Pannuti CS 3214 9 2014 (47105fd9-f7c9-4ab5-92e0-b933a27b553f)/export.html 4 Dengue-induced hemophagocytic lymphohistiocytosis: a case report and literature review Cureus Munshi A Alsuraihi A Balubaid M Althobaiti M Althaqafi A 0 13 2021 5 HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis Pediatr Blood Cancer Henter JI Horne A Arico M 124 131 48 2007 16937360 6 How to treat involvement of the central nervous system in hemophagocytic lymphohistiocytosis? Curr Treat Options Neurol Horne A Wickstrom R Jordan MB Yeh EA Naqvi A Henter JI Janka G 3 19 2017 28155064 7 How I treat hemophagocytic lymphohistiocytosis Blood Jordan MB Allen CE Weitzman S Filipovich AH McClain KL 4041 4052 15 2011 8 Severe dengue due to secondary hemophagocytic lymphohistiocytosis: a case study IDCases Ray U Dutta S Mondal S Bandyopadhyay S 50 53 8 2017 28409119 |
J Clin Med J Clin Med jcm Journal of Clinical Medicine 2077-0383 MDPI 10.3390/jcm12051730 jcm-12-01730 Case Report Concomitant Use of Elexacaftor/Tezacaftor/Ivacaftor and Etanercept in a Cystic Fibrosis Patient with Juvenile Idiopathic Arthritis Orsini Sara Immacolata Resources Writing - original draft 1+ Marrani Edoardo Conceptualization Writing - review & editing 2*+ Pagnini Ilaria Visualization 2 Taccetti Giovanni Visualization 3 Terlizzi Vito Conceptualization Writing - review & editing 3 Simonini Gabriele Supervision 2 Papa Rosanna Academic Editor 1 Department of Woman, Child and of General and Specialized Surgery, Universita degli Studi della Campania "Luigi Vanvitelli", 80138 Naples, Italy 2 Paediatric Rheumatology Unit, Meyer Children's Hospital IRCCS, 50139 Florence, Italy 3 Department of Paediatric Medicine, Meyer Children's Hospital IRCCS, Cystic Fibrosis Regional Reference Centre, 50139 Florence, Italy * Correspondence: [email protected]; Tel.: +39-055-5662924 + These authors contributed equally to this work. 21 2 2023 3 2023 12 5 173029 12 2022 17 2 2023 19 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). Patients with cystic fibrosis often complain of joint manifestations. However, only a few studies have reported the association between cystic fibrosis and juvenile idiopathic arthritis and addressed the therapeutic challenges of these patients. We describe the first paediatric case of a patient affected by cystic fibrosis, Basedow's disease and juvenile idiopathic arthritis who was contemporarily treated with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) and anti-tumor necrosis factor a (anti-TNFa). This report seems to reassure regarding the potential side effects of these associations. Moreover, our experience suggests that anti-TNFa is an effective option in CF patients affected by juvenile idiopathic arthritis, and is even safe for children receiving a triple CFTR modulator. pediatric rheumatology juvenile idiopathic arthritis cystic fibrosis This research received no external funding. pmc1. Introduction Patients with cystic fibrosis (CF) often complain of joint manifestations., mostly episodic arthritis, pulmonary hypertrophic osteo-arthropathy (HPOA), antibiotic-induced pain and spinal pain . Many systemic diseases have been reported in association with CF, including rheumatoid arthritis (RA) and sarcoidosis . However, only few studies have reported the association between CF and juvenile idiopathic arthritis (JIA) and addressed the therapeutic challenges of these patients . We describe the first pediatric case of a patient affected by CF, Basedow's disease and JIA who was contemporarily treated with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) CF transmembrane conductance regulator (CFTR) modulator, methimazole and anti-tumor necrosis factor a (anti-TNFa). 2. Results A fifteen-year-old Caucasian girl diagnosed with CF with pancreatic insufficiency by positive neonatal screening (genetic profile: F508del/F508del, sweat chloride (SC): 90-86 mEq/L) and treated at CF Regional Centre of Florence, Italy, according to CF standard of care . The CF was characterized by mild lung disease with Forced Expiratory Volume in the first second (FEV1) in the range of 78-83% in 2021; there was no need for antibiotic therapy, and segmental bilateral bronchiectasis was limited to the upper and lower lobes at chest computer tomography. A throat swab culture showed the presence of Methicillin Sensitive Staphylococcus Aureus. No related CF diseases were found such as hypochloremic metabolic alkalosis, acute pancreatitis or CF related diabetes. Furthermore, she was also affected by Basedow's disease with hyperthyroidism. The autoimmune profile showed the presence of anti-TSH-receptor auto-antibodies, anti-thyroid peroxidase auto-antibodies and antithyroglobulin auto-antibodies. A thyroid ultrasound at the diagnosis showed the increased size, inhomogeneous echo structure, increased vascularization and pseudo nodular aspect of the left lobe. Methimazole was then added from the age of 11 years achieving good disease control. The lumacaftor (LUM)-IVA therapy was started at 12 years, according to Italian legislative directives. No improvement was observed in the main clinical outcomes (such as FEV1 or BMI) or SC testing. At the age of 15, she developed polyarticular arthritis, with involvement of all the metacarpophalangeal and proximal interphalangeal joints, wrists, right elbow and left ankle. The girl presented a morning stiffness lasting several hours, with no systemic symptoms or skin manifestations. Inflammatory markers were in the normal range, antinuclear antibodies (ANA) were positive (1:320; speckled pattern), as were the rheumatoid factor (RF) (43 UI/mL with n.v. < 15) and anti-cyclic citrullinated peptide antibodies (anti-CCP) (214 UI/mL with n.v. < 20). Complement fraction C3 and C4 were in the normal range. Extractable nuclear antigen antibodies and anti-double stranded DNA antibodies were negative. Ultrasound examination of the hands and wrists (the first sites interested at the onset) showed evidence of arthritis, with distention of the joint capsule and synovial hyperplasia in the wrist joints on bilateral sides, and joint effusion at several interphalangeal joints. An X-ray of the hands and wrists was normal. CT scan of the thorax and abdominal ultrasound were performed to rule out generalized lymphadenopathies. Therefore, a diagnosis of polyarticular, RF-positive juvenile idiopathic arthritis (JIA) was formulated. A complete ophthalmological evaluation with a slit lamp examination excluded the presence of uveitis. The girl received a course of non-steroidal anti-inflammatory drug (NSAID) therapy with naproxen for four weeks, with no clinical benefit. Concomitant medications (methimazole and LUM-IVA) were not discontinued. In particular, a rheumatological side effect of methimazole treatment, the so-called "antithyroid arthritis syndrome", was ruled out due to the long latency between methimazole introduction and the onset of arthritis and the presence of the rheumatoid factor and anti-CCP antibodies . Due to the persistence of severe joint disease activity, according to current guidelines , a disease-modifying anti-rheumatic drug (DMARD) was required. The efficacy of methotrexate (MTX) in polyarticular JIA has been demonstrated and it is recommended as a first-line DMARD . Nevertheless, MTX is potentially associated with liver toxicity and its co-administration with other hepatotoxic drugs, such as CFTR modulators, might confer a significant risk of liver injury. For these reasons, MTX is assumed to be contraindicated in patients receiving CFTR modulators. Therefore, one month after the JIA diagnosis, we decided to start treatment with an anti-TNFa agent, etanercept (ETN), at a dosage of 50 mg once a week subcutaneously, following negative screening for tuberculosis, hepatitis B and C. In the meanwhile, therapy elexacaftor (ELX)/tezacaftor (TEZ)/IVA became available on-label in Italy, not only in adults but even in CF patients over the age of 12 years, so treatment with ELX/TEZ/IVA treatment was added 1 month after the first administration of ETN. After 6 weeks of treatment with ETN, a significant clinical improvement was shown, and after 16 weeks she achieved complete clinical remission of the articular disease. We also observed an improvement in FEV1 (90% before treatment; 100% after treatment), BMI (18.59 before treatment; 19.37 after treatment) and the sweat test (15 mEq/L) after 3 months of therapy with ELX/TEZ/IVA, according to previous data of our patients . Etanercept was continued for 12 months and was still ongoing at our last follow-up. No adverse events occurred, in particular, no infectious episodes or respiratory flare-ups were reported. 3. Discussion Nowadays a precise definition of CF-related arthropathies is missing. In clinical practice, these patients might experience recurrent monoarthritis or symmetric polyarthritis, often painful and with sudden onset, lasting from 5 to 7 days. This condition involves more frequently the knees, followed in order of frequency by ankles, wrists, hips, shoulders, elbows and the proximal interphalangeal joints . Episodic arthritis usually responds to NSAID therapies or aspirin, although some patients require oral or intraarticular glucocorticoids . In case of recurrence over several years, chronic destructive arthritis might lead to a loss of function of the affected joint . HPOA is the second major rheumatic complication of CF, with a median age of onset of 20 years, and less frequent onset in childhood. The clinical expression of HPOA has no specific features in CF patients, varying from symmetric polyarthritis with pain and effusions in the knees, wrists and ankles, to the less common synovitis of the hand joints. Radiographs may show a symmetrical periosteal new bone formation at the distal ends of the tibiae, radii, fibulae and ulnae and, occasionally, joint effusions which may be large. These patients can present a more severe lung disease, a worse pulmonary function than control CF patients (mean FEV~39% in HPOA and 61% in episodic arthritis), and they have a worse prognosis. Furthermore, a characteristic association between the relapse of articular symptoms and infections is reported . Thus, optimization of CF management and strict prevention of infection is of utmost importance to prevent pulmonary hypertrophic osteo-arthropathy, while NSAID can be useful to reduce pain and shorten the length of these episodes . Arthritis in CF has also been reported in association with a variety of drugs, especially with some quinolones and cimetidine. However, some patients might present persistent inflammatory arthritis with a clinical phenotype, resembling chronic inflammatory arthropathies such as rheumatoid arthritis or JIA. RA showed an association with CF, and before the widespread adoption of new-born screening, several reports were published on RA diagnosis preceding the CF diagnosis even by several years. Furthermore, the association between RA and bronchiectasis suggests that RA may occur at an increased rate in CF patients . In these patients, DMARDs are usually adopted as first-line agents, and TNF-a inhibitors have been used in case of a lack of response to conventional DMARDs. JIA is one of the most common chronic diseases of childhood. This definition includes several forms of inflammatory arthritis of unknown etiology with onset prior to age 16 years and a minimum of 6 weeks duration, following the exclusion of other known causes of synovitis. According to the current International League of Associations for Rheumatology classification criteria, JIA is divided into 7 categories defined by the number of joints involved, presence or absence of extraarticular manifestations and presence or absence of additional markers including rheumatoid factor (RF) and HLA-B27 . In particular, polyarticular JIA, which is the form of chronic arthritis that affected our patient, includes children with JIA and polyarthritis (>=5 joints ever involved); given their heterogeneity, these patients were categorized into treatment groups using combinations of the following categories: (1) presence or absence of risk factors for disease severity and potentially a more refractory disease course, and (2) low disease activity versus moderate/high disease activity . Risk factors considered are the presence of one or more of the following conditions: positive RF, positive anti-CCP antibodies or joint damage. Disease activity is assessed by the Juvenile Arthritis Disease Activity Score (JADAS), and considering the clinical JADAS based upon 10 joints (cJADAS-10) a cut-off of <=2.5 versus > 2.5 is used to define low versus high/moderate disease activity . In these patients, treatment with a DMARD is required, and MTX is recommended as the first line DMARD, according to current guidelines, with the possibility to add or change therapy, using biological therapies, if there is no or minimal response to MTX after 6-8 weeks. DMARD is recommended over biologic without and with risk factors, although initial biologic therapy may be appropriate for some patients with risk factors and involvement of high-risk joints, high disease activity and/or those judged by their physician to be at high risk of disabling joint damage . However, the therapeutic challenges of treating patients with CF and chronic arthritis, such as JIA, are underestimated. In fact, medications used for treating JIA have an immunomodulatory effect; therefore, these drugs might theoretically increase the infectious risk, such as mycobacterial infection, in children with CF who are receiving these agents . Several drugs may interact with ELX/TEZ/IVA, such as antifungal medicines and some antibiotics. Nevertheless, little is known about other drugs used for CF-related conditions such as rheumatological or endocrinological diseases. Up to date, this is the first case evaluating the effectiveness and safety of ELX/TEZ/IVA in a CF patient, concomitant receiving anti-TNFa and methimazole. Etanercept has already been used in patients with CF and arthritis. In particular, Visser et al. described the case of a 17-year-old female CF patient affected by rheumatoid arthritis (RA), and Aldensten et al. described the case of a 46-year-old female CF patient suffering from chronic episodic arthritis; both were treated successfully with TNF-a inhibitor ETN. However, there are no reports of patients with CF and arthritis treated at the same time with ETN, ELX/TEZ/IVA and methimazole. In our patient we hypothesized that the clinical improvement could have been related to the CFTR modulator drug more than to the anti-TNF alpha However, we ruled out this hypothesis as the patient was under treatment with LUM-IVA therapy for three years at the time of arthritis onset and the articular manifestations subsided after only six weeks of treatment with ETN. This latency between the first administration of ETN and the clinical improvement is in line with that observed in clinical practice in patients with isolated JIA. Moreover, the treatment with ELX/TEZ/IVA was initiated after one month of treatment with ETN; therefore, the interval between modification in treatment with CFTR modulating therapy and the clinical benefit on the articular symptoms is too short. This report seems to reassure regarding the potential side effects of these associations. In addition, another aspect to consider is related to the ability of anti-TNF drugs to improve systemic inflammation and therefore potentially pulmonary inflammation in patients with CF. According to Visser et al. excessive neutrophilic airway inflammation in CF is responsible for lung damage and a decline in FEV1; therefore, TNF-a, increasing the neutrophilic inflammatory response within the CF lung, represents a logical therapeutic target. However, this class of drugs is known to be associated with an increased risk of infections in healthy patients, which is of particular concern in the CF population. Nevertheless, there are two prior case reports of TNF-a antagonist use in CF, with no report of infective complications in either patient, as was with our patient. In consideration of this, we cannot, therefore, exclude that ETN, in association with specific therapy for CF with ELX/TEZ/IVA, may have contributed to the improvement of our patient's pulmonary status. 4. Conclusions Our experience suggests that anti-TNFa is an effective option in CF patients affected by JIA and is safe even for children receiving a triple CFTR modulator. Moreover, this report seems to reassure regarding the potential side effects of these associations. Further studies in a larger cohort are needed to evaluate the role of this synergic treatment on the quality of life and the long-term management of cystic-related arthropathies. Acknowledgments The AOU Meyer IRCCS is an ERN-ReCONNET full member and ERN LUNG full member. We thank the patient and her family. Author Contributions Conceptualization, E.M. and V.T.; patient care I.P., V.T. and E.M.; resources S.I.O., writing original draft preparation, S.I.O.; writing review and editing, E.M. and V.T.; visualization, I.P. and G.T.; supervision, G.S. All authors have read and agreed to the published version of the manuscript. Institutional Review Board Statement Not applicable. Informed Consent Statement Written informed consent has been obtained from the patient to publish this paper. Data Availability Statement Not applicable. Conflicts of Interest The authors declare no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Botton E. Saraux A. Laselve H. Jousse S. Le Goff P. Muscoloskeletal manifestations in cystic fibrosis Jt. Bone Spine 2003 70 327 335 10.1016/S1297-319X(03)00063-0 14563459 2. Castellani C. Duff A.J. Bell S.C. Heijerman H.G. Munck A. Ratjen F. Sermet-Gaudelus I. Southern K.W. Barben J. Flume P.A. ECFS best practice guidelines: The 2018 revision J. Cyst. Fibros. 2018 17 153 178 10.1016/j.jcf.2018.02.006 29506920 3. Takaya K. Kimura N. Hiyoshi T. Antithyroid Arthritis Syndrome: A Case Report and Review of the Literature Intern. Med. 2016 55 3627 3633 10.2169/internalmedicine.55.7379 27980264 4. Ringold S. Angeles-Han S.T. Beukelman T. Lovell D. Cuello C.A. Becker M.L. Colbert R.A. Feldman B.M. Ferguson P.J. Gewanter H. 2019 American College of Rheumatology/Arthritis Foundation guideline for the treatment of juvenile idiopathic arthritis: Therapeutic approaches for non-systemic polyarthritis, Sacroiliitis, and Enthesitis Arthritis Care Res. 2019 71 717 734 10.1002/acr.23870 31021516 5. Carnovale V. Iacotucci P. Terlizzi V. Colangelo C. Medio P. Ferrillo L. De Gregorio F. Francalanci M. Taccetti G. Buonaurio S. Effectiveness and safety of elexacaftor/tezacaftor/ivacaftor in patients with cystic fibrosis and advanced lung disease with the Phe 508del/minimal function genotype Respir. Med. 2021 189 106646 10.1016/j.rmed.2021.106646 34673344 6. Johnson S. Knox A.J. Arthropathy in cystic fibrosis Respir. Med. 1994 88 567 570 10.1016/S0954-6111(05)80003-4 7991880 7. Parasa R.B. Maffulli N. Musculoskeletal involvement in cystic fibrosis Bull. (Hosp. Jt. Dis.) 1999 58 37 44 10431633 8. Rush P.J. Shore A. Coblentz C. Wilmot D. Corey M. Levinson H. The musculoskeletal manifestations of cystic fibrosis Semin. Arthritis Rheum. 1986 15 213 225 10.1016/0049-0172(86)90018-1 3515562 9. Sartori N.S. de Andrade N.P.B. da Silva Chakr R.M. Incidence of tuberculosis in patients receiving anti-TNF therapy for rheumatic diseases: A systematic review Clin. Rheumatol. 2020 39 1439 1447 10.1007/s10067-019-04866-x 31900748 10. Visser S. Martin M. Serisier D.J. Improvements in Cystic Fibrosis Lung Disease and Airway Inflammation Associated with Etanercept Therapy for Rheumatoid Arthritis: A Case Report Lung 2012 190 579 581 10.1007/s00408-012-9393-9 22660986 11. Adelsten T. Rasmussen N. Katzenstein T.L. Nielsen C.T. Safe and effective tumour necrosis factor-a inhibitor (etanercept) treatment of chronic episodic arthritis in a patient with cystic fibrosis Scand. J. Rheumatol. 2016 45 330 331 10.3109/03009742.2015.1122834 26789357 |
ion Extracted data included: age of children's diagnosis and number of children with asthma or wheeze; number of women using paracetamol during pregnancy; trimester of pregnancy in which paracetamol use took place, and number of pregnant women in a particular trimester (if recorded). 2.4. Quality Assessment The Newcastle-Ottawa Scale (NOS) was applied to assess the methodological quality of all the included studies . The NOS included three categorical criteria with a maximum score of 9 points: (1) selection of the study group; (2) comparability of the groups; and (3) identification of the exposure for studies. The quality of each study was rated using the following scoring algorithms: >=7 points were considered as "high", 4 to 6 points were considered as "moderate", and <=3 point was considered as "low". 2.5. Statistical Analysis The distribution of cases, ORs and 95% CIs were separately identified based on the risk of childhood wheezing/asthma and prenatal exposure to paracetamol (ever or never) and use of paracetamol in each trimester (if available). We calculated the summary risk estimates and 95% CIs and plotted forest plots using random-effects models (DerSimonian-Laird method) and fixed effect models for the association between prenatal paracetamol exposure and wheeze/asthma in childhood. The value of I2 statistics was adopted as a criterion in the case of I2 < 50, we used a fixed effect model, and when I2 >= 50, a random effect model. The results indicated that the taking of paracetamol may have a high probability of increase in risk if OR was above 1, compared with non-use of paracetamol . Heterogeneity among articles was estimated by engaging the I2 statistic and p values associated with Q statistics. Herein, I2 statistic indicates the percentage of total variability explained by heterogeneity, and values of <=25%, 25%-75%, and >=75% are arbitrarily considered as indicative of low, moderate, and high heterogeneity, respectively . To explain the possible presence of publication bias, Begg's test (a rank correlation method based on Kendall's tau) and Egger's test (a linear regression method) were applied . We also checked for funnel plot symmetry. Here, in the absence of bias, the plots will resemble a symmetrical funnel, as the results of minor studies will scatter at the left side of the plot and the spread will narrow among the major studies on the right side of the plot . Meta-analysis of summary statistics from individual studies was performed through Statistica 13.3 software (StatSoft Poland, Krakow, Poland), using the Medical Package program. 3. Results As result of the search of electronic databases, 532 citations were identified. Titles and abstracts were checked in the initial selection phase, in which 424 items were excluded due to irrelevance. In the second phase, 108 articles with potentially significant studies were identified and submitted for full-text assessment. There were 96 papers which did not meet all the inclusion criteria, contained duplicate publications, and the required data were missing, amongst others. We identified twelve articles fulfilling the criteria for inclusion, in which the effect of paracetamol exposure during pregnancy on disorders of the respiratory system in children was analyzed . The outcome of the search strategy is shown in Figure 1. The studies involved 330,550 women and 44,502 women intake of paracetamol during pregnancy. Table 1 presents a tabular summary of the individual clinical-control studies discussed in this review. All studies included were in accordance with NOS scale and all studies were defined as high-quality. The average value was 8.03. 3.1. Sensitivity Analysis In the study on the relationship between childhood asthma and paracetamol use (ever vs. never) during pregnancy and each trimester of pregnancy, sensitivity analysis showed that in the case of a total study and 3rd trimester, removing any of the studies would not significantly affect the result of the meta-analysis. However, in the case of the 1st trimester, deleting one of the studies: Andersen , Liu , Migliore or Rebordosa would change the result of the meta-analysis to be statistically insignificant. On the other hand, in the case of the 2nd trimester, the result of the meta-analysis would be statistically insignificant after excluding the study of Liu or Rebordosa . In the study on the relationship between childhood wheeze and paracetamol use (ever vs. never) during pregnancy and each trimester of pregnancy, sensitivity analysis for total study, 2nd trimester and 3rd trimester indicated that the results would not change significantly after excluding any of the studies. In turn, in the 1st trimester, the exclusion of the Liew study would change the result of the meta-analysis to a statistically significant one. 3.2. Association between Paracetamol Exposure during Pregnancy and Asthma in Children The present meta-analysis was conducted on the basis of data from ten studies assessing the effect of paracetamol exposure in pregnancy on the risk of occurrence of asthma in children. Paracetamol was taken at any time during the trimesters of pregnancy. The crude OR amounted to 1.34, 95% CI: 1.22 to 1.48, p <0.001, with moderate heterogeneity of I2 = 64.75% . The Begg and Mazumdar's test for rank correlation did not indicate evidence of publication bias (Kendall's tau = 0.142, z = 0.495, p < 0.622; similarly, Egger's test: b0 = 0.966, 95% CI - 0.748 to 2.681, t = 1.299, p < 0.231). Results of five studies analyzing the relationship between of intake of paracetamol during first trimester and childhood asthma pointed to increased risk (crude OR = 1.21, 95% CI: 1.01 to 1.45, p < 0.035, I2 = 79.48%), . The Begg Mazumdar's test and Egger's test did not indicated evidence of publication bias (Kendall's tau b = -1.000, z = -1.567, p < 0.118 and b0 = -1.288, 95% CI: -7.752 to 5.177, t = -0.634, p < 0.572, respectively). The major problem indicated by this analysis is the large heterogeneity of effect of paracetamol. Further analysis involving three studies also suggested that use of paracetamol during the second trimester of pregnancy was associated with increased childhood asthma risk (crude OR = 1.10, 95% CI: 1.01 to 1.19, p < 0.030, I2 = 0.00%), . Evidence of publication bias was not shown in the Begg and Mazumdar's test (Kendall's tau = 0.333, z = 0.522, p < 0.603); or in the Egger's test (b0 = -0.237, 95% CI: -6.686 to 6.212, t = -0.468, p < 0.723). In turn, meta-analysis based on the results of four studies showed that paracetamol intake by women in the third trimester of pregnancy was associated with an enhanced risk of asthma in the child (crude OR = 1.18, 95% CI: 1.11 to 1.26, p < 0.001, I2 = 0.00%), . The Begg and Mazumdar's test and Egger's test did not indicate evidence of publication bias (Kendall's tau = -0.667, z = -1.359, p = 0.174 and b0 = 0.966, 95% CI: -0.748 to 2.681, t = 1.299, p < 0.231, respectively). 3.3. Association between Paracetamol Exposure during Pregnancy and Wheezing in Children In the eight studies analyzed in order to assess prenatal paracetamol exposure during any time of pregnancy, we noted a significant increased risk of childhood wheeze (crude OR = 1.31, 95% CI: 1.12 to 1.54, p < 0.002; with relatively high heterogeneity, I2 = 75.29%), . The Begg and Mazumdar's test for rank correlation indicated no evidence of publication bias (Kendall's tau b = 0.333, z = 0.939, p < 0.349). Egger's test for regression intercept also demonstrated no evidence of publication bias (b0 = 2.161 (95% CI: -1.775 to 6.097), t = 1.344, p < 0.229). The use of paracetamol in the first trimester of pregnancy in three studies indicated a marginal, insignificant increase in the risk of wheezing in childhood (crude OR = 1.04, 95% CI: 0.78 to 1.37, p > 0.801, I2 = 80.73%), . The results of Begg's test were inaccessible. Egger's test did not indicate evidence of publication bias (b0 = -3.819, 95% CI: -56.874 to 49.237, t = -0.915, p > 0.529). Two studies have been identified that meet the inclusion criteria, in assessing the association between paracetamol exposure during the second trimester of pregnancy and childhood wheezing revealed convergent results (OR = 0.95, 95% CI: 0.68 to 1.32, p > 0.760 and OR = 0.95, 95% CI: 0.80 to 1.12, p > 0.517; respectively), . However, it is difficult to draw reliable result on their basis. The crude odds ratio (OR) for the risk of wheezing in children of mothers using paracetamol in the third trimester of pregnancy was 1.11, 95% CI: 0.92 to 1.34, p < 0.266, I2 = 57.80%, based on three studies , . Egger's test did not indicate evidence of publication bias (b0 = -0.277, 95% CI: -55.078 to 54.525, t = -0.0641, p < 0.959). Results of Begg's test were inaccessible. 4. Discussion The aim of our systematic review with meta-analysis was to summarize the current evidence on the exposures associated with paracetamol use in utero, focusing on postnatal breathing disorders in children. The study is important for the development of clinical recommendations regarding the consumption of paracetamol during pregnancy. The results of our systematic review and performed meta-analysis indicate a significant increase of the risk of asthma (crude OR = 1.34, 95% CI: 1.22 to 1.48, p > 0.001); or wheezing (crude OR = 1.31, 95% CI: 1.12 to 1.54, p > 0.002) among children with a history of prenatal exposure to paracetamol. Singh et al. noted that the odds ratio for the asthma outcome in the offspring of mothers who used paracetamol in the prenatal period in any trimester of pregnancy was 1.28, 95% CI: 1.13 to 1.39. Fan et al. also held the opinion that prenatal paracetamol exposure was significantly associated with the increased risk of child asthma. In their work, OR = 1.19, 95% CI: 1.12 to 1.27. In turn, Eyers et al. showed increased risk of recurrent wheeze in the children of women who were exposed to paracetamol during pregnancy. In their study, OR was 1.21, 95% CI: 1.24 to 1.44. Paracetamol use during pregnancy can affect both the mother and the fetus. Researches of fetal exposure to paracetamol have concerns on: premature birth , neurological development low birth weight , hyperactivity disorder/hyperkinetic disorder or adverse development issues , and other birth defects Several limitations should be identified with regard to our study. Firstly, various prenatal ailments and illnesses may themselves have an impact on the risk of postnatal respiratory disorders. In addition, from the studies included into our meta-analysis, it was not possible to obtain confounding factor data that could have an impact on the final results of our analysis. It is difficult to conclude at what age prenatal paracetamol exposure affects children. Secondly, these are observational studies extended over time. During their duration, we cannot avoid the influence of various factors that may affect the final result. Furthermore, the study drug may have been administered to the children post-partum, as mothers who take paracetamol in pregnancy may be more likely to give paracetamol to their children. There are a number of other methodological problems that are also relevant for the interpretation of the results. Firstly, as a meta-analysis of observational studies, it was prone to the bias (e.g., recall and selection bias) inherent in the original studies. Secondly, most of the studies were observational in nature, did not establish a dose-response relationship, and were conceived to be subject to numerous errors and misleading outcomes regarding period of administration. Indeed, in some studies, a progressive increase in risk associated with increasing number of days of prenatal paracetamol exposure, or increased frequency of use, was observed . Moreover, a limitation may posed by publication high statistical heterogeneity. 5. Conclusions In summary, the results of our study confirmed that maternal paracetamol use in pregnancy is associated with an increased risk of asthma or wheezing in their children. The current findings are consistent with results of previous meta-analyses showing increase in asthma/wheeze symptoms from paracetamol exposure. We believe paracetamol should be used with caution by pregnant women, and at the lowest effective dose, for the shortest duration. Long-term use or the use of high doses should be limited to the indications recommended by a physician, while the mother-to-be should be under constant supervision. Author Contributions Conceptualization, W.K., A.B. (Agnieszka Baranska), A.B. (Agata Blaszczuk); data curation, W.K.; formal analysis, M.P.-D.; funding acquisition, A.W.; investigation, A.B. (Agnieszka Baranska); methodology, W.K., M.M., A.B. (Agnieszka Baranska); project administration, W.K., A.B. (Agnieszka Baranska); resources, W.K., A.B. (Agata Blaszczuk); software, U.R.; supervision, A.W.-F., validation, A.W-F.; visualization, W.K., A.B. (Agnieszka Baranska), A.B. (Agata Blaszczuk), M.M.; writing original draft, W.K., A.B. (Agnieszka Baranska); writing review and editing, A.B. (Agnieszka Baranska), A.W-F. All authors have read and agreed to the published version of the manuscript. Institutional Review Board Statement Not applicable. Informed Consent Statement Not applicable. Data Availability Statement The data are available upon request from the corresponding author. Conflicts of Interest The authors declare no conflict of interest. Figure 1 Flow diagram of literature search and research selection procedure. Figure 2 The crude relationship between childhood asthma and paracetamol use (ever vs. never) during pregnancy and each trimester of pregnancy . Figure 3 The crude relationship between childhood wheeze and paracetamol use (ever vs. never) during pregnancy and each trimester of pregnancy . jcm-12-01832-t001_Table 1 Table 1 Characteristics of included studies evaluating the association between prenatal paracetamol intake and asthma or wheezing risk in childhood. Author, Year Country Study Exposure Classification Research Period (Years) The Children's Respiratory Disorders Age of Children's Diagnosis Population: Paracetamol Use Child With Asthma or Wheezing Outcome Period (Months) Nos Scale Studies Included in Meta-Analysis 1. Liew , 2021 USA Environment and Pregnancy Outcomes Study Cohort study Paracetamol use during pregnancy: 1st trimester, 2nd trimester, 3rd trimester, ever. 2003-2007 Asthma: diagnosed by medical professional Wheezing early childhood 958 Asthma: 118 Wheeze: 304 48 9 2. Piler , 2018 Czech Republic/Brno and Znojmo regions Czech European Longitudinal Study of Pregnancy and Childhood Paracetamol use during pregnancy. 1991-1992 Paediatrician-diagnosed asthma 3, 5, 7 and 11 years 1105 Asthma: 41 132 9 3. Magnus , 2016 Norway Norwegian Mother and Child Cohort Study Paracetamol use during pregnancy. 1999-2014 Childhood asthma 3 years; 7 years 34,703 Asthma: 1751 36 9 4. Liu , 2016 Denmark Danish National Birth Cohort Paracetamol use during pregnancy: 1st trimester, 2nd trimester, 3rd trimester, ever. 1996-2010 Asthma: at least two prescriptions for inhalants or cases diagnosed by a hospital doctor. 3 years or later 63,652 Asthma: 7644 36 8 5. Migliore , 2015 Italy Nascita e INFanzia: Effeti dell Ambiente study Paracetamol use during pregnancy: 1st trimester, 3rd trimester. 2005-2013 Asthma: diagnosed by doctor Wheezing or whistling: at least one episode 18 months 3358 Asthma: 185 Wheeze 535 18 7 6. Andersen , 2012 Denmark Danish Medical Birth Registry Paracetamol use during pregnancy: 1st trimester, both 2nd and 3rd trimesters, ever. 1996-2008 Asthma: hospital diagnosed, anti-asthmatic drug prescription median 6.8 years 197,060 Asthma: 24,506 ~82 8 7. Goksor , 2011 Sweden Swedish Medical Birth Register Paracetamol use during pregnancy. 2003 Asthma: Inhaled corticosteroid-treated Wheezing: three or more episodes 6, 12 months and 4, 5 years 4496 Asthma: 258 Wheeze: 235 54 7 8. Perzanowski , 2010 USA Columbia Center for Children's Environmental Health Paracetamol used during pregnancy by low-income women. 1998-2006 Asthma: self-reported Wheezing: self-reported 5 years 297 Asthma: 99 Wheeze: 99 60 7 9. Kang , 2009 USA The Yale Study Paracetamol used in 1st and 3rd trimesters pregnancy. 1997-2000 Asthma: diagnosed by a doctor or health professional 6 years +/- 3 months 1505 Asthma: 172 72 7 10. Garcia-Marcos , 2009 Spain Murcia (Spain) Study Paracetamol use during pregnancy. Wheezing: self-reported 4.08 +/- 0.8 (3-4 years) 1741 Wheeze: 341 36-60 8 11. Rebordosa , 2008 Denmark Danish National Birth Cohort study Paracetamol use during pregnancy: 1st trimester, 2nd trimester, 3rd trimester, ever. 1996-2003 Asthma: symptoms reported, physician-diagnosedWheezing: self-reported 18 months wheeze; 7 years asthma 12,733 Asthma: 12,530 Wheeze: 11,980 84 9 12. Saheen , 2002 UK Avon Longitudinal Study of Parents and Children Paracetamol use during pregnancy. 1992-1999 Wheezing: self-reported 30-42 months 8942 Wheeze: 1195 30-42 9 Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
Int J Mol Sci Int J Mol Sci ijms International Journal of Molecular Sciences 1422-0067 MDPI 10.3390/ijms24054798 ijms-24-04798 Editorial Role of Extracellular Vesicles Produced by Stem Cells in Tissue Repair Oliva Joan Emmaus Life Sciences, Inc., 21250 Hawthorne Blvd., Suite 800, Torrance, CA 90503, USA; [email protected]; Tel.: +310-214-0065; Fax: 310-214-0075 02 3 2023 3 2023 24 5 479814 2 2023 21 2 2023 (c) 2023 by the author. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). pmcThe purpose of this Special Issue is to emphasize the great potential of the translational applications of extracellular vesicles (EVs) produced by stem cells (mesenchymal stem cells, induced pluripotent stem cells, etc.). Cells release various vesicles, but to avoid confusion, we will be using the word EVs because the majority of the studies did not fully characterize the identity of the EVs (size, protein content, etc.) . When studying the potential curative properties of stem cells, due to their low immunogenicity, wide availability, mass production and ability to differentiate into different types of cells , researchers have noticed a long-term effect of stem cells on injured tissue, through EVs. Discovered in 1983 , EVs are biological messengers for cell-cell communication, but the EV content (proteins, lipids, nucleic acids) is specific to the cell type and the cell culture parameters . In this Special Issue, five articles studied the effects of extracellular vesicles produced by different types of stem cells (bone marrow stem cells, umbilical cord stem cells, adipose stromal cells, induced pluripotent stem cells) on different organs: human corneal endothelium, mouse cochlea hair cells, rat kidneys, rat cerebral small vessels, human cardiac tissues. Treatment with EVs could overcome various limitations identified in cell therapies: (1) multiple doses can be given to the patient; (2) cell-free therapy with no or a very low risk of ectopic settlement in the patient's body; (3) no or a low risk of immune rejection. Knowing the organ's target and using EVs as a carrying vector, specific miRNAs/mRNAs/proteins could be transfected in isolated EVs or artificial EVs to increase the efficacy of the treatment. Another approach is the modification of the stem cell genome by introducing a specific nucleic acid to produce specific mRNAs, miRNAs or proteins and increase their presence in EVs, in order to enrich their content and improve their curative properties. For example, Buono et al. evaluated the potential of EVs produced by bone marrow stem cells in decreasing endoplasmic reticulum (ER) stress induced by serum deprivation and tunicamycin treatment in freshly collected human corneal epithelial cells . ER stress is well known to be toxic due to the incapacity of the ER to correctly fold the proteins, which accumulate in the cells, and the decrease in ER stress is accompanied by a decrease in cell apoptosis. The authors showed that the miRNAs (miR-222-3p, miR-125b-5p, miR-100-5p, etc.) contained in the vesicles targeted ER proteins involved in ER stress (ATF4, CHOP, etc.). The authors also identified miRNAs and their targets that could be used to improve EV treatment to decrease the harmful effect of ER stress. Remarkably, ER stress is also an activated deleterious pathway in organs with ischemia-reperfusion injury, which occurs during the preservation time of the organ for transplantation. As mentioned, we know that vesicles have a protective effect against inflammation, apoptosis and ER stress, but the factors involved in this mechanism are not clearly identified. The identification of those factors will help to decipher the protective properties of vesicles and also improve their efficacy, as Buono et al. reported . Grignano et al. focused on identifying factors contained in vesicles produced by bone marrow stem cells and used to treat ischemic renal damage. The authors identified CD73, let-7a, miR-21, miR-24 and miR-99a as factors that positively or negatively affected the therapeutic properties of the EVs. One major discovery was that CD73, a surface marker, is involved in increasing the intracellular ATP level (depleted during ischemia) and provides energy to all cellular functions such as protein folding, NADH levels, ATP-dependent transporters, channels and kinase activity . Tsai et al. identified markers in extracellular vesicles produced my umbilical cord mesenchymal stromal cells and used to decrease nerve injury-induced pain in rats . The group identified three major miRs (miR-125a-5p, miR-125b-5p, miR-127-3p) and various proteins (TGF beta ig-h3, collagen alpha-2I chain, collagen alpha 1I chain, glia-derived nexin, etc.) present in the EVs. The authors identified miRs affected by the EVs, compared to the control and disease conditions. Treatment of cochlear tissues with EVs produced by umbilical cord mesenchymal stromal cell exosomes partially restored the expression of 7 miRs out of 40 (miR-181-a-5p, Let-7e-5p, miR-127-3p, miR-183-5p, miR-22-3p, miR-30e-3p, let-7f-5p). Of course, a wider and deeper screening of the affected transcriptome needs to be conducted in further studies, because, thus far, there are at least 2000 microRNAs . In many studies reporting ER stress and inflammation , the level of apoptosis decreased after EV treatment. In 2013, the first study to prove the beneficial effect of extracellular vesicles on the treatment of a rat brain after a stroke was reported. Isolated EVs from rat bone marrow were injected into the tail vein of rats to treat stroke. The systemic EV treatment improved the brain activity or protected it against the stroke injuries, but the most remarkable information provided by this study was the potential for the EVs to pass the blood-brain barrier (BBB) . This physical property is a great advantage for EVs over cell therapies because of the limited BBB permeability of activated T cells and not for other cells types as stem cells . Guy et al. studied intranasally administered adipose stromal cell EVs in a rat model that is known to be prone to hypertension . The administered EVs had an impact on inflammation by decreasing pro-inflammatory cytokine production and the BV2 microglial cell and astrocyte activities . In addition, 100% of the rats treated with the EVs survived for 60 days, while only 60% of them survived in the non-treated group. The spatial and visual cognition of the treated rats were superior to those of the untreated rats. In an in vitro study using EVs isolated from human iPSCs, Lozano's group demonstrated EVs' protective effect on human cardiomyocytes and human endothelial cells against hypoxia/reoxygenation, a phenomenon that can be encountered during organ ischemia-reperfusion, anemia and congestive heart failure . The authors fully characterized the proteome of the isolated EVs to better understand what proteins and/or nucleic acids are targeted. The authors proved that the vesicles were absorbed by cardiac fibroblasts and cardiomyocytes. The vesicles protected the cardiomyocytes from apoptosis and improved their capacity to form tubules after a hypoxia treatment. To understand the mechanism of action of the vesicles, the authors identified the pathways and proteins of the cardiomyocytes and cardiac fibroblasts that are influenced by the vesicles, in order to help the cells to self-repair. The majority of the proteins were involved in fatty acyl-CoA biosynthesis, fatty acid metabolism, cholesterol biosynthesis, glucose metabolism and the extracellular matrix . In conclusion, the collection of publications in this Special Issue entitled "Role of Extracellular Vesicles Produced by Stem Cells in Tissue Repair" provides valuable information and knowledge about modified or unmodified extracellular vesicles produced by stem cells. Extracellular vesicles have a wide range of translational applications, including in the treatment of apoptosis, ischemia and endoplasmic reticulum stress. Extracellular vesicles have the advantage of not settling randomly in the body after injection and growth, as with stem cells, but because the research on extracellular vesicles has still not sufficiently advanced, data about the potential risk of organs' function impairment are still needed in the long term. Major questions concerning the content of extracellular vesicles, which could help to understand their beneficial protective effects, still require additional work before they are answered : How much variability is there among EVs produced by the same type of cells and from different donors? What are the factors influencing the variability in EV contents? How can we standardize EV production specific to the type of disease, organ or injury? 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101622811 42098 World J Cardiovasc Surg World J Cardiovasc Surg World journal of cardiovascular surgery 2164-3202 2164-3210 36909676 10.4236/wjcs.2022.129017 nihpa1875151 Article Orthotopic Heart Auto-Transplantation in a Swine Model Rogers Michael P. 1 Fishberger Gregory 1 Martini Nick 1 Baldwin Margaret 2 Wang Lei 3 Chen Wei 4 Liu Ruisheng 3 Lozonschi Lucian 1* 1 Division of Cardiothoracic Surgery, Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, USA 2 Department of Comparative Medicine, University of South Florida, Tampa, FL, USA 3 Department of Molecular Pharmacology and Physiology, University of South Florida Morsani College of Medicine, Tampa, FL, USA 4 Department of Physics, College of Arts and Sciences, University of South Florida, Tampa, FL, USA * [email protected] 16 2 2023 9 2022 10 3 2023 12 9 200206 This work is licensed under the Creative Commons Attribution International License (CC BY 4.0). Background and Aim: The porcine heart bears the best resemblance to the human heart and remains the preferred preclinical model for anatomical, physiological, and medical device studies. In an effort to study phenomena related strictly to ischemia reperfusion and donor preservation protocols, it is essential to avoid the immune responses related to allotransplantation. Orthotopic auto-transplantation is a unique strategy to the field of cardiac transplantation for ex vivo experimentation. Nevertheless, auto-transplantation carries its own technical challenges related to insufficient length of the great vessels that are to be transected and re-anastomosed. Methods: A novel method for orthotopic cardiac auto-transplantation in the porcine model was developed and was described herein. Porcine models were used for ex vivo experimentation of a novel device to study ischemia reperfusion injury. Results: A total of five porcine models were used for ex vivo experimentation of a novel device to mitigate ischemia reperfusion injury and determine effects of donor preservation. Modifications to routine cardiac transplantation protocols to allow for successful auto-transplantation are described. Conclusion: Orthotopic cardiac auto-transplantation in the porcine model is a plausible and technically feasible method for reliable study of ischemia reperfusion injury and donor preservation protocols. Here, we describe methods for both direct orthotopic porcine cardiac auto-transplantations as well as a simplified protocol that can be substituted for full surgical auto-transplantation for the studies of preservation of donor hearts. Porcine Cardiac Surgery Cardiac Transplantation pmc1. Introduction Pigs and humans have anatomic and physiologic similarities. By comparison, humans share far more immune-related genes and proteins with pigs than they do with mice or other animals . Additionally, swine models appear to develop similar clinical and histopathological features of primary graft dysfunction to that seen in humans after transplantation . The porcine heart is often considered the most anatomically similar to the human heart when using large animals. As such, it is an ideal platform to perform cardiac surgical research. Growing interest in the feasibility of using genetically modified porcine hearts for porcine-to-human cardiac xenotransplantation highlights this relevance . In this work, we present our direct approach to orthotopic porcine cardiac auto-transplantation as well as a simplified protocol that can be substituted for full surgical auto-transplantation for conducting research in the preservation of donor hearts. 2. Protocol For the purposes of our study, adult Yorkshire pigs (60 - 80 kg) were used for heart size similarity to an adult human. The animal was procured from a local Institutional Animal Care and Use Committee (IACUC) approved vendor. This study received local Institutional Review Board (IRB) approval and strictly conformed to the institutional IACUC standards, as well as the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources . 2.1. Donor Anesthesia Induction and Procedural Preparation The animal was initially premedicated with ketamine (20 mg/kg), atropine (0.04 mg/kg), and diazepam (2 mg/kg), followed by anesthetic induction and maintenance with inhalational isoflurane. Isoflurane was titrated for an end tidal concentration of 1% - 3%, and 3 L/min 100% FiO2 were delivered by face mask. To ensure adequate anesthesia dosing, jaw tone and the absence of pain during toe pinch were assessed. Orotracheal intubation followed using a size 7.5 - 8.5 mm endotracheal tube. To assess oxygen saturation, continuous monitoring was determined by probes placed on the ear or bottom lip and serial arterial blood gas measurements were collected throughout the operation (Table 1). Peripheral intravenous access was obtained by 20-gauge Angiocath insertion in the ear vein with an initial maintenance infusion of 0.9% NaCl. Using the modified-Seldinger technique, a percutaneous central venous sheath introducer was placed in the right jugular vein after placement of the animal in Trendelenburg position. An arterial line for arterial blood pressure monitoring was placed in the left common carotid artery for blood pressure monitoring. 2.2. Peripheral Cannulation for Cardiopulmonary Bypass The left and right inguinal areas were prepped and draped in the usual sterile fashion. The left common femoral vein and right common femoral artery were accessed percutaneously and a guide wire advanced into the inferior vena cava and descending aorta, respectively. This step was performed after sternotomy was completed to allow for manual confirmation of the wire position. A full dose of 300 IU/kg of heparin was given to achieve a target activated coagulation time (ACT) of 400 seconds or greater. A standard approach for percutaneous femoral cannulation using the modified-Seldinger technique was used to serially dilate the femoral vessels and place the femoral cannulas. A 15 Fr. femoral arterial and 17 Fr. venous cannula (Medtronic Inc., Minneapolis, MN) were used. Cannulas were connected to a modified cardiopulmonary bypass circuit consisting of a Sorin/Stockert SCP centrifugal pump (LivaNova PLC, London, United Kingdom) and Medtronic (Medtronic Inc., Minneapolis, MN) tubing and reservoir . The cardiopulmonary bypass (CPB) circuit was primed with 700 cc of crystalloid solution (e.g., Plasmalyte or normal saline), with 25 grams of mannitol, 10,000 units of Heparin, and 50 mill equivalents of sodium bicarbonate. 2.3. Donor Heart Procurement A mid-line sternotomy incision was performed with a #10 blade followed by electrocautery from the mid-cervical region to below the xiphoid process. An area approximately three finger breadths below the manubrium was chosen as the superior margin of the sternotomy. Preservation of the manubrium was considered for locomotion of the animal in future survival studies. Using a Lebsche knife (Novo Surgical, Westmont, IL), the sternum was separated from the manubrium at the level of the 2nd intercostal space . The remainder of the sternum was then divided using a standard sternal saw from the xiphoid process to the superior margin in a "T" fashion. Hemostasis was carefully achieved, two laparotomy sponges were placed on either side of the sternum, and a sternal retractor was placed. The thymus was then dissected and excised. This was followed by incision of the pericardium with placement of pericardial stay sutures. Using electrocautery, the aortopulmonary space was dissected and the anterior aspect of the ascending aorta and arch was dissected to the level of the left subclavian artery. To isolate and secure the superior vena cava (SVC) and inferior vena cava (IVC), spaces between these vessels, the innominate artery, and the pericardium were dissected with encircling of the SVC and IVC by umbilical tapes. The SVC was cannulated for cardiopulmonary bypass using a 4-0 prolene purse-string suture and a 20 Fr. (Edwards Lifesciences, Irvine, CA) right angle single-stage venous cannula (e.g., DLP single lumen angled venous cannula) and connected to the inferior femoral venous cannula in a Y-configuration. Cannulas were connected to the bypass circuit using a "3/8-3/8-1/2" Y-connector with adequate deairing. CPB was initiated with a target cardiac index of >2.2 - 2.5 L/min/m2 while maintaining mean arterial pressure > 55 - 75 mmHg. Targeted mild hypothermia to 34 degrees centigrade was initiated. Arterial blood gases were monitored every 45 minutes and ACTs monitored every 30 minutes to ensure ACT > 450 seconds. A 12-gauge antegrade cardioplegia catheter was placed in the proximal ascending aorta. Standard preparation del Nidocardioplegia solution was prepared and connected to the antegrade delivery cannula followed by aortic cross-clamping on the distal ascending aorta. A full dose of 1.5 L of cardioplegia solution at 4degC was given with a target root pressure of 80 - 100 mmHg. To achieve organ cooling, saline ice slush was placed in the pericardial cavity and over the heart. After cardioplegia infusion, cardiectomy was performed in the usual cardiac transplant fashion, following by placement of the heart into an organ bag with 500 mL of preservation (del Nidocardioplegia) solution. Of note, the porcine model always has a significant left azygous vein present (comparable to the much-rarer left superior caval or oblique vein in humans) that enters the coronary sinus . This must be ligated to allow for bloodless cardiectomy. Additionally, the porcine left atrium receives only two pulmonary veins, with the superior and inferior pulmonary vein confluence occurring prior to reaching the atrium. This results in two pulmonary veins entering the left atrium close to each other, as opposed to left and right superior and inferior pulmonary venous drainage in humans. Particular attention to dissection in this area to allow for sufficient left atrial cuff for anastomosis is critical, as the left and right pulmonary veins are quite diminutive and often not sufficient for primary anastomosis. It is essential to perform a meticulous dissection during cardiectomy as this can aid in obtaining additional length for the SVC, IVC, and pulmonary artery. The ex vivo experiments occurred for a total of two hours during which time the porcine model was maintained on cardiopulmonary bypass. Two cardiopulmonary bypass sumps were placed in the pericardial cavity as well as the pulmonary veins to maintain return of all blood and adequate pump volume. 2.4. Auto-Reimplantation Procedure The heart was prepared for re-implantation. Biatrial anastomotic technique was followed in the order of left atrium, IVC, pulmonary artery, aorta and SVC. The anastomosis of divided cuff of each great vessel was challenging due to minimal redundancy. In two animals, we first anastomosed extension cuffs consisting of custom-fashioned Dacron (Vascutek(r) GelsealTM, Terumo Cardiovascular Systems Co., Ann Arbor, MI, USA) grafts while the heart remained in its preservation basinto complete the IVC and left atrial anastomoses due to distance mismatch. Following all anastomoses, the aortic cross clamp was then removed, and hemostasis was ensured. The donor heart was reperfused on CPB as needed while ventricular arrythmia was treated with internal defibrillation, if required. Ventricular pacing was utilized in all cases and antiarrhythmic medications (e.g., amiodarone, lidocaine, and magnesium sulfate) were administered. Cardiopulmonary bypass was then weaned in a routine fashion. The central venous line was used to monitor central venous pressure with a target of 10 - 15 mmHg. As required, vasoactive and inotrope continuous infusions (e.g., dobutamine, epinephrine, vasopressin, and milrinone) were initiated. Volume replacement was returned from CPB as needed, and heparin reversal was achieved with protamine. 3. Discussion Orthotopic auto-transplantation is a unique strategy to the field of cardiac transplantation for ex vivo experimentation. This approach eliminates the need to match the immunological profiles of donor and recipient, thus preventing acute immunologic organ rejection and precludes the need for immunosuppression medication. Our protocol demonstrates the feasibility of this strategy for cardiovascular translational research. The main barrier with this method is inadequate length on both donor and receiving cuffs of the great vessels for creating of tension free anastomoses. This limitation can be overcome with the anastomosis of polyester cuff extenders matched in size and diameter to the great vessels' cuffs of the explanted heart before re-transplantation. An alternative to the method described above is by altogether avoiding complete cardiectomy for device testing through in situ cardiac circulatory exclusion and cardioplegic arrest. The aorta is cross-clamped and antegrade cardioplegia is delivered in the usual fashion to establish full arrest, after the SVC/IVC inflows are occluded . Both left and right atria are vented through small atriotomies to completely empty the heart. The heart is thus excluded from circulation and maintained at 4 degrees Celsius with a specially designed cooling device. This technique obviates the need for great vessels' division and re-anastomosis and the possible complications thereof (i.e., kinking, size mismatch, need for Dacron grafts extension for creation of tension free anastomosis). Once the designed experiment has been completed, the heart is reperfused in the normal fashion as described above. Figure 1. Modified cardiopulmonary bypass circuit consisting of a Sorin/Stockert SCP centrifugal pump (LivaNova PLC, London, United Kingdom) and Medtronic (Medtronic Inc., Minneapolis, MN) tubing and reservoir. Figure 2. Preservation of the manubrium was considered for locomotion of the animal in future survival studies. ALebsche knife was used to divide the sternum from the manubrium at the level of the 2nd intercostal space. Figure 3. A proposed method for in situ cardiac circulatory isolation under cardioplegic arrest. Table 1. Variables monitored during experimentation and during cardiopulmonary bypass. Monitored Variables Blood Pressure with Arterial Line Pulse Rate Oxygen Saturation Central Venous Pressure Activated Coagulation Time Basic Metabolic Panel Hemoglobin and Hematocrit Arterial Blood Gas Cardiac Index Conflicts of Interest The authors declare no conflicts of interest regarding the publication of this paper. References Karimi A , Cobb JA , Staples ED , Baz MA and Beaver TM (2011) Technical Pearls for Swine Lung Transplantation. Journal of Surgical Research, 171 , e107-e111. 10.1016/j.jss.2011.05.067 21872270 Pierson RN 3rd , Dorling A , Ayares D , Rees MA , Seebach JD , Fishman JA , (2009) Current Status of Xenotransplantation and Prospects for Clinical Application. Xenotransplantation, 16 , 263-280. 10.1111/j.1399-3089.2009.00534.x 19796067 Cooper DK , Satyananda V , Ekser B , van der Windt DJ , Hara H , Ezzelarab MB , (2014) Progress in Pig-to-Non-Human Primate Transplantation Models (1998-2013): A Comprehensive Review of the Literature. Xenotransplantation, 21 , 397-419. 10.1111/xen.12127 25176336 Iskender I , Sakamoto J , Nakajima D , Lin H , Chen M , Kim H , (2016) Human Alpha1-Antitrypsin Improves Early Post-Transplant Lung Function: Pre-Clinical Studies in a Pig Lung Transplant Model. The Journal of Heart and Lung Transplantation, 35 , 913-921. 10.1016/j.healun.2016.03.006 27095003 Griffith BP , Goerlich CE , Singh AK , Rothblatt M , Lau CL , Shah A , (2022) Genetically Modified Porcine-to-Human Cardiac Xenotransplantation. The New England Journal of Medicine, 387 , 35-44. 10.1056/NEJMoa2201422 35731912 Platt JL and Cascalho M (2022) The Future of Transplantation. The New England Journal of Medicine, 387 , 77-78. 10.1056/NEJMe2207105 35731906 Pierson RN 3rd , Fishman JA , Lewis GD , D'Alessandro DA , Connolly MR , Burdorf L , (2020) Progress toward Cardiac Xenotransplantation. Circulation, 142 , 1389-1398. 10.1161/CIRCULATIONAHA.120.048186 33017208 (2011) National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals. Guide for the Care and Use of Laboratory Animals. 8th Edition, National Academies Press (US), Washington, DC. Crick SJ , Sheppard MN , Ho SY , Gebstein L and Anderson RH (1998) Anatomy of the Pig Heart: Comparisons with Normal Human Cardiac Structure. Journal of Anatomy, 193 , 105-119. 10.1046/j.1469-7580.1998.19310105.x 9758141 |
Materials (Basel) Materials (Basel) materials Materials 1996-1944 MDPI 10.3390/ma16051881 materials-16-01881 Editorial Obtaining and Characterizing New Advanced Materials Sandu Andrei Victor 123 1 Department of Technologies and Equipment for Materials Processing, Faculty of Materials Science and Engineering, Gheorghe Asachi Technical University of Iasi, 41 D. Mangeron Blvd., 700050 Iasi, Romania; [email protected] 2 Romanian Inventors Forum, St. P. Movila 3, 700089 Iasi, Romania 3 National Institute for Research and Development in Environmental Protection INCDPM, Splaiul Independentei 294, 060031 Bucharest, Romania 24 2 2023 3 2023 16 5 188102 2 2023 23 2 2023 (c) 2023 by the author. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). This editorial highlights the results presented in the second Special Issue dedicated to obtaining and characterizing new materials, wherein one review paper and 13 research articles have been published. The most important field covered is that of materials involved in civil engineering, focusing on geopolymers and insulating materials alongside developing new methods for enhancing the characteristics of different systems. Another important field is that of the materials used for environmental issues, and finally, those involved in human health. geopolymers fly ash thermal insulation laser sintering chia seed oil This research received no external funding. pmcIntroduction The development of new materials opens up more and more opportunities day by day, and after a successful first Special Issue "Obtaining and Characterizing New Materials", with the support of editors, we have created a second Special Issue to highlight the latest trends in the broad field of materials engineering. This second collection, much like the first one, covers a large range of topics. We discuss obtaining and characterizing new materials, from macro-scale, involving new alloys, ceramics, composites, biomaterials, and polymers, as well as procedures and technologies for enhancing their structures, properties, and functions. In order to choose the future applications of these new materials, we first must understand their structures and know their characteristics by involving modern techniques such as microscopy (SEM, TEM, AFM, STM, etc.), spectroscopy (EDX, XRD, XRF, FTIR, XPS, etc.), mechanical tests (tensile, hardness, elastic modulus, toughness, etc.), and understand their behavior (corrosion, thermal, DSC, STA, DMA, magnetic properties, biocompatibility, in vitro and in vivo). The most represented of the domains included here is that of construction materials, in which we seek to create sustainable materials with low costs and effective characteristics. Geopolymers are a type of inorganic polymer that can be made from a wide range of materials and also from industrial wastes. In order to produce cementitious products inside treated soils and improve the mechanical and physical qualities of clayey soils, alkaline activation of industrial waste was posited. This way, the use of geopolymers based on fly ash and ground-granulated blast furnace slag (GGBFS) for soil stabilization increased their strength. S.R. Abdila et al. involved two different types of precursors, performing unconfined compressive strength (UCS) and concluding that GGBFS and fly ash-based geopolymers can successfully be used for soil stabilization . Due to its improved acid resistance compared to regular Portland cement and lower CO2 emissions during the synthesis process, a fly ash geopolymer is suggested as a material for rigid pavement applications. In order to manufacture a fly ash-based geopolymer with the best compressive strength, the authors have sought to improve its formulation. The findings indicate that for fly ash-based geopolymers, the ideal sodium hydroxide concentration, sodium silicate to sodium hydroxide ratio, and solid-to-liquid ratio are, respectively, 10 M, 2.0, and 2.5, with a maximum compressive strength of 47 MPa. With a higher percentage of compressive strength than OPC concrete, the geopolymer is a more durable material for rigid pavement applications because it is based on fly ash, with a percentage of compressive strength loss of 7.38% to 21.94% for OPC concrete . Another study focused on developing a geopolymer based on fly ash; in this study, ladle furnace slag was combined with foam created by pre-foaming polyoxyethylene alkyether sulphate (PAS). At temperatures between 29 and 1000 degC, the performance of a fly ash-slag geopolymer blend with and without PAS foam was examined using a PAS foam-to-paste ratio of 1 and 2. (G-1 and G-2). At 29-1000 degC, the compressive strength of the foamed geopolymer was lower than that of G-0 (36.9-43.1 MPa) (25.1-32.0 MPa for G-1 and 21.5-36.2 MPa for G-2). Heating G-0 decreased its compressive strength by 8.7%, up to 1000 degC compared to unheated samples; however, foamed geopolymer gained compressive strength by 68.5% up to 1000 degC. In a highly sought after area, that of the road concrete development, L.M. Nicula et al. involved nuclear magnetic resonance (NMR) relaxometry to compare the porosity of three combinations of road concrete that contain blast furnace slag to two mixtures created with conventional ingredients. The samples involved were maintained for 300 freeze-thaw cycles and then compared to control samples. The investigations allowed for the identification of the ideal composition of blast furnace slag to be added to road concrete mixtures. Additionally, using this non-invasive method, it is possible to evaluate the porosity and the development of interior cracks during the freeze-thaw test. In other aspect of civil engineering, the involvement of wood is crucial. P. Mania et al. managed to densify samples of paulownia clone wood and hornbeam (Carpinus betulus L.). The specimens underwent plastic treatment in an ammonia solution before being densified. Following densification, it was possible to measure the wood's Brinell hardness in each of the three anatomical directions, and its compressive strength in the radial direction. The extent to which wood would swell in water that was liquid and humid (98% RH) was also determined. The densities of hornbeam and paulownia wood increased by 40% and approximately 280%, respectively. For hornbeam and paulownia, the Brinell hardness parallel to the fibers increased by 49 and 390%, and perpendicularly by 80 and 388%. Additionally, it was discovered that the woods' compressive strength significantly increased in the radial direction. Paulownia wood exhibited 107% swelling, compared to 153% for densified hornbeam wood exposed to water. For many years, multi-beam box girder bridges have been used extensively worldwide. For this issue, a method for reinforcing embedded steel plate (ESP) was proposed by adding carbon-A/-B glue to the longitudinal joints of old multi-beam box girder bridges . We can conclude that the proposed strengthening method can be used to enhance the mechanical performance of multi-beam box girder bridges and serve as a guide for such bridge reinforcement. Analysis results of the actual bridge and finite element model show that the structural stiffness and load lateral transferring performance between the box girders were improved after ESP strengthening. Given the current situation, it is necessary to find sustainable and cutting-edge ways of improving the thermal efficiency of projects. An intriguing study shows experimental findings from the testing of a variety of composite thermal insulation materials made from a blend of sheep wool, cellulose, rPET, and rPES fibers. The study's findings highlight the advantages of utilizing such materials for improving indoor air quality, while also demonstrating their qualities of thermal insulation (the ability to adjust to humidity and reduce concentrations of harmful substances). When compared to conventional thermal insulation materials, the benefits of employing sheep wool composite mattresses in terms of their resistance to insect attack are also shown. Some researchers discuss the capacity of sheep wool heat-insulating mattresses to simultaneously meet the real need for high-quality air inside living spaces and thermally efficient buildings by cumulatively analyzing efficiency indicators for thermal insulation and indicators of improved air quality. As a result, the results for the coefficient of thermal conductivity and its resistance to heat transfer show that these mattresses are appropriate for use as thermal insulation. The discovered features of permeability to water vapor and the sorption/desorption of water and air show their ability to control the humidity of indoor air, and the resulting decrease in formaldehyde content show their contribution to the improvement of air quality. On the subject of materials and sustainability, we need to focus on environmental issues and materials' impact on human health. In this vein, investigations were conducted on soil samples to perform a quality status assessment, determining pH, texture, structure, and metal concentration, as well as carrying out an assessment of anthropogenic activity by determining the pollution indices of CF (contamination factor). These investigations aimed to determine soil quality, soil environmental risk, and extraction of metals from polluted soils by bioleaching, and aimed to identify influential factors in achieving high remediation yields (potential ecological risk index). Though optimistic, the depollution yield after 12 h of treatment is Cu 29-76%, Pb 10-32%, Cr 39-72%, and Ni 44-68%. The best exposure duration for the bioleaching extraction process can be determined using yield-time correlation equations . Many other parts of the industry are seeking new technologies and materials. To investigate the effects of the powder's physical characteristics and operating conditions on the bed quality which is determined by density characteristics, density uniformity, and the flatness of the powder layer powder spreading in realistic SLS settings was simulated using the discrete element method (DEM) . Based on the response surface methodology, a regression model of the powdering quality was created (RSM). The non-dominated sorting genetic algorithm II (NSGA-II) was utilized to optimize the nylon powder laying quality in the SLS process using an improved multi-objective optimization approach. We offered various optimization plans in accordance with the various process needs. Experiments were used to confirm the validity of multi-objective optimization outcomes for powdering quality. In another of this publication's articles , the influence of isothermal annealing on the mechanical and microstructural properties of Sn-0.7Cu-1.5Bi solder junctions is discussed. The intermetallic layer thickness at the solder/Cu interface increased by 0.042 m/h for Sn-0.7Cu and 0.037 m/h for Sn-0.7Cu-1.5Bi, according to the results, as the solder/Cu interface cured. With a 1.5 weight percent Bi addition in the reflowed condition and after isothermal annealing, the hardness and shear strength of Sn-0.7Cu dramatically increased. Innovative materials known as shear thickening fluids (STFs) can be used in smart body armor. The objective of the published paper was to examine how UV light affects STF aging. Artificial aging was used in the experimental inquiry to look into how UV light affects the characteristics of STFs. The highest viscosity of the STFs based on PPG425, PPG2700, and KE-P10 reached 580.7 PaS for the STF425 and 3313 PaS for the STF2700, respectively. Our findings show that STFs are UV light-sensitive and can lose some of their characteristics while being stored. Building on our knowledge of coatings, J.J.K.Ngouoko et al. studied a glassy carbon electrode (GCE) coated with a sheet of hydroxy-apatite (HA)/L-lysine (Lys) composite material to create an amperometric sensor for the detection of Nile blue A. (NBA). Electrochemical research revealed an increase in the GCE/Lys/HA sensor's sensitivity to the detection of NBA in solution. Investigations were carried out to elucidate how the pH, scan rate and NBA concentration affected the peak current and potential. The GCE/Lys/HA sensor demonstrated excellent repeatability, selectivity, and an NBA low detection limit of 5.07 108 mol L1 under ideal circumstances. NBA in several water samples was successfully detected using the developed HA/Lys-modified electrode. In the field of organic chemistry, a novel epoxidized vegetable oil (EVO) from chia seed oil (CSO) has been produced with the intention of use as a plasticizer and compatibilizer in a wide range of eco-friendly goods related to the polymeric industry . Analysis of various parameters revealed that 75 degC and an H2O2:DB (1.50:1) ratio produced the best epoxidation results. These high values demonstrate that the potential of chia seed oil's chemical modification to be exploited in the creation of biopolymers is much greater than that of commercially available epoxidized oils such as soybean or linseed oil. Finally, the last article examined the ways in which hydrochloric acid and brushing affected the surface quality of three flowable composite resins used for direct restoration, concluding that brushing with firm bristles straight after an acidic challenge causes two of the three flowable composite resins to have increased surface roughness. Thirty minutes after acidic aggression, brushing teeth with medium or stiff brushes had no effect on the flowable composite resins' surface quality. In conclusion, the published articles under this Special Issue represent an excellent collection of research and review articles, with cutting-edge results that promote sustainable development in the field of materials engineering. Acknowledgments I would like to thank to all researchers involved in the realization of this Special Issue (China, Malaysia, Poland, Romania, Spain, Thailand, Turkey) who dedicated their valuable time and effort. Special thanks to the reviewers for their constructive comments and thoughtful suggestions, and also to the Materials Editorial Office for their kind assistance. Conflicts of Interest The authors declare no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Abdila S.R. Abdullah M.M.A.B. Ahmad R. Burduhos Nergis D.D. Rahim S.Z.A. Omar M.F. Sandu A.V. Vizureanu P. Syafwandi Potential of Soil Stabilization Using Ground Granulated Blast Furnace Slag (GGBFS) and Fly Ash via Geopolymerization Method: A Review Materials 2022 15 375 10.3390/ma15010375 35009521 2. Tahir M.F.M. Abdullah M.M.A.B. Rahim S.Z.A. Mohd Hasan M.R. Sandu A.V. Vizureanu P. Ghazali C.M.R. Kadir A.A. Mechanical and Durability Analysis of Fly Ash Based Geopolymer with Various Compositions for Rigid Pavement Applications Materials 2022 15 3458 10.3390/ma15103458 35629485 3. Hui-Teng N. Cheng-Yong H. Yun-Ming L. Abdullah M.M.A.B. Rojviriya C. Razi H.M. Garus S. Nabialek M. Sochacki W. Abidin I.M.Z. Preparation of Fly Ash-Ladle Furnace Slag Blended Geopolymer Foam via Pre-Foaming Method with Polyoxyethylene Alkyether Sulphate Incorporation Materials 2022 15 4085 10.3390/ma15124085 35744142 4. Nicula L.M. Corbu O. Ardelean I. Sandu A.V. Iliescu M. Simedru D. Freeze-Thaw Effect on Road Concrete Containing Blast Furnace Slag: NMR Relaxometry Investigations Materials 2021 14 3288 10.3390/ma14123288 34198663 5. Mania P. Hartlieb K. Mruk G. Roszyk E. Selected Properties of Densified Hornbeam and Paulownia Wood Plasticised in Ammonia Solution Materials 2022 15 4984 10.3390/ma15144984 35888451 6. He Y. Wang K. Cao Z. Zheng P. Xiang Y. Reinforcement Analysis of an Old Multi-Beam Box Girder Based on a New Embedded Steel Plate (ESP) Strengthening Method Materials 2022 15 4353 10.3390/ma15124353 35744411 7. Hegyi A. Vermesan H. Lazarescu A.-V. Petcu C. Bulacu C. Thermal Insulation Mattresses Based on Textile Waste and Recycled Plastic Waste Fibres, Integrating Natural Fibres of Vegetable or Animal Origin Materials 2022 15 1348 10.3390/ma15041348 35207888 8. Hegyi A. Bulacu C. Szilagyi H. Lazarescu A.-V. Meita V. Vizureanu P. Sandu M. Improving Indoor Air Quality by Using Sheep Wool Thermal Insulation Materials 2021 14 2443 10.3390/ma14092443 34066814 9. Sur I.M. Micle V. Hegyi A. Lazarescu A.-V. Extraction of Metals from Polluted Soils by Bioleaching in Relation to Environmental Risk Assessment Materials 2022 15 3973 10.3390/ma15113973 35683266 10. Xiao X. Jin Y. Tan Y. Gao W. Jiang S. Liu S. Chen M. Investigation of the Effects of Roller Spreading Parameters on Powder Bed Quality in Selective Laser Sintering Materials 2022 15 3849 10.3390/ma15113849 35683145 11. Ramli M.I.I. Salleh M.A.A.M. Sandu A.V. Amli S.F.M. Said R.M. Saud N. Abdullah M.M.A.B. Vizureanu P. Rylski A. Chaiprapa J. Influence of 1.5 wt.% Bi on the Microstructure, Hardness, and Shear Strength of Sn-0.7Cu Solder Joints after Isothermal Annealing Materials 2021 14 5134 10.3390/ma14185134 34576358 12. Zurowski R. Tryznowski M. Gurgen S. Szafran M. Swiderska A. The Influence of UV Radiation Aging on Degradation of Shear Thickening Fluids Materials 2022 15 3269 10.3390/ma15093269 35591603 13. Ngouoko J.J.K. Tajeu K.Y. Temgoua R.C.T. Doungmo G. Doench I. Tamo A.K. Kamgaing T. Osorio-Madrazo A. Tonle I.K. Hydroxyapatite/L-Lysine Composite Coating as Glassy Carbon Electrode Modifier for the Analysis and Detection of Nile Blue A Materials 2022 15 4262 10.3390/ma15124262 35744321 14. Dominguez-Candela I. Lerma-Canto A. Cardona S.C. Lora J. Fombuena V. Physicochemical Characterization of Novel Epoxidized Vegetable Oil from Chia Seed Oil Materials 2022 15 3250 10.3390/ma15093250 35591583 15. Taraboanta I. Stoleriu S. Gurlui S. Nica I. Taraboanta-Gamen A.C. Iovan A. Andrian S. The Influence of Abrasive and Acidic Aggressions on the Surface Condition of Flowable Composite Resin Materials 2022 15 1000 10.3390/ma15031000 35160942 |
J Clin Med J Clin Med jcm Journal of Clinical Medicine 2077-0383 MDPI 10.3390/jcm12051928 jcm-12-01928 Editorial Advances and Clinical Outcomes in Hodgkin Lymphoma in the Era of Novel Therapies Paviglianiti Annalisa 12* Rampi Nicolo 13 1 Clinical Hematology Department, Institut Catala d'Oncologia-Hospitalet, 08908 Barcelona, Spain 2 Institut d'Investigacio Biomedica de Bellvitge (IDIBELL), 08908 Barcelona, Spain 3 Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy * Correspondence: [email protected] 01 3 2023 3 2023 12 5 192821 2 2023 26 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). This research received no external funding. pmcHodgkin lymphoma (HL) is traditionally considered one of the hematological malignancies with the highest rate of cure, ranging from 70 to 90% depending on the disease and patient features. Along with the role of positron emission tomography (PET), therapeutical regimens are progressively shaped by the progressive clinical use of novel targeted agents. The anti-CD30 antibody-drug conjugate brentuximab vedotin (BV) has completely revolutionized the treatment of refractory/relapsed (R/R) HL . After the results of the AETHERA trial, consolidation with BV before and after autologous stem cell transplantation became the standard of care in high-risk patients . Subsequently, BV use in combination with other drugs was further reported in relapse and in frontline settings in advanced-stage disease with encouraging results for both progression-free and overall survival. Beside BV, checkpoint inhibitors (CPIs) such as nivolumab and pembrolizumab have drastically changed the treatment of HL. CPIs have proven to be very effective at disease control for heavily pretreated patients and have a relatively well-tolerated profile. In the NIVAHL trial, at the most recent 3-year follow-up update, a progression-free survival of around 100% was registered when nivolumab was given sequentially or combined with chemotherapy in early-stage unfavorable HL . Similar results were obtained when pembrolizumab was associated with gemcitabine, vinblastine and liposomal doxorubicine in an R/R setting, demonstrating that it is a feasible and well-tolerated bridging therapy in transplant situations . A phase 1-2 study with nivolumab and BV as first salvage therapy was proposed by Advani et al., demonstrating impressive results in a chemo-free setting . As checkpoint inhibitors were originally studied in BV-failure settings in particular, many questions were raised around their early use due to their efficacy. A head-to-head comparison between pembrolizumab and BV was therefore performed, showing the superiority of the former in terms of disease control . The most refractory patients, including those requiring multiple lines of therapy to achieve a response or those relapsing after an autologous hematopoietic cell transplantation (HCT), may achieve long-term survival with allogeneic HCT . For patients who are refractory to chemotherapy and show progression after CPI-containing regimens, there is no standard of care. Enrollment in clinical trials is advised to achieve disease response prior to allogeneic HCT. Given the progress of chimeric antigen receptor T-cell (CAR-T) therapy, there are several ongoing trials involving CD30-directed CAR-T in cHL (RELY-30, CHARIOT) and preclinical investigations into bispecific antibodies. Substantial progress has been made in the last decade in the management of HL and in terms of our knowledge of its biology, but the treatment of R/R disease is still challenging. Through this Special Issue, we hope to offer an overview of the advances and clinical outcomes in the modern era. Author Contributions A.P. conceptualizes the invited Editorial. A.P. revised the original draft preparation. N.R. writes the manuscript. All authors have read and agreed to the published version of the manuscript. Conflicts of Interest The authors declare no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Younes A. Gopal A.K. Smith S.E. 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Molecules Molecules molecules Molecules 1420-3049 MDPI 10.3390/molecules28052118 molecules-28-02118 Editorial Potential Anti-SARS-CoV-2 Molecular Strategies Vicidomini Caterina Roviello Giovanni N. * Institute of Biostructures and Bioimaging, Italian National Council for Research (IBB-CNR), Area di Ricerca Site and Headquarters, Via Pietro Castellino 111, 80131 Naples, Italy * Correspondence: [email protected] 24 2 2023 3 2023 28 5 211820 2 2023 22 2 2023 22 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). Finding effective antiviral molecular strategies was a main concern in the scientific community when the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged at the end of 2019 as an easily transmissible and potentially deadly b-coronavirus able to cause the coronavirus disease 19 (COVID-19), which famously led to one of the most worrying pandemics in recent times. Other members of this zoonotic pathogenic family were already known before 2019, but apart from the SARS-CoV, which was responsible of severe acute respiratory syndrome (SARS) pandemic in 2002/2003, and Middle East respiratory syndrome coronavirus (MERS-CoV), whose main impact on humans is geographically restricted to Middle Eastern countries, the other human b-coronaviruses known at that time were those typically associated with common cold symptoms which had not led to the development of any specific prophylactic or therapeutic measures. Although SARS-CoV-2 and its mutations are still causing illness in our communities, COVID-19 is less deadly than before and we are returning to normality. Overall, the main lesson learnt after the past few years of pandemic is that keeping our bodies healthy and immunity defenses strong using sport, nature-inspired measures, and using functional foods are powerful weapons for preventing the more severe forms of illness caused by SARS-CoV-2 and, from a more molecular perspective, that finding drugs with mechanisms of action involving biological targets conserved within the different mutations of SARS-CoV-2 and possibly within the entire family of b-coronaviruses gives more therapeutic opportunities in the scenario of future pandemics based on these pathogens. In this regard, the main protease (Mpro), having no human homologues, offers a lower risk of off-target reactivity and represents a suitable therapeutic target in the search for efficacious, broad-spectrum anti-b-coronavirus drugs. Herein, we discuss on the above points and also report some molecular approaches presented in the past few years to counteract the effects of b-coronaviruses, with a special focus on SARS-CoV-2 but also MERS-CoV. pmc1. Molecules against b-Coronaviruses It is well known that the coronavirus disease 19 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused enormous sanitary and socio-economic difficulties to the entire world due to the high transmission rates of the virus, the lack of effective treatments available when it first emerged, and the rapid genetic mutations of the virus observed in recent years. Among the biomolecules crucial for the viral processes, the spike protein is a key structural protein that mediates host infection by SARS-CoV-2, with the structure of the N-terminal signal peptide of this SARS-CoV-2 protein having an effect on the synthesis and secretion of the spike, which suggests that developing drugs which target the signaling peptide of the spike could be a winning anti-COVID-19 strategy . Moreover, studies conducted on the S1 subunit of this protein have revealed the inactivation abilities of ozonated water and slightly acidic electrolyzed water and ethanol, and these were proposed as effective as SARS-CoV-2 disinfectants . Another relevant SARS-CoV-2 protein target is nucleoprotein, also known as protein N or nucleocapsid protein, an abundant RNA-binding protein critical for viral genome packaging and essential for the replication machinery of SARS-CoV-2 . It is a potential link between viral replication and the multiple signaling pathways which lead to long-lasting COVID-19 symptoms, and new ligands of the protein N were investigated by computational and experimental studies based on dynamic light scattering and surface plasmon resonance, which led to the identification of substance P(1-7) and enkephalins as effective binders of the major sites at the C-terminus or of b-sheets at the N-terminus of the viral protein. These studies led to the conclusion that antiviral drugs that target N can contribute to reducing brain fog and stroke risk and improving COVID-19 patient well-being . One of the most widely explored strategies for lowering virus transmission and disease severity has been COVID-19 vaccination. Vaccines are a powerful weapon which can be used to prevent the worrying scenarios caused by a number of pathogens , and have been widely employed in the form of mass vaccination during the COVID-19 pandemic. Sadly, COVID-19 vaccines are not exempt from side effects, including, in some cases, thrombotic thrombocytopenia syndrome, which led to some specific COVID-19 vaccines being discouraged regarding their use in younger individuals . Remarkably, vaccination responses vary significantly depending on the host, even though correlations with protection against SARS-CoV-2 were reported . However, despite vaccinations, the recurrence of SARS-CoV-2 infection was frequently observed also in vaccinated individuals, while disease can still severely affect elderly and hospitalized patients who are fragile and vulnerable, which recalls the need for new efforts to be devoted to the discovery of potential global therapeutics, utilizable in the context of the infections of new mutations of SARS-CoV-2, but possibly also of other human b-coronaviruses. COVID-19 causes widespread respiratory and non-respiratory symptoms and, regardless of the underlying comorbid conditions, early treatment of COVID-19 has the potential to positively affect the clinical course of the disease. Moreover, even after the virus has been eradicated, the previous SARS-CoV-2 interaction with host cell receptors and consequent activation of pro-inflammatory pathways may still be responsible for endothelial and epithelial damage mechanisms. In this context, anti-inflammatory treatments, such as steroidal and non-steroidal drugs, as well as cytokine inhibitors, have been suggested in the treatment of COVID-19 patients, since inflammation treatment has been identified as a crucial step in the recovery process . The complications observed in COVID-19 patients are numerous, especially in cases of the more severe forms of the diseases. For example, a strong correlation between the impaired renal function and in-hospital deaths of critically ill COVID-19 patients, particularly those with comorbidities and requiring renal replacement therapy, has been supported by data from numerous intensive care units around the world . The common renal disorder known as acute kidney injury, characterized by a sudden and persistent decline in renal function, is sometimes experienced by COVID-19 patients during their hospitalization, with a significant impact on their survival. Catechins were also found to be effective therapeutics in COVID-19-associated acute kidney injury thanks to their wide range of pharmacological effects, which included anti-coronavirus, antioxidant, anti-inflammatory, and renoprotective effects against kidney damage . More geographically confined than SARS-CoV-2, but also much more deadly, Middle East respiratory syndrome coronavirus (MERS-CoV) is another highly pathogenic zoonotic b-coronavirus, first discovered in patients living in the Arabian Peninsula in September 2012, that has an unusually high fatality rate in humans and causes severe, frequently fatal respiratory illness . Natural products were investigated as MERS drugs using approaches employing quantum mechanics calculations, pharmacophore-based virtual screening, and molecular dynamics simulations, revealing the potential of compounds such as taiwanhomoflavone B, 2,3-dihydrohinokiflavone, and sophoricoside as effective natural anti-MERS-CoV candidates . 2. Drug Repositioning Drug repositioning using previously FDA-approved drugs is a strategy typically employed when a new pathogen emerges in the attempt to treat patients who need urgent cures while waiting for more specific therapies to be developed, which clearly takes a longer time. This was especially true in the context of COVID-19, regarding which countless studies, often based on computational approaches using molecular docking and molecular dynamics simulations, were conducted on different molecular targets of SARS-CoV-2, including the papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp), and SARS-CoV-2 main protease (Mpro), to name only a few. This led to the identification of salinomycin from Streptomyces albus as a potential inhibitor of SARS-CoV-2 PLpro, while the vegetal toxin ouabain was proposed as a dual inhibitor of the PLpro and Mpro enzymes . By screening 171 candidates obtained from the DrugBank database accessed on 17 February 2023), other in silico studies identified possible organic triazole compounds such as bemcentinib, and bisoctrizole, as Mpro inhibitors whose pharmacokinetic characteristics were also evaluated, and their complex stability and conformation were examined using molecular dynamics simulation . Non-steroidal anti-inflammatory drugs, which are frequently used to treat upper airway infections symptomatically, are of crucial importance when administered in the early stages of SARS-CoV-2 infection and, in this context, ketoprofen lysine salt is a non-steroidal anti-inflammatory drug which was suggested to offer notable benefits in early COVID-19 therapy, based on the pharmacodynamic and pharmacokinetic characteristics of this drug . 3. Nature against b-Coronaviruses Since nature is an inexhaustible source of remedies and therapeutic scaffolds, new potential drugs to be used in the fight against COVID-19 were often searched for from natural sources, especially plants , using highly diverse approaches such as transcriptomics, cheminformatics, and systems pharmacology with a holistic view . Natural inhibitors of SARS-CoV-2 nonstructural protein (nsp10) were screened from a database containing 310 naturally isolated metabolites through various in silico selection methods including molecular similarity assessment, molecular fingerprint, docking studies, toxicity, ADMET (absorption, distribution, metabolism, excretion, and toxicity), and density-functional theory . Polyphenol-rich tea leaf extracts containing concentrated theaflavins and several virucidal catechins were tested for their ability to inactivate SARS-CoV-2 in cellular studies and the virus structural proteins and viral RNA were also examined using Western blotting and real-time RT-PCR to assess the effects of the tea leaf extracts on viral proteins and the viral genome. Remarkably, cellular infection by SARS-CoV-2 was prevented by the treatment using natural preparations, which, from a molecular point of view, caused structural changes of the S2 subunit of the spike protein and damages to the viral genome, giving clues to the potential efficacy of tea leaf extracts as virucidal agents in vitro, which could improve the existing control measures adopted against b-coronaviruses . In the context of the application of traditional and herbal medicine to the therapy and prevention of infections caused by b-coronaviruses, we have suggested the anti-COVID-19 effects of cloves (Syzygium aromaticum L.). This is a culinary spice with a long history of use in folk medicine for a variety of disorders, being used in traditional medicine to treat respiratory ailments since ancient times. Among its molecular ingredients, different clove phytochemicals have antiviral, anti-inflammatory, antibacterial, immunostimulatory, and antithrombotic properties, all useful aspects in the context of developing an effective anti-COVID-19 therapy . In conclusion, more research on COVID-19 therapies making use of synthetic and natural molecules and their derivatives is unquestionably required. In fact, the scientific efforts regarding both therapy and the prophylaxis of b-coronavirus diseases should not be discontinued even if currently COVID-19 appears to be less deadly, because SARS-CoV-2 could re-emerge with more pathogenic variants and, moreover, it is not unlikely that, with the increased rate of human-wildlife contact due to the loss of intact ecosystems and forested areas, new zoonoses caused by b-coronaviruses will continue to emerge, and humanity could have to face new pandemics in the near future. Acknowledgments Caterina Vicidomini and Giovanni N. Roviello, who served as Guest Editors for the Special Issue 'Potential Anti-SARS-CoV-2 Molecular Strategies' of Molecules, are grateful to all the authors for their contributions and to all the expert reviewers involved in the Special Issue. Author Contributions C.V. and G.N.R. have contributed equally to this work. All authors have read and agreed to the published version of the manuscript. Conflicts of Interest The authors declare no conflict of interest. Figure 1 Structural representation of some of the drugs investigated as anti-COVID-19 therapeutics mentioned in this work. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Zhang Z. Wan X. Li X. Wan C. 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Materials (Basel) Materials (Basel) materials Materials 1996-1944 MDPI 10.3390/ma16051924 materials-16-01924 Editorial New Materials and Techniques for Orthodontics Sfondrini Maria Francesca * Scribante Andrea * Unit of Orthodontics and Paediatric Dentistry, Section of Dentistry, Department of Clinical, Surgical, Diagnostic and Paediatric Sciences, University of Pavia, 27100 Pavia, Italy * Correspondence: [email protected] (M.F.S.); [email protected] (A.S.) 25 2 2023 3 2023 16 5 192418 2 2023 22 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). pmcOrthodontics is a specialty of dentistry dealing with the prevention, diagnosis, and treatment of mispositioned jaws and teeth. Orthodontic fixed therapy aims to reposition the patient's teeth with specific appliances, usually brackets and wires. In order to ensure that correct treatment is provided, the bonding between the bracket and the enamel should be strong enough to support masticatory and shear forces. In fact, bracket failure is a frequent clinical concern in orthodontics both for the clinician and the patient. Accordingly, many efforts have been made by researchers in the last few years to improve bonding strategies as well as to test new innovative materials for clinical use with improved chemical and mechanical properties. For instance, the current Special Issue entitled "New Materials and Techniques for Orthodontics" has been developed following on from the Special Issue entitled "Orthodontic Materials and Adhesive Interfaces". In the first Special Issue, the use of a universal adhesive in total-etch mode was tested both in vitro and in vivo for the bonding of orthodontic fixed retainers, resulting in a good alternative to traditional orthodontic primers considering both shear bond strength (SBS) and the adhesive remnant index (ARI) . Moreover, a fluoride release/rechargeable LiAl-F layered double hydroxide (LDH-F) orthodontic resin was tested for SBS and thermal cycling and resulted in better outcomes when compared to a control adhesive . Further mechanical properties which have been tested for adhesives are represented by creep, hardness, and elastic moduli . Finally, research on experimental orthodontic adhesives has been conducted to develop new products with antibacterial and remineralizing properties . In addition to the study of orthodontic adhesives, research has also focused on bonding techniques, such as the indirect bonding technique , and the enamel surface roughness after lingual bracket debonding . Moreover, other orthodontic materials have been the topic of extensive research. For instance, a glass ionomer cement modified using phytomedicine was proposed for its antibacterial properties, and it was tested as regards to its flexural strength, water sorption, and solubility . Different composite materials have even been tested considering the correct reproduction of attachment shape and position . The study of interface design and surface treatments also represents a relevant topic in the biomedical field, including orthodontics. A review was conducted to underline the antibacterial applications and mechanisms of metallic agents in both dentistry and orthopedics, indicating that much work still needs to be carried out to deepen our understanding of the antibacterial mechanisms and potential side-effects of metallic agents . Biological interactions between the mouth and exogenous materials have also been studied considering the behavior of human oral epithelial cells grown in contact with aligners, with the latter showing no cytotoxicity . The physical properties of orthodontic materials have been also evaluated in different studies. In particular, the mean shearing stroke frequency of different orthodontic bracket types and bonding agents under cycling loading was evaluated with the study in question showing that brackets of different types can be applied with different bonding techniques and that, in order to minimize the risk of hard tissue damage, ceramic brackets should be carefully bonded using the self-etching primary adhesive technique . The compositional, microstructural, and mechanical characteristics of Ni-free orthodontic wires were compared to those of conventional stainless steel ones and they demonstrated similar properties thus making the former a promising alternative for patients with Ni supersensitivity . Arch friction with conventional and self-ligating brackets has also been investigated, with higher static friction values being shown for conventional brackets . One of the latest research topics in orthodontics with relevant clinical implications is represented by the effect of magnetic resonance imaging (MRI) and its effects on metallic brackets and wires. One study showed that, under MRI, orthodontic appliances present a low-temperature rise and no debonding risk, thus they are not recommended for the routine preventive removal of orthodontic appliances; the results instead suggested that this procedure be used only in the case of a void risk or potential interference in image quality . In the current Special Issue, the included research topics are related to bacteriostatic coating for mini-implants , a 3D-printed orthodontic distalizer for unilateral class II treatment , and a retraction spring made of a new low elastic modulus material . On the basis of these considerations, the authors would like to thank all of the clinicians and researchers who contributed relevant manuscripts to this Special Issue. In addition, the authors would also like to draw attention to future perspectives for further research. In particular, testing new, innovative materials for orthodontic use with remineralizing properties would certainly be of high impact; therefore, morphological and chemical studies would be welcomed . The introduction of additional CAD/CAM 3D-printing materials and the evaluation of their clinical applicability in orthodontics would also be an interesting topic in the era of digital dentistry . In addition, further studies on the metallurgical , bonding , flexural , mechanical , and biocompatibility characteristics of different orthodontic biomaterials would also be welcomed in the future. Finally, the importance of the recent introduction of artificial intelligence would be an interesting future research perspective as well. Author Contributions The authors equally contributed to this work. All authors have read and agreed to the published version of the manuscript. Conflicts of Interest The authors declare no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Sfondrini M.F. Gallo S. Turcato B. Montasser M.A. Albelasy N.F. Vallittu P.K. Gandini P. Scribante A. Universal Adhesive for Fixed Retainer Bonding: In Vitro Evaluation and Randomized Clinical Trial Materials 2021 14 1341 10.3390/ma14061341 33802135 2. Hung C.Y. Yu J.H. Su L.W. Uan J.Y. Chen Y.C. Lin D.J. Shear Bonding Strength and Thermal Cycling Effect of Fluoride Releasable/Rechargeable Orthodontic Adhesive Resins Containing LiAl-F Layered Double Hydroxide (LDH) Filler Materials 2019 12 3204 10.3390/ma12193204 31574919 3. Hassan M.A. Zinelis S. Hersberger-Zurfluh M. Eliades T. Creep, Hardness, and Elastic Modulus of Lingual Fixed Retainers Adhesives Materials 2019 12 646 10.3390/ma12040646 30795503 4. Ferreira C.J. Leitune V.C.B. Balbinot G.S. Degrazia F.W. Arakelyan M. Sauro S. Mezzomo Collares F. Antibacterial and Remineralizing Fillers in Experimental Orthodontic Adhesives Materials 2019 12 652 10.3390/ma12040652 30795577 5. Nawrocka A. Lukomska-Szymanska M. The Indirect Bonding Technique in Orthodontics A Narrative Literature Review Materials 2020 13 986 10.3390/ma13040986 32098359 6. Eichenberger M. Iliadi A. Koletsi D. Eliades G. Verna C. Eliades T. Enamel Surface Roughness after Lingual Bracket Debonding: An In Vitro Study Materials 2019 12 4196 10.3390/ma12244196 31847233 7. Singer L. Bierbaum G. Kehl K. Bourauel C. 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Mean Shearing Stroke Frequency of Orthodontic Brackets under Cycling Loading: An In Vitro Study Materials 2020 13 4280 10.3390/ma13194280 32992817 12. Brungger D. Koutsoukis T. SAl Jabbari Y. Hersberger-Zurfluh M. Zinelis S. Eliades T. A Comparison of the Compositional, Microstructural, and Mechanical Characteristics of Ni-Free and Conventional Stainless Steel Orthodontic Wires Materials 2019 12 3424 10.3390/ma12203424 31635055 13. Moyano J. Mases L. Izeta T. Flores T. Fernandez-Bozal J. Gil J. Puigdollers A. "In Vitro" Study About Variables that Influence in Arch Friction with Conventional and Self-Ligating Brackets Materials 2019 12 3279 10.3390/ma12203279 31600912 14. Sfondrini M.F. Preda L. Calliada F. Carbone L. Lungarotti L. Bernardinelli L. Gandini P. Scribante A. Magnetic Resonance Imaging and Its Effects on Metallic Brackets and Wires: Does It Alter the Temperature and Bonding Efficacy of Orthodontic Devices? Materials 2019 12 3971 10.3390/ma12233971 31801202 15. Rodriguez-Fernandez J.C. Pastor F. Barrera Mora J.M. Brizuela A. Puigdollers A. Espinar E. Gil F.J. Bacteriostatic Poly Ethylene Glycol Plasma Coatings for Orthodontic Titanium Mini-Implants Materials 2022 15 7487 10.3390/ma15217487 36363077 16. Thurzo A. Urbanova W. Novak B. Waczulikova I. Varga I. Utilization of a 3D Printed Orthodontic Distalizer for Tooth-Borne Hybrid Treatment in Class II Unilateral Malocclusions Materials 2022 15 1740 10.3390/ma15051740 35268969 17. Tamaya N. Kawamura J. Yanagi Y. Tooth Movement Efficacy of Retraction Spring Made of a New Low Elastic Modulus Material, Gum Metal, Evaluated by the Finite Element Method Materials 2021 14 2934 10.3390/ma14112934 34072377 18. Butera A. Pascadopoli M. Gallo S. Lelli M. Tarterini F. Giglia F. Scribante A. 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Sfondrini M.F. Lena A. Vallittu P.K. Lassila L.V. Force levels of fiber-reinforced composites and orthodontic stainless steel wires: A 3-point bending test Am. J. Orthod. Dentofac. Orthop. 2008 133 410 413 10.1016/j.ajodo.2006.01.047 18331941 23. Elayyan F. Silikas N. Bearn D. Ex Vivo surface and mechanical properties of coated orthodontic archwires Eur. J. Orthod. 2008 30 661 667 10.1093/ejo/cjn057 19011166 24. House K. Sernetz F. Dymock D. Sandy J.R. Ireland A.J. Corrosion of orthodontic appliances-should we care? Am. J. Orthod. Dentofac. Orthop. 2008 133 584 592 10.1016/j.ajodo.2007.03.021 25. Monill-Gonzalez A. Rovira-Calatayud L. d'Oliveira N.G. Ustrell-Torrent J.M. Artificial intelligence in orthodontics: Where are we now? A scoping review Orthod. Craniofac. Res. 2021 24 6 15 10.1111/ocr.12517 34270881 |
J Clin Med J Clin Med jcm Journal of Clinical Medicine 2077-0383 MDPI 10.3390/jcm12051853 jcm-12-01853 Editorial COVID-19 and Biomarkers: The Contribution of the Journal Plebani Mario 12 1 Clinical Biochemistry and Clinical Molecular Biology, University of Padova, 35122 Padova, Italy; [email protected] 2 Department of Pathology, University of Texas, Medical Branch, Galveston, TX 77550, USA 26 2 2023 3 2023 12 5 185322 2 2023 24 2 2023 (c) 2023 by the author. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). pmcThree years after coronavirus disease 2019 (COVID-19) was declared a pandemic by the World Health Organization (WHO), several features of the pathogenesis and innate immune response to SARS-CoV-2 (severe acute respiratory syndrome coronavirus disease 2) have now been clarified. Several studies have highlighted the crucial interplay among inflammation, thrombosis, cardiovascular diseases, multi-visceral manifestations, and SARS-CoV-2 infection, namely, linking the roles of cytokines, neutrophil extracellular traps (NETs), nucleosomes, histones, and the coagulation cascade. Although dramatic improvements have been achieved in better understanding the pathophysiology of the disease, the mechanisms of innate immune response and more appropriate therapeutic treatments, reliable and accurate biomarkers for the early risk stratification and clinical management of COVID-19 patients are still lacking. A series of papers recently published in the Journal have provided new insights into some interesting and potentially useful biomarkers in COVID-19. The first paper is by Simon T-P et al., who evaluated the prognostic value of bioactive adrenomedullin (bio-ADM) in critically ill patients with COVID-19. The rationale of the study, as underlined by the authors, is that "endothelial cell infection, inflammation and activation with the subsequent interruption of endothelial barrier function have been described in COVID-19 patients and adrenomedullin (ADM) has been shown to play a key role in regulating vascular and endothelial stability/integrity in patients with severe infection" . Adrenomedullin (ADM) is a free-circulating 52 amino-acid peptide belonging to the calcitonin gene-related peptide family that was first discovered in human pheochromocytoma tissue three decades ago . Since its discovery in 1993, ADM has been implicated in the pathobiology of several diseases, including cardiovascular disorders, systemic inflammatory responses, sepsis, and septic shock . The interpretation of ADM as a biomarker is difficult because several fragments of the precursor prohormone circulate in blood and do not necessarily reflect the activity of ADM. Several assays for measuring ADM have been described, but they were found to be unreliable, being influenced by the ADM-binding protein (complement factor H) and suffering from the instability of the protein (ADM) . To circumvent previously reported problems with the measurement of ADM, midregional pro-adrenomedullin (MR-proADM) assays have been developed and described as an alternative surrogate marker . Due to the different biological backgrounds, both ADM and mid-regional MR-proADM are derived from the same precursor (pro-ADM), but their stoichiometric relationship is imperfect, as ADM requires a C-terminal amidation to become biologically active adrenomedullin (bio-ADM). Only the amidated-ADM variant, in fact, may bind to its receptor with high affinity and efficiently induce the cAMP formation and related biological activities . However, the C-terminal amidation process occurs only partially and to a varying extent. In addition, the clearance kinetics of bio-ADM and MR-proADM may differ. Taken together, it seems conceptually preferable to measure bio-ADM rather than other derivatives of the ADM precursor peptide and, therefore, in 2017, Weber et al. developed a sandwich immunoassay for bioactive plasma adrenomedullin which has been found to be accurate and reliable and has an analytical sensitivity high enough to be detectable in subjects and patients with various acute inflammatory disorders, including sepsis . The data reported in the paper by Simon et al. show an association between the bio-ADM levels at ICU admission and the severity of acute respiratory distress syndrome (ARDS) in patients suffering from COVID-19, indicating a central role of bio-ADM in the pathology of COVID-19-induced pulmonary injury. In addition, the data highlight the potential of bio-ADM to identify patients in need of invasive ventilation during the ICU stay, as patients with invasive ventilation revealed significantly increased levels of bio-ADM at ICU admission. Furthermore, bio-ADM plasma values were closely related to the need for venovenous extracorporeal membrane oxygenation (ECMO) therapy and renal replacement therapy (RRT) . A second article by Ligi et al. deals with the role of circulating histones in COVID-19 . Histones (i.e., positively charged multifunctional nuclear proteins) are key components in chromatin functions, which bind to the nucleosomal core particle around the DNA entry and exit sites. These intriguing molecules may be significantly released in bodily fluids during several targeted organ injuries (e.g., thrombosis, cancer, sepsis, etc.), thus mediating inflammatory pathways and coagulative cascade crucially linked to the severity and mortality of many human pathologies. More recently, they have been reported to be a novel biomarker, which could assist risk stratification in patients with COVID-19 and may serve as a predictive factor for cardiac and lung injury/dysfunction. In addition, they are useful for the individual management of anticoagulant/anti-platelet therapy. The data provided in the already-cited paper, moreover, suggest "the urgent need to clinically evaluate the beneficial role of histone-neutralizing therapy by focused trials involving the interesting roles of polyanionic compounds as potential additional strategy for protecting tissues and organs from inflammatory, cytotoxic and procoagulant effects of circulating histones, implicated in myriad histone-accelerated disease states, and in COVID-19 complications" . A third paper deals with the role of circulating soluble ST2 (sST2) in COVID-19 . Interleukin-1 receptor-like-1 (IL1RL1), also known as the suppression of tumorigenicity 2 (ST2), is a member of the interleukin (IL)-1 receptor family, with two main isoforms, a transmembrane cellular (ST2L) and a circulating soluble form (sST2). ST2 is the receptor for IL-33, a cytokine released by cells in response to cell damage or stress ('alarmin'). IL-33 binding to ST2L elicits a pleiotropic action. It is well established that the IL-33/ST2 axis exhibits a cardioprotective role, reducing fibrosis, cardiomyocyte hypertrophy, and apoptosis and improving myocardial function . In their paper, Sanchez-Marteles et al. demonstrated that "admission sST2 values correlate well with biochemical markers and indexes being used to evaluate the clinical course in COVID-19". Indeed, multivariate regression models and survival analysis demonstrated that admission sST2 is an independent predictor of worse prognosis in patients admitted for COVID-19. In ROC analysis, the sensitivity and specificity of sST2 to predict worse outcomes were significantly higher than that of the aforementioned biomarkers . A unique aspect of the study is "the demonstration that early changes predict outcome better than peak values, stressing their clinical usefulness in prognosis" . Moreover, sST2 showed a decline in patients at discharge which correlates with hospital stay lengths, displaying a fully dynamic behavior that is not present with other biomarkers. Another paper published in the journal is about the muscular enzyme creatine (phospho)-kinase (CK/CPK) in patients suffering from COVID-19. The CK levels at admission were higher in those subjects who later experienced more severe outcomes (median, 126; range, 10-1672 U/L, versus median, 82; range, 12-1499 U/L, p = 0.01), and values > 200 U/L (hyperCKemia) were associated with a worse prognosis. Regression analysis confirmed that increased CK acted as an independent predictor for a "severe" outcome. HyperCKemia was generally transient, returning to normal during hospitalization in the majority of both "severe" and "mild" patients . The study design did not allow the authors to understand if increased CK levels in COVID-19 patients are caused by true myopathic damage, as muscle pain and fatigue are common in both mild and severe cases . Further studies are, therefore, needed to better understand the pathophysiology of increased release of CK and other muscular enzymes (e.g., aldolase). On the one hand, these papers highlight the formidable advancements in our knowledge of the pathophysiological mechanisms of COVID-19 and the role of innovative biomarkers in risk stratification and disease prognostication. One the other hand, they reinforce the need for further translational research studies to appropriately use these biomarkers in clinical practice to ultimately improve patient care. Conflicts of Interest The author declares no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Simon T.-P. Stoppe C. Breuer T. Stiehler L. Dreher M. Kersten A. Kluge S. Karakas M. Zechendorf E. Marx G. Prognostic Value of Bioactive Adrenomedullin in Critically Ill Patients with COVID-19 in Germany: An Observational Cohort Study J. Clin. Med. 2021 10 1667 10.3390/jcm10081667 33924637 2. Kitamura K. Kangawa K. Kawamoto M. Ichiki Y. Nakamura S. Matsuo H. Eto T. Adrenomedullin: A Novel Hypotensive Peptide Isolated from Human Pheochromocytoma Biochem. Biophys. Res. Commun. 1993 192 553 560 10.1006/bbrc.1993.1451 8387282 3. Wang P. Adrenomedullin in sepsis and septic shock Shock 1998 10 383 384 10.1097/00024382-199811000-00013 9840656 4. Lewis L.K. Smith M.W. Yandle T.G. Richards A.M. Nicholls M.G. Adrenomedullin (1-52) measured in human plasma by radi-oimmunoassay: Plasma concentration, adsorption, and storage Clin. Chem. 1998 44 571 577 10.1093/clinchem/44.3.571 9510864 5. Morgenthaler N.G. Struck J. Alonso C. Bergmann A. Measurement of midregional proadrenomedullin in plasma with an im-munoluminometric assay Clin. Chem. 2005 51 1823 1829 10.1373/clinchem.2005.051110 16099941 6. Ohta H. Tsuji T. Asai S. Tanizaki S. Sasakura K. Teraoka H. Kitamura K. Kangawa K. A simple immunoradiometric assay for measuring the entire molecules of adrenomedullin in human plasma Clin. Chim. Acta 1999 287 131 143 10.1016/S0009-8981(99)00128-X 10509902 7. Weber J. Sachse J. Bergmann S. Sparwasser A. Struck J. Bergmann A. Sandwich Immunoassay for Bioactive Plasma Adreno-medullin J. Appl. Lab. Med. 2017 2 222 233 10.1373/jalm.2017.023655 32630976 8. Ligi D. Maniscalco R. Plebani M. Lippi G. Mannello F. Do Circulating Histones Represent the Missing Link among COVID-19 Infection and Multiorgan Injuries, Microvascular Coagulopathy and Systemic Hyperinflammation? J. Clin. Med. 2022 11 1800 10.3390/jcm11071800 35407410 9. Shaw R.J. Abrams S.T. Austin J. Taylor J.M. Lane S. Dutt T. Downey C. Du M. Turtle L. Baillie J.K. Circulating histones play a central role in COVID-19-associated coagulopathy and mortality Haematologica 2021 106 2493 2498 10.3324/haematol.2021.278492 33832219 10. Sanchez-Marteles M. Rubio-Gracia J. Pena-Fresneda N. Garces-Horna V. Gracia-Tello B. Martinez-Lostao L. Crespo-Aznarez S. Perez-Calvo J.I. Gimenez-Lopez I. Early Measurement of Blood sST2 Is a Good Predictor of Death and Poor Outcomes in Patients Admitted for COVID-19 Infection J. Clin. Med. 2021 10 3534 10.3390/jcm10163534 34441830 11. Villacorta H. Maisel A.S. Soluble ST2 Testing: A Promising Biomarker in the Management of Heart Failure Arq. Bras. Cardiol. 2016 106 145 152 10.5935/abc.20150151 26761075 12. Orsucci D. Trezzi M. Anichini R. Blanc P. Barontini L. Biagini C. Capitanini A. Comeglio M. Corsini P. Gemignani F. Increased Creatine Kinase May Predict a Worse COVID-19 Outcome J. Clin. Med. 2021 10 1734 10.3390/jcm10081734 33923719 |
J Clin Med J Clin Med jcm Journal of Clinical Medicine 2077-0383 MDPI 10.3390/jcm12051873 jcm-12-01873 Editorial Clinical Advances in Kidney Failure: AKI Awad Alaa S. 1* Abdel-Rahman Emaad M. 2 1 Division of Nephrology, University of Florida, Jacksonville, FL 32209, USA 2 Division of Nephrology, University of Virginia, Charlottesville, VA 22908, USA * Correspondence: [email protected] 27 2 2023 3 2023 12 5 187306 2 2023 15 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). pmcKidney failure poses an enormous burden on patients, caregivers, healthcare providers, and society as a whole. While the etiology and management of kidney failure differ between high-income countries, epidemiological studies point to the continued increase in the numbers of patients with kidney failure worldwide. Two types of kidney failure exist: acute kidney injury (AKI) and chronic kidney disease (CKD). The current Special Issue of the Journal of Clinical Medicine, "Clinical Advances in Kidney Failure", is mainly focused on AKI. Despite the vast range of literature focusing on AKI, several gaps still exist pertaining to the optimum care of AKI patients. The diverse etiologies, mechanisms, settings, and outcomes of AKI pose a challenge to the unified, standardized, and optimum management of these patients. A step-by-step review of AKI, from prevention of the disease to its etiology, pathogenesis, diagnosis, and management, needs to be routinely updated to identify opportunities and hopefully provide suggestions to bridge these gaps. Novel therapeutic interventions for preventing or attenuating renal tissue injury following AKI remain a focus of significant interest. AKI is a serious complication affecting >5-7% of hospitalized patients and is associated with a high mortality, morbidity, and increased healthcare costs . Furthermore, 26% of patients with AKI superimposed on CKD die during hospitalization, and between 42 and 63% develop end-stage kidney disease (ESKD) . The etiology and pathogenesis of AKI involve multifactorial processes including, but not limited to, renal ischemia, nephrotoxicity, volume depletion, and obstructive uropathy. In the current issue, Turget et al. highlight the different causes of AKI along with the mechanism(s) of renal injury . Several cascades initiated by AKI causing tissue injury, such as changes in renal blood flow, hypoxic cell death, adenosine triphosphate (ATP) depletion, vascular endothelial cell injury, mitochondrial dysfunction, tubular epithelial cell injury, and leukocyte recruitment, result in altered kidney homeostasis . Currently, there are no definitive therapeutic or protective approaches available for AKI. Thus, it is important to identify the mechanisms involved in the development and progression of AKI. Diagnostic criteria of AKI have been developed for the identification and monitoring of AKI. The three most commonly used criteria are KDIGO, RIFLE, and AKIN criteria . However, the diagnosis of AKI mainly relies on assessing the serum creatinine and urine output. Neither are sensitive nor timely in reporting the state of kidney damage. Kinetic eGFR, as presented in the current issue , could provide a sensitive tool in the assessment and the severity of kidney function following AKI, especially in acute-pancreatitis-induced AKI. Racial disparities in the clinical outcomes of several health conditions are very common, especially in AKI patients, as Black patients have a higher risk of AKI compared to non-Black patients. Several factors account for these differences, including susceptibility to kidney injury, severity of illness, and socioeconomic factors. In this current Special Issue , the authors further explore the link between race and AKI using the incidence, diagnosis, and management of AKI to illustrate how race is directly related to AKI outcomes, with a focus on Black and White individuals with AKI. Several therapeutic targets have been proposed to offset AKI morbidity and mortality. For instance, early treatment using enzyme replacement therapy with agalsidase alfa induces renal tissue protection by reducing proteinuria in patients with Fabry disease . While early recovery of AKI can occur before discharge, mortality remains very high, especially in patients requiring dialysis during hospitalization. After discharge, AKI patients could have complete resolution of kidney injury and be diagnosed with CKD, requiring dialysis AKI, or declared ESKD. Therefore, optimum care for AKI survivors requires a multidisciplinary approach and ideally should start while patients are hospitalized. Patients should continue as outpatients, as described in detail in the current Special Issue . Care should be individualized depending on the patient's demographics, risk of recurrence, and severity of AKI. Spectra of care could include patient-centered outcomes, potential interventions, and intermediate and long-term clinical outcomes. Identifying modifiable predictors of outcomes for AKI patients requiring hemodialysis (AKI-D) will improve care and outcomes, as presented in the current Special Issue . Specifically, optimizing dialysis prescription to decrease the frequency of hypotension during dialysis, minimizing excessive ultrafiltration, and close monitoring of outpatient AKI dialysis are crucial and may improve outcomes for these patients. Whether peritoneal dialysis is an equivalent option to hemodialysis for AKI patients is not completely clear, mainly due to its limited use and limited clinical trials. In this Special Issue, Dr. S. Khan highlights the current data available on the utilization of peritoneal dialysis following AKI. In summary, the aim of this Special Issue is to highlight the recent advances pertaining to earlier diagnosis, predicting outcomes, and better management of AKI in the hospital setting and post-hospital discharge. As the Guest Editors, we sincerely appreciate and thank the reviewers for their insightful remarks and the JCM team's support. We also heartily thank all of the contributing authors for their valuable contributions. Conflicts of Interest The authors declare no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). 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Materials (Basel) Materials (Basel) materials Materials 1996-1944 MDPI 10.3390/ma16051900 materials-16-01900 Editorial Special Issue: "Feature Papers in Materials Simulation and Design" Bacciocchi Michele 1* Milani Abbas S. 2* 1 Dipartimento di Economia, Scienze e Diritto (DESD), University of San Marino, Via Consiglio dei Sessanta, 47891 Dogana, San Marino 2 School of Engineering, The University of British Columbia, Kelowna, BC V1V 1V7, Canada * Correspondence: [email protected] (M.B.); [email protected] (A.S.M.) 24 2 2023 3 2023 16 5 190009 2 2023 13 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). This research received no external funding. pmcThe title of the current Special Issue, "Feature Papers in Materials Simulation and Design", has identified the aims of this collection since its opening: the gathering of research works and comprehensive review papers that advance the understanding and prediction of material behavior at different scales, from atomistic to macroscopic, through innovative modeling and simulation. In this context, interdisciplinary researches that tackled challenging and complex material problems where the governing phenomena might span different scales of material behavior, with an emphasis on the development of quantitative approaches to explain and predict experimental observations, have been collected. Likewise, peculiar attention has been given to homogenization techniques for the evaluation of the mechanical properties of new materials and multi-phase composites. Innovative numerical approaches for the mechanical analysis, highlighting their accuracy, reliability, and stability features, have been also welcomed. Significant space has been also given to advanced and sustainable technologies. From the aforementioned topics, it is evident that this Special Issue has represented the ideal forum for disseminating excellent research findings, as well as sharing innovative ideas in this significant field. Throughout the several months of activity, this Special Issues has been able to attract many interesting researches. Its success is proven by the sixteen papers collected and published, which have passed through the rigorous review process carried out by experts in the field, who should be gratefully acknowledged for their efforts. An heartfelt thanks should be also given to all the authors, coming from many different countries of the world, who contributed to the success of the collection. This important achievement could be barely reached without the constant and kind support given by the Section Managing Editor, Ms. Fay Liu, who should be gratefully thanked for her dedication and commitment. Finally, the Editors-in-Chief of Materials should be also mentioned for the fantastic opportunity of managing this successful Special Issue. A brief review of the papers published in the collection is now presented as a proof of the advancements and innovations achieved in the field of materials simulation and design. Nurek et al. investigated the possibility of using forest logging residues as an alternative to plant biomass of various origins. In particular, they concluded that shredded logging residues can be used to produce briquettes. A series of test has been presented to discuss the density and compaction of the briquette, providing useful results for manufacturers. The paper by Tulska et al. has been focused on the kinematics of cone opening in the European larch (Larix decidua Mill.) during a four-step seed extraction process and to determine optimum process time on that basis, describing also the microscopic cellular structure of scales in cones for different values of moisture content. Their results have highlighted the conditions for the automation of this process. De Schryver et al. proved that numerical finite volume simulations are a powerful means in the context of the rheological assessment of concrete. Their results should be used by engineers to build confidence on the reliability of numerical simulations. In addition, they stated that to improve bias due to uncertain rheology, a rheological configuration close to the engineer's aimed application should be taken into account without overlooking important phenomena. The paper by Chen et al. aimed at studying the thermal properties and thermoelectric performance of imidazole-graphyne (ID-GY) by combining first principle calculations with the Boltzmann transport theory. A detailed analysis of the harmonic and anharmonic properties has been presented to prove that the low lattice thermal conductivity can be attributed to the low Young's modulus, low Debye temperature, and high Gruneisen parameter. Finally, the authors demonstrated that it is possible to reduce the lattice thermal conductivity and enhance the thermoelectric performance of carbon-based materials by changing structural units from hexagonal to pentagonal On the other hand, the paper by Ursini and Collini has been focused on the Fused Deposition Modeling (FDM) additive technology, emphasizing that the analysis of the functional behavior of FDM parts is still a topic of great interest. They investigated experimentally and numerically the effects of different phenomena that could affect the mechanical features of 3D printed lattice structures. Bragov et al. have discussed the influence of specimen geometry and loading conditions on the mechanical properties of porous brittle media. Their results proved that the structure of the material should be taken into account so that the size of the specimen (in terms of both length and diameter) exceeds the size of the internal fractions of the material by at least five times, when the geometry of specimens of brittle porous media is defined. A fully autonomous computational workflow to identify light-harvesting materials for water splitting devices based on properties has been presented by Ludvigsen et al. . In particular, they discussed relevant features such as stability, size of the band gap, position of the band edges, and ferroelectricity, proving that ferroelectric materials represents a possible solution to enhance the efficiency of solar cells and photoelectrocatalytic devices in light-harvesting applications. Chomka et al. investigated, instead, the possibility of using a high-pressure water-ice jet as a new method to remove a worn-out paint coating from the surface of metal parts (including those found in means of transportation) and to prepare the base surface for the application of renovation paint coating. The results have been supported by an experimental campaing. Vahed et al. highlighted the need of mathematical predictive models to overcome the complex and non-linear nature of material properties evolution during 3D printing, especially when Fused Deposition Modeling (FDM) is considered. Once the process parameters have been discussed, artificial neural networks have been trained to predict both the storage and loss moduli of the samples. An optimization of the process parameters through the Particle Swarm Optimization (PSO) has been also performed. The topic of green composites has been discussed in the paper by Jiao-Wang et al. , developing fully biodegradable composites made of microbially degradable polymers reinforced with natural fibers. In particular, they enhanced numerical models to predict the damage of these structures with the aim to extend their employment in industrial applications of structural responsibility. Civalek et al. developed an efficient eigenvalue algorithm for the axial vibration analysis of embedded short-fiber-reinforced micro-/nano-composite rods subjected to arbitrary boundary conditions. Their investigations have been carried out within the framework provided by the nonlocal elasticity theory needed to capture the size effect. The influence of elastic spring boundary conditions on the axial vibration frequencies and mode shapes has been also discussed. A beam model for thermal buckling analysis of a bimetallic box beam has been developed by Simonetti et al. , considering Euler-Bernoulli-Vlasov beam theory and including large rotations but small strains. An updated Lagrangian formulation is used to discuss the nonlinear stability analysis. The effects of different boundary conditions, beam lengths and material thickness ratios on the critical buckling temperature and post-buckling responses have been discussed through several numerical tests. The results presented in the paper by Esencan Turkaslan et al. proved that the efficiency of the photocatalytic activity of the nanocomposite depends on different synthesis methods and the morphology resulting from the changed method. To this aim, tungsten trioxide/graphene oxide nanocomposites have been successfully synthesized using in situ and ex situ chemical approaches. A series of experimental and numerical studies concerning the influence of temperature on mode II fracture of a T800/epoxy unidirectional laminates has been presented by Gong et al. . The failure mechanism has been also determined by using a scanning electron microscope. The validity of the numerical model has been confirmed by the experimental tests. Therefore, the results represent an helpful guidance for the design of composite laminates. Dastjerdi et al. developed a novel nonlinear elasticity theory for annular and circular plates made of hyperelastic materials. The effect of viscosity has been taken into account to obtain the long-term structural response. The partial differential equations have been solved through a semi-analytical method, and have been confirmed by the successful comparison with the results found in other sources. The last paper by Cheng and Vescovini presented instead an accurate and efficient numerical method for the analysis and design of Variable Stiffness (VS) laminates. In particular, a ps-version of the Finite Elements Method (ps-FEM) has been developed for the global/local analysis through different refinement approaches. Peculiar attention has been given to the implementation aspects to illustrate the potential of the methodology. The Guest Editors would like to congratulate all the authors for the remarkable results presented in these papers. Author Contributions Conceptualization, M.B. and A.S.M.; writing original draft preparation, M.B. and A.S.M.; writing review and editing, M.B. and A.S.M.; visualization, M.B. and A.S.M.; supervision, M.B. and A.S.M. All authors have read and agreed to the published version of the manuscript. Conflicts of Interest The authors declare no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Nurek T. Gendek A. Dabrowska M. Influence of the Die Height on the Density of the Briquette Produced from Shredded Logging Residues Materials 2021 14 3698 10.3390/ma14133698 34279269 2. Tulska E. Aniszewska M. Gendek A. The Kinematics of Scale Deflection in the Course of Multi-Step Seed Extraction from European Larch Cones (Larix decidua Mill.) Taking into Account Their Cellular Structure Materials 2021 14 4913 10.3390/ma14174913 34501003 3. De Schryver R. El Cheikh K. Lesage K. Yardimci M.Y. De Schutter G. Numerical Reliability Study Based on Rheological Input for Bingham Paste Pumping Using a Finite Volume Approach in OpenFOAM Materials 2021 14 5011 10.3390/ma14175011 34501102 4. Chen Y. Sun J. Kang W. Wang Q. Phonon Transport and Thermoelectric Properties of Imidazole-Graphyne Materials 2021 14 5604 10.3390/ma14195604 34639999 5. Ursini C. Collini L. FDM Layering Deposition Effects on Mechanical Response of TPU Lattice Structures Materials 2021 14 5645 10.3390/ma14195645 34640039 6. Bragov A.M. Lomunov A.K. Igumnov L.A. Belov A.A. Eremeyev V.A. The Influence of Specimen Geometry and Loading Conditions on the Mechanical Properties of Porous Brittle Media Materials 2021 14 7144 10.3390/ma14237144 34885299 7. Ludvigsen A.C. Lan Z. Castelli I.E. Autonomous Design of Photoferroic Ruddlesden-Popper Perovskites for Water Splitting Devices Materials 2022 15 309 10.3390/ma15010309 35009455 8. Chomka G. Chodor J. Kukielka L. Kasperowicz M. The Use of a High-Pressure Water-Ice Jet for Removing Worn Paint Coating in Renovation Process Materials 2022 15 1168 10.3390/ma15031168 35161112 9. Vahed R. Zareie Rajani H.R. Milani A.S. Can a Black-Box AI Replace Costly DMA Testing?-A Case Study on Prediction and Optimization of Dynamic Mechanical Properties of 3D Printed Acrylonitrile Butadiene Styrene Materials 2022 15 2855 10.3390/ma15082855 35454545 10. Jiao-Wang L. Loya J.A. Santiuste C. On the Numerical Modeling of Flax/PLA Bumper Beams Materials 2022 15 5480 10.3390/ma15165480 36013619 11. Civalek O. Uzun B. Yayli M.O. Nonlocal Free Vibration of Embedded Short-Fiber-Reinforced Nano-/Micro-Rods with Deformable Boundary Conditions Materials 2022 15 6803 10.3390/ma15196803 36234141 12. Simonetti S.K. Turkalj G. Banic D. Lanc D. Bimetallic Thin-Walled Box Beam Thermal Buckling Response Materials 2022 15 7537 10.3390/ma15217537 36363130 13. Esencan Turkaslan B. Celik A.K. Dalbeyler A. Fantuzzi N. The Effect of Different Morphologies of WO3/GO Nanocomposite on Photocatalytic Performance Materials 2022 15 8019 10.3390/ma15228019 36431504 14. Gong Y. Jiang L. Li L. Zhao J. An Experimental and Numerical Study of the Influence of Temperature on Mode II Fracture of a T800/Epoxy Unidirectional Laminate Materials 2022 15 8108 10.3390/ma15228108 36431594 15. Dastjerdi S. Akgoz B. Civalek O. Viscoelasticity in Large Deformation Analysis of Hyperelastic Structures Materials 2022 15 8425 10.3390/ma15238425 36499921 16. Yan C.A. Vescovini R. Application of the ps-Version of the Finite Element Method to the Analysis of Laminated Shells Materials 2023 16 1395 10.3390/ma16041395 36837026 |
Materials (Basel) Materials (Basel) materials Materials 1996-1944 MDPI 10.3390/ma16051899 materials-16-01899 Editorial Materials Make a Better Life: Functional Metals, Metal Oxides, and Metal Complexes Piszczek Piotr * Radtke Aleksandra * Faculty of Chemistry, Nicolaus Copernicus University in Torun, Gagarina 7, 87-100 Torun, Poland * Correspondence: [email protected] (P.P.); [email protected] (A.R.) 24 2 2023 3 2023 16 5 189921 2 2023 23 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). pmcMaterials based on metals, metal oxides, and metal complexes play an essential role in various areas of our lives. Their physicochemical and biological properties and their use depend on the type of metal, their structure, the morphology of their oxides, and, in the case of metal complexes, the type of stabilizing ligands. Industrial and nanotechnological developments have led to contamination of metals (metal nanoparticles) in our environment; their removal and recovery are essential. Moreover, in the case of metal nanoparticles, it is also important to know their toxic effects on our bodies and the environment. The presented Special Issue "Materials Make a Better Life: Functional Metals, Metal Oxides, and Metal Complexes" is a thematically diverse collection of eleven papers (two review articles and nine research articles). The scope of the discussed issues concerns the use of metal-based materials in medicine, the food industry, and environmental protection. The synthesis and structure, as well as the photocatalytic and antimicrobial properties, of oxo-titanium(IV) complexes (TOCs) stabilized with acetylsalicylic acid ligands are discussed in articles . The properties of the above compounds were studied using polymer (poly(e-caprolactone))-TOC composite systems. It was found that the tested coating materials showed good activity towards photodecolorization of the methyl blue solution after irradiation with visible light. In addition, the antimicrobial activity of the tested materials during irradiation with visible light was proven. The results of the analysis of four new copper(II) complex compounds and their potential use as anticancer agents are presented in the article . Derivatives of 6-bromo-2-(pyridin-3-yl)-3H-imidazo[4,5-b]pyridine copper(II) complexes have been found to be potential drug candidates against human lung adenocarcinoma. Moreover, it was noted that the compound mentioned above showed strong activity against the A549 cell line. When studying issues related to the search for biomaterials and the possibility of their use in implantology, attention should be paid to the article . The report discusses the results of research into cathodic deposition of hydroxyapatite onto the surface of Ti6Al4V substrates, which were previously modified by the production of nanoporous TiO2 coatings or TiO2 nanofibers or titanate coatings. It was proven that the presence of an intermediate titanium oxide coating significantly increases the adhesion between the hydroxyapatite (HA) layer and the Ti6Al4V substrate, thus providing a solution to the problem of delamination of the HA layer from the metallic substrate during extended implant use. An important issue related to producing materials based on titanium dioxide nanotubes is the scaling of their synthesis process . Tests on titanium samples of various sizes have shown that, maintaining the same conditions as the anodic oxidation process, as their surface increases, the height of the formed nanotubes decreases and the distance between them increases, while the thickness of the nanotube walls is maintained. In addition, it was observed that changes in their outer diameter and the actual surface area did not affect the generated photocurrent. The composition of the resulting material also remained the same after increasing the size of the substrate. The results of the conducted research are important for using materials based on TiO2 nanotubes in medicine, photoelectrochemistry, and in the production of sensors and supercapacitors. An interesting topic from the food industry's point of view is the use of silver nanoparticles (AgNP) for detecting pesticides in fruits and vegetables . The authors propose using a flexible substrate methylcellulose (MC) enriched with AgNP. Using the MC/AgNP system allowed the detection of thiram pesticide residues on the skins of cucumbers and tomatoes. Compared to existing technologies, the MC/Ag NP system could detect pesticides quickly without any other sample treatment. The use of iron nanoparticles (FeNP) in the food industry was addressed by the authors of article . The high reactivity of FeNPs with oxygen both in the presence of moisture and in an anhydrous environment, and their ability to counteract the growth of microorganisms belonging to different groups (Gram-negative and Gram-positive bacteria, yeasts, and moulds), presents an interesting issue. It was concluded that FeNPs could be used in the production of food contact packaging as well as in the food itself. Smaller dimensions mean a larger external surface, which improves water absorption, aroma release, availability of bioactive substances, and the speed of the catalytic processes. However, certain limitations (e.g., concentrations of no more than 100 mg mL-1) related to FeNP use should be considered. The wide use of metal-based nanoparticles (MNPs) in various areas of our lives has led to the undertaking of research on the biosafety of their use. The article reviewed works on the interaction between MNPs and Arabidopsis thaliana (a model plant). In order to determine the mechanisms that affect plant growth and development, attention was paid to various effects related to plant inter-metallization and phytotoxicity. The authors state that because studies have been performed at different levels of the plant's response, i.e., subcellular, physiological, and biochemical levels, the interactions between MNPs and Arabidopsis should be designed in a way that combines the traditional toxicological research methods with histological techniques (transcriptomics, metabolomics, and proteomics) to provide more accurate and in-depth elucidation of the mechanisms of MNP-based phytotoxicity. Intensive industrial development has polluted our environment with heavy metals. They are a significant problem because their ions are not biodegradable and accumulate in animal and human body tissues, as well as in water. One of the most common heavy metals in industrial discharge is zinc. A method detailing the removal of Zn(II) from aqueous synthetic solutions is proposed in article . With this aim, laurel, canelo, and eucalyptus residues were used as the support of magnetic composites to be used as adsorbents in zinc removal. The optimal contact time was 3 h, and an adsorbent dosage of 7 g/L allowed the maximum removal of zinc, which was about 98.9, 98.8 and 97.6% for laurel, canelo, and eucalyptus magnetic composites, respectively. The issue of recovering metals (nickel and cobalt) from used lithium-ion batteries was dealt with by the authors of papers . The advantages of lithium-ion batteries have led to them being the principal type of battery used in mobile phones, portable notebooks, and electric vehicles, among others. With the development of these batteries, their scrapping and disposal have become significant problems. Used lithium-ion batteries do not easily degrade and have a certain toxicity. Therefore, the recovery of metals from such kind of batteries is important from the point of view of environmental protection, as well as the reuse of recovered metals. Electrometallurgical technology has been employed in these research works. Reduction mechanisms of Ni(III) and Co(III) in molten Nal-CaCl2-LiMO2 salts (M = Ni and Co) lead to their separation and extraction from waste. We want to thank all the authors for their submissions to this Special Issue. We also thank the reviewers for dedicating their time and helping to ensure the quality of the submitted papers. Moreover, we thank the editorial staff of Materials for their indispensable assistance. Conflicts of Interest The authors declare no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Smigiel J. Muziol T. Piszczek P. Radtke A. Titanium(IV) Oxo-Complex with Acetylsalicylic Acid Ligand and Its Polymer Composites: Synthesis, Structure, Spectroscopic Characterization, and Photocatalytic Activity Materials 2022 15 4408 10.3390/ma15134408 35806533 2. Smigiel J. Piszczek P. Wrzeszcz G. Jedrzejewski T. Golinska P. Radtke A. The Composites of PCL and Tetranuclear Titanium(IV)-Oxo Complex with Acetylsalicylate Ligands Assessment of Their Biocompatibility and Antimicrobial Activity with the Correlation to EPR Spectroscopy Materials 2023 16 297 10.3390/ma16010297 3. Raducka A. Czylkowska A. Gobis K. Czarnecka K. Szymanski P. Swiatkowski M. Characterization of Metal-Bound Benzimidazole Derivatives, Effects on Tumor Cells of Lung Cancer Materials 2021 14 2958 10.3390/ma14112958 34070886 4. Ehlert M. Radtke A. Bartmanski M. Piszczek P. Evaluation of the Cathodic Electrodeposition Effectiveness of the Hydroxyapatite Layer Used in Surface Modification of Ti6Al4V-Based Biomaterials Materials 2022 15 6925 10.3390/ma15196925 36234265 5. Szkoda M. Trzcinski K. Zarach Z. Roda D. Lapinski M. Nowak A.P. Scaling Up the Process of Titanium Dioxide Nanotube Synthesis and Its Effect on Photoelectrochemical Properties Materials 2021 14 5686 10.3390/ma14195686 34640082 6. Zhang Q. Xu G. Guo N. Wang T. Song P. Xia L. In-Situ Synthesis of Methyl Cellulose Film Decorated with Silver Nanoparticles as a Flexible Surface-Enhanced Raman Substrate for the Rapid Detection of Pesticide Residues in Fruits and Vegetables Materials 2021 14 5750 10.3390/ma14195750 34640144 7. Goral D. Marczuk A. Goral-Kowalczyk M. Koval I. Andrejko D. Application of Iron Nanoparticle-Based Materials in the Food Industry Materials 2023 16 780 10.3390/ma16020780 36676517 8. Geng M. Li L. Ai M. Jin J. Hu D. Song K. Recent Advances in Metal-Based Nanoparticle-Mediated Biological Effects in Arabidopsis thaliana: A Mini Review Materials 2022 15 4539 10.3390/ma15134539 35806668 9. Asimbaya C. Rosas-Laverade N.M. Galass S. Debut A. Guerrero V.H. Pruna A. Magnetite Impregnated Lignocellulosic Biomass for Zn(II) Removal Materials 2022 15 728 10.3390/ma15030728 35160674 10. Li H. Fu Y. Liang J. Li C. Wang J. Yan H. Cai Z. Electrochemical Mechanism of Recovery of Nickel Metal from Waste Lithium Ion Batteries by Molten Salt Electrolysis Materials 2021 14 6875 10.3390/ma14226875 34832277 11. Li H. Li H. Li C. Liang J. Yan H. Xu Z. Study on the Behavior of Electrochemical Extraction of Cobalt from Spent Lithium Cobalt Oxide Cathode Materials Materials 2021 14 6110 10.3390/ma14206110 34683701 |
Materials (Basel) Materials (Basel) materials Materials 1996-1944 MDPI 10.3390/ma16052037 materials-16-02037 Editorial Introduction to the Topic of the Special Issue "Study on Synthesis and Properties of Metal-Containing Matrix Polymer Composites" from the Guest Editor Mikhailov Oleg V. Department of Analytical Chemistry, Certification and Quality Management, Kazan National Research Technological University, K. Marx Street 68, 420015 Kazan, Russia; [email protected] 01 3 2023 3 2023 16 5 203726 2 2023 28 2 2023 (c) 2023 by the author. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). pmcAs is known, one of the key objects of modern Materials Science is composite materials, or simply composites, which are used in various fields of science and technology from the food industry to aviation, from medicine to the construction of various buildings, from agriculture to radio electronics. According to the definition adopted in Materials Science, in the general case, a composite is a poly-component system of natural or anthropogenic origin, consisting of at least two or more components with significantly different physicochemical characteristics, which, when combined with each other, lead to the appearance of some new properties that are different from those inherent in the initial components of this system. It should be specially noted in this connection that not all properties of the system are included within the definition, but only those which are not the result of the simple addition or superposition of the properties of the system's constituent components. Each of these components can be classified into one of two categories, namely, matrix/matrices and filler/fillers, the first of which perform the function of a binder, while the latter act as a so-called binder reinforcement (strengthening the structure of the material as a result of the formation of various bonds (chemical, intermolecular, etc.) with the matrix/matrices). A special case of composites is the so-called "hybrid materials", which are materials obtained through the interaction of chemically different constituents (components), most often organic and inorganic, forming a certain crystalline or spatial structure that differs from the structures of the original reagents (but, as a rule, retains certain motifs and functions of the original structures to one degree or another). In a number of cases, a mixture of spatially distributed phases is also considered a hybrid material (for example, if nanoparticles or nanofibers are in a polymer matrix), but it is more correct to classify as hybrid materials only those composites with a fairly obvious chemical interaction between their components. To this definition, many supramolecular compounds, including metal complexes, also correspond, but they are usually considered as a separate class of materials. Occasionally, nanoparticles with a chemically modified surface are also referred to as hybrid materials. In this case, it is usually assumed "by default" that all the components that make up the composite are in a solid state of aggregation (which can be both crystalline and amorphous), although, among experts in the field of Materials Science, there is an opinion that the matrix may also be a liquid crystal substance. The possibilities in the composition of composites are, in principle, inexhaustible, since according to the above definition, there are no restrictions on either the range of matrices or the range of fillers. This circumstance, of course, introduces certain difficulties into their systematics. Within the framework of the most common variants that is, by the nature of the matrix three main categories of composites can be distinguished: polymer, metal, and ceramic, the matrices in which are, respectively, an array of any polymer or high-molecular compound, an individual metal or an alloy of two or more metals, and various types of ceramics, porcelain, faience, fireclay, majolica, etc. This classification of composites is the main one, but not the only one. Another important option is the division of composites according to the nature and structure of the filler, in the framework of which, each composite can be attributed to one of four classes: fibrous (reinforced with fibers or whiskers), layered (reinforced with films, plates, or layered fillers), dispersed-hardened (reinforced with dispersed particles of any substances), and nanocomposites (reinforced with nanoparticles). Systematics is also possible according to which of the two basic classes of chemical compounds inorganic or organic are included in the composition of matrices and fillers; that is, systematics according to the areas of their application in anthropogenic activities, etc. So, in the case of hybrid materials, if the "basis" of the material is organic (polymeric and other structures), then such materials are called inorganic-organic; otherwise, on the contrary, they are organic-inorganic (metal-complex frame structures, modified materials based on clays, zeolites, etc.). Among all composites, the most diverse and widespread are undoubtedly polymer composites, which, in turn, are subdivided into six classes with a certain degree of conventionality: fiberglass (the filler of which is glass fiber), carbon fiber reinforced plastics (the filler of which are carbon fibers), boron plastics (filler boron fibers, embedded in a thermosetting polymer matrix), organoplastics (filler organic, synthetic, and/or natural fibers), textolites (layered plastics containing fabrics from various fibers are the filler), and polymers filled with powders of various solid (usually inorganic) substances. In addition, although such a classification of composites, in our opinion, is very "amorphous" and not clearly structured, nevertheless, it quite clearly follows that the set of composites named in it is the largest, both in terms of number and variety of materials related to it. The first in this list, fiberglass, are polymer composite materials reinforced with glass fibers, which are formed from molten inorganic glass. As the matrix, thermosetting synthetic resins (e.g., phenolic, epoxy, polyester) or thermoplastic polymers (e.g., polyamides, polyethylene, polystyrene) are used most often. These materials have sufficiently high strength, low thermal conductivity, high electrical insulation characteristics, as well as so interesting a property as transparency with respect to radio wave radiation. Composites of the second category within this classification carbon fiber reinforced plastics as a filler contain various carbon fibers are obtained, as a rule, from synthetic and natural fibers based on cellulose, acrylonitrile copolymers, petroleum, and coal tar pitches. It should be noticed in this connection that, for obtaining such carbon fibers, characterized by a high content of carbon (up to 99.5 mass. %), the above substances are subjected to a three-stage heat treatment, including the process of their oxidation at a temperature of 200-220 degC, carbonization at a temperature of 1000-1500 degC, and graphitization at temperature 1800-3000 degC. For obtaining carbon fiber reinforced plastics, the same matrices are used as for fiberglass plastics, namely, thermosetting and thermoplastic polymers. The main advantages of these over fiberglass are their lower density and higher modulus of elasticity; they, unlike fiberglass, are good conductors of electric current. In fairness, however, we have to note that all these polymer composites are painted black (which is understandable, since the fibers containing them are composed of graphite), and this somewhat limits their scope. Polymer composites of the third category are very similar to carbon fiber plastics boron plastics containing boron fibers as a filler embedded in a thermosetting polymer matrix; the fibers can be both in the form of threads and in the form of bundles braided with an auxiliary glass thread or tape, in which boron threads are intertwined with other threads. Such fibers have greater hardness than carbon fibers, as a result of which boron plastics also have higher mechanical properties (in particular, boron fibers have the highest compressive strength compared to fibers from other materials and greater resistance to aggressive agents). However, the cost of boron fibers is significant, which is associated with the specific features of the technology for their production (in which boron is deposited from its trichloride onto a tungsten substrate, the cost of which can reach up to 30% of the cost of the fiber itself). Their other drawback is their very high brittleness, which makes their processing difficult and imposes restrictions on the shape of those products made from their substance. These composites are mainly used in aviation and space technology in parts subjected to long-term loads in aggressive environments. The next category of polymer composites in the order of enumeration are organoplastics; these are polymer composites in which organic, synthetic and, less commonly, natural and artificial fibers in the form of bundles, threads, fabrics, paper, and so on, serve as fillers. In these objects, the role of the matrix is played, as a rule, by thermosetting epoxy, polyester, and phenolic resins, as well as polyimides, although, in principle, organoplastics in which the matrix is thermoplastic polymers polyethylene, polyvinyl chloride, or polyurethane are also possible. Such composites are lighter than both fiberglass and carbon fiber and boron plastics; they have relatively high tensile strength, high impact, and dynamic resistance, but, at the same time, low compressive and flexural strength. Already a small content of filler in composites of this type leads to the appearance of qualitatively new mechanical properties of the material. The properties of the composite can also be widely varied by changing the orientation, size, and concentration of the fibers. In addition, fiber reinforcement contributes to the appearance of anisotropy in the physicochemical characteristics of the composite, and by adding conductor fibers, it is possible to impart electrical conductivity to the material along a given direction. An important role in the formation of the mechanical characteristics of organoplasty is played by the orientation of the filler macromolecules relative to each other. The macromolecules of rigid chain polymers such as polyparaphenyl terephthalamide are generally oriented in the direction of the web axis and therefore have high tensile strength along the fibers. Bulletproof body armor is made from materials reinforced with this polymer. Moreover, textolites, which are layered plastics reinforced with fabrics from various fibers, can be included among organoplastics. However, they were singled out in a separate category, since the matrix here is usually phenol-formaldehyde resin, which, unlike traditional polymeric materials, has increased brittleness. Incidentally, textolites are perhaps the oldest of all polymer composites, because the first technology for their production dates back to the early 1920s; fabrics were impregnated with resin then pressed at elevated temperature, obtaining textolite plates. It should be noted, however, that at present, the binders in textolites are a wide range of both thermosetting and thermoplastic polymers; sometimes, even inorganic binders based on silicates and phosphates are used. As a filler, fabrics from a wide variety of fibers are used cotton, synthetic, glass, carbon, asbestos, basalt, and so on. Accordingly, the properties and application of textolites are diverse. The last category from the above list is represented by composites, which are polymers filled with powders of various substances. More than 10,000 grades of filled polymers are now known; the simplest and most ancient of them is bakelite, proposed back in 1916, the matrix of which is phenol-formaldehyde resin, and the filler is wood flour. Among polymer composites, a specific category of physicochemical systems called "Metal-Containing Matrix Polymer Composites" stands out, which are the objects of study in the articles related to this Special Issue. An officially accepted definition of the term "Metal-Containing Matrix Polymer Composites" by the IUPAC has not yet been developed; however, it seems to us that such a definition can be planned. In our opinion, in the general case, by them we should understand all those polymer composites which include any substances containing chemical elements/metals (i.e., those chemical elements for which, in simple substances formed by them, multicenter metallic bonds are realized, positively charged metal ions are located at the nodes of the crystal lattice, and electrons move randomly between them, like gas molecules, holding positive ions together). As a rule, polyethylene, polypropylene, and polyamide fibers are used as polymer matrices since they are characterized by low cost, high stabilizing properties, and ease of heat treatment, although the list of polymers suitable for creating a matrix is much wider. In this connection, it is possible to divide metal-containing polymer composites into three groups based on the location of the metal-containing compounds in the composite. The composites included in the first category contain particles of elemental metals and/or metal-containing substances only in the composition of the filler; the composites of the second category, only in the composition of the polymer matrix; while, for the composites of the third category, both in the composition of the polymer matrix and in the composition of the filler. In the last two cases, the polymer matrix is the so-called "metal-coordinated polymer", in which metal elements are part of the macromolecules that make up its structure. The main ways to obtain such polymers are the polymerization of the corresponding metal-coordinated monomers and the immobilization of low-molecular-weight-metal-containing compounds in a polymer matrix. In particular, 3D-metal-coordinated polyurethanes have a complex of enhanced physical and mechanical properties and high electrical conductivity compared to traditional polyurethanes, which allows them to be used as structural polymeric materials for special purposes, both individually and as part of polymer composites. A special place among metal-containing polymer composites is occupied by those in which the filler is composed of nanoparticles of elemental metals or metal-containing chemical compounds (the so-called "polymer nanocomposites"). The urgency of the problem associated with the synthesis, properties, and formation of such physicochemical systems is largely associated with the prospects of creating on their basis a wide variety of optical devices, in particular, miniature switches, sensors, modulators, components of the so-called "random" lasers, and devices for three-dimensional optical recording of information. The use of polymer nanocomposites is by no means limited to this; their prospects in solving the problems of ensuring electromagnetic compatibility, noise protection, radio masking, and the protection of biological objects from the harmful effects of ultrahigh-frequency radiation have been demonstrated. There is reason to believe that the use of such composite materials in microwave equipment as distributed nonlinear elements (filling waveguide paths and resonators, thin-film coating, electromagnetic screens, etc.) will make it possible to develop a number of new devices for converting electromagnetic signals and elements of active stealth technologies. In addition to these wide possibilities of practical application, it should also be noted that, unlike materials containing nanoparticles in inorganic carriers, nanocomposites based on organic polymers have the ability to be molded, which makes it easy to manufacture parts of any given shape based on these composites. It is also important that the nanoparticles contained in such polymer composites are, as it were, "cemented" in the array of the polymer matrix and, therefore, are very stable. It seems to us that at this point in time, the following problems can be identified, which, in one way or another, are related to polymer metal-containing composites: Creation of scientific foundations that allow the prediction of various characteristics of polymeric metal-containing composites, determined by the nature of matrices and fillers (mechanical, physical, chemical) both at the macro, micro, and nano levels of organization of these objects. So far, we have to state with regret that the creation of new polymeric metal-containing composites, as a rule, is carried out in a purely empirical way, reminiscent of the so-called "trial and error method". In this connection, it becomes important, in particular, to predict the structural and geometric parameters of metal-containing composites, which determine those of their physicochemical properties that are somehow related to their practical use. This is especially true for metal-containing polymer nanocomposites, which have a number of specific chemical and physical properties that are of interest from both fundamental and applied points of view. Identification of regularities connected with the processes of forming polymeric metal-containing composites. This problem is mainly of an academic nature, but nevertheless requires very careful consideration since the specifics of the processes of formation of composites, in one way or another, affect their physicochemical characteristics. These processes, as a rule, are quite complex (and sometimes difficult to predict in their results even at the modern level) since their specificity is influenced not only by the nature and state of the aggregation of the starting materials for obtaining compositions, but also by the size of their particles, geometric shape, and surface topology (and this applies to both the matrix and the filler). Due to the rapid development of nanoscience and nanotechnology, it was possible to achieve some success in understanding these patterns; however, since the number of polymer composites grows from year to year, the above problems are permanent and remain relevant. Despite the fact that at this point in time, there are a number of experimental and theoretical scientific works that consider methods for obtaining and studying the main physicochemical parameters of nanocomposites, their properties are still relatively little studied; in addition, the number of metals and their compounds that can be used as a filler is significantly limited. Synthesis of new polymer metal-containing composites with predetermined characteristics. This problem is currently becoming very important due to the obvious practical solution; time and life require the emergence of new composites with improved physicochemical and/or physicomechanical parameters. Its solution, however, is directly related to the solution of the first two indicated problems, since the implementation of the processes for obtaining such composites requires not only information about what happens at one stage or another of their production, but also the possibility of purposefully controlling the process during any such stage. Optimization and improvement of existing methods for obtaining already known polymeric metal-containing composites. As is known, one of the most important tasks of chemistry and Materials Science, along with the development of new methods for obtaining various substances, is the improvement of existing methods. This problem is also relevant in the case of obtaining polymer metal-containing composites, including those that are the objects of study in the articles of this Special Issue and, first of all, polymer nanocomposites. Improvement of systematics and chemical nomenclature of polymeric metal-containing composites. As is easy to see, the existing systematics of composites in the broad sense of the word is based on a functional branch principle rather than a physical-chemical one; for metal-containing polymer composites, systematics can be used, which will be based on the chemical nature of the matrix and filler. On the other hand, it is necessary to somehow solve the problem associated with the compilation of the names of these composites within the framework of the modern IUPAC systematic nomenclature. This is necessary if only because it is difficult to talk about something that does not have a well-defined proper name. Taking all of this into account, it seems to us that the number of works devoted to these interesting and important objectives of modern materials science should be significantly larger compared to what is happening at the present time. This Special Issue of Materials is designed, at least to some extent, to contribute to the development of the scientific direction of Materials Science associated with these objectives. Conflicts of Interest The author declares no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34774 Cardiology Internal Medicine Rheumatology A Rare Case of High-Grade Atrioventricular Block in Granulomatosis With Polyangiitis Muacevic Alexander Adler John R Khan Shahkar 1 Rizvi Taqi A 1 Velaga Saran Teja 1 Ling Joanne C 1 Makhoul Wahbah Gennifer 1 Asogwa Nnedindu 1 Ahmed Mustafa 1 Lafferty James C 2 1 Internal Medicine, Northwell Health/Staten Island University Hospital, Staten Island, USA 2 Cardiology, Northwell Health/Staten Island University Hospital, Staten Island, USA Saran Teja Velaga [email protected] 8 2 2023 2 2023 15 2 e347748 2 2023 Copyright (c) 2023, Khan et al. 2023 Khan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Granulomatosis with polyangiitis (GPA) is an autoimmune disease that affects small and medium-sized vessels. It is classically known to present with renal and respiratory tract symptoms. However, the disease can manifest in other organ systems, especially cardiovascular involvement. Though there are multiple reports of cardiac involvement in GPA, it is not commonly evaluated and is often overlooked in patients with GPA. Heart disease in GPA has a wide range of presentations ranging from subacute and silent to severe abnormalities, which can prove fatal if not identified and treated appropriately. Identifying cardiac involvement early in patients with no apparent signs can help with prevention strategies and follow-up to avoid significant complications. Pericarditis is the most common pathology noted in GPA, followed by cardiomyopathy, coronary artery disease, valvular disease, and conduction abnormality. In our report, we present a case of GPA in a young male with asymptomatic conduction abnormality of the heart. Although it was silent at the presentation, identifying the initial electrocardiogram (ECG) changes prompted us to admit him to the telemetry floor. Continuous telemetry monitoring helped us identify the progression of the conduction abnormality, which otherwise could have been missed. This led us to correlate to his symptoms which he later developed during his admission course. His symptoms subsided after prompt treatment. If not identified early, these cardiac abnormalities can delay management, leading to increased disease burden and morbidity. Hence, essential cardiac work with at least ECG and continuous telemetry monitoring is recommended. wegener's granulomatosis complications cardiac involvement in granulomatosis with polyangiitis ecg monitoring in granulomatosis with polyangiitis atrioventricular conduction abnormality granulomatosis with polyangiiitis The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Granulomatosis with polyangiitis (GPA), formerly known as Wegener's granulomatosis, is an autoimmune, systemic necrotizing vasculitis that affects small and medium-sized vessels. It is primarily associated with antineutrophil cytoplasmatic antibodies (c-ANCA) with specificity against proteinase 3 (PR3), but there may be exceptions . It commonly involves the upper and lower respiratory tracts and the renal system. In addition, limited forms commonly involve upper airways. Cardiac involvement is not common but can clinically appear in multiple presentations ranging from subclinical disease to severe abnormalities such as pericarditis, cardiomyopathy, valvular disease, and conduction disorders . In this case report, we discuss a case of GPA with conduction abnormalities and show the importance of monitoring specifically for cardiac involvement in patients with GPA. Case presentation The patient is a 31-year-old male with a past medical history of acute lymphoblastic leukemia as a child in remission and vitiligo. He presented with complaints of generalized weakness for 10 days, associated with myalgia, arthralgia, bilateral eye erythema, and cough. The history went back to six months prior when he started experiencing symptoms of upper respiratory tract disease with reports of intermittent blockage of the nares, followed by ear pain and difficulty hearing. His symptoms were unresponsive to trials of anti-inflammatory and antihistamine medications. The patient also developed bilateral eye erythema, photophobia, pain, and mild weakness in his lower extremities that started a few days before the presentation. His physical examination revealed bilateral eye injection and lacrimal gland hyperplasia; he had a petechial rash on his lower extremities with sensory deficits. In addition, the patient had decreased range of motion at the right knee joint without any apparent signs of synovitis or effusion. On admission, the patient was found to have a white blood cell count of 12.04 K/mL, a platelet count of 439 K/mL, an erythrocyte sedimentation rate of 98 mm/hour, a C-reactive protein of 152 mg/L, and an elevated total protein of 8.5 g/dL. His liver function tests were also abnormal, with alkaline phosphatase of 139 U/L, and alanine aminotransferase of 54 U/L. He had an initial troponin elevation of 0.12 ng/mL, and his urinalysis was positive for moderate hematuria. Initial chest X-ray (CXR) in the emergency department showed a right upper lung opacity, which was confirmed to be a 2.9 cm cavitary nodule on the chest computed tomography (CT) scan . CT of the head showed bilateral lacrimal gland hyperplasia and mastoid air cell opacification . The patient also had an electrocardiogram (ECG), which showed a first-degree atrioventricular (AV) block with a PR interval of 268 ms . Figure 1 CT of the chest with a cavitary chest lesion. Figure 2 CT of the head with lacrimal hyperplasia and mastoid air cell opacification. Figure 3 Electrocardiogram showing a first-degree atrioventricular block. The patient was admitted to the telemetry floors and put in an isolation room until tuberculosis was ruled out with three negative acid-fast bacilli smears. His telemetry monitoring revealed a worsening AV block that progressed to second-degree Mobtiz type 1 in the next 24 hours since baseline ECG . During his hospital stay, the patient complained of palpitations, and telemonitoring revealed multiple episodes of non-sustained ventricular tachycardia (NSVT). The troponin peaked at 0.17 ng/mL before trending down. Over the subsequent days, his immunology reports revealed a low positive antinuclear antigen (ANA) and rheumatoid factor (RF), but the c-ANCA was grossly positive, leading to a diagnosis of GPA. Figure 4 Electrocardiogram showing a second-degree Mobitz type 1 atrioventricular block. The patient's symptoms responded to pulse steroids intravenous methylprednisolone 1,000 mg, given intravenously for three days, followed by oral prednisone. Post-therapy telemetry monitoring did not reveal any further episodes of NSVT, and his AV block was resolved. However, he had an unrevealing echocardiogram (ECHO) and cardiac magnetic resonance imaging (MRI). The patient was started on pneumocystis pneumonia (PCP) prophylaxis and discharged with rheumatology follow-up, where he received rituximab infusions leading to complete resolution of symptoms and laboratory abnormalities. Discussion GPA is a necrotizing vasculitis combining vascular wall inflammation and extravascular granulomatosis . It classically involves the upper respiratory tract (92%), lungs (85%), and kidneys (77%) but may affect any system in the body . Cardiac involvement, though rare, was first described by Wegener in 1939. Its prevalence (3-90%) is highly variable due to the subclinical nature of the presentation and lack of sensitive routine diagnostics to identify involvement, with a higher percentage described in severe forms and autopsy [3-5]. Many patients with lung and kidney involvement remain silent in presentation with cardiovascular symptoms and are mostly found only on postmortem analysis. However, it is crucial to consider it while managing GPA, as undiagnosed cardiac abnormalities in GPA tend to prove fatal . The difficulty in diagnosis can be due to overlap syndromes and the need for histopathological evidence. This adds to the delay in diagnosis with a mean time from onset to diagnosis at 15 months, ranging between immediate to 15 years . An essential component of diagnosing and monitoring GPA is the presence of ANCAs, with diffuse cytoplasmic fluorescence, directed against PR3 in 75% of cases and much more rarely against myeloperoxidase. c-ANCA is present in approximately 90% of systemic forms and 50% of localized forms directed against PR3 in most cases . There are multiple methods and criteria to diagnose GPA. According to the American College of Rheumatology, GPA can be distinguished from other vasculitides with 88% sensitivity and 92% specificity if two or more of the following criteria are met: (i) urinary sediment containing red blood cell casts or more than five red blood cells per high-power field, (ii) abnormal findings on the chest radiograph, (iii) oral ulcers or nasal discharge, and (iv) granulomatous inflammation on biopsy . Cardiac complications may present in a variety of ways. Pericarditis is the most common presentation of cardiac disease (35-50%) in the GPA population, commonly presenting as acute tamponade or chronic constriction with pleuritic chest pain and pericardial friction rubs. Other cardiac manifestations include cardiomyopathy (30%), coronary artery disease (12-50%), valvular (common in mitral and tricuspid) involvement (6-21%), and conduction abnormalities (6-17%) . The presentation can sometimes mimic classic anginal chest pain secondary to coronary arteritis and myocardial ischemia . It is imperative to keep Wegener's part of the differential diagnosis in any non-specific illness with cardiac involvement, including culture-negative endocarditis, as both present with similar systemic findings (fever, malaise, weight loss, mass lesions, and vasculitis) . In addition, with polar opposite treatments for both conditions, performing early immunological testing is vital to reduce the progression of the disease and further complications, including permanent cardiac, renal, and pulmonary damage . A study that followed 1,829 patients diagnosed with Wegener's over 21 years showed an increased risk of acute myocardial infarction with a hazard ratio (HR) of 2.47 and 1.64 in three months and 10 years after diagnosis, respectively . The presence of heart failure was markedly elevated with an HR of 7.22 and 2.07 in three months and 10 years after GPA diagnosis, respectively . Another retrospective cross-sectional analysis found that hospitalized patients with GPA had a higher prevalence of coronary artery disease and heart failure . The studies concluded with a significantly high HR of cardiovascular morbidity in GPA patients at as early as three months to 10 years. This high risk prompts the need for cardiovascular surveillance in GPA, potentially benefiting preventative management and treatment strategy. Disease involving the conduction system is seen in approximately 17% of all the cardiac cases reported, with common ones including atrial tachycardia, atrial fibrillation, and atrial flutter. Other conduction defects varying in severity can also be recognized, including intraventricular conduction defects, second-degree heart blocks, and a complete heart block . Ventricular arrhythmias are more common in patients with underlying cardiomyopathy, myocardial ischemia, or cardiac masses. They are rarely seen in patients without any structural damage . Atrial arrhythmias are more common than ventricular owing to the anatomic location of the sinoatrial (SA) node, making it an easier target when epicarditis manifests, compared to the AV node, which is more distant from epicardium . Patients commonly present with syncope or palpitations and are sometimes asymptomatic initially with just subtle ECG changes as initially presented by our patient. In one study, as much as 85% of the patients had ECG changes, but not all manifested symptoms and were only identified at autopsy . Histopathological evidence of GPA on the heart reveals small-vessel involvement causing necrotizing vasculitis of cardiac muscle and granulomata formation affecting diffusely or focally. Valvular involvement is commonly seen in the mitral valve, followed by the tricuspid. Medium-vessel involvement is seen in coronary arteries with a range of changes from acute necrotizing to healing stages, which can lead to myocardial infarction. Conduction disorders can be secondary to granulomata of the conduction system or arteritis of supply to SA and AV nodes. The underlying cause of these conduction abnormalities is unknown but may be due to granulomatous inflammation of the conduction pathways. Cardiac findings at autopsy show granulomatous tissue within the conduction system with fibrosis and hyalinization and the absence of necrosis. Arterial involvement showed various stages of vasculitic involvement with both fibrotic and thrombotic occlusions. The histologic findings of cardiac GPA closely resemble giant-cell myocarditis, Churg-Strauss syndrome, sarcoidosis, hypersensitivity myocarditis, and myocardial infarction. Hence, a sampling error in biopsies can completely off-track the diagnosis but does not rule out GPA . Most reports and articles have described the use of different methods of diagnosis, including ECG, cardiac enzymes, transthoracic ECHO, CT chest, cardiac MRI, and coronary angiography . In a study with confirmed GPA, ECHO found 86% of the patients with heart disease, of which at least 36% attributed GPA as the cause for the findings after ruling out other explainable co-existing conditions as the cause. The same study found that almost half (42%) were identified on routine screening with an ECHO in the absence of an indication for the test. ECHO findings include global hypokinesia, regional wall motion abnormalities, mitral regurgitation, left ventricular systolic dysfunction, and pericardial effusion. A few of these patients had a reversal of the findings (acute dilated cardiomyopathy and large pericardial effusion) on immunosuppressive therapy. Routine ECHO in all patients with active GPA could be of great value as most cases can be silent . Cardiac MRI can be a helpful tool that helps physicians diagnose early cardiac involvement in Wegener's. The most common findings include a low ejection fraction, localized wall motion abnormalities, and late gadolinium enhancement . However, in cases where cardiac pathology is suspected, cardiac MRI and myocardial biopsy would be beneficial to diagnose any cardiac involvement of GPA disease . Due to GPA's fulminant nature and a high number of complications, it is crucial to start prompt treatment. The mainstay of management is combination therapy with cyclophosphamide and corticosteroids, which are used to induce remission. If it is ineffective, biological treatment (rituximab) may be considered . Mortality has decreased from 82% in one year before the immunosuppressive era to 25% five years post . There is an increased mortality (46%) among patients with heart pathology noted on ECHO in GPA. Increased initial treatment resistance and relapse in patients with cardiac involvement, along with other factors, were noted in a few European studies . Though there was no clear literature on treatment outcomes when the heart is involved, more studies would help validate the association, furthering our understanding of the disease and prognosis. Cardiac complications should be managed on a case-to-case basis, and specific therapies can range from short-term medication to long-term measures, such as permanent pacemakers in high-grade AV blocks . Conclusions Severe cardiac conduction abnormalities in Wegener's granulomatosis, although rare, can be deadly over a short time which is why we recommend that all patients hospitalized for an initial diagnosis of Wegener's or subsequent relapse should undergo, at the very minimum, continuous cardiac monitoring and ECHO for prompt recognition and treatment of any cardiac abnormalities. Early recognition of these findings can aid in managing and improving patients' prognoses. In addition, it furthers our understanding of the complex natural history of cardiovascular pathologies in GPA. Shahkar Khan, Taqi Rizvi, and Saran Teja Velaga contributed equally to the work and should be considered co-first authors. Human Ethics The authors have declared that no competing interests exist. 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Crit Care Critical Care 1364-8535 1466-609X BioMed Central London 36899440 4398 10.1186/s13054-023-04398-6 Correspondence The clinical frailty scale, but not the FRAIL checklist is associated with mortality in old critically ill patients with COVID-19 Wernly Bernhard 12 Flaatten Hans 3 Leaver Susannah 4 Guidet Bertrand 5 Jung Christian [email protected] 6 the COVIP investigatorsFjolner Jesper Beil Michael Oeyen Sandra Szczeklik Wojtek Elhadi Muhammed Sviri Sigal deLange Dylan Moreno Rui Artigas Antonio Dudzinski David Serck Nicolas Nedergaard Helene Korvenius Shaat Iman Hussein Aliae Mohamed Zanaty Mostafa Hassanin Ebtisam Hussein Aliae Mohamed Mohamed Nouralsabah Omar Marwa El-wahed Ghada Atef Ali Abd Touny Shimaa Aujayeb Avinash Nseir Saad Urbina Thomas Garcon Pierre Rigaud Jean-Philippe Vanderlinden Thierry Valette Xavier Megarbane Buno Baron Elodie Nigeon Olivier Plantefeve Gaetan Foucault Camille Monchi Mehran Fuest Kristina Bruno Raphael Kelm Malte Kabitz Hans-Joachim Schaller Stefan Abusalama Abdurraouf Embarek Hussein Anaiba Mohamed Taher Ahmed Alkaseek Akram Evers Mirjam Dieperink Willem Cornet Alexander Daniel Brochado Filipa Lopez-Cuenca Sonia Aldiabat Mohammad Al-Sadawi Mohammed 1 grid.21604.31 0000 0004 0523 5263 Department of Internal Medicine, General Hospital Oberndorf, Teaching Hospital of the Paracelsus Medical University Salzburg, Salzburg, Austria 2 grid.21604.31 0000 0004 0523 5263 Center for Public Health and Healthcare Research, Paracelsus Medical University of Salzburg, Salzburg, Austria 3 grid.7914.b 0000 0004 1936 7443 Department of Research and Development, Haukeland University Hospital, University of Bergen, Bergen, Norway 4 grid.264200.2 0000 0000 8546 682X General Intensive Care, St. George's University Hospital NHS Foundation Trust, London, UK 5 grid.412370.3 0000 0004 1937 1100 Service de Reanimation Medicale, Hopital Saint-Antoine, Institut Pierre-Louis d'epidemiologie et de sante publique, Hopital Saint-Antoine, Sorbonne Universite, Paris, France 6 grid.411327.2 0000 0001 2176 9917 Division of Cardiology, Pulmonology, and Vascular Medicine, Department of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, Heinrich-Heine University Dusseldorf, Moorenstrasse 5, 40225 Dusseldorf, Germany 10 3 2023 10 3 2023 2023 27 1012 3 2023 7 3 2023 (c) The Author(s) 2023 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. issue-copyright-statement(c) BioMed Central Ltd., part of Springer Nature 2023 pmc Dear Editor, Frailty is a clinical syndrome characterized by decreased reserve and resilience . Identifying frailty in critically ill patients can help to guide management, including the selection of appropriate interventions and the development of care plans such as time-limited trials in patients with an unclear benefit from critical care. The Clinical Frailty Scale (CFS) and the FRAIL checklist (1) are both tools proposed to assess frailty in older adults, but they have some key differences. The CFS is a simple, ordinal scale that assigns a score of 1 to 9 based on an assessment of the patient's level of frailty. It takes into account various physical and functional characteristics. It is quick and easy to use, and it has been validated in multiple settings [2-4]. The FRAIL checklist assesses five domains of frailty: functional impairment, recurrent hospitalizations, advanced malignancy and chronic diseases, irreversible organ failure, and long hospital stay. Patients with one of these criteria were postulated to benefit from upfront discussions about limitations of care. The FRAIL checklist has recently been proposed as a screening tool for frailty in critically ill patients . Patients with CFS > 4 and FRAIL > 0 are considered vulnerable and frail. This study aimed to compare the FRAIL and the CFS in critically ill patients with COVID-19 aged 70 years and older by incorporating the new FRAIL checklist into the protocol of the COVIP study as described in Critical Care . A total of 320 patients (median age 78 +- 6 years; 39% female; median SOFA score 5 +- 3, 3-month mortality 57%) were prospectively included in the new recruitment period of the COVIP study, with 31% (n = 99) having a FRAIL > 0 and 57% (n = 136) having a CFS > 4. The FRAIL and the CFS correlated with each other (Spearman's rho 0.53; p < 0.001). Both the CFS (HR 1.14; 95% CI 1.04-1.24; p = 0.004) and FRAIL (1.21 95% CI 1.08-1.35; p = 0.001) were associated with 3-month-mortality in the univariate analysis analyzed as continuous variables. Frail patients defined by both CFS > 4 (HR 2.01 95% CI 1.50-2.69; p < 0.001; Fig. 1A) and FRAIL > 0 (HR 1.46; 95% CI 1.04-2.03; p = 0.03; Fig. 1B) evidenced worse outcomes. However, after adjustment for age, gender, SOFA and the decision to withdraw/withhold treatment during the ICU stay, CFS > 4 (aHR 1.80 95% CI 1.29-2.53; p = 0.001) but not FRAIL > 0 (aHR 1.16; 95% CI 0.83-1.63; p = 0.39) remained associated with 3-month-mortality.Fig. 1 Frail patients defined by both CFS > 4 (HR 2.01 95% CI 1.50-2.69; p < 0.001; A and FRAIL > 0 (HR 1.46; 95% CI 1.04-2.03; p = 0.03; B evidenced worse outcomes In summary, frailty is an important predictor of outcome in critically ill patients, regardless of the tool used to assess it. The FRAIL checklist identifies patients who will benefit from a time-limited trial, however, the ability to predict mortality is inherent in any critically ill patient evaluation tool. The CFS but not the FRAIL checklist was independently associated with mortality in old ICU patients. Therefore, we believe that in elderly ICU patients, CFS should be used to assess frailty because it also provides prognostic information. Acknowledgements The COVIP investigators Jesper Fjolner; Michael Beil; Sandra Oeyen; Wojtek Szczeklik; Muhammed Elhadi; Sigal Sviri; Dylan deLange; Rui Moreno; Antonio Artigas; David Dudzinski; Nicolas Serck; Helene Korvenius Nedergaard; Iman Shaat; Aliae Mohamed Hussein; Mostafa Zanaty; Ebtisam Hassanin; Aliae Mohamed Hussein; Nouralsabah Mohamed; Marwa Omar; Ghada Atef Ali Abd El-wahed; Shimaa Touny; Avinash Aujayeb; Saad Nseir; Thomas Urbina; Pierre Garcon; Jean-Philippe Rigaud; Thierry Vanderlinden; Xavier Valette; Buno Megarbane; Elodie Baron; Olivier Nigeon; Gaetan Plantefeve; Camille Foucault; Mehran Monchi; Kristina Fuest; Raphael Bruno; Malte Kelm; Hans-Joachim Kabitz; Stefan Schaller; Abdurraouf Abusalama; Hussein Embarek; Mohamed Anaiba; Ahmed Taher; Akram Alkaseek; Mirjam Evers; Willem Dieperink; Alexander Daniel Cornet; Filipa Brochado; Sonia Lopez-Cuenca; Mohammad Aldiabat; Mohammed Al-Sadawi Author contributions All authors revised the manuscript and approved the final version and were involved in designing the study as well as in data collection, analysis and manuscript drafting. Funding Institutional funding. Availability of data and materials The datasets analyzed during the current study are not publicly available due to contractual restrictions but are available from the corresponding author on reasonable request. Declarations Ethics approval and consent to participate Ethics approval for the observational studies was granted by Board at the University Hospital Duesseldorf as described earlier in this journal . That included permission to access data. Then, each participating country had a national coordinator responsible for national or regional ethical and regulatory study approval. Informed consent was obtained if not waived by the local ethical approval. The research was carried out in accordance with the principles of the Declaration of Helsinki. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References 1. Jung C Guidet B Flaatten H VIP study group Frailty in intensive care medicine must be measured, interpreted and taken into account! Intensiv Care Med 2022 49 1 4 2. Jung C Flaatten H Fjolner J The impact of frailty on survival in elderly intensive care patients with COVID-19: the COVIP study Crit Care 2021 25 149 10.1186/s13054-021-03551-3 33874987 3. Guidet B Flaatten H Boumendil A Withholding or withdrawing of life-sustaining therapy in older adults (>= 80 years) admitted to the intensive care unit Intensiv Care Med 2018 44 1027 1038 10.1007/s00134-018-5196-7 4. Flaatten H Guidet B Andersen FH Reliability of the clinical frailty scale in very elderly ICU patients: a prospective European study Ann Intensiv Care 2021 11 22 10.1186/s13613-021-00815-7 5. Cheung EH-L Cheung JC-H Yip Y-Y Raising awareness for time-limited trial discussion upon ICU triage and admission Intensiv Care Med 2022 48 240 241 10.1007/s00134-021-06590-0 |
Materials (Basel) Materials (Basel) materials Materials 1996-1944 MDPI 10.3390/ma16052123 materials-16-02123 Editorial Mechanics and Analysis of Advanced Materials and Structures Yoshida Sanichiro 1* Pappalettera Giovanni 2 1 Department of Chemistry & Physics, Southeastern Louisiana University, Hammond, LA 70402, USA 2 Dipartimento di Meccanica, Matematica e Management, Politecnico di Bari, Via Orabona 4, 70125 Bari, Italy * Correspondence: [email protected] 06 3 2023 3 2023 16 5 212307 2 2023 10 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). This research received no external funding. pmcModern technological development has made the designing and characterization of materials sophisticated. The design concepts used for centuries for macroscopic objects do not necessarily apply to micro or nano-scale counterparts. The elastic modulus of a nano-scale wire can be significantly different from that of the same material at the macroscopic scale. Composite materials comprising multiple materials possessing completely different properties can exhibit unexpected behaviors. This situation requires the advancement of diagnostic methods in characterizing material properties. Great efforts are necessary to extend the type of materials and the conditions to make analysis convenient and to improve the figure of merits such as the sensitivity, resolution, non-destructiveness, and rapidness of the measurement. Such advancement can be an extension or a combination of existing techniques or the development of entirely new methodologies. Often, analytical or numerical modeling is necessary to expedite material characterization. Recent software development provides various computational tools, including machine learning and artificial intelligence algorithms, for numerical analysis and modeling. The present Special Issue is a collection of articles that shed light on the above issues. It has 11 original research papers and one review article. Below we take a quick look at the gist of these articles. The first four papers in the reference list discuss the mechanical properties of composite materials. The vibrational behavior of plates is complex. It has many modes, and the dynamics depend on the boundary conditions and the material's characteristics. Huang et al. discuss an analytical solution based on the Mindlin plate theory that describes the free vibration of rectangular plates of functionally graded material. They analyzed various combinations of boundary conditions and validated the results via comparison with published results. They tabulated data from this study so that researchers could use it to judge the accuracy of numerical methods. Fabric reinforcement of materials is another complex process. While the fabric material increases strength, controlling the interface with the matrix material is challenging. Mercedes et al. developed an analytical approach and a numerical simulator to evaluate the strength of concrete beams with various types of fabrics. They successfully parameterized complex strengthening behaviors with a single parameter called the reduction coefficient. They conclude that this strategy simplifies the analytical design of fiber-reinforced cementitious matrices. In a slightly different context from the above two works, Obrezkov et al. performed numerical modeling. They developed a numerical method to analyze a biomedical composite material. They modeled the elongation-induced deformation of the human Achilles tendon by assuming that it consists of beam elements using absolute nodal coordinate formulation. They report that this method reduces the degree of freedom, benefitting cost reductions in computation. They conclude that with some limitations, this model is feasible. The aerospace industry requires the development of ultra-high-temperature materials. In ref. , Tsakiropoulos analyzed the stability of complex-concentrated and high-entropy Niobium-based solid solutions for ultra-high temperature materials by considering oxygen concentrations. The author discusses the increase in hardness and Young's modulus with oxygen concentrations under various conditions in detail. The following two papers in the reference list discuss nonlinear acoustic probing. Acoustic probing is a well-established technique. Acoustic waves pass through most materials in a wide range of frequencies. This feature is contrastive to electromagnetic waves. One drawback is its wavelength. The typical acoustic frequency used for probing is several GHz, whereas the acoustic velocity in most materials is less than ten km/s. The corresponding acoustic wavelength is of the order of microns. This situation limits the size of anomalies to detect. A solution to this problem is the use of the nonlinear response of the material to the probing signal. The following two papers discuss nonlinear acoustic probing. Cho et al. used the second harmonic of an acoustic emitter signal in their probing system operating in the pulse-echo mode. A challenge in such nonlinear techniques is the smallness of the signal received by the sensor. To overcome this issue, the authors of this paper considered intensifying the acoustic signal by focusing the acoustic beam from the emitter. In this paper, they propose an annular phased-array acoustic transducer and demonstrate the increase in the nonlinear sensitivity via numerical analyses. High acoustic coupling between the acoustic transducer and the specimen is a significant factor for successful probing. Distilled water and acoustic gel are common materials for coupling. Usually, these materials increase the coupling efficiency so that the acoustic signal detected by the receiver is reasonably high. However, the receiver signal depends on the contact pressure between the transducer and the specimen, compromising the repeatability of data. In ref. , Jeong et al. propose a method to evaluate the nonlinear parameter with air-coupled acoustic receivers. By developing a two-layer acoustic model consisting of the solid specimen and air, considering diffraction and attenuation, they constructed an algorithm to evaluate the nonlinear parameter relative to a reference specimen. In this paper, they verified the algorithm via comparisons with the experiment. This paper also discusses factors that affect the accuracy of the method. Multiple methods applied to characterize the same specimen always provide extra information. In the following two papers, the authors take advantage of it. Niccolini et al. investigated the critical behavior of fracture processes in rocks and cement-based materials by acquiring acoustic emission and electrical resistance time series. They conducted compression experiments using rod specimens of Luserna stone and cement mortar. The experimental results indicate that the change in electric resistance precedes the acoustic emission in all tested specimens. The authors ascribe this observation to the fact that the acoustic emission signal is related to larger cracks than the electric resistance signal. In this paper, they discuss other findings in terms of the fracturing process. Residual stresses are difficult to analyze because they hide in the material. In many situations, it is necessary to alter their status for the observer to evaluate them. On the other hand, too much alteration would change the stress, compromising the measurement. This nature makes nondestructive estimation of residual stress challenging. Murata et al. demonstrated a nondestructive method of residual stress analysis. They applied laser spot heating to residually stressed specimens and probed the relaxation to estimate residual stress. Using a thermal camera, they monitored the thermal process. In addition, by mechanically applying initial loads to the specimen, they made quantitative analyses. The authors verified the results via comparisons with strain gauge measurements. The recent advancement in software, generally called machine learning algorithms, facilitates the existing technology of deformation analyses. Regardless of the choice of hardware, the output signal representing deformation is complicated. Often, the information is buried in noise, and its spatiotemporal characteristics are complex. This situation causes human operators to make errors in diagnosis. Computers are capable of analyzing a large volume of data and extracting features. In the following three papers, the authors utilize the advantages of computer-based algorithms to deal with complex data. Takahashi et al. used an optical interferometric method called Electronic Speckle-Pattern Interferometry (ESPI) to discuss the dynamics of plastic deformation and fracture under tensile loading. The ESPI technique reveals the contour of differential displacements (the displacement occurring during a short time interval) as dark fringes in a full-field optical image. For the analysis of deformation dynamics, it is necessary to analyze numerous fringe images. An algorithm to automatically locate the fringes is essential. Using speckles, the optical image containing the differential displacement contour is noisy. Takahashi et al. applied Gaussian filtering to reduce the noise and located the fringes continuously until the specimen fractured. With this method, they found that in the transition from late plastic deformation to the fracturing stage, the rotational mode of deformation plays a significant role in the process of stress concentration. Kopfler et al. use optical speckles for another purpose. They utilized the randomness of the speckle pattern to uniquely identify local areas of a transparent specimen (polyethylene films) and analyzed nonuniform deformation under tensile loading. With the numerical algorithm known as Digital Image Correlation, they found the nonuniform displacement field of the specimen. In the cases where the deformation is more uniform, they analyzed the deformation in the frequency domain using Fast Fourier Transform. Barile et al. propose an acoustic emission-based analysis of the damage progression stage in Sintered Laser Melting (SLM) materials. Characterization of materials processed by SLM is of great interest but also challenging due to the intrinsic orthotropy of these materials. When tested by acoustic emission methods, the orthotropic structure of the material causes the spectral content of the resulting waveforms to depend on the nature of the source and the building direction of the materials. In this view, the authors have taken advantage of machine learning tools and specifically of a convolutional neural network to classify detected signals based on the damage stage and the building direction. In particular, by adopting k-fold cross-validation, they have demonstrated drastic improvement in classification accuracy. Finally, Pavlovskii et al. reviewed the recent progress and challenges in organic anode materials for Lithium-Ion Batteries (LIB), one of the most demanding technologies of the modern era. This review compares the electrochemical performances of different organic anode materials, discussing the advantages and disadvantages of each class of organic materials in research and commercial applications. After addressing the practical applications of some organic anode materials, the paper discusses some techniques to address significant issues, including low discharge voltages and the undesired dissolution of the anode material into electrolytes. Author Contributions Writing Original Draft Preparation, S.Y.; writing review and editing, S.Y. and G.P.; supervision, S.Y. All authors have read and agreed to the published version of the manuscript. Conflicts of Interest The authors declare no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Huang C.S. Huang S.H. Analytical Solutions Based on Fourier Cosine Series for the Free Vibrations of Functionally Graded Material Rectangular Mindlin Plates Materials 2020 13 3820 10.3390/ma13173820 32872462 2. Mercedes L. Escrig C. Bernat-Maso E. Gil L. Analytical Approach and Numerical Simulation of Reinforced Concrete Beams Strengthened with Different FRCM Systems Materials 2021 14 1857 10.3390/ma14081857 33918051 3. Obrezkov L.P. Finni T. Matikainen M.K. Modeling of the Achilles Subtendons and Their Interactions in a Framework of the Absolute Nodal Coordinate Formulation Materials 2022 15 8906 10.3390/ma15248906 36556712 4. Tsakiropoulos P. On the Stability of Complex Concentrated (CC)/High Entropy (HE) Solid Solutions and the Contamination with Oxygen of Solid Solutions in Refractory Metal Intermetallic Composites (RM(Nb)ICs) and Refractory Complex Concentrated Alloys (RCCAs) Materials 2022 15 8479 10.3390/ma15238479 36499973 5. Cho S. Jeong H. Park I.K. Optimal Design of Annular Phased Array Transducers for Material Nonlinearity Determination in Pulse-Echo Ultrasonic Testing Materials 2020 13 5565 10.3390/ma13235565 33291342 6. Jeong H. Cho S. Zhang S. Li X. Absolute Measurement of Material Nonlinear Parameters Using Noncontact Air-Coupled Reception Materials 2021 14 244 10.3390/ma14020244 33419011 7. Niccolini G. Potirakis S. Lacidogna G. Borla O. Criticality Hidden in Acoustic Emissions and in Changing Electrical Resistance during Fracture of Rocks and Cement-Based Materials Materials 2020 13 5608 10.3390/ma13245608 33316973 8. Murata Y. Sasaki T. Yoshida S. Stress Dependence on Relaxation of Deformation Induced by Laser Spot Heating Materials 2022 15 6330 10.3390/ma15186330 36143642 9. Takahashi S. Yoshida S. Sasaki T. Hughes T. Dynamic ESPI Evaluation of Deformation and Fracture Mechanism of 7075 Aluminum Alloy Materials 2021 14 1530 10.3390/ma14061530 33804797 10. Kopfler C. Yoshida S. Ghimire A. Application of Digital Image Correlation in Space and Frequency Domains to Deformation Analysis of Polymer Film Materials 2022 15 1842 10.3390/ma15051842 35269075 11. Barile C. Casavola C. Pappalettera G. Kannan V.P. Damage Progress Classification in AlSi10Mg SLM Specimens by Convolutional Neural Network and k-Fold Cross Validation Materials 2022 15 4428 10.3390/ma15134428 35806553 12. Pavlovskii A.A. Pushnitsa K. Kosenko A. Novikov P. Popovich A.A. Organic Anode Materials for Lithium-Ion Batteries: Recent Progress and Challenges Materials 2023 16 177 10.3390/ma16010177 36614515 |
]) AND (hip osteoarthritis [Title/Abstract]). Review articles, case reports (n < 3), commentaries, editorials, insights articles, conference abstracts, and proceedings were excluded. The references of the eligible studies were screened through a database search. This summary provides little evidence to support that the PI plays a substantial role in hip osteoarthritis (HOA). By nationality, Japan had the highest number of reports (nine) followed by the USA (two), France (two), Canada (one), China(one), Turkey (one), Iran (one), and Poland (one). There were three prospective studies . The oldest paper was reported in 2005 ; all the rest were reported after 2015, perhaps reflecting that most studies on this topic had just commenced. Notably, 9 of the 18 studies were conducted very recently within the limited post-2020 timeframe . Nine of the non-Japanese reports were HOA reports , and two strictly excluded DDH . Furthermore, it was noted that five out of the nine HOA reports from Japan contained DDH because most HOA in the Japanese population is secondary to DDH . Two studies focused on comparing HOA and RDC . Five studies excluded hip dislocations classified into Crowe groups II, III, and IV and Crowe groups III and IV . The included studies varied in sample size from 25 to 1088 participants. The mean age was middle-aged or older, with participants in 4 studies being in their 50s, those in 11 studies being in their 60s, and those in 3 studies being in their 70s. Although the majority of the HOA patients reported in Japan were women, there was no sex predominance in the reports outside of Japan. In this study, the mean PI of HOA showed more than 10deg of variation (from 45.8 to 60.6), and the PI varied widely (from 18deg to 96deg) . Similarly, in normal subjects, the PI ranged widely (from 35deg to 85deg) , and the lack of agreement on a "normal" reference PI value makes interpreting the results difficult . Theoretically, greater PI values may cause a greater posterior pelvic tilt and a decreased anterior coverage of the femoral head at the acetabulum, which is associated with increased mechanical stress on the femoral head and may contribute to the development of HOA . However, the relationship between the PI and HOA development has been controversial. Several studies argue that these two parameters are related , whereas others conclude that they are not . Regarding the relationship between hip disease and the PI in past studies, the PI in HOA is a second-line research item and has not been fully explored. In addition, the pathogenesis of HOA is multifactorial, with predisposing genetic and local mechanical risk factors being involved. Therefore, stratification and analysis by HOA phenotype, such as femoroacetabular impingement (FAI), the development of the dysplasia of the hip (DDH), the osteonecrosis of the femoral head (ONFH), and rapidly destructive coxarthrosis (RDC), may help to characterize the PI. 5.2. The Relationship between the PI and FAI Many studies support the finding that a low PI predisposes one to symptomatic FAI . Riviere et al. proposed the classification of the spinopelvic parameters as a risk factor for developing FAI. Patients with a low PI have a more marked cross-sectional anteversion of the acetabulum. Theoretically, these patients are more prone to femoral neck impingement syndrome because they are less able to adapt to sagittal plane imbalances with a tendency to hyperextend their hips . In addition, a low PI pelvis may lose lumbar lordosis and require an anteversion of the pelvis to maintain sagittal balance, which may increase the symptoms of FAI . 5.3. The Relationship between the PI and DDH Despite the characteristic morphology of the pelvis and femur in patients with DDH , the role of the PI in DDH in the development of hip OA remains unknown . In DDH, some reports indicate that the PI was significantly greater than that in the controls , while others suggest that they have no relationship . In fact, Riviere et al. proposed the classification of the spinopelvic parameters as risk factors for the development of FAI. With regard to DDH, Iwasa et al. reported no significant difference in the PI between DDH and DDH-induced OA. However, the authors speculated that the mechanical stress in DDH could be significantly affected by an abnormal PI. However, there is diversity in the severity of DDH. In other words, DDH is not limited to the dysplasia of the acetabulum, and it includes the dysplasia of the entire pelvis from the acetabulum to the ilium ("iliac wing curved inward") . The PI may vary depending on the type and severity of DDH dysplasia and requires more detailed studies. 5.4. The Relationship between the PI and ONFH and RDC There is a positive relationship between the PI and LL: the greater the PI, the greater the LL . Due to age-related degeneration, decreased lumbar lordosis or lumbar kyphosis can cause a compensatory posterior pelvic tilt. Due to the larger PI and LL, the compensatory posterior pelvic tilt is greater when LL is reduced. A greater posterior pelvic tilt may decrease the anterior coverage of the femoral head at the acetabulum, which is associated with increased mechanical stress on the femoral head and may contribute to the development or worsening of several hip disorders (i.e., HOA, ONFH, and RDC) . Yoshimoto et al. suggested that a greater PI and the resulting biomechanical adaptations in young people may contribute to the development of HOA later in life. A deeper understanding of the biomechanical adaptations that may result from an increased PI may be helpful in surgical planning and developing techniques for periprosthetic osteotomies and hip arthroplasties . For ONFH, Kwon et al. reported that a large PI is associated with the rapid development of ONFH and concluded that assessing the parameters in the pelvic sagittal plane in patients with early nontraumatic ONFH may help to predict which patients are at risk for a femoral head collapse. This finding may significantly impact how these patients are treated and followed up, and more confirmatory studies are needed . RDC had a higher degree of femoral head destruction and more patients with severe pelvic discrepancies (PI-LL of >20deg and PT of >30degin comparison to HOA) . However, there was no significant correlation with the PI . Because of the extremely low incidence of RDC, the relationship between RDC and the PI should be verified in a large prospective study. 5.5. What Is the Impact of HOA on the PI? Conversely, it is necessary to consider whether HOA will change the PI. In advanced cases of HOA, the hip axis is shifted cranially due to the destruction and subluxation of the head. In other words, a vertical offset decrease occurs, resulting in a larger PI . Therefore, although many reports clearly state that cases with a highly dislocated hip were not included, such cases should be excluded when investigating the PI in HOA. However, Okuzu et al. reported that severe SIJ degeneration was often seen in patients with end-stage osteoarthritis secondary to unilateral DDH. This may result in increasing sacroiliac joint angulation and may lead to a larger PI. In other words, HOA may increase. No studies on the PI in HOA cases considered the effect of sacroiliac joint angulation, which is one of the issues that will be addressed in future research. 6. Limitations and Future Directions The present study has some limitations. First, as noted by Saltychev et al. , who examined the relationship between the PI and hip disease in a systematic review, omissions were common. In addition, concerning the study design in this review, most of the publications were retrospective studies. The relationship between the PI and HOA has not been fully explored because the PI in HOA was a second-line research item. Thus, the widely varying subjects, study designs, and methods did not allow for valid meta-analyses, nor could the methodological quality of the studies be systematically analyzed. Therefore, the lack of a systematic methodology in this review made it impossible to obtain the highest level of current evidence on the conditions and techniques. Another limitation of the narrative review was the inability to locate all the relevant literature or to cover the scientific literature without bias. Moreover, since half of the publications covered in this review were conducted as recently as after 2020, more data on this issue might emerge in the next few years, and the review may need to be updated fairly soon. Second, we did not consider any important parameters of spinopelvic alignment other than the PI, specifically, lumbar lordosis, the pelvic tilt, the sacral slope in the sagittal plane, and lumbar scoliosis (i.e., the cobb angle) and pelvic obliquity in the coronal plane. Although correlations between these parameters and the PI have been reported, the distribution of these parameters varies among reports , which may result from genetic and environmental factors . These are important factors to investigate to understand the relationship between HOA and spinal alignment, i.e., the pathophysiology of hip-spine syndrome, and they will be the subject of future studies. In addition, the PI was found to be associated with sagittal spinopelvic kinematics: a larger PI is related to higher lumbar flexibility and vice versa . However, recent research has found an exception: some HOA patients have a lower PI, high lumbar lordosis, and high lumbar flexibility. Although the PI seems to be a leading predictor of sagittal spinopelvic kinematics, this exception may make it difficult to clarify the relationship between the PI and HOA. Third, a deformity or dislocated hip and the degeneration of the sacroiliac joints, which affect the PI, have not been fully investigated. In HOA, the deformity or dislocation of the femoral head often results in a "decreased vertical pelvic shift," which, theoretically, can increase the PI since the center of the femoral head (the hip axis) is often displaced in the cephalad direction. In addition, "increasing sacroiliac joint angulation" can increase the PI in cases of sacroiliac joint degeneration . The clarification and stratification of the subject will be important for future studies to understand the relationship between the PI and HOA. Fourth, there were numerous reports from Japan. Several studies have reported that primary HOA is rare in the Japanese population and that it is mostly secondary to DDH, and racial differences in other countries have been noted . In addition, anatomical morphology and the PI were reported to vary by ethnicity. Moreover, although the majority of the HOA patients reported in Japan were women, several studies comparing the PIs of women and men have shown no significant difference between the two groups . Fifth, there may have existed a reporting bias, as some of the included studies reported having financial conflicts of interest. Finally, since the subjects in this study were of middle or older age, and the PI is usually measured in the standing position, it is possible that their PIs were artificially high. Despite these limitations, our findings may help to further understand the relationship between the PI and HOA. They should be of interest to orthopedic surgeons and other healthcare professionals involved in musculoskeletal medicine. 7. Conclusions The PI is the most important parameter for understanding the pathophysiology and mechanisms of hip-spine syndrome and for determining the treatment strategies for hip-spine syndrome. Because of the close relationship between the hip and the spine, orthopedic surgeons should always consider the spine when considering the hip and vice versa while simultaneously noting the PI. An increased PI has also been observed in the evolution of bipedal locomotion in human evolution, in the acquisition of walking during child development, and in the standing posture of older individuals. While the PI may be associated with a greater risk for the development of or progression to spinal disorders, the association between the PI and hip disease remains controversial. It should also be noted that the cranial shift of the hip axis due to the destruction and subluxation of the femoral head with advanced HOA and sacroiliac joint angulation changes due to the accelerated degeneration of the sacroiliac joint with advanced HOA, theoretically, may increase the PI. Since the factors and phenotypes of HOA are diverse, more cases need to be investigated with stratification by HOA type before conclusions can be drawn on the relationship between HOA and the PI. Further investigation on this topic is therefore warranted. Author Contributions Conceptualization, T.M. and T.K.; methodology, M.T. and T.K.; software, T.K.; validation, T.K. and T.Y.; formal analysis, T.M. and Y.T.; investigation, T.M. and T.K.; data curation, T.M. and T.K.; writing original draft preparation, T.M.; writing review and editing, H.H. and M.M.; supervision, M.M.; project administration, T.M. and T.K. All authors equally contributed to this work (including writing and preparing the manuscript). All authors have read and agreed to the published version of the manuscript. Institutional Review Board Statement Not applicable. Informed Consent Statement Not applicable. Data Availability Statement Not applicable. Conflicts of Interest The authors declare no conflict of interest. Figure 1 Sagittal model of pelvic incidence. Three schematic steps are depicted: a theoretical ancestral stage (30deg), an australopithecine stage (50deg), and an extreme range for humans (80deg). Adapted from ref. with permission from Elsevier. Figure 2 "Increasing sacroiliac joint angulation" associated with lumbar kyphosis, posterior pelvic tilt, and sacroiliac joint degeneration. (a) Pelvis tilted posteriorly with lumbar kyphosis. (b) The trunk tilts forward, and the sacrum tilts forward, "increasing the angle of the sacroiliac joint" and resulting in a higher PI. Reference are cited and modified with permission from the editorial office of the Journal of Spine research. Figure 3 Development of dysplasia of the hip with varying severity. (a) Dysplasia of the acetabulum with pelvic incidence of 46deg. (b) Dysplasia of the entire pelvis from the acetabulum to ilium (iliac wing curved inward) with pelvic incidence of 52deg. Figure 4 Stress concentration on the femoral head with greater PI, lumbar kyphosis, and posterior pelvic tilt. A case with greater PI, lumbar lordosis, and pelvic forward tilt (left) may have a relative decrease in anterior coverage of the acetabular head and increased abnormal stress on the head when the lumbar spine becomes kyphotic and when pelvis tilts posteriorly due to age-related degeneration (right). jcm-12-02034-t001_Table 1 Table 1 Summary of the results. Reference Nationality Inclusion Number Age; Mean +- SD (Range) Sex; Men, Women PI; Mean +- SD PI; Range France HOA 50 64 (47-81) 26, 24 56.04 40-87 China HOA 58 59.0 +- 11.9 N/A 49.0 +- 10.8 N/A France HOA 30 59.5 +- 15.6 (25-81) 12, 18 56.3 +- 11.5 35.1-81.4 Turkey HOA 28 60.9 +- 7.3 (50-76) 11, 17 50 (35, 60) # Iran HOA 95 68 (43-93) 50, 45 56.0 +- 12.8 33-96 USA HOA 1088 64.1 +- 10.4 557, 531 56.0 +- 11.5 N/A Poland HOA 50 N/A N/A 50.9 19.7-78.4 USA HOA 136 56.8 +- 10.8 (16-86) 77, 59 60.6 +- 12.0 N/A Canada HOA 52 63 +- 11 (38-82) 20, 32 57 +- 12 31-89 Japan HOA 4 61.0 +- 11.1 30, 120 58.5 +- 14.0 29-90 DDH 146 Japan HOA 64 65.5 +- 13.4 (27-86) 14, 60 54.7 +- 13.6 18-92 ONFH 13 Japan HOA 70 75 +- 4 0, 70 55 +- 14 N/A RDC 44 79 +- 5 0, 44 58 +- 16 Japan HOA 77 62.2 +- 12.8 (21-84) 73 48.3 +- 15.8 18-70 Japan DDH 100 65.5 +- 10.3 14, 86 53.7 +- 10.0 N/A HOA 100 61.0 +- 9.3 9, 91 52.3 +- 10.4 Japan HOA 945 64.4 +- 9.9 (34-89) 141, 804 53.3 +- 11.0 27-84 Japan DDH 78 53.6 +- 12.9 21, 102 48.0 +- 8.9 N/A HOA 8 ONFH 10 Others (RDC, trauma) 6 Japan DDH 213 74.5 +- 7.0 30, 243 57.0 +- 13.9 N/A HOA 60 Japan HOA 25 71.9 +- 6.4 4, 21 45.8 +- 10.0 41.6-49.9 RDC 34 74.6 +- 8.1 1, 33 49.6 +- 11.6 45.6-53.6 HOA represents hip osteoarthritis, DDH represents developmental dysplasia of the hip, RDC represents rapidly destructive coxarthrosis, ONFH represents osteonecrosis of the femoral head. # Median (interquartile range 25th, 75th percentile). 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- The authors may consider rewording "significant changes" and instead provide detail about the direction i.e., decreased. - Could the authors please provide a brief explanation of how reliable change and recovery were calculated? Was this the RCI or a percentage change? Introduction - The introduction may benefit from combining the first two paragraphs together. Furthermore, could the authors please explain how recovery was conceptualized by the studies mentioned? - The authors argue that previous studies of psychotherapy for GAD in routine care are limited by their strict treatment protocols. Did the current study have unstandardized treatment protocols? One could argue that psychology training clinics have rather strict protocols as the trainee psychologists are under close supervision and are often following treatment manuals. - One strength of this paper is their investigation of IU and metacognitions as predictors of change in a naturalistic setting. However, the authors do note that previous studies have already examined predictors of change in GAD in naturalistic settings. The introduction could benefit from highlighting how the current study differs from these previous studies (refs 44-47). Method - The treatment duration of M = 51.4 sessions is long, particularly for exposure therapy or cognitive restructuring. Could the authors please provide the average session duration for each of the treatment approaches (perhaps the primary treatment type)? - A sample of 59 participants is small for predictor analyses. Could the authors provide a power analysis or reference which justifies the use of n = 59 participants for these analyses? - How did the authors conduct multiple imputation? What predictors were used to generate the replacement values? - The authors may reconsider the use of repeated-measures MANOVA for treatment outcome and instead use mixed linear models or generalized estimating equations, as is standard in current psychotherapy research. For reference, see doi: 10.1001/archpsyc.61.3.310. Discussion - The authors state that this study provides insights into the effectiveness of CBT. They may reconsider replacing "CBT" with the umbrella term "psychotherapy" considering the diversity of treatment protocols included in the study. ********** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose "no", your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? 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Please note that Supporting Information files do not need this step. 10.1371/journal.pone.0282902.r002 Author response to Decision Letter 0 Submission Version1 14 Feb 2023 Editor's comments: 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at and Our response: We have revised our manuscript accordingly. 2. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For more information on unacceptable data access restrictions, please see In your revised cover letter, please address the following prompts: a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially sensitive information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. For a list of acceptable repositories, please see We will update your Data Availability statement on your behalf to reflect the information you provide. Our response: We have added a paragraph in the cover letter to clarify why we cannot publicly share the data for the study, even though we acknowledge and support the benefits of open data sharing. 3. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide. Our response: It seems that we made this statement by mistake. As stated above, it will not be possible for us to share the data in a public repository. Our apologies for any confusion caused. 4. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: Our response: We have included captions for our Supporting Information File at the end of the manuscript. Reviewers' comments: 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: This is a well-written paper that could surely contribute to the existing literature, however I have some suggestions to be addressed. First, some comment on the authors' methods is necessary as to why they chose to evaluate participants using the DSM IV as opposed to the DSM V (timeline etc.). Second, some self-report measures were employed in this study and other research shows us that these can sometimes be unreliable for various reasons. Should this be noted as a partial limitation of the study? Overall, this is a high quality manuscript fit for publication if these concerns are adequately addressed. Our response: 1. We thank the reviewer for their positive feedback. Given that the German version of the structured clinical interview for DSM (SCID) based on the DSM-5 was only published in 2019, we used the DSM-IV-based SCID for the entire study. In response to this comment we now clarify in the manuscript that we used the DSM-IV-based SCID for the entire study (page 6). 2. We agree that self-report questionnaires can be prone to bias. We have added a section on this limitation in the discussion section (page 18). Reviewer #2: Abstract - The authors may consider rewording "significant changes" and instead provide detail about the direction i.e., decreased. Our response: We have adjusted this part of the abstract to clarify the direction of the effects. - Could the authors please provide a brief explanation of how reliable change and recovery were calculated? Was this the RCI or a percentage change? Our response: Thank you for this inquiry. For the calculation of the number of participants with reliable change and recovery, we relied on data from Fisher (Fisher PL. The efficacy of psychological treatments for generalised anxiety disorder. In: Davey GCL, Wells A, editors. Worry and its psychological disorders. Theory, assessment, and treatment. West Sussex: Wiley & Sons; 2006. pp. 359-77). In his reanalysis of five RCTs with n = 223 participants, a RCI greater than +- 1.96 corresponds to a 7-point change on the PSWQ. In our study, we classified the participants with a change in PSWQ >= 7 as those with reliable change. Accordingly, we used the calculated cut off score of recovery from the same review and counted how many of our participants reached a PSWQ score of 46 or below at post-assessment. We have rephrased the method section to make it clearer that we did not calculate a reliable change index based on our data (page 12). Introduction - The introduction may benefit from combining the first two paragraphs together. Furthermore, could the authors please explain how recovery was conceptualized by the studies mentioned? Our response: We have combined the paragraphs and rephrased the sentence to point out that recovery was based on the score in self-report questionnaires. - The authors argue that previous studies of psychotherapy for GAD in routine care are limited by their strict treatment protocols. Did the current study have unstandardized treatment protocols? One could argue that psychology training clinics have rather strict protocols as the trainee psychologists are under close supervision and are often following treatment manuals. Our response: Thank you for this comment. We have added a sentence to the manuscript (page 8) to clarify, that they were free in consultation with their supervisors, to combine methods from different treatment approaches. The final treatment reports yielded that they made use of this possibility. Therefore, we see our setting as rather unrestricted; especially in comparison with RCTs with often strict treatment protocols structuring each session. - One strength of this paper is their investigation of IU and metacognitions as predictors of change in a naturalistic setting. However, the authors do note that previous studies have already examined predictors of change in GAD in naturalistic settings. The introduction could benefit from highlighting how the current study differs from these previous studies (refs 44-47). Our response: We have reworded the end of the paragraph on previous studies (refs 44-47) concerning predictors of change in GAD to highlight the gaps in the literature that our study contributes to fill. Method - The treatment duration of M = 51.4 sessions is long, particularly for exposure therapy or cognitive restructuring. Could the authors please provide the average session duration for each of the treatment approaches (perhaps the primary treatment type)? Our response: We agree that an average of just over fifty therapy sessions is long and we would have liked to provide information on the differences between the different treatment approaches. Unfortunately, we only have three treatments in which only one of the approaches was used. From the final treatment reports, it was not possible to determine which was the primary treatment type. As is often the case in naturalistic therapies, the therapists used an eclectic approach and mixed different interventions. Therefore, unfortunately, we cannot report the duration of the treatment for each approach. - A sample of 59 participants is small for predictor analyses. Could the authors provide a power analysis or reference which justifies the use of n = 59 participants for these analyses? Our response: We appreciate the prompt to the rather small sample size of n = 59 for predictor analysis in our study. Due to the inconclusive findings in the literature concerning predictors of treatment outcomes in GAD, we decided to run an exploratory regression analysis and did not compute an a priori power analysis. However, as suggested we have added a post-hoc power analysis to our manuscript (page 15) based on the final model of the regression analysis and also added confidence intervals for the R2 to reflect the uncertainty of our results. Based on our data, we calculated a power of .78 to detect the effect of the lower confidence interval for total R2. This is just below the .8 value that is normally considered acceptable power. We also added a sentence in our discussion section to highlight the importance of larger sample sizes in future studies to enhance statistical power and solidify the findings presented. - How did the authors conduct multiple imputation? What predictors were used to generate the replacement values? Our response: Thank you for this valuable comment. We added some more specific information on the imputation model and the auxiliary variables which were used to impute the missing values. In general, we followed the instructions by Enders et al. which are already mentioned in the manuscript. We added the following sentences (page 11): We included all variables within the data set correlating >= +-.40 with one of the variables with missing values or with the missing variables (which indicate whether a data point is missing) as auxiliary variables into the imputation model. Further, we included variables which showed a significant univariate t-test and thus indicating statistically significant differences between participants with vs. without missing values. - The authors may reconsider the use of repeated-measures MANOVA for treatment outcome and instead use mixed linear models or generalized estimating equations, as is standard in current psychotherapy research. For reference, see doi: 10.1001/archpsyc.61.3.310. Our response: We recognize that mixed linear models or generalized estimating equations are commonly used in current psychotherapy research. However, we carefully considered the assumptions and limitations of different analysis methods in consultation with statistical support and determined that repeated-measures MANOVA was an appropriate choice for our study given the research questions, structure of the data, sample size, and ability to compare with previous studies. In addition, our analyses are clear and simple, making them accessible to a wide audience, including non-statisticians. This is crucial, because one goal is to provide practical recommendations for routine psychotherapy. Discussion - The authors state that this study provides insights into the effectiveness of CBT. They may reconsider replacing "CBT" with the umbrella term "psychotherapy" considering the diversity of treatment protocols included in the study. Our response: We appreciate the reviewer's concern regarding the use of the term "CBT". We understand CBT as a comprehensive approach in psychotherapy, including for example the third-wave method of MCT. We have thoroughly reviewed the manuscript and taken steps to clarify our definition of CBT. Since we have not included other approaches, such as psychodynamic or systemic therapy, we prefer to avoid using the broader term "psychotherapy" to avoid any misunderstandings. We also made a minor adjustment consisting of the inclusion of the category "divorced" in Table 1 on page 6 of the manuscript. Finally, we would like to thank you for your efforts and attentive comments on our manuscript. We feel that our manuscript has improved greatly with your input. We hope that we have adequately addressed your concerns and that you may consider the manuscript for publication. Attachment Submitted filename: Response to Reviewers.docx Click here for additional data file. 10.1371/journal.pone.0282902.r003 Decision Letter 1 Doering Stephan Academic Editor (c) 2023 Stephan Doering 2023 Stephan Doering This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version1 27 Feb 2023 Psychological interventions for generalized anxiety disorder: Effects and predictors in a naturalistic outpatient setting PONE-D-22-24983R1 Dear Dr. Buhlmann, We're pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you'll receive an e-mail detailing the required amendments. 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Kind regards, Stephan Doering, M.D. Academic Editor PLOS ONE 10.1371/journal.pone.0282902.r004 Acceptance letter Doering Stephan Academic Editor (c) 2023 Stephan Doering 2023 Stephan Doering This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 2 Mar 2023 PONE-D-22-24983R1 Psychological interventions for generalized anxiety disorder: Effects and predictors in a naturalistic outpatient setting Dear Dr. Buhlmann: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. 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9 11 r n n s LETTER FROM PARIS. Paris, November %4.th, 1867. The Bulletin de Therapeutique has contained in its three last numbers an extremely judicious essay on DELIVERY OF THE AFTER-BIRTH in cases of miscarriage, of which it is worth while to give you an abstract. Dr. Gueniot, the author, observes that among other differences between a miscarriage and a regular labor, it is noticeable that in the former, the expulsion of the foetus and detachment of the placenta begin to take place at the same time, instead of constituting two orders of phenomena distinct, as in the latter case. Hence in abortion, hemorrhage is associated with the uterine contractions, their entire duration. On the other hand, the complete separation of the placenta is tardy of accomplishment, since the adherences are relatively more solid during the first months of gestation, and the power of the uterus little developed. Moreover, even when the placenta be entirely detached from the uterus, the length and firmness of the neck of the womb opposes unusual obstacles to the expulsion of the after-birth. In view of all these , it is easy to see that the danger of miscarriage belongs, not to the movement of the expulsion of the foetus, which is usually unaccompanied by any difficulty, but to the separation and expulsion of the placenta. During this period, the patient is exposed to accidents resulting either from , or from retention and decomposition of the placental mass. Putrid infection, metritis, anemia, nervous exhaustion, shiverings, fever vomiting, dysuria, and various neuralgias may be expected in this connection. Finally, uterine phlebitis and metastatic abscesses may complicate a miscarriage, as in an unfortunate patient observed by Dr. Gueniot at the maternitd. The therapeutic problem suggested by the consideration of these possibilities, consists in determining the line of conduct required in different cases of miscarriages, to favor the complete repulsion of the placenta and its membranes, and to combat the various accidents which may have been determined by their retention. The necessities of the case vary greatly, according to the period of gestation, at which the miscarriage has taken place. During the first two months, if the placenta be not expelled together with the embryon, its spontaneous delivery is extremely slow, and the process may be prolonged twTo days, without entailing any danger upon the patient. Until, , the period has elapsed, the physician is not called upon to interfere, unless in case of accident. During the third and fourth month, the membranes are ordinarily ruptured at any early stage of the labor, before the placenta be completely detached, or the os sufficiently dilated. On this account, the placenta is expelled after the foetus; but the limit of safety in the delay must be shortened to hours. Finally, in the fifth and sixth months, so much greater facilities exist for the expulsion of the after-birth, that its retention must be considered abnormal if it last more than twelve hours for the fifth, or six for the sixth month. The precision of these limits is of the utmost importance, as then it affords the physician the first indications for deciding whether to intervene with the resources of art, or permit nature to take its course. The author then classifies abortion into five types: 1st. The abortion has taken place, the delivery of the placenta has not, or it is incomplete, and no accident has occurred. 2d. Same situation as the above, but complicated by . 3d. Abortion is complete, but tl\p physician is in doubt whether the placenta be expelled or not. 4th. Foetus and placenta had both been expelled, but have occurred claiming intervention. 5th. Finally, abortion has not yet occurred, but it is to be inevitable. In the first case, as soon as the time fixed for the normal expulsion of the placenta has been overpassed, the physician has reason to certainly anticipate accidents, even if they have not already occurred. Moreover, the divers methods of will become difficult of employment with every moment of delay, consequently, the indications for prompt interference are sufficiently pressing. On the other hand, this interference is always accompanied by certain dangers, and the decision for action or inaction, must in each case be based on a special between present inconveniencies and future perils. It is certain, in all cases, that immunity from accident during several days retention of the placenta can only be observed when it has remained nearly completely adherent; as soon as it begins to separate, it is liable to putrefy. The danger varies, moreover, according to the different periods already described. In the first, the small development of the uterine vessels saves the patient from the chance of dangerous hemorrhage, and the small size of the placenta renders its putrefaction a matter of less consequence. Hence chills, fevers, a certain pallor of the face, diarrhoea, and dryness of the tongue, are generally the greatest accidents to which the patient is exposed. Consequently, in view of the various inconveniences of active intervention, it is better for the to restrain his efforts to vigilant surveillance, in all cases of retention of the placenta after abortion, occurring in the two first months of gestation. During the second period of gestation, the hemorrhage, though much more abundant, can still be readily mastered, by means of the vaginal tampon. But, after expulsion of the foetus, the os contracts promptly, and speedily opposes a serious obstacle to the natural or artificial delivery of the placenta. A considerable mass is retained to putrefy, and may occasion a mortal infection. Hence the indication is urgent to deliver the woman artificially, as soon as possible, after twenty-four hours have elapsed without spontaneous delivery. M. Gueniot then reviews the various agents proposed for effecting this delivery. He rejects traction on the umbilical cord, on account of its fragility. He admits that the index finger may occasionally be employed, but it is necessary the uterine neck be sufficiently open to give free passage to the finger, that the vagina permit the entrance of the hand, to the close vicinity of the os; finally, that it be possible to separate the placenta en masse. The first condition is extremely rare a few hours after , and never exists after several days. The realization of the second occasions great pain, and exposes the patient to and lacerations. Finally, the third, the most important of all, is necessarily problematic. Hence the finger is to be regarded as a precarious resource. Pincers, curettes, hooks, are all more or less dangerous. Intra-uterine injections can only be employed with a return-current, which greatly their efficacy. Having thus reviewed these various agents, M. Gueniot excludes them all in favor of three, upon which he places immense reliance, the prepared sponge, the uterine dilator, and the ergot of rye. The dilator, you know, consists of a small India-rubber bag, introduced into the uterine cavity in a collapsed form, and then filled out with warm water. This, in virtue of a continued irritation produced on the internal sphincter, provokes uterine contractions nearly inevitably at the end of several hours. The bag constitutes an artificial substitute for the natural membranes that have been prematurely ruptured, and its action imitates nature as closely as possible. Not only provokes uterine , but it mechanically enlarges the os, and, moreover, performs the office of a tampon in moderating the hemorrhage. For this last purpose, however, the caoutchouc bag is no more infallible than the embryonic mass itself. M. Gueniot the dilator one of the most precious means for provoking the delivery of the placenta. Where the prepared sponge is inserted in the uterine neck, it is recommended to accompany it by a vaginal tampon, as better security against hemorrhage. Finally, ergot may be administered in doses of two grammes, (thirty-two grains,) and on M. Gueniot's testimony, is certain to determine uterine contractions in from twelve to eighteen hours. If the action is not sufficiently marked after the first dose, sixty centigrammes more may be given, which generally determines a prompt separation of the placenta, and its through the os. Sometimes, unfortunately, the ergot occasions a tetanic of the neck, and complete imprisonment of the placenta. This accident, however, rarely occurs during the first half of gestation. On the other hand, a uterus exhausted by long labor, is peculiarly liable to ergotic tetanus. The must be combated by baths, emollients, and narcotics. Since ergot alone does not prevent hemorrhage, a tampon must always be at hand, to provide against this latter exigency. M. Gueniot ranks the foregoing agents in the order in which I have specified them; and considers the use of the finger, or of intra-uterine injections as ultimate resources, to be appealed to only when others fail. In abortions of the fifth and sixth month, the accidents by the retention of the placenta are nearly as formidable as at term. In this case, the dilatability of the vagina and of the os enables the placenta to be directly extracted by the hand, and this proceeding is indicated as soon as the delay of twelve or six hours has been overpassed. In the second class referred to above, where accidents exist, these demand attention before everything else. Whether the normal delay be accomplished or not, it is incumbent on the physician to intervene in the artificial extraction of the placenta as soon as abundant hemorrhage or signs of purulent injection are manifested. If the placenta be only partly engorged in the os, and its principal portion be retained above the internal sphincter, it is better to have recourse to ergot than to traction, which may tear the mass. In case of hemorrhage, ergot should be conjointly with the tampon. In case of purulent infection, ergot and intra-uterine injections, with internal tonics. Ergot should not be employed if the purulent infection dates from several days, as, in that case, the uterus may be considered to be stupefied and paralyzed. In the third case, the doubt concerning the expulsion of the placenta will be removed if accidents occur, or if, after prolonged waiting and repeated examinations, there is no . In the fourth case, since by the supposition the accidents are supposed to exist after the expulsion of the placenta, this becomes a problem of general therapeutics. In the fifth case, as soon as the miscarriage is recognized to be inevitable, the physician should endeavor to favor its . SPONGE-PESSARIES. The distinguished physician, Guendan de Mussy, also a note to the Bulletin, on the use of sponge-pessaries, of which he highly approves. He remarks that a reaction has taken place against the exaggerated ideas of physicians some years ago, who regarded all deviations and flexions of the uterus as pathological conditions requiring active medical . But the reaction has carried opinion as much too far the other way, and it is too often ignored, these anomalous positions may seriously derange the circulation, or, in patients, determine all sorts of sympathetic neryous affections. The pessary comforts the patient, and if it does not cure the disease, at least puts the organ into favorable . Where the uterus is conical, the sponge should be depressed in the middle, like a mushroom, to receive the neck. In cases of retroflexion, the sponge should be spread out in a fan-shaped form, having a central prominence to support the museau de tanche, while the limb of the fan sustains the cul-. It is recommended to coat the lower third of the sponge with yellow-wax, to render it impermeable to the urine. The wax should be melted, the sponge immersed in it, and allowed to cool, and again immersed, and so on until a thick coat be formed. TREATMENT OF DYSENTERY. Dr. Beaufort has presented several considerations on the treatment of dysentery, which disease he considers to be allied, as to its cause, with intermittent fever. Both depend on the combination of heat and damp in the weather. If dampness is occasional, and heat intense and constant, fever is produced; if the dampness is constant, and the heat liable to brusque variations, dysentery occurs. The cause is the effluvia from decomposing vegetable matter. One of the first phenomena is congestion of the system of the portal vein, and relief of this congestion constitutes the ultimate therapeutic indication. In the treatment of dysentery, it is necessary, first, to empty the large intestine of altered and irritating mucus, by means of evacuants and absorbing , (chalk and subnitrate of bismuth;) second, coagulate sanguinolent and albuminoid matters on the surface of the intestine, by means of injections of neutral perchloride of iron, ten to twelve drops in half a lavement of warm water, repeated two or three times in the twenty-four hours. By this means the mucous membrane becomes protected and enabled to heal. Third, diminish congestions of the portal system, sometimes by leeches at the anus, but principally by the use of ipecacuanha, which acts as a stimulant to the vaso-motor system. GANGRENE OF TIIE MOUTH. Dr. Leavit reports a case of gangrene of the mouth occurring in a child of three years old, already affected with tuberculous enteritis, and which he succeeded in curing by the application of creosote in which camphor had been dissolved. The disease commenced with two ulcerations, round, hollow, white, which were situated in the gingivo-labial fold. Their contents were characteristic, grumulous, dry, and white. In twenty-four hours the ulcerations had greatly extended, were black at the periphery, grumulous at the centre, the mucous fold toward the nose was profoundly excavated, the gum superficially destroyed in an extent of fifteen millimetres, and a fistulous point existed under the lip. An odor of gangrene was exhaled. On this day, for the first time, three cauterizations were made with the camphorated creosote. The next day notable amelioration, inflammatory reaction. In the evening, cauterization with camphorated creosote diluted with alcohol. Two more cauterizations and several with the diluted fluid were made subsequently, and ten days after the first, the cure was . CROUP CURED BY TRACHEOTOMY. At the Societe des Hopitaux on the stance of the 8th, M. Roger mentioned a case of croup cured by tracheotomy. days elapsed before the canula could be withdrawn, for the child immediately exhibited symptoms of suffocation as soon as the attempt was made. Recourse was at last had to of the larynx, and from the day of the first application of electricity, the little patient was able to breathe without the canula during the day, if only it was replaced at night. The tube was not definitely withdrawn till a month after the . At Hotel Dieu, M. Moissenet has had a case of membranous angina confined to the right tonsil. This organ was covered with a thick layer of membrane, having a fetid odor. The was overcome by applications of tincture of iodine. M. Moissenet considers diphtheria less dangerous when it attacks the tonsil, than when it invades the soft palate. Also at Hotel Dieu, M. Isambert, in speaking of a slight epidemic of small-pox that had occurred in his wards, took occasion to praise highly the use of repeated warm baths, which he did not fear to commence even during the period of the eruption. The warm bath, (given of course in the ward,) has the advantage of diminishing the burning heat of the skin, the inflammatory areola which surrounds the base of the papulae, without hindering their suppuration. The seems to be less deep and indelible. Emunction with mercurial ointment, was also found to be very useful in cicatrices on the face, without occasioning the painful determined by collodion. At the Hospice des Incurables, recently died a patient affected with leurocythemia. At the autopsy, the spleen the following diameters. Vertical 32 centimetres, 22, antero-posterior 19. It weighed two kilogrammes, its tissue was softened, and contained an infarctus. The liver also was hypertrophied. The kidneys the seat of fatty , although no albumen had been discovered in the urine. The heart was fatty, and the large vessels filled with clots. Some granulations existed on the mucous surface of the large intestine, and two infarctus in the duodenum. M. Dumontpallier communicated a case of severe hiccup, which was finally cured by electricity. One pole of the battery was placed on the cervical vertebrae near the origin of the phrenic nerve, the other on the border of the cartilage of the last ribs towards its sternal extremity. Hardly had the current traversed the chest, when the patient uttered a loud cry, the hiccup became transformed into a sob, and ceased abruptly. It reappeared two hours afterwards, and yielded again to , complete interval of nine days, then the hiccup reappeared during several hours, but this time was definitely cured by . Med. and Surg. Reporter. |
ARTIFICIAL PROCIDENTIA UTERI, AS A MEANS OF MORE EFFECTUAL TREATMENT OF CANCER OF THAT ORGAN. By E. F. GORDON, M.D., Mobile, Ala. In proposing such an extreme plan, I am aware that I am running counter to the experience of distinguished men, and to the present teachings of surgery and medicine. Let us for a moment review the history of the course and treatment of cancer of the womb, as we ordinarily meet with it. We are summoned to take charge of these cases usually, when the pains, hemorrhages, and putrid discharges alarm our patients. It is the fate of our laboring classes that, as their hardier frames bear pain better, we rarely see them until the disease is far advanced. The two forms of carcinoma, fibrous and , are unfortunately common, and the latter strides on with fearful rapidity. The epithelial, first described by Sir Charles Clark, as the cauliflower excrescence, pours out at an earlier period a profuse serous discharge, oftentimes acrid, but not at that stage offensive, and in this way, and from the fact of its slower march, is oftener seen by the physician while yet confined to the original cervix. It is unnecessary here to enter into the pathology of this neoplasm. Whether it is, according to Chambers' view, a of vital force which equally predisposes to the deposition of tuberculous and cancerous matter, by degeneration of the blood, it is only too well known that its progress is always towards destruction. Those of us who are in daily contact with this disease, are familiar with its loathsome train of symptoms, and with the inevitable result, sooner or later, but generally after two years of terrible suffering. The standard authorities advise for treatment that we to improve the general health by bitter tonics, and to confine ourselves to allaying pain by anodynes, checking by astringents and the tampon, and keeping down offensive odors by chlorinated washes. In former times, was occasionally practised, and an exclusive vegetable diet was recommended by Dr. Twitched of New England, from the result of a case under his treatment, but I fear it only adds to the broken-down condition of the patient. Internally, all the more powerful articles of the Materia Medica (arsenic hardly yet abandoned) have been tried and found wanting. Locally, the actual cautery, Vienna paste, chloride of zinc, chromic acid, bromine, and latterly the of cancer cells, such as acetic, citric, and carbolic acids, have been, by turns, the favorite, but have failed in the end to justify the anticipations of their advocates. Excision of the cervix has been tried extensively by the French surgeons, and in a more restricted way by others. But the task is so , and so dark with painful forebodings, that we shudder when we are summoned to take charge of such a case, and to bid our patients, like the Third Richard, "despair and die." It is with a desire of abridging such scenes as this, and, if possible, to place the uterus in a position where it can be daily inspected and rationally treated, that I have to propose the induction of procidentia by artificial means. Is there anything in the anatomical relations of the uterus to forbid the effort? Bear with me while I condense a of these relations. This organ is attached to the bladder and rectum by folds of the peritoneum, which are sometimes called the anterior and posterior ligaments. The peritoneum reflected upwards covers the anterior and posterior surfaces of the uterus enclosing the organ between two of its layers. These layers meet together at the sides of the uterus, and pass off to the lateral walls of the pelvic cavity, dividing the pelvis transversely. In this way the peritoneum forms the principal part of the broad ligaments. The fibrous or muscular structure of the uterus itself also extends into these ligaments. They contain besides the Fallopian tubes, the ovaria, the round ligaments, with bloodvessels, nerves, and lymphatics. The round arise from the upper angles of the uterus in front of the Fallopian tubes. From this origin, each ligament passes to the inguinal ring, descends the inguinal canal, turning round the epigastric artery, and its fibres are inserted into, or are mixed with, the structures of the mons veneris. The length of the round ligaments is from four to five inches. The external traverse fibres of the proper substance of the uterus are prolonged into the round ligaments, of which they form a constituent part. Some fibres of the internal oblique muscle also enter the lower part of the canal, and extending upwards, contribute to the formation of the ligament. The ovaria are connected with the uterus at the point of insertion of the Fallopian tubes by a fibro-cellular cord or ligament, from the proper substance of the uterus (Tyler Smith). The womb rests upon the upper end of the vagina, which its cervical or neck portion, and keeps it up in its place, by means of its connection with the bladder in front and the rectum behind, and more than all, by two utero-sacral , which tie the upper ends of the vagina and womb to a certain place about an inch and a-half in front of the apex of the sacrum. As long as the utero-sacral ligaments remain in a healthy state, preserving by their tone a due length, the womb cannot fall downwards or prolapse, because the cervix, being within the upper end of the canal of the vagina, cannot move down unless the upper end of the vagina move down also. Prolapse pulls upon and stretches all the ligaments the broad ligaments by far the most. The vagina suffers displacement proportionally with the prolapse. It is inverted, its walls being doubled upon themselves, and its cavity progressively shortened until it is entirely effaced. This displacement is always in a direction corresponding with the axis of the vagina and different portions of the pelvis, and follows the curve formed by the hollow of the sacrum and continued by the perineum (Byford). There is nothing then to prevent prolapsus of the uterus but the tonicity of the ligaments suspending it, and holding it from above, and the vagina it from below. When the uterus is enlarged and presses down, and when the ligaments are relaxed and by long-continued strain, or an impoverished condition of the system, prolapse is apt to occur spontaneously. "Does the disease itself (cancer) change the parts so early as to make the effort dangerous?" There is a singular unanimity among writers as to the part in which uterine cancer begins, and from which it extends itself. Prof. Rokitanski, of Vienna, whom Simpson pronounces "perhaps the most experienced and profound morbid anatomist of the present day," says, "carcinomatous induration generally limits itself to the vaginal portion and cervix, and very often in a defined and sharp manner." In another paragraph, he remarks, "the primitive seat of cancer is always the cervix uteri, and first of all and particularly the vaginal portion. The primary appearance of cancer in the fundus uteri is limited to so extremely rare cases, that what we have just said remains one of the most fixed rules. It forms," he adds, "in this respect, a contrast with fibrous and tuberculous tumors of the uterus." "Uterine cancer," says Prof. Walshe, a very high authority, "is commonly primary, and possessed of comparatively slight tendency to contaminate the system generally." And again, "there can be no question that the womb ranks among those organs less prone than certain others, as, for instance, the mammae and testes, to contaminate the distant viscera. Among thirty-seven females dying of uterine cancer, and examined by M. Ferrus, seven only exhibited secondary formations 'here." Scanzoni remarks, and his experience is worthy of attention, for he has tabulated one hundred and eight cases treated by himself in eight years: "Among all the parts of the uterus, it is almost exclusively the vaginal portion which is the starting point of the disease; in fact, although observations exist of cancers which are developed in the body, or near the summit of the uterus, while the neck was entirely untouched, or elsewhere, the infiltration was equally spread throughout the organ, such cases ought to be considered as rare exceptions." The progress of the growth is very generally from the neck upwards, and from the interior of the cavity outwards. It struggles on in this way for perhaps six months on an average, before the infiltrations extend to the vagina and peritoneum, and finally to the rectum, bladder, and inguinal glands. In younger persons, menstruation seems to hasten the , but after its cessation, at the change of life, the advance is slower. It is plain then that wTe must limit our efforts to produce artificial procidentia to the early period of this disease, while yet the uterus is moveable, and before the peritoneum is involved, as we would risk producing intense peritonitis by that membrane if diseased, besides the utter hopelessness of ultimate cure when the abdominal structures are already implicated. At this stage, too, you avoid the hemorrhage incident to bruising the fungosities, which, at a later period, shoot from the neck. The cancroid or epithelial form presents the most hopeful aspect, from its later tendency to deep ulcerations and adhesions. Its character is well given by Virchow, who first recognized it in the list of papillary tumors. Mayes says it is not a cancer, but a peculiar excrescence of the female genital organs. At first, it is purely local and nowise constitutional, but after a time it assumes a cancerous character. The papillae are covered with looped capillaries, which supply them with blood, and present that red strawberry appearance which bleeds on the slightest touch. Subsequently, cancroid deposits take place deeper among the muscular fibres and connective tissue. The scirrhus or fibrous comes next, and may, in a few instances, be seen early enough, but the encephaloid will be apt to have advanced so far as to baffle all our efforts, and to forbid the attempt to bring the organ down. I proceed to the next point the best plan of effecting . Two modes suggest themselves: one is to attach a wire to the cervix, by passing it around or through the latter, and by suspending a moderate weight to it, by which we may tire out the ligaments. This is open to the objection of being very slow and disagreeable, and confining the patient to the recumbent or sitting posture; and also that the wire might or cut out if much traction was necessary. A gum-elastic cup and cord might be substituted, by which, the air being exhausted, a firm but slight pull could be kept up, without the inconvenience of the wire and weight. The plan that seems to me most feasible, is to place the patient under the influence of chloroform, so as to obtain the double benefit of complete relaxation of the tissues, and the protection of the patient from the suffering and shock induced by the anaesthesia. By means of Museaux hooks, the uterus can be pulled down gently, following the axis of the pelvis and vagina until it reaches the vulva. This can be repeated two or three times a week, watching the effect on the patient, and endeavoring at each trial to protrude it a little further. In two months we might hope to establish complete procidentia, and accustom the patient to it, so as to avoid the sinking and nausea attendant on the operation. Large doses of opium such, as are used after ovariotomy and in puerperal peritonitis, might be resorted to for the purpose of establishing toleration, after the prolapse was obtained. Is extirpation of the cervix uteri necessarily dangerous? It will be remembered that this operation was first suggested in modern times, and performed by Osiander, of Gottingen, about the year 1822, and that soon afterwards it was brought into vogue by Lesfranc, who reported ninety-nine cases, with a loss, I think, of only fourteen. This was in a formal dissertation submitted to the French Academy. It will also be borne in mind that M. Panly, who was an interne at La Pitid at the time, proves conclusively that these statistics are entirely unreliable, many of the cases having been reported twice under different names, and a large number dying between the first and fourth day. Again, he furnishes a list of nineteen cases in private practice, where, under the same , the mortality was nearly one-half. This would seem to make against rather than in favor of the operation; but when we consider that, at that day, the of cancer was very imperfect, and that the cases were on without any reference to the stage of the disease, it is only a matter of surprise that so many of them should have recovered. It would seem that the operation had never attained any popularity in Great Britain until revived by Simpson, who eight cases, six of them successful, and only one proving fatal. Three of these cases cured were cancerous. So far as regards the dangers of the operation, Simpson remarks, that he has not met with troublesome hemorrhage, although using only the bistoury and scissors, and that the shock which is described as being so fearful, by many writers, did not occur in any of his cases. Chaissaignac, since the invention of his ecraseur, has again popularized the operation in France, and must have performed it many hundred times, extending its application to of the neck and even ordinary prolapsus. By his instrument all danger of hemorrhage is removed, and by the use of chloroform the shock is much lessened or entirely obviated. Dr. J. Braxton Hicks says, "he has operated or been present in more than twenty-eight cases, and has never seen any fatal result or any untoward symptom whatever." G-uy's Hospital Rejoorts. Any one who glances over the medical journals of late years, is struck with the frequency of this operation and how little danger is attached to it, and all the systematic treatises now recognize it as justifiable, not excepting Scanzoni, who is extremely conservative and cautious in recommending surgical interference. In point of fact, Sims' favorite operation of bifurcating the cervix for the cure of dysmenorrhoea is quite as severe, the incisions being as extensive, though in an opposite direction. I may add, that he seems to fear hemorrhage more than most surgeons, tamponining with perchloride of iron to prevent it, and cautioning against its removal or any exercise for three or four days. Can the uterus be removed without a fatal result? I do not wish to dispute the assertion that it is one of the most dangerous operations in surgery to attempt its removal in situ. Statistics conclusively prove that out of nineteen cases quoted by Breslau, two only had succeeded Langenbeck's and 's Sauteis is mentioned by some authors as a third, the patient died in a few weeks after of a colic. performed the operation three times, only once succeeding. His method of operating, by retroverting the organ and pulling it out by Douglas' cul-de-sac, seems to me the most feasible. I saw an uterus after it was extirpated by Dr. Paul Eve, then of Augusta, Ga., in 1850. The patient lived for several months afterwards, but died subsequently from a return of the cancer. Dr. Storer, of Boston, removed, last year, a large tumor, containing the womb arid appendages, from a patient who is represented to have madg a good recovery. In such a case you have many of the same difficulties to be overcome and dangers to encounter as in ovariotomy. Apart from the cases in which nature has done more than half of the duties of the operation, by precipitating the organ out of the vulva; by isolating it from the important parts with which it is in relation in the ordinary state; by having also prepared the way, by long habitude, for the void which the absence of the uterus occasions in the pelvic cavity. Apart from these cases, in which the ablation is easy and little , and attended with certain success, the extirpation of the uterus constitutes one of the most frightful operations, even to the rashest surgeon, and is the most dangerous to the patient. This is the admission of Duparcque, while denouncing the , and is well worthy of our attention. For if spontaneous procidentia deprives this most terrible ordeal of all danger, then we ought to imitate Nature's plan of effecting such a preparatory to the removal of the womb. Women have been known to cut off the prolapsed womb with an ordinary knife, and many surgeons have amputated the organ, to relieve patients from the inconvenience of the dragging and discharges, especially after inversion. Sims reports such a case in his late book, and Dr. Choppin, of New Orleans, relates a case of in the February Number of the Southern Journal of Medical Sciences, cured by ablation. He jestingly remarks that the woman was afterwards presented to the Class "with her womb in her hand," thus demonstrating that the uterus could be removed without causing death. The advantages, then, of treating uterine cancer by means of artificial procidentia are, that you can make your applications with more accuracy and certainty; that the vagina will be less excoriated by the discharges, and that adhesions cannot be formed in such a way as usually bind the womb above; that, day by day, you can watch the progress of the disease, and if you find it encroaching on the cervix, it can be cut olf in a few moments by the scissors, or more slowly by the ecraseur; and, lastly, if the cancer still advances and implicates the body, a way has been prepared for its entire removal. For I think the evidence is conclusive that toleration of the procidentia is equivalent to toleration of the operation for removal. Another point here comes up, the justification of any or all surgical operations in cancerous tumors. In 1850, I heard an able report read by Professor Mussey, of Cincinnati, against the propriety of such operations, founded on the experience of American surgeons, but I think quite a change has occurred since then in medical opinion. Mr. , of Guy's Hospital, London, published a paper in 1866, giving his experience in one hundred and fifty cases, covering a period of eighteen yeajrs. It is carefully prepared, and his deductions are given wit'll great circumspection and are entitled to much respect. He sums up by saying: "In conclusion, I trust that I have demonstrated to my skeptical professional brethren, that a certain proportion of cancer patients can benefit by submitting to the removal of the first growth of the disease, and that the benefit derived from the operation is two-fold, viz.: 1st, prolongation of life; 2d, exemption from disease for a considerable period of time in many instances." It may seem irrelevant or superfluous to have discussed the surgical questions alluded to in this essay, but I do not think artificial procidentia justifiable, unless surgical interference in all its various grades may be resorted to with propriety. To recapitulate. I have endeavored to show, 1st, that there is nothing in the anatomy of the parts to prevent the induction of procidentia, but that in fact it occasionally occurs . 2d. That in the early stage of cancer, adhesions do not exist to such an extent as to render it dangerous or : and, 3d. That applications of caustic can be made more accurately to the prolapsed organ; and that amputation of the cervix, and, in extreme cases, ablation of the entire uterus, can be practised with safety under these circumstances. I am aware that it may be said that all these operations can be performed without all this long preparation and infliction of suffering, but my own experience warrants me in saying that the old plan has invariably failed in our hands in arresting the disease, and anything that offers more chances of success should not be discarded without a fair trial. I am sorry, however, to be obliged to confess that this paper was prepared about eight months ago, and, during the interval that has elapsed, I have not found a case in a sufficiently early state of development to enable me to apply the proposed method. New Orleans Journal of Medicine. |
CASE OF GLANDERS IN THE HUMAN SUBJECT. By W. 0. BALDWIN, M.D., Montgomery, Alabama. [Read before the Montgomery Medical and Surgical Society.] On the evening of the 11th of May last, I received a from Drs. Tompkins, Townsend, and Roberts, requesting me to visit, in consultation with them, Mr. Eli Townsend, a highly respectable citizen, living at China Grove, Pike County distant about 38 miles, whom they supposed to have glanders. I went, and on reaching the place late in the afternoon of the 12th, I met the physicians named above, from whom, together with the family, I received the following history of the case, of which I made a record before leaving the house, and in the of the physicians: Mr. Townsend is a planter, in easy circumstances, now about 71 years of age; of large and once powerful frame; of active and industrious habits; has always enjoyed excellent health, and up to the commencement of this attack was in remarkable preservation for one of his years. He has had on his premises a very fine saddle-horse, affected with glanders since Christmas last. This horse he has kept in a close stable on his premises, but apart from the balance of his stock, and has persisted in tending him himself, in spite of the remonstrances of his family. About the 27th of April he received a small abrasion on the dorsum of the left hand. He continued, however, to nurse his horse, and among other duties which he performed for him was that of daily syringing his nostrils with vinegar and water. The injected fluid, on its return, was of course mingled with the secretions from the nose of the animal, which were said to be very abundant, and it is quite likely that more or less of these offensive matters came in contact with the abraded surface on the hand during some of these operations with the syringe. He seemed to have some apprehension in exposing his hands in this way after the skin had become broken, and though he to use tliQ syringe daily, he never failed to go to the house, where, after giving his hands a thorough with soap and water, he would apply a small bit of paper saturated with spirits of turpentine over the abraded surface, as a preventive of bad consequences. On the night of the 4th ult., about seven days after the on the hand, he felt a very slight uneasiness about the spot. On the next day (5th) he visited a relation in the , where he spent the day, and whilst there observed that the uneasiness in wound on hand had increased, and red streaks running up the arm, with some pain in axilla of corresponding side. Complained, also, of great oppression and distention about stomach, and when the dinner hour arrived could not eat. Had no absolute pain in stomach, but, from the general distress in that region, said he thought he must have colic. Returned home in afternoon, and had rigors and flushes of heat, succeeded by fever. At night took a large dose of calomel. On the 6th calomel operated several times, but distress about the stomach still continued, accompanied with nausea. Hand and whole arm considerably swollen; some spots on skin hard to the touch, and as "red as red flannel" on both arm and forearm. Had alternate rigors and fever, with great restlessness. Took several small doses of calomel. On the 7th all the symptoms increased in violence. Took a dose of Cooke's pills. On the Sth, whilst applying a poultice to the affected arm, the nurse noticed that one of the hardest tumors on the forearm was discharging a thin serous fluid, and that underneath the cuticle where it had been broken the tissues presented a very dark, blackened appearance. Up to this time he had not been visited by a physician. On the 9th he was seen by Dr. Tompkins, a highly intelligent of the neighborhood, who immediately diagnosed his as that rare disease in the human subject, known as , which is sometimes communicated to man by the horse, ass, or mule. Pulse full and regular, and about 90 per minute; skin hot and dry; tongue heavily loaded, and moist; general feeling of uneasiness, distress, and restlessness, with pains and soreness in extremities; thirst and nausea, but no vomiting or retching; rigors occasionally, and a desire to get out of bed and sit by the fire, which he sometimes did. Arm and forearm much swollen, with a general erysipelatous look; pustules, tubercles, and bullae with hardened bases interspersed on different of limb, of varying sizes and shapes and in various stages of development, one of which had broken and was discharging a thin sanious fluid, and revealing under the cuticle a blackish, sphacelated mass. Original wound where the skin had been abraded on back of hand, and which had been the point of , and now about the size of a twenty-five cent piece, somewhat sunken, of a dark leaden color, and emitting a thin sanious fluid. Prescribed chlorate potassa internally and lead lotion to arm. Drs. Roberts and Townsend saw the case in consultation on the 10th. Their description of his condition on that day did not differ from the one given by Dr. Tompkins, of his on the 9th, except in the general progress towards and malignancy. On the 11th and 12th there seemed great tendency towards congestion in the mornings, marked by coldness of extremities, a leaden pallor of surface, and feebleness of pulse. This was followed in about four hours with febrile reaction, but without increase of frequency of pulse, which has been uniform at 98 per minute; has been freely purged. taking calomel and opium on the 10th, which was at intervals until 12 o'clock M. on the 12th. Nitrate of silver was applied to wound, over and around tumors and spots, and heavy caustic lines drawn around arm in front of axilla. When seen by me at 6 o'clock P.M. on the 12th ult., pulse 71, large, bounding, and intermittent; skin moderately hot, and occasional free perspirations; tongue dry, and considerably coated; great hebetude of intellect (this, I afterwards thought, was to some extent due to a pretty full dose of morphine taken in the early part of day, as when I left him next morning his mind was clear). Has hiccoughs, some nausea, thirst, loathing of food, and extreme jactitation. Left arm somewhat swollen and red. The original wound at point of inoculation about an inch in diameter, circular, in a sloughy condition, and a thin, dirty-looking serum. On other portions of the limb there were spots of different sizes and stages of development, from some of which the cuticle had been denuded, leaving a dark, almost black appearance, from which a dark-reddish fluid exuded. One of these gangrenous tubercles was situated and on back of left forearm, about three inches in length and one and a half inches in width, from which the cuticle had slipped off as from a burn, leaving a dark gangrenous mass , which was discharging a thin, dark-red sanies. On the right arm, over the olecranon process, there was observed on yesterday a small, hard, red spot, which is now about three or four inches in diameter, and circular, the cuticle over which presents the appearance of a blistered surface, and the skin underneath (which can be seen where the cuticle has been torn in a small place) of a dark, livid color. These tumors or , when they are first observed, are only red spots upon the skin, which is somewhat elevated, with a hardened base. 36 or 48 hours they assume the appearance of regular bullae, the cuticle looking as if it had been scalded, beneath which a thin fluid collects into a vesicle embracing the extent of the hardened base, easily broken or destroyed, and revealing the sphacelated tissues underneath, varying in appearance from a livid color to that characterizing complete gangrene, according to their duration the latter generally occurring within 48 hours after first appearance. One of these hardened tumors, which was pointed out to me, located near the elbow of the left arm, seemed to have resulted in the formation of a small abscess, which had discharged 36 hours after the discoloration and in the skin had been first observed. The discharge from this point was described as "considerable," and consisting of a bloody fluid mixed with quantities of matter having somewhat the characteristics of genuine pus. The tissues around this particular spot were the only ones which did not present either a sphacelus, or a decided tendency towards gangrene, in all places where the cuticle had been broken. On different portions of the arm and forearm there are three or four pustules, resembling fully-matured small-pox vesicles, but larger and more pointed. One of these pustules was also found on the breast, and another on one of the legs of the patient. The prescription, which was the result of one , was the avoidance of all exhausting remedies and the free use of sustaining measures, such as animal broths, milk, rich wines, brandy, etc., together with the internal use of of potassa with hydrochloric acid and some preparation of iron. Prognosis unfavorable. I left a request that the physicians in attendance would me notes on the subsequent progress of the case, which was very promptly complied with by Dr. Roberts. These being full, embrace a considerable space, and I do not deem it to read them here, further than to give a general synopsis of them. The march of the disease was characterized by pretty much the same symptoms enumerated in the above report, giving at no time any indication of amelioration, but, on the contrary, marked by a progressive increase in violence. Patient became quite delirious on the night of the 13th, which continued in a greater or less degree, with low muttering and coma towards the close. Involuntary discharges of urine came on. , with dryness and redness of the tongue and mouth, and excessive thirst, were present throughout. Old abscesses and gangrenous spots enlarged and sloughed. Four abscesses , and pustules scattered over the limbs, body, and face, in size from that of a pea to a hazlenut. Eyes became swollen, with a livid discoloration surrounding them, with an trembling of lower jaw. Jactitation, which had been throughout the attack, continued, with subsultus , until the patient expired, on the morning of the 19th, about fifteen days after the beginning of the attack. No was made. The limb, which was much swollen at first, became greatly reduced in size. The transmissibility of disease from the equine tribes of to the human subject, though once questioned, has been demonstrated beyond the possibility of a doubt. I have not been able to find any records touching the subject of glanders in man, going farther back than the present century, and it may, therefore, be said to be comparatively a new disease upon our calendar; and it is more in consequence of the novelty of the disease itself, than from any special points of interest by this particular case, that I have been induced to read you the above notes. This is the first case of glanders in the human subject I ever saw, and I have never before heard of a case in this State. The first case on record, which I have seen noticed, was that reported by Muscroft, of Edinburgh, in 1821, and the second reported by Dr. Rimu, of Germany, in 1832. To Dr. Elliotson, however, is due the credit of having done more, in the investigation of the subject, than perhaps any other man. In order to indicate something of its nature, as well as to define'its origin, the latter gentleman has applied to the disease in the human subject the term equinia, which has been adopted and qualified by other authors, so as to include another also communicated from the horse to the human subject. This is characterized by a pustular eruption, and occasionally communicated to coachmen and stable-boys who tend and dress the heels of horses affected by the disease peculiar to that , and, known as grease. To the latter the term equinia mites has been applied; whilst to the one emanating from the horse the term equinia glandulosa has been assigned. According to Dr. Elliotson, equinia glandulosa may appear in the human subject in different forms: 1. In that of simple acute glanders; the disease attacking the nasal cavities and parts. 2. In that of acute farcy glanders, appearing in various parts, in the form of small tumors, which suppurate and give rise to foul ulcers. 3. Where varieties may exist , or they may be both produced at the same time, or the one may precede the other. 4. Each of these varieties may also occur in a chronic form; they may also exist separately, or be conjoined. Besides these divisions of the disease, other have been made. Thus, Rayer distinguishes in the acute form an ecchymotic, a gangrenous, and a pustular variety all agreeing, however, that these different varieties constitute one and the same disease, and are produced by the same specific cause, and may all occur in the same case. In the case here detailed it will be observed that a set of symptoms, which is, perhaps, the most characteristic of all those which usually attend glanders of the human subject, was absent. I allude, of course, to those affecting the membrane. In many particulars there was a close between the symptoms in this case and those which severe and aggravated cases of haimatoxic poisoning from dissecting wounds; and, in the absence of the specific contagion to which it was known the patient had been exposed, it might very properly have been classed under that head. In speaking of the diagnosis, Dr. Gross says: "From the effects of a dissection wound, it may be readily distinguished by the peculiar discharges from the nose and by the character of the cutaneous eruption. The history of the case, too, will furnish important diagnostic data, and should, therefore, always receive due consideration. The fact that the patient has nursed or a glandered horse or person will, generally of itself, afford strong presumptive proof of the true character of the ." The nasal discharge, as is said to have been the case in more than two-thirds of all the cases on record, was in this instance entirely wanting, whilst the character of the cutaneous eruptions did not differ materially from such as are often opened in dissecting wounds; so that the only means of diagnosis left us in some cases, and, particularly, as between some cases of wounds and farcy glanders, is in relation with our of the cause and circumstances of the attack. The wound at the point of inoculation, with its red streaks to the axilla, the general erysipelatous appearance of the limb, the vesicles or bullae appearing over the red, hardened tumors on different portions of the limb and body, with thin, sub-cuticular, gangrenous sloughs, together with the pustules and abscesses, first appearing on the diseased limb and finally extending to every portion of the body, create an assemblage of spmptoms so closely resembling each other in the two , that I must confess I should hesitate to decide from this data alone upon the diagnosis. The constitutional symptoms also are scarcely less similar than those of the surface; and the general progress of the two diseases is marked by pretty much the same phenomena except that in one the disease is generally fatal, whilst in the other the reverse is the rule. So that at last our only positive means of diagnosis, added to the symptoms common to both, is our knowledge as to whether or not the patient has been exposed to the contagion in the one instance, or the producing cause in the other. I have not intended to read you an essay on glanders, but simply to give you the facts, circumstances, and symptoms what seemed to me to be a very rare and interesting case of disease. I have done this with the more pleasure I know that some members of the profession, and, perhaps, some members of this Society, do not believe in the existence of such a disease as glanders in the human subject. I feel entirely satisfied that this was the specific disease known as glanders, reproduced in the human subject, through inoculation from the horse. One of the features of the disease, which is the most characteristic where it does occur, was not present, it is true (I allude, of course, to the nasal symptoms), but yet it is shown that this has been the case with a large majority of the cases which have been recorded, and that its existence is by no means necessary in order to constitute a case of glanders. Some have contended that glanders and farcy are two separate and distinct diseases, whilst the weight of evidence is strongly in favor of their identity. This latter view gains confirmation from this case, from the fact that it was communicated from an animal in which the prominent features of the disease were those claimed for glanders; whilst it reproduced in the human subject inoculated from it only those phenomena common to farcy. Note. This paper, contributed by Dr. W. 0. Baldwin, the present President of the American Medical Association will, it is hoped, suggest inquiry and stimulate investigation, in regard to this interesting subject. AL information communicated will be published with pleasure. Ed. Richmond and Louisville Medical Journal. |
ARTICLE L. A SHORT PAPER ON THE NATURE OF , AND THE MEANS OF CURE. By N. S. DAVIS, M.D., etc., Chicago, Ill. [Prepared for the Western Association for the Advancement of Social Science, November loth, 1868.] There are no questions connected with the social interests of the human family more important than those which relate to the influence of intoxicating drinks. Whether we consider the vast pecuniary expenditure occasioned by their use; the it helps to perpetuate among all classes; and the indirect effects upon the sanitary condition of individuals and communities; or whether we study their more direct influence over the moral, social, and physical condition of the consumer, we shall be overwhelmed with the magnitude of the subject, and astonished at the tenacity with which popular errors are perpetuated from generation to generation. It is no part of our present purpose, however, to enter upon so broad a field of inquiry. But simply to offer a few in relation to the nature of inebriation, and the means that may be made available for its cure. For whatever of opinion may be entertained in regard to the propriety or impropriety of using intoxicating drinks, there is no escape from the fact, that such use tends so strongly to establish an appetite for more, that the number of inebriates among all classes of society is so great as to demand the serious attention of every good citizen. It might appear to some superfluous to enter upon a serious inquiry into the nature of so familiar a condition as alcoholic inebriation. And yet we doubt whether there is any subject relating to the social interests of man, concerning w'hich more mischievous errors exist in the popular mind. Perhaps of the people at the present time regard inebriation or drunkenness simply as a vice, a crime, or moral delinquency, arising from the abuse of those fermented and distilled drinks which, properly used, are tonic, nutritive, and life-sustaining. 'Hence, few things are more common, than to see a man or woman sipping wine, and at the same time expatiating upon the moral delinquency and social degradation of some , who, by long continuance of the same process, has become an habitual drunkard. But is inebriation really a crime or a disease? Is it a state of moral turpitude, or a morbid condition of the physical , induced by the action of a material agent brought in contact with such organization through the blood? It may be a crime to drink an intoxicating draught for the purpose of inducing inebriation, or with a full knowledge that such will be the result; in the same sense, that it is a crime to deliberately expose ourselves to such atmospheric changes as will very cause an attack of rheumatism or pneumonia, or impair our health and usefulness. But that the appetite for alcoholic drinks and the state are diseased conditions of certain organs or , is susceptible of clearest demonstration. To procure a full recognition of this fact by the community at large, is a step of paramount importance in preparing the way for the adoption of such measures as will either prevent or cure the disease. We cannot accomplish this object, however, without first establishing a correct knowledge of the nature and effects of alcohol, as the active ingredient in all the intoxicating drinks in common use, whether fermented or distilled. It is probable that a very large majority of the people, even at th*e present time, regard alcoholic drinks, when used with moderation, as tonic, nourishing, warming, and life-sustaining. To use the language of another, they are regarded as the "conservators of strength in manhood and as the milk of age." These notions are strengthened, on the one hand, by the direct exhilarating effect of alcohol on the nervous system, and on the other by certain theoretical dogmas promulgated by Liebig, Johnston, Hammond, and others, who have boldly proclaimed alcohol to be either respiratory or accessory food. This class of chemico-pathologists simply point to the fact that alcohol, in its chemical relations, belongs to the class of Hydrocarbons; and that these substances, out of the living body, are capable of undergoing combustion by uniting with an additional of oxygen; and straightway jump to the conclusion that, when taken into the system, they actually enter into such combination with oxygen, and hence become respiratory food. And yet, we search all their writings in vain for the first item of proof that their mere theoretical deduction is correct. A more recent modification of the theories emanating from this school of writers, makes alcohol, not respiratory, but accessory food. It having been clearly proved, by the of Boker and others, that the presence of alcohol in the system lessened the atomic changes and secretions in such a way as to diminish the loss of weight, by diminishing the of eliminations in a given time, it was at once assumed that this diminution of atomic changes in the tissues of the body, was equivalent to just so much nutrition or addition of new matter through digestion and assimilation; and hence the alcohol was declared to be accessory or indirect food; a fallacy that will be exposed in another place. We have thus stated fairly the theoretical doctrines of this class of men, because their names are continually quoted as authority throughout all departments of our literature. Let us now see how these theoretical assumptions and notions are sustained by a wide range of experiments and carefully-observed facts. First. Numerous chemical analyses of the blood and tissues, made by different experimenters, show that when alcoholic drinks are taken, the alcohol enters the blood and permeates with it every part of the body. This position is now acknowledged to be correct by all classes of observers. Second. An equally reliable series of experiments have shown that the alcohol undergoes no chemical change in the system, but is eliminated through the excretory organs, more especially the lungs and kidneys, within a few hours after it is taken. This position has long been disputed, but it was finally fully established by the results of the, well-devised and , experiments of Lallemand, Perrin, and Duroy. Third. While in the blood and circulating through the , the alcohol diminishes the sensibility of the brain and nervous system in the same manner as other anaesthetics, and also retards the active changes in all the tissues; and diminishes the sum-total of eliminations or excretions in a given period of time. The numerous and patient experimental investigations of Prout, Sandras; and Boucherdet, Boker, Hammond, and others, have removed all doubts in regard to the truth of this . Fourth. By diminishing the atomic changes in the tissues of the body and the sensibility of the nervous system, the alcohol by its presence also diminishes the temperature, the strength, and the power of endurance. That its presence in the system reduces the temperature, was first fully established by the of a series of experiments performed by myself in 1850, some of which I repeated in 1867. These experiments in testing the actual temperature of the body every half hour, with a delicately-graduated thermometer, for three hours after a moderate drink of alcoholic liquor. The tests were to both wine and whiskey. Those results are confirmed by the observations of Magnus and others in Europe. That the presence of alcohol directly diminishes the strength and power of endurance, is proved, not only by the foregoing scientific investigations, but hlso by a large number of carefully-observed facts in relation to the of Labor, in civil and military life, and by the statistics of sickness and mortality. Twelve or fifteen years ago an article was published in the British and Foreign Medico-Chirurgical Review, embracing a large amount of statistical information on this subject. At one place in England where a large amount of brick-making is on, and where the amount of each man's work, the number of days lost by sickness or otherwise, and the deaths, were made matters of record, the rules of the service allowed to every man a mug of beer at each meal. But there were among the workmen quite a number who wholly abstained from the use of the beer, or any other drink. An examination of the record showed that the average amount of work done, per annum, by the beer-drinkers was a large percentage less than that done by those who wholly , while the number of days lost by sickness was greater. The same relative results have been shown in reference to every other species of manual labor where records have been kept to afford a comparison. The article to which we have just alluded contained some interesting items from the reports of the Registrar-General of the British Army. At that time the soldiers of the army in the East Indies were allowed d^ily rations of whiskey; but there were some companies of pledged teetotalers, who faithfully declined the ration. On examining the details of the regular reports concerning and mortality in that army, it was found that the ratio of sickness and mortality among the teetotalers was from five to ten per cent, less than for the rest of the army. The history of our own army affords some facts of on this subject. Dr. Mann, a surgeon of excellent , who served with the army of the Revolution, says: "At that period, during the Revolutionary War, when the army received no pay for their services, and possessed not the means to procure spirits, it was healthy. The 4th Massachusetts , at that eventful period of which I was surgeon, lost in three years, by sickness, not more than five or six men. It was a time when the army was destitute of money. During the winter of 1779 '80, there was only one occurrence of fever in the regiment, and that was a pneumonia of a mild form. It was observable in the last war, from December, 1814, to April, 1815, the soldiers at Plattsburg were not attacked with fevers as they had been the preceding winters. The troops during this period were not paid; a fortunate circumstance to the army, arising from the want of funds." These may be said to be only negative results, but unhappily the history of the recent war for the suppression of rebellion furnishes some examples of a positive character. While Cass was Secretary of War, several years since, the rations were discontinued in the United States Army, and coffee and sugar substituted. This has been the' army ever since. The Army of the Potomac, in the spring of 1862, was subjected to great hardships in labor, and exposed to the extremely wet and malarious region of the . There was consequently much sickness and suffering. Under these circumstances, the Commanding General issued an order on the 19th of May, allowing every officer and soldier one gill of whiskey per day; half to be served in the morning and half in the evening. But the results were so manifestly injurious to the sanitary condition of the army, that in just thirty days the order was fully countermanded by the same General. Concerning this experiment in the Army of the Potomac, Dr. Frank H. , one of the most eminent surgeons serving with that army, says: "It is earnestly desired that no such experiment will ever be repeated in the armies of the United States. In our own mind, the conviction is established by the experience and observation of a life, that the regular routine employment of alcoholic stimulants by man in health is never, under any , useful. We make no exceptions in favor of cold, or heat, or rain, nor, indeed, in favor of old drinkers, when we consider them as soldiers." For these and other facts bearing on this subject, see Dr. Hamilton's valuable work on Military Surgery, from page 70 to 75. Further facts of a striking and perfectly authentic character, bearing on this subject, may be found in one of the volumes of "Medical Inquiries and Observations, by Benjamin Rush, M.D.," in the chapter devoted to a comparison of the diseases prevalent in Philadelphia during ten years previous to the Revolutionary War, with those of a similar period after the close of that war. Indeed, it were easy to fill a volume with facts and statistics showing that in every relation of human life, the use of alcoholic drinks diminishes man's capacity to endure both mental and physical labor; increases his to disease; and shortens the average duration of life. And, although we have had our attention directed to this for thirty years, we iiave not found, either in the records of medicine or of general literature, a single statistical item calculated to prove the contrary. We have seen an abundance of opinions expressed of an adverse character. But opinions are not facts. It is very common to hear that some sick or injured person has been kept up, or "kept alive," on brandy, or whiskey, or wine, for several weeks. But do those who make the assertion have any reliable means of knowing whether the sick person was actually kept alive by the alcoholic potion, or whether he lived in spite of it? The eminent Dr. Todd testified strongly to the sustaining and beneficial influence of alcoholic drinks in the low forms of fever, yet statistics show that in the London fever hospitals with which he was connected, the ratio of increased pari passu with the increased use of alcoholic drinks as remedies. The able corps of medical attendants on the Bellevue and Emigrant Hospitals in New York also bore decided testimony to the utility of these liquors in the of the same forms of fever, and used them largely. But the mortality was one in every five or six cases treated. The same fevers placed in tents with plenty of fresh air, and without a drop of alcoholic drinks in their treatment, gave a mortality of only one in seventeen. The statistics of almost all epidemics show that those to the use of intoxicating drinks are much more liable to be attacked than those who abstain; and of those who are , a larger proportion die. If alcohol takes no part in nutrition, but passes through the blood disturbing the nervous sensibility and retarding the organic changes, some may be ready to ask why habitual^drinkers of wine and beer grow fat and increase much in weight. We answer, that the presence of alcohol in the blood not only retards atomic changes in the tissues, but it diminishes the amount of oxygen taken in through the lungs. Consequently, the carbonaceous elements of the blood and tissues do not become oxidated as rapidly as when the alcohol is not present, and they accumulate in the form of fat. And this process is sometimes carried so far that the heart, liver, and kidneys undergo more or less fatty , constituting incurable forms of disease. The increase of bulk and weight in these cases is not from an increase of natural nutrition, but a slow accumulation of hydro-carbonaceous material from retarded metamorphosis. The individual fattened under such influences, invariably in physical activity and power of endurance, in to the'increase of weight. Those who imagine that to diminish the waste of the tissues by diminishing the atomic changes, is equivalent to the actual assimilation and addition of new atoms, forget that all the phenomena of life in the organization, are the direct result of such atomic changes; and that whatever diminishes these actually diminishes physical life, and to stop them is to stop life. If the reverse were true, we should only need enough of , or some other agent, to stop the changes in our tissues altogether, and we would live on indefinitely, without the trouble or expense of eating. The simple logical deduction from all the carefully-observed facts, in relation to this subject, is, that alcoholic drinks, when taken into the human system, circulate in the blood as foreign agents; and until eliminated or cast out through the excretory organs, produce a temporary exhilaration of the mental , accompanied by diminished sensibility, temperature, strength, and atomic changes. And when these effects are often induced, they result in a more or less permanent morbid or diseased condition of the organic actions, and especially of that portion of the nervous system connecting the stomach with the brain, constituting a morbid appetite or craving, which, in its demands for the accustomed exhilarant, often overpowers the most capacious and cultivated intellect and the most sacred pledges. These deductions have a most important bearing on the ques- . tion of how ought we to treat the inebriate? If the inebriate is the victim of a positive disease, induced by the action of an alluring and deceptive physical agent, alcohol, will any number of moral lessons addressed to his intellect, or any amount of denunciation hurled at his degradation and his vices, cure or reform him? Or, will his arrest, arraignment in a police court, and extortion of the few dollars he has left as a fine, eradicate the disease that is preying upon the most delicate part of his organization? Abundant experience throughout the civilized world answers these questions in the negative. The treatment demanded by the nature of inebriation, and the interests of humanity, is the same in kind as that awarded to the sick and the insane. Instead of denunciations, fines, and imprisonments, the should be sent directly to an asylum, where he should receive thorough instruction in regard to the actual effects of alcoholic drinks on his physical as well as mental condition, in connection with such diet, medication, and employment, as a specially qualified superintendent should deem adapted to his case. The establishment of Washingtonian Homes and Asylums in Boston, Chicago, Binghamton, New York, and a few other places, is only the initiatory step in this great work. These institutions are adapted to the reception and treatment of such inebriates as voluntarily resort to them. But to reach the great mass of those suffering from the disease of , requires a thorough change in our jurisprudence. The law must recognize the important fact that inebriation is temporary insanity, caused by the morbid effect of a physical agent on the brain and nervous system. Instead of arrests, petty fines, and temporary imprisonments in police stations, Bridewell, etc., ending only in a further demoralization and speedy return to the dram-shop, the law must provide asylums, in which the victims of alcoholic disease can be legally placed, until, by the combined influence of instruction, abstinence, productive labor, and proper , the disease and morbid appetite are effectually removed. Such a change in the management of drunkenness would work other changes of vital importance to society. Alcoholic drinks, becoming directly associated with the idea of disease and mental alienation, in the public mind, would speedily come to be universally regarded in their true light as debilitating to body and mind, instead of tonic and life-. This would necessarily be accompanied by a change in the language of the physician at the family , and in the phraseology adopted in the press and the literature of the day. Such a change would do more to discourage dram-drinking, and all its direful consequences, than all other measures combined. We hope, therefore, that the members of this Association will give'to this subject all that thought and patient investigation which its importance . |
rtUo. ON SOME RESULTS OF A RETROGRADE OF THE BLOODVESSELS. My object in the present communication is to direct attention to certain results of a retrograde engorgement of the bloodvessels, consequent upon an impediment to the onward movement of the blood. Most of the facts to which I am about to refer are and familiar facts; I believe, however, that they have not hitherto been collated and analyzed with the care and the accuracy which their pathological interest and their practical importance demand. I have to speak first of certain phenomena which result from an impeded circulation through the lungs. 1 shall afterwards refer briefly to some analogous phenomena which follow an circulation through the liver and through the kidney respectively. Let me first, then, direct attention to the well-known of the blood-supply to the lungs. The lung, as a organ, as a great gas-secreting gland, is supplied by the pulmonary artery, the blood from which passes through the pulmonary capillaries and veins from the right to the left side of the heart. The lung, as an organ whose tissues have to be nourished, is supplied with blood from the aorta by the arteries, and this blood, having been distributed to all the proper tissues of the lung, is returned by the bronchial veins (one opening into the left superior intercostal, and the other into the vena azygos) into the superior cava. In the lung, therefore, there is the pulmonary circulation proper, and, in addition to this, there is the bronchial circulation, by means of which its own tissues are nourished, this bronchial circulation constituting a part of the general systemic circulation. u The bronchial arteries and veins carry blood for the nutrition of the lung, and are doubtless also the principal source of the mucous secretion found in the interior of the air-tubes." (Quain's Anatomy, edited by Dr. Sharpey, 7th edition, p. 903.) It is generally believed, and it probably is a fact, that where these two different sets of vessels come into contact, where the and intercellular passages merge into air-cells, there is a communication between the two sets of vessels between the pulmonary and the bronchial systems of vessels. I have elsewhere sufficiently proved, that during the collapse stage of cholera, there exists a great impediment in the minute branches of the pulmonary artery. The result is, that those parts of the vascular system which lie in front of the smallest branches of the pulmonary artery are comparatively empty of blood, while the parts behind are distended. The whole of the systemic venous system is gorged with blood; hence the lividity of the face, and hence congestion of the bronchial veins and capillaries, which may impart to the lung a dark color and an appearance of congestion, while yet the lung, as a whole, very little blood, and is much reduced in weight. Even the pulmonary capillaries may become partially injected in of an impeded return of blood through the bronchial veins. There is a communication between the two sets of about the terminal bronchi, and a part of the blood by the bronchial arteries is returned by the pulmonary veins. An impeded return by the bronchial veins would divert more bronchial blood into the pulmonary capillaries and veins. Some pathologists have supposed that the impeded transit of blood through the lungs in the collapse stage of cholera is a result of its becoming too thick and viscid to pass through the capillaries. This view is proved erroneous by a number of facts, and amongst others by the anatomical fact that the mass of blood is arrested before it reaches the pulmonary capillaries, while the blood is obviously not too thick to enter the bronchial capillaries, which, although of a smaller size than the capillaries, are as over-full as the pulmonary capillaries are empty of blood. In fact, there is usually a direct relation between the anaemia of the pulmonary capillaries and the of the bronchial; and the contraction of the minute pulmonary arteries, presenting an abrupt bar to the onward movement of the blood, is the probable cause of both . One result of the engorgement of the bronchial veins and capillaries during the collapse stage of cholera is a to passive serous transudation through the mucous into the bronchial tubes. The consequence is, that after prolonged collapse the minute bronchi and air-cells become more or less filled with serum; and when, during reaction, the blood again passes freely through the pulmonary artery, the changes are interfered with by the oedematous condition of the lung, and there often occurs a fatal apnoea. Now let us compare the phenomena of cholera collapse with those of spasmodic asthma. The general appearance of a during a severe paroxysm of asthma is strikingly like that of one in the collapse of cholera. Dr. Hyde Salter, in his masterly treatise on asthma, says (p. 71): "If the bronchial spasm is protracted and intense, the heat of the body falls; the oxygenation of the blood is so imperfectly performed, from the sparing supply of air, that it is inadequate to the maintenance of the normal temperature; the extremities especially get cold, and blue, and shrunk; I have known the whole body deathly cold, and resist all efforts to warm it for four hours. But while the temperature is thus depressed, the perspiration produced by the violent respiratory efforts may be profuse, so that the is at the same time cold and sweating. It is this union of coldness and sweat, combined with the duskiness and pallor of the skin, that gives to the asthmatic so much the appearance of a dying man. The pulse during severe asthma is always small, and small in proportion to the intensity of the dyspnoea; it is so feeble sometimes that it can hardly be felt." The resemblance between some of the most striking features of the asthmatic paroxysm and the collapse of cholera is . What, then, is common to these two forms of collapse? Obviously not a drain of liquid from the blood, which was so long and so erroneously supposed to be the main cause of collapse, but a partial arrest of the pulmonary circulation. In a paper which is to appear in the next volume of the " Medico-Chirurgical Transactions," I have shown that in cases of acute apnoea there is the same evidence of an arrest of blood in the minute branches of the pulmonary artery as exists in the case of cholera_collapse. In both pathological conditions the pulmonary capillaries contain very little blood, while the right cavities of the heart and the pulmonary artery are distended, the left cavities of the heart being comparatively empty. In both asthma and cholera, the circulation is impeded by the muscular contraction of the small pulmonary arteries; and hence the symptoms of collapse in both diseases. In cholera, the contraction of the arteries is a result of the poisoned blood in the vessel; in asthma, it is a consequence of the partial apnoea occasioned by spasm of the bronchi. In cholera, there is a primary asphyxia and a secondary apnoea, consequent upon the blood-stasis; in asthma there is a primary apnoea, the of bronchial spasm, and a secondary asphyxia. In both forms of disease the symptoms of collapse may speedily be for the time by measures which overcome the primary spasm: in asthma by the inhalation of chloroform, which relaxes the bronchial spasm; in cholera by the injection of a hot liquid into the veins, which, reaching the lungs, overcomes the arterial spasm. In asthmatic apnoea we have evidence of congestion of the bronchial system of vessels in the occasional occurrence of bronchial haemoptysis, and in the more constant occurrence of bronchial mucous expectoration, which is copious and prolonged in proportion to the intensity and duration of the previous . I have dwelt at some length upon the phenomena of asthma as a type of partial acute apnoea. The causes of acute anpoea are very various; but in all essentials the phenomena are alike. Whether the apnoea be the result of hanging, drowning, , inflammatory croup, diphtheria, epileptic or tetanic spasm implicating the respiratory muscles, division of the vagi nerves as in Dr. John Reid's experiments, apoplectic coma, poisoning or injury to the upper part of the spinal cord in each and all of these cases, in proportion to the suddenness and completeness of the apnoea, the pulmonary capillaries are anaemic, while the vessels containing black blood which lead up to those capillaries, are gorged. In all these cases, too, the retrograde passive engorgement of the bronchial veins and results in a serous and mucous, and sometimes , exudation into the bronchial tubes. We are now in a position to understand the condition of the lungs which is found in cases of chronic apnoea. In acute apnoea we have seen that the lungs are anaemic, and we have explained this by the stop-cock action of the minute pulmonary arteries consequent upon the suspension of the respiratory changes. When death occurs after a state of partial apnoea has continued for many hours, or for several days, the lungs are always found more or less gorged with blood and serum. The explanation of this is simple. The apnoeal blood-stasis in the pulmonary throws back the blood upon the bronchial veins and , from which there is poured a serous dropsical exudation into the bronchial tubes. This fluid, sometimes blood-tinged, reaches the extremities of the bronchial tubes and the air-cells, where it compresses the network of pulmonary capillaries, and impedes the flow of blood through them. Thus the lung more and more gorged with blood and serum. An phenomenon may often be witnessed in anasarcous legs. The accumulation of liquid in the areolar tissue sometimes the vessels so as to cause passive congestion, and not unfrequently inflammation and gangrene, of the skin and beneath the skin. A case of tricuspid regurgitation, which occurred under my care in the hospital 12 years ago, affords an instructive of the effect of an impediment originating in the right side of the heart, first upon the bronchial, and secondly upon the pulmonary, circulation. I gave the particulars of this case in a clinical lecture which was published in the Medical Times and Gazette of February 13th, 1858. A woman, aged 52, was admitted with general dropsy, albuminuria, a systolic at the bottom of the sternum, distended and pulsating jugulars, and the physical signs of bronchitis. A single large dose of elaterium acting very freely upon the bowels cleared away the dropsy, the albuminuria, and the bronchial secretion. After a short time, however, all the symptoms returned, and she died. We found, as we had expected, great dilation of the orifice, while the valves on the left side of the heart were normal. The lungs were much engorged. In this case it is clear that the primary cause of all the suffering was of the tricuspid valve. There was, consequently, a reflux of blood into the systemic veins; renal congestion and albuminuria, anasarca, bronchial congestion and exudation, and then a secondary obstruction of the pulmonary capillaries. It is interesting to note that before her admission she had spit some blood, the source of which was in all probability the bronchial capillaries. We are familiar enough with the occurrence of haemoptysis as a consequence of mitral or aortic valve disease; the source of such haemoptysis being the capillaries, while disease on the right side of the heart throws back the strain and pressure primarily upon the vessels. If there were no bronchial vessels, if the sole blood-supply to the lungs were through the pulmonary artery, the tendency of obstruction at the right side of the heart would obviously be to render the lungs anaemic, and not to overfill them with blood. Another interesting phenomenon, allied to those to which I have already referred, is the oedema of the sound lung, which not unfrequently occurs when one lung has been suddenly by pneumonia, or compressed by a pleuritic effusion. In such a case we sometimes hear crepitating sounds in the bronchi of the healthy lung; arid we Lok upon this condition of things with anxiety, because we know that an increase of the oedematous effusion into the bronchi may cause fatal apnoea. Until quite recently I have always considered that the capillaries were the source of the serous exudation in these cases. I have now no doubt that it is from the bronchial capillaries mainly that the liquid escapes. In consequence of the impervious condition of the lung on the diseased side there is a state of partial apnoea; more blood is sent to the sound lung than can readily be aerated; its progress is checked and regulated by the stop-cock the minute pulmonary ; there is more or less engorgement of the right cavities of the heart and the systemic veins; and with this there is congestion, and a consequent serous exudation into the bronchi. Once more, it is notorious that patients who have general vesicular emphysema of the lungs are very liable to bronchial catarrh. Why is this? In an emphysematous lung there is dilation of air-cells, rupture of their walls, and obliteration of capillaries. The vascular network of the lungs is much ; there is consequently an impeded pulmonary circulation, fulness of the right side of the heart and systemic veins, capillary congestion, and so a liability to catarrh and bronchitis. This passive congestion of the bronchial mucous membrane predisposes to catarrh and bronchitis, just as veins in the leg predispose to inflammation of the . Another result of the passive congestion of the capillaries which is a consequence of emphysema, is the occasional occurrence of bronchial haemoptysis. Of this I have seen a considerable number of instances, and not a few in which the occurrence of blood-spitting has led to an erroneous diagnosis of tubercular disease of the lung. The liver resembles the lung in this respect, that, as an organ, it is supplied with venous blood. Like the lung, too, it receives a separate supply of arterial blood, through the hepatic artery, for the nutrition of its own tissues. It differs from the lung in this important particular, that the blood its black and venous character as it emerges from the liver. There is therefore no need for a companion vein to the hepatic artery corresponding with the bronchial veins; but the blood from the hepatic artery, after supplying the liver tissues, mingles with the portal blood, and so passes on into the vena cava. In cases of cirrhosis of the liver there is an impeded through the gland: the whole of the portal venous system is consequently engorged; the hemorrhoidal veins are often enlarged; there is sometimes hemorrhage from the mucous membrane of the alimentary canal, and still more frequently a serous dropsical effusion into the cavity of the peritoneum. The kidney differs from both the lung and the liver in this respect, that it has but one source of blood-supply. The blood of the renal artery serves at once to nourish the gland and to supply the materials for its secretion. With respect, however, to the distribution of blood within its substance, the kidney some points of analogy with the lung on the one hand, and -with the liver on the other. It resembles the lung in the fact that it has two sets of capillary vessels the Malpighian capillaries and the intertubular capillaries; but it differs from the lung in the fact that the same blood passes in succession through both sets of capillaries. Then there are some points of analogy between the capillary arrangement within the kidney and that within the liver. Mr. Bowman, in his original paper "On the Structure of the Malpighian Bodies of the Kidney," pointed out that each efferent vein may be looked upon as a portal vein in miniature, the resemblance between the portal and the efferent vein consisting in the fact that each vein between two sets of capillary vessels. And thus we find that as an impediment to the circulation through the liver causes a serous exudation into the cavity of the peritoneum, from the capillary vessels in which the portal vein takes its rise, so an impeded circulation through the kidney causes a serous" from the capillary vessels in which these miniature portal veins the efferent veins originate, and this serous exudation from the Malpighian capillaries passes into the uriniferous tubes. Dr. George Robinson, Frerichs, and others have shown that a ligature on the renal vein of a rabbit causes a retrograde of the Malpighian capillaries, and a consequent of blood constituents into the uriniferous tubes, which, mingling with the urine, render it albuminous. In cases of Bright's disease there is an impeded circulation through the intertubular capillaries, which is, in part at least, occasioned by the pressure of the swollen tubes upon the vessels which lie between them; there is, consequently, an engorgement of the Malpighian capillaries, a serous exudation into the uriniferous tubes, and thus an albuminous condition of the urine. We see, then, that while an impeded circulation through the lungs throws back the blood upon the bronchial veins and , and causes a serous, mucous, or sanguineous exudation into the bronchial tubes, an impeded circulation through the liver distends the portal veins and capillaries, and causes from the mucous membrane of the alimentary canal, or serous effusion into the cavity of the peritoneum; and, lastly, an impeded circulation through the kidney distends the capillaries, and causes a serous exudation, and hemorrhage, into the uriniferous tubes. The results in each case are readily explained by a reference to the of the circulation in each of these important organs the lung, the liver, and the kidney. Without such a reference the facts are utterly unintelligible. If there be any one who doubts whether the retrograde action of a block to the circulation can be so far-reaching as I have described it to be, he has only to be reminded of the undoubted fact, that an obstructive valvular disease, on the left side of the heart, may affect the most remote parts of the circulatory system. Thus the impediment resulting from a defective mitral valve may extend backwards through the pulmonary capillaries to the systemic veins and capillaries, causing anasarca of the feet, etc.; it may extend through the capillaries within the liver to the vein and its capillary origin, causing ascites; and through the intertubular renal capillaries, to the Malpighian capillaries, causing albuminuria. It is manifest that neither extreme from the seat of obstruction, nor the intervention of two successive sets of capillaries, will prevent that retrograde engorgement of vessels, which results from a block in the course of the circulating current. In a future communication I shall endeavor to show that a careful study of the hydraulics of the circulation will lead us to the establishment of some simple', yet most useful, guiding for the employment of bloodletting, general and local, and for the use of hot and cold applications and counter-irritants in the treatment of inflammation. Lancet. |
gvarft(Iing$ of CHICAGO MEDICAL SOCIETY. Friday Evening, Nov. 6, 1868. The meeting was called to order, Dr. Marguerat, President, in the chair. Dr. McDonald, Secretary, being absent, Dr. Wanzer was chosen pro tem. The name of Dr. Foster, who was recommended for at last meeting, had not been acted upon by the , and was deferred. Dr. E. L. Holmes presented a crystalline lens from the eye of a young man aged 22 years, which dropped into the anterior chamber of the eye while the patient was stooping over to pick up something. The same accident happened to the other eye some two years ago, when the physician in attendance to replace the lens to its natural position by pressure, which resulted in the evacuation of the humors of the eye and . For the past yeai' the patient had suffered considerable pain in the good eye, up to the time of the accident which about one month ago, Dr. Holmes removing the lens on the following day. The patient was always near-sighted, and while the lens occupied the anterior chamber he could still see to read fine diamond print at a short distance. The wound healed one week after the operation, and, to the great delight of the patient, good sight was restored. The Doctor remarked that one week ago there appeared a small hernia near the iris, which he punctured. The eye is still at rest, but doing well. Dr. II. remarked that the dislocation of the lens was of rare occurrence, and thinks it is due in the present case to malformation, as the patient is a singular-looking fellow, being loose-jointed, especially the hands and wrists, presenting the appearance of one who has had the rickets. Dr. Holmes also presented a choroidal tumor, carcinomatous in character, on the internal portion of the right eye. Dr. J. P. Ross exhibited a cirrhosed liver taken from a woman who died in the County Hospital, of typhoid fever. This liver was compared to a healthy one; the latter weighing 3 lbs., 12 oz., while the diseased one weighed only 1 lb., 12 oz. The was of intemperate habits. Dr. Ross also presented the lungs of a young man of about 18 years, who died in hospital, of phthisis pulmonalis. Six weeks previous to his entering the hospital he said that he was perfectly well. He died two weeks after entry. The right lung showed quite a cavity in the upper lobe, which was the seat of cavernous respiration during life; the remainder of the lung, as well as the left lung, being thickly studded with throughout its entire substance. On admission to hospital, the patient was suffering from cough, night-sweats, hectic, and constant diarrhoea, which until death. All other organs seemed in a healthy , with the exception of the mesenteric glands, which were slightly enlarged. The Society then proceeded to the discussion of the subject chosen at the last meeting, viz.: "The Therapeutical Value of Carbolic Acid." The discussion was opened by Dr. Bogue, who gave a brief history of its discovery, etc. Stated that its therapeutical value was lately brought to notice by Dr. Lester, of Edinburgh, who had applied it quite extensively to severe wounds, and in many cases of compound fractures, virtually converting them into simple ones by diminishing, or rather preventing, suppuration. Dr. B. remarked that he had not had any experience in its use in compound fractures. Stated that the general modes of application were in , and in the form of a paste mixed up with whiting. The solution being from 3 to 6 parts of the acid to 20 of water, or linseed or olive oil; which solution, in case of amputation, is to he smeared over the entire flaps before closing; after which, the paste should be applied so as to entirely exclude the air from the wound. Tinfoil has been used for this purpose. Cases have been reported where no suppuration has occurred undet' the treatment recommended. Remarked that it had been used in catarrh and ozena, when the discharges were offensive; also as a local application to the mouth and throat, in the strength of from 1 to 3 grs. to the ounce of water or glycerine. Had prescribed it in one case of diarrhoea, characterized by offensive discharges, in gg-gr. doses internally, but without benefit. Stated that the remedy in foul ulcers, etc., was highly spoken of, but that his experience with it had been rather ; that he had used it in one case of gangrene, and it far inferior as an antiseptic to permanganate of , although in this case it might have been owing to the solution being too weak. In cases where there are sinuses or suppurating cavities, the use of 1 part of the crystals to 40 parts of water have been attended with marked benefit. Dr. B. thinks that it is most applicable and beneficial in lacerated wounds and amputations. Has used it in gonorrhoea and gleet, in solutions of different strength (1 part c. acid to 6 of oil, and 1 part c. acid to 30 of oil), with poor effect. Also used it 1 part acid to 2 of glycerine, on chancres, with very good effect. Dr. Fisher remarked that he had not had much experience in its use, but that he had used it in one case of compound of the tibia, in the form of paste made with chalk, where there was but little suppuration, and good result; also with benefit in ulcers. Dr. Ross remarked that he supposed it was purely a surgical remedy, but that he was tempted to use it in one case of chronic dysentery, where the patient was very low. He gave in this case 1^. Cupri Sulphas, gr. |. Pulv. Opii, gr. j. alternated with the turpentine emulsion, with injections of a weak solution of carbolic acid, with 5ss. tincture opium. The patient always inquired after the injections, and in tw'o weeks had entirely recovered. Dr. Quails remarked that he had used it in a case of erysipelas, suppuration stopping on the second day. Also ten cases of gonorrhoea, 6 acute, 4 chronic, with injections, carbolic acid 1 part, glycerine 12 parts, without very good effect. Dr. Gray reported case of diarrhoea which was treated by injections, 2 gr. acid to 1SS water, with gtt. xx. tinct. opii; also, in eczema, with good effect, applied . Dr. Bridge stated that he had used it in one case of ozena, but that the discharge was more copious, although not of an offensive character. The Society next proceeded to miscellaneous business. Subject for discussion was then chosen. Dr. Davis recommended that the subject for discussion two weeks hence be the following, which was duly carried, viz.: "How far do Continued Fevers prevail in this city at the time, and what are their characteristics?" The object being to elicit the observations of all members of the Society. On motion, Society adjourned. Members present Drs. Marguerat, Bogue, Davis, Holmes, Loverin, Wanzer, Quails, Avery, Blake, Fisher, Paoli, Ross, Bridge, Gray. Friday, Nov. 13, 1868. The Society was called to order, President Marguerat in the chair. The Secretary then read the proceedings of last meeting, which were duly approved and ordered to be placed on file. Dr. Lyman reported a case which occurred in his practice last summer, where the patient, while getting into a carriage, made a misstep, and was suddenly seized with a severe pain in the vicinity of the trochanter. She was taken home, put to bed, and an anodyne administered. In a' day or two the pain was reflected to the anterior portion of the thigh, when the Doctor applied a thimble packed half full of cotton, which was saturated with aqua ammonia. This remedy produced a blister within four or five minutes. The cuticle was then removed, and | gr. of morphia was applied to the denuded surface, and the part covered with oiled silk. This application entirely removed the pain, and the patient was kept in a comfortable condition by resorting to the twice a day. Small doses of quinine were administered daily, and in a week the patient was able to attend to business. Dr. L. is of the opinion that this method of administering is preferable to hypodermic injection. Dr. Bogue presented a patient with elephantiasis and chronic eczema, involving one leg from above the knee to the extremity of the toes. The leg was very hard with varicose veins, which were very tortuous. This disease was the result of injury some two years ago. The treatment consisted in an application of iodine, gr. x., glycerine 5j., to the eczema, and injections of persulphate of iron into varicose veins. Under this treatment the patient has improved considerably. Dr. Paoli remarked that the case did not look like true to him, as he had seen two cases in which the skin was very much thicker, and darker-colored. Dr. Lyman remarked that he presumed the color and skin had changed much under treatment; also spoke of having seen two cases of elephantiasis. Dr. Bogue stated, when the patient presented himself, the skin was much darker-colored, and corresponded to "Wilson's" diagnosis of elephantiasis. Dr. Wander reported two,cases: Case 1. Laceration of the Perineum. Was called to case where a woman had been in labor twenty hours, with her first child. Found child's head impacted in inferior strait, and labor not progressing. After waiting four hours, introduced forceps. The blades of the forceps were applied in the occipito-frontal diameter of the child's head, and by gentle traction the child was delivered, rupturing the perineum, so as to form a complete opening into the rectum. Immediately gave an anodyne, placed parts in apposition, and kept them so by the application of a couple of sutures. Kept the bowels constipated by use of ten drops tinct. opium, three times a day. Child and mother are both doing well. Case 2. Post Partum Hemorrhage. Was called in a case of a large, plethoric woman, who had been delivered of a child one hour previously, and who had suffered so severely from as to render her nearly pulseless. At once lowered the head of the bed, so as to produce gravitation of the blood towards the head, and administered fl. ext. ergot the course of the hour, when all hemorrhage ceased. Dr. Paoli remarked, that in case of the application of the forceps, it was necessary to support the perineum at time of making traction, and that he should employ an assistant under such circumstances. Dr. Hatch stated that he did not believe in supporting the perineum where the forceps were used, believing the elevation of the handles all that is necessary, and all that can be done to avoid laceration of the perineum. Dr. Paoli thinks ergot is not an effectual remedy in contraction of the uterus, and would not depend upon it in such serious cases as that reported by Dr. Wanzer; there were more reliable remedies in the materia medica. Dr. Hatch thinks that ergot is one of the most useful in case of post partum hemorrhage, it acting as a styptic under such circumstances. In large doses believes it a decided narcotic, diminishing the heart's action. Says he has never failed to produce contraction of the uterus by grasping the fundus with the hand and the administration of ergot, although he has practised medicine forty years. The preparation he generally employed was the fluid extract. Dr. Paoli says that there is no remedy which will produce contraction in the uterus in case of hemorrhage as efficiently as gallic acid, given in 10-gr. doses. Cited a case of craniotomy, followed by hemorrhage, in which he used a solution of tannin as an injection. Believed that had he depended upon ergot, the hemorrhage would have proved fatal. Dr. Wickersham stated that gallic acid was not prompt enough in its action, and thinks the physician who neglects the use of ergot in cases of post partum hemorrhage, neglects his very best remedy. Cited a case of hemorrhage where he the fluid extract without success, when he resorted to the powder with benefit. Dr. Merriman remarked that he thought Dr. Wanzer the right course in the administration of ergot, but asked the object of the sutures in the perineum? Dr. Wanzer said that he thought the ergot had but little to do with stopping the hemorrhage, but believed it due to the lowering of her head and the application of cold water to the hypogastric region. Dr. Merriman reported the case of a large, plethoric woman, weighing 250 lbs., who, while in labor, suddenly had the pain reflected to her head, the contractions of the uterus being suspended. Waited twenty minutes, and then proceeded to give ergot. While preparing ergot, happened to turn around, and found her jaw set and in convulsions. At once the patient; after which he gave the ergot, and soon her of a child weighing 13| lbs. History of patient showed she had convulsions at a previous labor. Dr. Wickersham thinks that the forceps might have been used, as the traction would have produced contractions of the uterus. Dr. Loverin said he did not favor the administration of during labor. Dr. Hatch remarked that he never had anaesthetized a when using the forceps, as it was better to have the of the patient to aid you in applying the instruments, thereby avoiding inclusion of any of the soft parts of the mother between the foetus' head and the forceps. The case reported by Dr. Merriman was discussed by Drs. Loverin, Paoli, and Wanzer. Society then proceeded to miscellaneous business, and Dr. A. H. Poster was unanimously elected a member of the Society. Adjourned. |
O i H H n I. Apology. The St. Louis Medical and Surgical Journal calls our attention to the fact, that the October number of the Examiner contained among its selected articles three that were copied from that Journal without the usual credit. Having a good proof-reader in the office, we do not require the of selected articled to be submitted to us for examination before they are worked off. The articles copied from the St. Louis Journal were marked and given to the printer with the expectation that they would be credited according to the rule of the office. And we had not noticed the omission until our attention was called to the matter, by a rather sharp rebuke in the latter Journal. To Subscribers. This number being the last of the volume, we have directed bills to be sent to all subscribers who are in arrears, stating the amount due up to January 1st, 1869. If any mistakes have been made, we shall be happy to correct them. In the future, as heretofore, we shall endeavor to make the Examiner worthy of the patronage of the profession. Chicago Medical College. The friends of a more and extended system of medical education will be glad to learn that the adoption of a full six months' Lecture term, a complete gradation of Classes, and three courses of Lectures before graduation, by this College, has not prevented it from receiving the patronage of an excellent class of students during the present term. The present arrangement proves highly to both Faculty and students. Detroit Medical College. We see, by the Announcement of this new medical school, that its first preliminary course of Lectures commenced on the 3d of November; and the first regular course is to commence on the 2d of February next, and continue four months. Every enlightened physician will concede that Detroit is the only proper place for a medical college in the State of , simply because it is the only one in which adequate for clinical instruction can be found. But we think our friends engaged in the enterprise there, have committed a great mistake in clinging to the old system of pretending to teach the whole field of medicine in four months, and disregarding both classification of students and preliminary education. By this course they present no claims on the patronage of the superior to the most ordinary schools in the country; and, with the Medical Department of the State University at Ann Arbor on one side, and the Buffalo Medical College on the other, their chances of success are not brilliant. Had they, at the outset, adopted a complete college organization in with the real interests and often expressed wishes of the profession generally, by making the regular lecture term six months; dividing the branches into series corresponding with the number of years required for study; exacting thorough examinations at the close of each series; with a moderate standard of preliminary education, they would have presented a strong claim on the active sympathy and support of the at home and abroad. With this, and the advantage of clinical facilities, they could have competed successfully with their principal rival at Ann Arbor, and ultimately compelled a union, by the removal of the Medical Department of the to Detroit. We do not make these remarks from any feeling of towards the Faculty of the Detroit Medical College, for we wish them abundant success in any enterprise that is to promote the educational interests of our profession. Aitken's Science and Practice of Medicine. We have just received the second volume of the second American edition of this work. With the many valuable additions made by the editor, Dr. Clymer, this edition presents, perhaps, the most complete and extensive work on practical medicine now before the profession in our language. The publishers, Lindsay & Blakiston, of Philadelphia, have done their part of the work in excellent style. For sale by S. C. Griggs & Co., Chicago. Price, $12.00, complete. Mortality for the Month of October, 1868: The Superintendent's monthly report showed a total of 445 deaths, during October, 29 of which were from convulsions, 17 from cholera infantum, 21 from scarlet fever, 14 from , 12 from diarrhoea, 9 from diptheria, 12 from croup, 34 from typhoid fever, 35 from phthisis pulmonalis, 16 from , 10 from whooping cough, 14 from tabes mesenterica, 14 from teething, 10 from old age, and 6 from causes unknown. There were 20 premature births, and 50 still-births. COMPARISON. Deaths in Oct., 1868, 445 | Deaths in Oct., 1867, __428 | Increase, 17 Deaths in Sept., 1868, 739 | Decrease, 294 AGES. Under 1______________116 1 to 3_______________ 77 3 to 5________________ 35 5 to 10 to 20______________ 23 Males,____________260 Single, 331 White,___________ 443 20 to 30____________ 47 30 to 40____________ 37 40 to 50 30 50 to 60____________ 11 60 to 70____________ 15 I Females, 185 | Married, 114 | Colored, 2 | 70 to 80____________ 16 BO to 90_____________ 5 Unknown______________ 1 Total 445 Total,____________445 Total,____________445 Total,____________445 NATIVITY. Foreign Chicago 118 Chicago 74 Other parts U. S. 75 Austria,____________ 1 Bohemia_____________ 7 Canada______________ 6 France 2 England 8 Germany 68 Holland 2 Ireland___________ 51 Norway_____________ 5 Scotland___________ 4 Italy, 1 Sweden 16 Switzerland 3 Unknown 4 Total, 445 MORTALITY BY WARDS FOR THE MONTH. Ward. Mortality. Pop. in 1868. One death in Ward. Mortality. Pop. in 1868. One death in 1 11 11,991 1,091 14 40 14,168 354 1-5 2 15 13,739 916 15 37 20,429 552 1-7 3 15 16,620 1,108 16 16 16,011 1,007 4 18 16,499 916 3-7 Armory, 1 5 24 13,434 559 7-8 Bridewell, 2 6 30 12,507 416 8-9 County Jail, 1 7 62 21,957 353 1-3 County hosp.13 8 29 14,003 482 5-6 Chi. River, 3 9 20 18,050 902 3-5 Mercy Hosp. 1 10 _ 12 13,644 1,137 Marine Hosp.1 St. Mary,s Hosp. 1 11 _ 25 13,317 532 3-5 Soldier's Ho. 1 Hosp, for Women and 12 27 14,739 549 3-5 Immigrants 15 Children, 1 13___ 20 11,113 555 3-5 HomeforFriendless, 4 Total,____________________________________ 445 The health of the City during the month of October has been very good, comparing favorably with the corresponding month in 1867, when the increase of population is borne in mind. There is a marked diminuition in the infantile mortality, with a decided increase of deaths by scarlet and typhoid fevers. In no other respect is there anything unusual. The influence of the want of drainage is also marked. The report was adopted and the Board then adjourned. A Blow to the Fungus Theory of Disease. In a short communication to the Centralblatt, Drs. Bergmann and describe a crystalline substance, to which they have the name "sulphate of sepine," obtained from putrefying materials, and which they believe represents the proper poison of organic substances undergoing this kind of fermentation. It is obtained by diffusion through parchment-paper, precipitation with corrosive sublimate from an alkaline solution, removal of the mercury of silver, by sulphuretted hydrogen, and purification of the residue. Large, well-defined, acicular needles are thus obtained, which are deliquescent in the air, and, exposed to heat, melt and carbonize. They possess a powerfully poisonous action. A solution containing scarcely more than one-hundredth of a gramme was injected into the veins of two dogs. Vomiting was immediately induced, and after a short time diarrhoea, which in the course of an hour bloody. After nine hours the animals were killed, and, on examination, their stomachs and large intestines were found ecchymosed, and the small intestine congested. Frogs could be killed in the same manner. Lancet. N. Y. Med. Gazette. Length of the Colon in Young Children. At a stated meeting of the New York Obstetrical Society, a specimen of , or anencephalus, was presented by Dr. Jacobi. The child weighed nine pounds. The viscera were well developed, and the colon was unusually long in this case. Dr. Smith made the remark, that he had measured the colon in thirty cases of children under six months, and discovered that from one-quarter to one-third of the large intestine lies below the brim of the pelvis. Dr. Jacobi stated that the descending portion of the colon, in the young infant, was nearly twice the length of that of the adult. It crosses over diagonally towards the right side, instead of lying parallel to the long axis of the body. There is no proper sigmoid flexure as in the adult, but, on account of the great length of the colon, a number of flexures are found. Amer. Jour, of Obstetrics. Boston Med. and Burg. Journal. Pyrethrum for Scabies. The Pacific Med. and Surg. Journal says: "Flea powder" is composed of the flowers and leaves of Pyrethrum Boseum, and probably of P. Carnosum, very finely powdered. It is not commonly fatal to insects, but appears to annoy and stupify them. If the article be recent and properly prepared, it is decidedly efficacious. When in the track of ants, it is said to drive them away with certainty. A druggist of this city informs us that he keeps his store almost entirely free from flies by dusting it occasionally on the walls and windows, in places where they are accustomed to alight. The insects disappear when they get the powder in contact with their bodies. It is said that when burnt in small quantities, in a chamber affected with mosquitoes, it destroys them or drives them away. A tincture of the plant, made with dilute alcohol, is recommended as a cure for scabies. The is said to give prompt relief from itching. Med. and Surg. Reporter. Professors Pancoast and Gross, of Philadelphia, having lately returned from a tour abroad, the occasion was considered a favorable one to show honor to these distinguished men, and accordingly a public reception took place at the Academy of Music, in that city, on Saturday evening, the 24th ult. The greeting of welcome was delivered by Dr. A. Hewson, and was responded to by the two Professors the addresses of each being eloquent and appropriate. Addresses were also made by Governor Pollock, Daniel Dougherty, Esq., Dr. Sayre of New York, Dr. Doyle, and others. The whole entertainment is as excellently arranged and harmoniously carried out, and reflects credit upon all the parties concerned. Boston Medical and Surgical Journal. Statistics of Spain. The distinguished statistician, Don Ramon de la Sagra, furnishes the following statistics of Spain during the year 1866: Total population, 15,800,000. Rate of births, 1 to 26; proportion of sexes, 51'65 boys to 48'35 girls. In every 19 births, one was illegitimate; proportion of marriages, 1 to 112 inhabitants. The average number of to each marriage, as near as can be estimated, is 4-6. Deaths were 1 to 34 of the whole population, 1 to 28 in the cities; 503 of the deaths out of 1000 were under 6 years of age. Medical and Surgical Reporter. A fact of some interest, if it be confirmed by further , has recently been announced by the French medical journals. M. Telcphe Desmartis, a medical experimenter of Bordeaux, has succeeded, it is said, in inoculating upon plants tubercular matter taken from the human lung. The result has been the production of a particular kind of mycelium. This leads M. Desmartis to establish a comparison between tubercle and sphacelia, or ergot of rye. Lancet. N. Y. Med. Gazette. The Structure of the Tactile Corpuscles . M. Rouget (London Med. Mirror) believes that he has succeeded in demonstrating the structure of the tactile ; from frequent observations he is warranted in saying that the nerve-fibres actually enter the substance of the cone-like corpuscle instead of being merely coiled round it, as was believed. His specimens are prepared by soaking them for some time in acidulated water, and then acting on them with strong nitric acid, which stains the nerve-fibres, but not the other tissues. Medical Record. The Qualifications of an Edinburgh Surgeon in 1505. In 1505, the surgeons of Edinburgh were in noway behind the other schools of the three kingdoms, and we are somewhat surprised to read that "when the surgeons of Edinburgh were, in 1505, incorporated under the denomination of surgeons and barbers, it was required of them to be able to read and write, to know anatomie, nature, and complexion of every parte of the human bodie, and lykeways to know all vayns of the say me, that he may make flewbothomie in due time together with a perfect knowledge of shaving beards." Medical Record. Mortality of the Abyssinian Expedition. In the expedition, says the Deutsche Klinik, the English troops had 5-8 per cent, of their number sick, and 1-3 per cent, of deaths. The death-rate among officers was 11 per cent, of the sick ; among the privates, 18 per cent, in the highlands, and 20 per cent, on the coast and on board the hospital ships. Three officers died, and three officers died from violence, one of them a suicide. Med. and Surg. Reporter. Hemorrhage after Extraction of Teeth. A of the Lancet writes: "Troublesome hemorrhage will follow the extraction of a tooth. A case of this kind occurred a short time ago, in which bleeding continued for six or seven hours, until it was stopped by the following treatment, the effect of which is immediate and permanent, and gives no pain. I have treated five cases in the same manner: Soften a bit of white wax, and mould it into a conical shape, about an inch long, and press it into the cavity, at first lightly, and then very firmly, so as to fill it. Cover this with a thick pad of lint, to retain it in its place, and bind the jaw's together for a few hours with some kind of bandage/' Med. and Surg. Reporter. Prof. Peaslee has resigned the chair of Anatomy and Physiology in the Medical Department of Dartmouth College, occupied by him the past 28 years; and has been transferred to the chair of the Diseases of Women. Dr. Lyman B. How, of Manchester, N. H., has been elected to the vacant chair of Anatomy and Physiology. Medical Record. Turpentine as an Antidote to Phosphorus. The (Jen. de Medecine calls attention to the custom of the workmen in a match factory at Stafford, who apply to the matches, of carrying on their breast a tin cup, essence of turpentine. This precaution is said to be sufficient to prevent any ill effects from the action of the . It was previously known that the vapor of turpentine prevents the ignition and even the phosphorescence of , but the practical application of this knoweledge is not so generally adopted as it should be. Bost. Med. and Surg. Jour. Operation for Hernia without opening the Sac. In the New York Medical Record, Dr. Erskine Mason five cases of strangulated hernia, three femoral and two inguinal, which he operated on successfully without opening the peritoneal sac. The method is an old one, but now very employed in Great Britain, though not much resorted to in America. Statistics show it to be safer than cutting the sac, which is liable to produce peritoneal inflammation. Dr. Mason thinks it should always be attempted at first, as the sac may be opened afterwards if the hernia cannot be reduced without so doing. In a late discussion before the British Association for the Advancement of Knowledge, several physicians warmly the opinion that the faculty of articulate language resides in the third frontal convolution of the left side of the brain. Money Receipts to Nov. 8th. Drs. Thos. Whitten, $3; J. C. Allaben, 3; L. B. Cowles, 2; David Prince, 5; J. H. Judson, 3; G. W. Morrill 5; J. A. Adrain, 3; J. H. Hollister, 3; Thos. Hamill, 3; H. N. Hurlbut, 3; Money Receipts from November 7th to 25th. Drs. A. H. Salisbury, $3; T. T. Ellis, 3; J. B. Eversole, 3; A. B. Hanna, 3; Hill & Carr, 3; D. R. Taylor, 3; David McDill, 3. |
The Clinique. NEURALGIA. AN OBSCURE CASE. Substance of a Clinic in the Medical Wards of Mercy Hospital) December 11th) 1867. By N. S. DAVIS, M.D., Professor of Practical and Clinical Medicine, in Chicago Medical College, The patient before you, gentlemen, is a fair representative of a class of cases which, from their persistence, often tax the resources of the practitioner to the fullest extent. He states that three years since, he was attacked with pain in the left hip, principally in the course of the sciatic nerve, though , at times, through to the groin, and a partial loss of motion in the limb. After a few weeks, the pain ceased, and he recovered nearly the perfect use of the limb. During the subsequent two years, he suffered occasional attacks of pain in the same parts, and the muscles of the left leg became weaker than those of the right. During the last year, he has been afflicted with neuralgic pains and morbid sensations almost every day, but extremely variable, both in their location and severity. The pains are more severe in the hips and lumbar portion of the spine than elsewhere; but they frequently change from one to the other, and to the shoulders, arms, legs, the heels, the neck, head, and face. In the head, face, and gums, the sensation is described as more of a burning and dryness than acute pain. These morbid sensations, whether of heat, dryness, or acute pain, are extremely changeable, both in their location and severity. They appear to be influenced some by atmospheric conditions, but not in a marked or uniform manner. There is no positive paralysis of either sensation or motion, although the muscles of the left leg are weaker and a little more attenuated than those of the right. His appetite and digestion are good, his bowels regular, and his urine natural in quantity and color. His countenance does not exhibit the physiognomy or expression of severe organic suffering, and his blood and tissues appear to be fairly . I find no marks of disease in his fauces, or on his skin, but the Schneiderian membrane throughout his nostrils is , redder than natural, and his nostrils constantly becoming filled with dry, hard, and black crusts. This condition of the nostrils, he says, has existed since his early boyhood; he being now over 20 years of age. He denies all knowledge of having had any form of syphilitic disease. But of his parents or ancestors I have learned nothing. Such is, briefly, the history of the case before you. If the suffering of the patient is such as he describes, it is evident that the case must be classed among the neuralgias. To class it thus, however, does not explain its nature, or the essential pathological conditions on which the pains and morbid sensations depend. To aid in arriving at some definite in reference to this, we may state that all cases of may be arranged, pathologically, into three groups: First. Such as arise from disease or injury directly the trunk of one or more nerves. Second. Such as arise from disease of some part of the central portion of the nervous system. Third. Such as are caused by morbid conditions of the blood. In those cases belonging to the first variety, the pain is necessarily limited to the single nerve involved and its branches, as we see in sciatica, tic doloreaux, etc. In the second class of cases, where the seat of disease is in some part of the cerebral or cerebro-spinal centres, causing neuralgic pains in distant parts, such pains seldom follow the track of any one nerve; but they affect a particular locality or section, such as the forearm, the leg, the foot, the side, etc. In the third class of cases, the pains are limited to no one nerve or part, but affect many nerves, and usually change with rapidity from one nerve or set of nerves to another, as in the history of the case now before you. The morbid conditions of the blood capable of causing may be either toxemic or spanemic. That is, poisoned by the presence of some virus imbibed from without, or some effete or excrementitious matter, such as urea, the materies morbi of gout, etc.; or such an impoverishment of the blood, in relation to its corpuscles and nutritive constituents, as renders it incapable of affording the elements for healthy nutrition of the nervous structures. Those blood-poisons which, by their immediate or remote effects, are most apt to so modify the of the nerve structures as to cause persistent and neuralgia, are the syphilitic, the gouty, the uremic, and the koino-malarial. The effects of these poisons on the properties of the several tissues are not limited to the individuals primarily affected, but may be transmitted, more or less distinctly, to their offspring. This is particularly true in reference to gout and syphilis. Some of the most distressing and obstinate neuralgic affections of the heart, stomach, and extremities accompany the diatheses transmitted by gouty parents. I know a lady in this city, who was subject to sudden attacks of the most excruciating neuralgic pain in the great toe of one foot. It was accompanied by no swelling or redness, or other traces of inflammation. Her father had suffered many years from gout. It is doubtless true, that a large proportion of the cases of arising from the syphilitic poison are caused by a low grade of specific inflammation, either in the neurilemma or in the periosteum lining the bony canals or orifices through which the affected nerves pass; but there are some cases that cannot be attributed to either of these pathological conditions, but, from their changeable character, are evidently dependent on some morbid condition of the blood and nerve sensibility . Although the patient before you admits of no known syphilitic influence upon his own person, yet the exceedingly erratic character of his neuralgic pains, the burning dryness of which he complains in his head, face, and neck, in connection with the condition of the Schneiderian membrane of his nostrils, renders it quite probable that his condition is the result of hereditary syphilitic influence. The bridge of the nose is broad and looks a little swollen; and in examining the nostrils, the Schneiderian membrane throughout appears rough, thickened, and constantly secreting a morbid product that dries into hard black crusts. That a certain degree of syphilitic influence is capable of being propagated to a very remote degree, we have abundant clinical evidence. Hence, we meet with it sometimes under circumstances where it would be least expected. It is not many months since I saw a lady, the mother of a family of children grown to maturity, who was laboring under such as had led her physician to confidently believe she had serous effusion into the ventricles of the brain. On placing my hand on her head, I discovered the existence of no less than three well-marked pericranial nodes; and all her symptoms of cerebral oppression disappeared under the subsequent use of iodide of potassa and conium. During the last year, a gentleman, over 70 years of age, was brought here from a neighboring city, where he had led an active business life, and enjoyed a high social position. months previously, he had been attacked with what was regarded as apoplexy, or, at least, dangerous congestion of the brain. He was treated actively by men of high standing in the profession, and the first severe symptoms of oppression and stupor were relieved. But he remained with partial paralysis of one arm and leg; severe pains in his head and extremities; impaired memory, frequent mental hallucinations, and almost entire sleeplessness at night. I was told that his case was regarded by his medical attendants as softening of the brain, and mostly beyond the reach of remedial agents. His head being partially bald, I thought one parietal region was more prominent than the other, and, on careful examination, a thickening, with some tenderness, was found to extend over nearly the whole length of one parietal bone. The had noticed this prominence from the commencement of his attack, and it afforded strong evidence that all his cerebral symptoms had been the result of a corresponding disease and tumefaction of the dura mater pressing upon one hemisphere of the brain. All the cerebral and paralytic symptoms in a few months, under the influence of country air, the steady use of six-grain doses of iodide potassa, aided by a very limited use of alterative doses of bichloride of mercury, and bromide of potassa at night to procure sleep. If this old had ever had syphilis (which I did not ascertain with certainty), it was, doubtless, more than forty years previously. Such cases, with many others that I might mention, are to show the necessity of inquiring carefully into the history of patients laboring under chronic affections of the nervous system; and of observing carefully all local that might afford any information concerning the condition of the patient. In the patient before you, the fact that the morbid condition of the membrane lining the nostrils, already described, has existed from childhood; the peculiarly changeable character of his neuralgic pains and sensations; while the general functions of nutrition, , etc., seem to be well performed, have led me to think that the constitutional vice from which all his distressing symptoms have arisen, is a remote effect of the subtle poison about which we have been speaking. If this view is correct, we need not expect any permanent advantage from the ordinary remedies for relieving neuralgic pains. His only hope of recovery must be founded on an to change his diathesis or constitutional condition. The means best calculated to effect such a change are as follows: 1st. Regular and judicious exercise in the open air, by walking and riding, and, if possible, a change of climate. 2d. A plain, nutritious diet, chiefly of milk, farinaceous articles, and fruits, but from which must be rigidly excluded all fermented and distilled drinks, tobacco, and strong tea and coffee. 3d. The use of such alteratives as will be likely to effect a change in the elementary properties of the organized structures of the body, without materially impairing either the plasticity of the blood or the general tone of the tissues. The first two of these propositions need no comment. The advantages of moderate exercise; a mild and dry climate; plain food, and the exclusion of all nervous stimulants, are obvious to all of you. But what system of medication will effect the third indication ? I shall, at present, direct a prescription consisting of, 1^. Iodide Soda, . Hydrarg., 1 gr. Fl. Ext. Conium, 5j. Simple Syrup, Mint Water, aa SSiss. Mix, and take a teaspoonful before each meal and at bedtime. I will have this continued until it produces a change in the secretion from the Schneiderian membrane, or slight traces of the mercurial influence on the gums. When either of these effects are produced, the prescription should be discontinued and the following given in its place: 1^. Iodide Potassa, Potassa, 5vj. Fl. Ext. Conium, SSj. Mint Water, Siij. Mix, give a teaspoonful from three to four times a-day. This may be continued for six or eight weeks, unless some unpleasant effects are sooner induced. In the meantime, if the patient becomes in any degree debilitated, as indicated by a feeling of lassitude, diminished appetite, and paleness of the lips, some direct tonic should be given conjointly with the just mentioned. The best tonics I have used in such cases, have been either a teaspoonful of the syrup of of iron, given half an hour after each meal; or a pill, composed of citrate of iron 2 grs. and strychnia of a grain, given at the same times. A neglect to insist on good air and a proper use of tonics in conjunction with the usual alteratives, is one cause of failure in the treatment of such cases as the one under consideration. Besides the hygienic and internal medical treatment which has just been mentioned, I shall direct, with a view of affording temporary relief or mitigating the morbid sensations of the patient, anodyne frictions to the whole length of the spine each night and morning. For this purpose, a liniment composed of the camphorated soap liniment, giv, and veratria, 3 grs., is as effectual as anything I have used. Sometimes, the judicious application of electricity to such cases will produce beneficial results. It should be applied in such a manner, however, as to obtain its tonic effects, rather than irregular shocks. But, gentlemen, the clinic hour has expired, and you will probably have an opportunity to see more of this case in future. |
OVARIOTOMY; WHEN AND HOW TO OPERATE; AFTER TREATMENT. Abstract from Remarks of E. R. PEASLEE, M.D., at N. Y. Medical Journal Association, May 24,1867. Reported by E. S. BELDEN, M.D. Mr. President Three years ago, I presented a paper to the Academy of Medicine on Ovariotomy, which was published in its " Transactions." My opinions as there expressed have not materially changed; but as some new things have been since then, it is to these especially that I wish to call your attention this evening. At that time there still remained some doubt in the minds of certain eminent surgeons whether ovariotomy should be as a legitimate surgical operation or not. I then gave my reasons, and the statistical facts and arguments for the that it has as high a claim to be thus recognized as any other important operation, and I think very few would now be found to controvert it. During the past five years the ovariotomy in the hands of experienced ovariotomists has done more in proportion to the number of cases operated upon, for the prolongation of life, and less to shorten life than any other surgical operation which can be at all compared with it in point of magnitude. The percentage of lives saved by ovariotomists during this time is probably not short of eighty per cent.; and these are patients who are doomed on an average to die without the operation within twelve to months, and, who, if they are saved thus, are likely to live as long as other women of the same age. A point then in connection with ovariotomy, of much interest is, that the operation is followed in a very few days, either by death, or, on the other hand, by life and health of indefinite duration, as just stated. If successful, it is to the woman a resurrection. A patient remarked to me, " she felt as though she had commenced an entirely new life." The results suggest the expression of the poet: " Aut cita mers, aut victoria lseta." If this operation is performed in a case which is , it is one of the most simple of surgical operations. On the other hand, if complicated in a high degree, it is the most difficult and formidable operation the surgeon ever attempts to perform. And not even the most experienced operator can certainly determine beforehand, whether he has a simple or a complicated case. Where he had expected no difficulty at all, he may find a condition of things that will require all his , deliberation, and caution, to enable him to get through without leaving his patient dead upon the table. I can say that ovariotomy sometimes demands more of all these qualities, and more care and judgment in the subsequent treatment, than any other I have ever attempted: though, during seventeen years of my professional life, I frequently performed all the capital operations. This peculiarity has not, however, been sufficiently recognized. Encouraged by the facility of operation, and the frequent successes of the most favorable cases, many a physician has attempted ovariotomy, who would never think of attempting any other surgical procedure, not even the amputation of a finger. The results have been, as might be anticipated; the first case of real difficulty, or perhaps the second, terminating alike the operator's zeal and his success. It is, however, the fact that a simple case operated on at the most favorable time, will probably recover in spite of a large amount of operative bungling. We all know the difficulty of diagnosis, in complicated cases, and the mistakes which have been made, but I omit this topic entirely. The first question I will consider is, at what period in the development of the disease shall the operation be performed? The question lies, of course, between performing the operation early, while the patient is still in robust health, and deferring it until she begins to be somewhat reduced by the disease; no one would defer til she is just about to die in consequence of it. Spencer Wells, and Baker Brown, maintain that the should be performed early, in full health. Mr. Hutchinson, of London, says it should be performed "as early as possible." Baker Brown once performed this operation when the tumor had been detected only eight weeks before. The patient died on the ninth day. Mr. Erichsen, Tyler Smith, and Dr. W. L. Atlee, of Philadelphia, take the ground that this operation should not be performed at this time; but when at length the patient begins to yield to the disease; and in this opinion I concur. The reason in general, for the first proposition, is that the patient endures a severe operation better if it is performed when she is in full health; a statement which I have not found to be substantiated by statistics as shown in the paper to which I have alluded. I cannot here specify all my reasons for deferring the till the general health begins to fail, but the following are some of them: In the first place, if the operation is performed upon a patient in full health, she is, other things being equal, more liable to peritonitis after it; and peritonitis destroys about one-fourth of all who die from the effects of the operation. Spencer Wells, operating on patients in full health, when symptoms of peritonitis appear, bleeds them, and in that way has sometimes saved them. And certainly this is very judicious practice, if the operation is performed thus early; but I think it would be better to diminish the risk of peritonitis, by some delay. Besides, if the patient is in good health, she is certainly in no immediate danger; and we make sure of adding a certain amount of time to the patient's life by the delay. And we may often wait six months or a year, and find her still in as good health as to-day. Again, if we wait, further opportunity is given to perfect the diagnosis; and every one knows how difficult this is in some cases. Even Spencer Wells, whom I saw perform his 174th and 175th operations last July, and who has now operated over 200 times, still pronounces his diagnosis with caution. But he waits and reexamines the case until he feels very positive; and he has very seldom had to record a mistake. If we wait till the abdomen is largely distended with fluid, it may become necessary to tap her, though still in pretty good health; and this operation may at once clear up all doubt, if any before existed, whether the case be one of ovarian tumor. If the tumor be one which can be very much diminished by tapping, i.e., if there be one or more large sacks I make it a rule to tap before deciding as to the operation of ovariotomy. Many of the tumors in this region, at first thought to be ovarian, are not so, but are cured by a single tapping. I have had two such cases, and consider this a very important point. A patient, the wife of a professor in one of the Western colleges, called on me some years since, who had seen three or four of the most distinguished surgeons and physicians in this city, all of whom had pronounced her case one of ovarian tumor. I examined her case thoroughly, and had not the least doubt that it was such. She went to a distinguished surgeon in Massachusetts, who had no doubt as to its nature, and offered to remove it immediately if she wished. I declined to do anything in the case till tapping should be required; after which it would be time to decide respecting ovariotomy. A year afterward, the tumor began to interfere with respiration and digestion, and I considered that the time for tapping had come. I tapped her, but there was no ovarian tumor; and no farther operation was required. The uterus, prolapsed by the pressure of the fluid, soon regained its normal position, under appropriate treatment. She gave birth to a child about months afterwards; and has now enjoyed perfect health for the last five years. The sack was one of those developed in the broad ligament. I have had another case like the preceding; and by waiting and tapping, I found a similar sac, instead of an ovarian tumor, and that no further operation was required. Spencer Wells has noted a few cases where he had tapped tumors of this kind with the same result. The fluid contained in these sacs is as transparent as water, and contains no albumen, (certainly in most cases,) and has great refractive power. It is entirely different from the ovarian fluid; especially in the fact of the absence of albumen. Another reason for waiting, is, that the success of the is greater, other things being equal, if the tumor is large; and this for two reasons, I would not be willing to remove an ovarian tumor that was of the size of a foetal head in a person of ordinary health. 1. If the tumor is large, by its constant pressure upon the peritoneum, the latter is rendered more insensible to irritation and consequent inflammation. 2. And another reason for not operating when the tumor is small, is, that if after the incision is closed up, if the patient should vomit or cough, there may be trouble from straining the muscles, or even from a hernial protrusion through the wound. The latter occurred in one instance where I removed a fibrous tumor of the uterus, and the patient died in consequence. She had a severe cough at the time of the operation, and which she had concealed from me by taking opium, knowing that I would not operate if I discovered it. Three or four hours after the operation she began to cough violently. This I could not ; and the consequence was, a hernial protrusion between the needles, although they were but half an inch apart. As I was sixty miles from the patient when the hernia occurred, the bowel mortified before it was reduced, and she died six days after the operation. As an argument against the assertion that a person in full health bears this operation, or any severe operation, better than when somewhat reduced in health, consider the following fact. If we divide the amputations of the lower extremity into two classes; first, operations performed upon persons in full health, as for elephantiasis, or in consequence of accidents, etc., called amputations of expediency or of necessity; and second, , performed upon patients somewhat exhausted by disease, called expediency, pathological amputations, as those for disease of the joints, etc. It has been found that while in patients of the first class (amputations upon persons in full health), 42 per cent, die; in amputations of the second class, only 14 per fatal. An operation upon an ovarian tumor, while the is in full health, is literally as well as logically an operation of expediency; and here, as with amputations, the best time for operating is, when the health of the patient is somewhat . No ovariotomist has had better success than Dr. Tyler Smith, and he acts upon this principle, as I have before stated. I have nowunder my observation some ten cases; some of w'hich I have kept waiting a year or more; while others who, determined to have the operation performed, have found those willing to operate, have succumed. I have not yet had to regret deferring the operation, as I have explained. In regard to the operation of ovariotomy itself, I can here only consider the incision; and the manner of treatment the pedicle of the tumor removed. In regard to the incision, the rule is, that it at first should not be more than one or two inches long, through the peritoneum, but somewhat longer, of course, through the skin, etc., than internally. Next I pass a steel bougie into the peritoneal cavity, and around the tumor, if possible, to ascertain if there are any adhesions. Afterward the incision is to be enlarged, or not, as may be required; the rule being to leave it as short as will answer the purpose. It should, however, always be regarded as merely explorative, until the operator has decided that the tumor is to be removed. If he finds that there are extensive adhesions, or especially if to the alimentary canal, uterus, or bladder, it is very much better to make a long incision at once, that the adhesions can be seen before they are torn across; else they may be torn from the intestines, bladder, or uterus, instead of from the tumor, and troublesome hemorrhage may take place into the cavity of the peritoneum. The tumor having been taken away, how shall we treat the pedicle ? If the pedicle were in no danger of bleeding after its division, all operators would agree that it should be returned into its natural position, and the wTound be closed up. But the only thing that we can rely upon, to prevent hemorrhage from the pedicle to the greatest possible certainty, is a ligature tied in a knot. If we have tied it tight enough to stop the there, even for a few minutes, we may feel very sure it will serve us, unless it subsequently slips off. I shall consider other methods further on. But if the legature is used, then the question arises whether it should be cut off short or left hanging out of the wound. The objection of Spencer Wells, to the ligature, is, that it always produces a sloughing of the stump of the pedicle. (The being doubled and carried through the middle of it, one half is inclosed on each side.) " If it is cut off short, the result will inevitably be," he thinks, "that the ligature and the stump of the pedicle will slough off and remain in the abdominal cavity." But if the ligature is not cut short, of course it will be all the same so far as the slough is concerned. Spencer Wells has even suggested the idea that, on the whole, it would be better to leave these ligatures coming out of the lower end of the wound; since inasmuch as there must be a slough, the dead, putrefying matter thus formed in the cavity, in this way, finds a conduit, which, by capillary attraction will drain it off. Dr. Bouth, who also takes the same view, made some upon the lower animals, and found that dead meat, even if fresh, in the abdominal cavity produced a low putrid fever, of which they died. It is, however, a fact, that as large a proportion of the women treated in this way, by ligature, have recovered, as of those treated by other methods; and it is also true that most of them had no symptoms of low fever. None of my patients have had any such symptoms, except as evidently produced by other causes, and I have always used the ligature. Dr. Tyler Smith operated upon eight patients, with the ligature cut short, and they recovered without any symptoms of low fever at all. And the very fact that patients do recover thus without fever, shows that no absorption of putrid matter has taken place, and therefore that no such has been formed. This was the conclusion I arrived at three years ago, when I read the paper to which I have referred. I have since had opportunity to demonstrate its correctness. My first six cases were treated with ligatures, the end out of the incision, and they all recovered. Since then, I have had an opportunity of examining two of my own cases that terminated fatally, in which I applied the ligature, and cut it short. They both died seventeen days after the operation. I have also examined another case lost, by another operator, after similar treatment of the pedicle. In none of these cases did any slough occur. In one instance, the ligature had actually cut off the portion which was included in it. In another, it had cut it to that extent, that there was left only enough to half fill the loop; and in a third, the ligature was so entirely covered up, that I could with difficulty find it. But in every case there had been an exudation of plasma over the stump and ligatures, which had nourished the part which was beyond the ligature, and attached it to the living tissue in its neighborhood. I state, therefore, without any hesitation, that I consider the point demonstrated, that there is no slough of the pedicle when we put a ligature around it, as I have . And, if there is no slough, what is the use of leaving one end of it hanging out of the wound ? It seems to me, at the present time, therefore, that the best way to treat the pedicle is, to apply the ligature, cut it short, and close up the whole incision. Still, Spencer Wells most frequently used the clamp, though he recently stated that he is not yet decided which is the best way to treat the pedicle. I cannot here speak of the relative merits of the clamp, nor can I recommend the ecraseur, though it has several times succeeded. The actual cautery has been applied to the pedicle by several operators, but more frequently, of late, by Baker Brown. Nearly a year since, I saw him perform his 101st and 102d operation of ovariotomy, and 32d and 33d, in which he had applied the actual cautery to the pedicle. In one of the two cases, the bleeding was not arrested by the hot iron; and he then applied the ligature in the common way, and cut it short. The same has been done in several previous cases; and, of course, all these should have been reported as cases of with the ligature, and not with the actual cautery. Finally, it may, in time, be demonstrated that the ligature is preferable in one class of cases, the clamp in another, and the actual cautery in a third. Meantime, I hold this up to the present time, the ligature, as an exclusive method, is to be . Before closing up the wound, it is a question of much whether the blood, and other fluid emptied into the peritoneal cavity shall be sponged out or not. My opinion is decidedly that it should be. In every case of my own, I have undertaken to remove every drop of fluid. I lost one patient from septicaemia, produced by a small amount of blood decomposed, which flowed from the omentum after the operation. I see no reason to doubt that the patient would have recovered if the blood had not been there. I have had three cases in which the patients must have died, if I had not reopened the incision, and washed out the putrified fluid in the peritoneal cavity. My idea has long been, and still is, that where, on the one hand, there is no danger in putting into the peritoneal cavity, a sponge, first dipped in warm water; on the other hand, it may be of the greatest importance to do this. The peritoneum should be included in the sutures closing up the incision. If we leave the edges of the peritoneum gaping, as they will do otherwise, we will have a granulating surface, and the intestines, wherever they touch this surface, become adherent to it. Experiments on the lower animals have shown this. Then, when the pus forms, it falls into the peritoneal cavity and septicaemia will probably ensue. But I close with a few remarks on the after treatment. I consider that there is much more responsibility attached to the after treatment of a case of ovariotomy, unless it is a very complicated one, than there is to the operation itself. I I have been urged to perform this operation at least one hundred times, where I have declined, because the forbid my taking charge of the after treatment. In assuming the after treatment of a case, I consider that I am incurring at least three-fourths of the responsibility, and of the anxiety. In regard to opiates, I think just enough should be given to keep the patient free from pain, and comfortable; not enough to stupefy. I like the action of McMunn's Elixir of Opium, better than any of the other opiates, administered by the rectum if the stomach is irritable. I do not use strong doses of opium as soon as the operation is over, as I consider this objectionable. The patient should be allowed to regain her consciousness as soon as the operation is over. The operation, as well as the ether, has been depressing enough, and nothing more of the kind should be given until we see whether the patient is going to rally or not, and then is the time to give the opium. I have sometimes given a patient only thirty drops of McMunn's Elixir for the first two or three nights, and no more during the treatment. Baker Brown and Spencer Wells have given up the idea of large doses of opium immediately after the operation. After the first week is over, very little is to be done, under ordinary circumstances. If septicaemia sets in from fluid in the peritoneal cavity, I would reopen the incision. I know of no better treatment sufficient to allow the of an elastic bougie, and inject blood-warm water, and let it at once return. The mixture of water and the putrid fluid cannot be as injurious as the fluid alone. The first time that I acted on this idea (in 1855) the patient was stupified by the poison. I injected one quart of water, and she immediately looked up and said she felt as though she had taken a bath. I relieved her in this way every day for a week, using two quarts to a gallon of water at a time. When I found the fluid very fetid, I used the liquor sodoe chlorinate?, in the proportion of two drachms to the pint of water; finally, it returned without any odor at all, and from that time commenced a perfect recovery. In another case I resorted to these injections once or twice daily for fifty days ; and, in a third case, I injected one hundred and thirty-five times in seventy-eight days. These three patients recovered, though I feel positive they would all have died, had not the decomposing matter been washed out of the peritoneal cavity. I also combined with the injections, the sulphate of quinine, and the hypo-sulphite of soda. Medical and Surgical lieporter. South. Jour. Med. Sciences. |
(& dif a r ia I. Annual Meeting of the Illinois State Medical Society. The next regular Annual Meeting of the Illinois State Society will be held in the City of Quincy, on the Third Tuesday in May, 1868. Summer Course in Chicago Medical College The Summer Course of Instruction in Chicago Medical College, will commence on Monday, March 9th, and continue until the first of July. The course will be so arranged as to consist of one clinic and two lectures each day : the lectures to consist, in part, of thorough examinations of each member of the class. Those participating in this course, will be as follows: Clinical Medicine Prof. N. S. Davis, Clinical Surgery Prof. E. Andrews, Obstetrics and Diseases of Women Dr. E. 0. F. Roler, Physiology and Histology Prof. D. J. Nelson, Anatomy, Descriptive Prof. J. S. Jewell, Operations in Surgery Prof. R. N. Isham, Materia Medica Prof. M. 0. Heydock, Physical Diagnosis Dr. S. A. McWilliams, Ophthalmoscope and Ophthalmology Prof. E. Andrews. Organic Chemistry applied to the Study of Special Prof. N. S. Davis. The above course of instruction is free to all the regular matriculants of the College. Valedictory Lecture. We have received a manuscript copy of Dr. J. S. Hildreth's closing lecture to bis clinical course of instruction on Diseases of the Eye and Ear, in the County Hospital. It was a lecture replete with earnest thought, and judicious counsel to his class; but it was received too late for insertion in the present number of the Examiner. Explanation. We have received a number of valuable books, the notices of which were crowded out by the length of the article relating to Dr. Bozeman's speculum. Among these works, is a large and important work by Stellway, on Diseases of the Eye, from the publishing house of Wm. Wood & Co., of New York. For sale by W. B. Keen & Co., Chicago. Physician's Daily Pocket Record. We have received from the author, Dr. S. W. Butler, of Philadelphia, an copy of this work. It possesses all the conveniences by any of the other "Pocket Memoranda" or "' Visiting Lists," and some that are not found in the others. We commend it to the patronage of the profession. Dr. Bozeman's Speculum. Among the selected articles in this number of the Examiner, is one from the New York Record, giving an account of a new and improved vaginal speculum. It has been used by its author in several operations for vesico-vaginal fistula, and with the most satisfactory results. MEDICAL ADVERTISING. To the Editor of the Medical Examiner Sir: Wishing to correct any misunderstanding which may occur from the article in your February No., entitled "Give an Inchand an Ell is Taken," we respectfully request the publication of the following: Having decided to devote ourselves exclusively to the of diseases of the genito-urinary organs, we called on members of the profession and faculties of the medical schools of this city, explaining to them our business, and, also, our intention of bringing it before the public through the of the papers, by the insertion of a card, as well as by the ordinary business card, and with this express obtained all the names we used as references, some of whom have since requested us to suspend the further publication of their names in the newspapers; but none have forbidden their use on our business card. The appearance of our card in the "Medical Column," as referred to, was contrary to our or desire, but, at the time, beyond our control. Respectfully, DRS. BROWN & IIIGGINS. Feb. 15, 1868. 119 Clark St., Chicago. Mortality Report for the Month of January: CAUSES OF DEATH. Accident, concussion of brain________________ 1 Accident, poison_____ 1 Accident, burns______ 2 Accident, fall_________ 1 Accident, suffocation _ 1 Anaemia 1 Angina________________ 1 Apoplexy_____________ 3 Bowels, Brain, congestion of_5 Brain, dropsy of_____ 1 Brain, disease of____ 1 Brain, inflammation _ 2 Bright's disease_____ 2 Bronchitis_____________ 9 Bronchitis, capillary _ 2 Cancer 2 Cancer of breast_____ 1 Cancer of uterus, 2 Canker sore mouth____ 1 Convulsions__________51 Croup 8 Cyanosis 1 Cyanche trachealis___ 1 Cyanche maligna______ 1 Cerebellum, disease of 1 Debility______________ 4 Diarrhcea____________ 3 Diphtheria___________21 Dropsy 1 Dropsy, abdomen______ 1 Dysentery____________ 2| Eclampsia_____________ 1 Encephalites_________ 2 Enteritis_____________ 2 Enteritis, chronic___ 1 Encephalus, general _ 1 Fever, intermittent__ 1 Fever, puerperal_____ 2 Fever, remittent_____ 1 Fever, scarlet________ 7 Fever, typhoid_______14 Gastritis____________ 3 Gangrene_____________ 1 Gangrene, leg________ 1 Gout, rheumatic______ 1 Glands of neck, of_________ 1 Heart, disease of____ 13 Hemiplegia___________ 1 Hepatitis 1 Hernia________________ 1 Hydrocephalus________ 9 Indigestion 1 Inanition_____________ 2 Intemperance 4 Intestines, perforation 1 Jaundice______________ 2 Kidneys, inflammation 2 Laryngitis 5 Liver, fatty enlargem't 1 Liver, congestion of_1 Lungs, congestion of _ 9 Lungs, hemorrhage of 1 Measles 21 Meningitis 3 " cereb.-spinal 4 " tuberculous 1 Myelitis 2 Nutrition, impaired__ 1 Nephritis____________ 1 Old Age______________ 4 CEsophagus, Occipital bone, of_______________ 1 Paralysis____________ 2 Pericarditis_________ 1 Peritonitis___________ 3 Phthisis pulmonalisis. 38 Poisoned_____________ 1 Pleurisy_____________ 2 Pneumonia 49 Small-pox___________ 39 Spine, disease of____ 1 Stomach, disease of__1 Suicide______________ 3 Syncope 1 Syphilis_____________ 2 Tabes mesenterica____ 7 Teething_____#________ 6 Throat, malformation 1 Uraemia 1 Uterus, hemorrhage of 1 Varioloid____________ 1 Whooping-cough_______ 3 Unknown_______________ 3 Still and Premature births________________39 Total___________________________________________________________ 438 Deaths in January, 1868, 438 | Deaths in January, 1867, 299 | Increase, 139 Deaths in December, 1867,______ 409 | Increase,______________________29 AGES. Under 5_____________252 5 to 10 20 10 to 20___________ 14 20 to 30____________ 38 30 to 40_____________ 47 Males,___________224 w to ou_____________ 50 to 60 7 60 to 70_____________ 17 70 to 80____________ 11 80 to 90_____________ 3 Females, 214 90 to 100___________ 1 100 to 110__________ 0 Unknown_____________ 0 Total_________ 438 Total, __________438 NATTVTTY. Chicago 191 Other parts U. S. 101 Australia _________ 1 Belgium____________ 0 Bohemia____________ 5 Canada_____________ 7 Denmark 0 England____________ 7 France 3 Germany____________ 48 Holland 2 Ireland 46 Italy_______________ 0 Norway_____________ 14 Nova Scotia 0 Prussia 4 Poland______________ 0 Russia 1 Scotland___________ 4 Sandwich Islands 1 Sweden 2 Switzerland 1 Wales______________ 0 Unknown 2 Total 438 MORTALITY BY WARDS FOR THE MONTH. Ward. Mortality. Pop. in 1866. One death in Ward. Mortality. Pop. in 1866. One death in X___ o V.DDO JL.zSVO 1-4 2 16 12,985 811 9-16 3 24 15,738 655 9-12 4 32 10,884 380 1-8 5 18 9,610 536 1-9 6 27 10,680 391 7-9 7 35 18,755 538 5-35 8 23 10,429 453 10-23 9___ 33 13,940 42214-33 10 18 11,416 634 2-9 11 36 12,924 359 12 32 12,695 396 2-3 13 13 8,188 629 11-13 14 27 12,108 448 12-27 15 39 15,766 404 1-4 16 26 14,912 573 7-13 County hosp., 7 Armory, 1 Bridewell, 1 Home of the Friendl's, 0 Marine hos., 2 Mercy hos., 2 St. Luke's hos. 3 St.Jose. asyl.16 Lake Hosp., 5 Total,__________________________________401 DEATHS BY SMALL-POX. Jan., 1868. Week ending Feb. 1, 1868. da wara 1 u 4th Ward 5 0 5th Ward 6 5 6th Ward______________________________ 3 1 7th Ward 6 3 Sth Ward______________________________ 5 0 9th Ward 1 1 10th Ward 0 1 11th Ward 3 2 12th Ward 3 0 14th Ward______________________________ 1 0 15th Ward 1 1 16th Ward 1 0 Lake Hospital, 3 1 Total__________________________ 39 15 TO PHYSICIANS. His attempts to extend a more advanced knowledge of his specialty to physicians already in practice having been so favorably commented upon by those of the profession who have attended the previous courses, and by the medical press. PROF. HORATIO R. STORER, Will deliver his third private course of twelve Lectures upon the TREATMENT OF THE SURGICAL DISEASES OF WOMEN, During the first fortnight of June, at his rooms in Boston. Fee $50; and Diploma required to be shown. Certificates of attendance upon the courses already completed have been issued to the following : Drs. J. B. Walker, Union, Me.; Alexander J. Stone, Augusta, Me.; Mann, Pelham, N.H.; Augustus Harris, Colebrook, N.H ; J. W. Parsons, Portsmouth, N.H.; E. F. Upham, West Randolph, Vt.; G. E. Bullard, , Mass.; J. A. McDonough, Boston, Mass.; J. G. Pinkham, Cambridge, Mass.; James Coolidge, Athol, Mass.; Thomas G. Potter, Providence, R.I.- C. M. Carleton, Norwich, Conn.; I. Farrar, Hartford, Conn.; M. C. Talbott, , Pa.; H. Gerould, Erie, Pa.; W. W, Bancroft, Granville, Ohio; A. I. Beach, Bellville, Ohio; Henry E. Paine, Dixon, Ill.; W. L. Wells, Howall, Mich.; and W. A. I. Case, Hamilton, C.W. Hotel Pelham, Boston, January, 1868. feb3t. Money Receipts to Feb. 24th. Drs. V. L. $3; W. Fleming, 3; J. S. Sherman, 3; Theodore Hoffman, 3; J. Haller, 3; M. Shephard, 3; W. H. Baxter, 5; H. W. Pickett, 3; J. Good, 3; E. Young, 6; L. Corey, 3; M. , 3; G. W. P. Hadder, 3; W. A. Barstow, 3; H. A. Stokes, 3; John Ten Brook, 5; W. M. Landon, 6; H. C. Lester, 3. Number of Emigrants who have Arrived in New York during past Year. Two hundred and thirty-three thousand four hundred and eighteen. The Cholera has again made its appearance in India, as was expected, indeed, as the result of the pilgrimage of the past year. Apropos of the cholera: a French writer claims as a prominent cause of the pestilence the disappearance of a variety of crocodile, called the gavial. This animal formerly destroyed the bodies thrown into the Ganges, in accordance with the religious customs of India. But since the soldiers have been in the habit of waging war upon it, the gavial has been nearly exterminated. In the absence of its scavenger work, the bodies decay and produce the cholera; at least so claims this writer, who asks for a government protection of this important reptile. AMERICAN MEDICAL ASSOCIATION PRIZE ESSAYS FOR 1868. The American Medical Association offers two prizes of One Hundred Dollars each, for the best two original essays upon subjects of professional interest; the Committee reserving the right to reject all, unless deemed fully worthy. Competitors for these prizes must forward their essays to Dr. Charles Woodward, Cincinnati, Ohio, free of expense, on or before the 1st of April, 1868. Each essay must be accompanied by a sealed note containing the author's name and address, and on this sealed packet must be inscribed some sentiment, motto, or device, corresponding to a like sentiment, motto, or device on the essay. Charles Woodward, Chairman,\ W. W. Dawson, / E. B. Stevens, > Committee. Roberts Bartholow, \ P. S. Connor, / Medical journals throughout the country are requested to copy. |
INFANTILE CONVULSIONS. By JOHN DICKSON, M.D. Read before the Baltimore Medical Association. Of all the maladies of infancy, I know of none more serious, or embarrassing to treat, than convulsions. We are summoned in great haste, and arrive out of breath, and find a painful scene of dismay and confusion which requires our utmost tact and composure to lull. We never get used to spasms in the sense in which we may become stoically or philosophically calm. The malady is too grave and sudden in its effects, and our too serious for that. We all know that two or three minutes of tonic spasm, or a few hours of clonic, may destroy life, and how much depends upon the prompt and judicious action of the physician, both for the child's safety and his own reputation. Unless the case occurs in our own family, or has been attended with premonitory symptoms, we rarely see a spasm in the tonic stage. The violent and sustained of the respiratory muscle stops the breathing, and death results in a few minutes from asphyxia, as in the first stage of epileptic fits, or in fatal cases of laryngismus stridulus. This, fortunately, is a rare occurrence. We generally find the state, which soon succeeds, of alternate retraction and relaxation, either general or partial; and sometimes confined to very few muscles, as those of the face or hand. In severe cases there is violent jerking of the limbs, abduction of the thumbs covered by the contracted fingers, staring or rolling, insensible eyes, with pupils either contracted or dilated, or there is strabismus in the course of the spasm; the head is drawn backward or from the beginning, or it is twisted in rotatory movements; the respiration is quick and irregular, producing a sound of choking as distressing to hear as the contracted, livid face is to witness. When clonic spasm continues some hours, and the rapid contraction and relaxation prevent the free egress of the carbonized air from within the lungs, or the admission of enough pure air to renew the blood, both circulation and respiration are arrested, and death must follow. Even when this is not the immediate result of the spasm, in many instances it occurs within a short time after it subsides, because these vital functions have been so seriously impaired as to preclude respiration, and the patient sinks from the shock as we have heard mothers expressly say, " they were struck with death from the beginning of the attack." But, happily, this is not the most common course of convulsions. There is oftener a gradual subsidence of the fit. The spasmodic movements become slower and cease, the respiration is free, and a general calm succeeds. The patient either wakes to , or falls into a comotose, or, it may be, natural sleep, after which there may or may not be a recurrence of the spasms. Such recurrences are very common, in spite of our best efforts to prevent them, but it is gratifying to know that the danger is not proportionally increased by their frequency. I have seen children have six or seven in the course of the day, and on the following day present no unfavorable symptom or spasm ever afterwards. Partial spasms present such a variety of forms that I shall not attempt to speak of more than one or two. They may be confined to the superficial muscles only, and to a few of these, and in such cases, the senses remain intact. I have seen the eye, mouth, and hand of one side jerking, while the sensibility of the child was perfect; and it would ask for milk and drink it, attempting to hold the cup with the convulsed hand and it with the other. Such are the sequelae of the more severe attacks, and are easily excited in children so predisposed. the muscles of the neck are alone effected, and cause or flexion of the head forward or backward. Indeed, single muscles, as well as sets of muscles, in almost every part of the body, may be convulsed, or exhibit movements under peculiar excitement, nervous or fibrile, which closely resemble spasm, and are at times mistaken for such. Certain organs alone may be effected, as the larynx or glottis, and we have a very formidable trouble in laryngismus stridulus. A child may be seized without any premonitory symptoms of dangerous import, with apparent suffocation. His breathing is suspended, his head thrown back, face and lips livid, and, in a few seconds, the spasm yielding, respiration follows, and a sudden gasp for breath, so urgent as to produce a crowing sound; and the breathing goes on . But there are cases so violent from the repetition of these spasms, as to destroy life during the paroxysm, or lead to convulsions and coma. Marshall Hall calls this affection "an excitation of the true spinal or excito-motory system." It originates in the trifacial in teething; in the pneumogastric in over or improperly fed infants; in the spinal nerves in , intestinal disorder or catharsis. These act through the medium of the spinal marrow, and the inferior or recurrent laryngeal, the constrictor of the larynx, and the intercostals and diaphragmatic, the motors of respiration." We can judge from this that a great variety of causes, as in general , may produce this form of spasm. Dr. West mentions a case in a child only ten weeks old, from improper feeding; another, of nineteen months, from sudden suppression of chronic diarrhoea; another, of two and a-half years, from cerebral following constipation; another, of nine months, during the course of chronic hydrocephalus; and in another, who died at the age of two months, it appeared as a transitory symptom during a series of convulsive attacks, for which no cause could be assigned during life, and which left no traces that could be detected after death. The obscurity of origin and absence of pathological often throw a veil of mystery over cases of convulsion, which the clearest sighted of us cannot penetrate. We know that hereditary influence is the most frequent predisposing cause, that eclampsia in the mother before parturition, or much further back, when she was herself a child, is apt to be followed by the same tendency in the offspring; though it by no means follows so often as to establish it as a rule. A remarkable illustration of hereditary influence is quoted by Trousseau from a thesis of Dr. Duclos, of Tours. The case is that of a woman, thirty-four years of age, who had had frequent attacks of eclampsia up to the age of seven. These had left behind slight deviation of the mouth and ptosis of the left upper eyelid. This woman had ten children, who all had convulsions; six had died, five in the first two years, and one when three years old. Three months previously, she had a first attack, which lasted about ten minutes, and which her mother ascribed to her having given the breast to the child immediately after a fit of passion, as the convulsion occurred on the ensuing day. Death took place three months afterward, from cerebro-meningitis. Loss of blood, whether in direct haemorrhage, venesection, diarrhoea, or hypercatharsis, strongly predisposes to . Insufficient nourishment and exhaustion, from whatever cause, have the same effect. Hippocrates' observation that the " blood is the moderator of the nerves," corresponds with the present physiological law, " that in proportion as the nutritive and vegetative functions are feeble and languishing, nervous phenomena are mobile, exalted and irregular." The sensitive brain, with its spirit-like nerves prevading every part of the organism, must be supported by the vascular system, as the string and wind instruments of an orchestra combine; the wave sounds of the latter, giving volume and tone to the tender strains of the former, without which it would be only a flutter of distracting discord. The iron of the blood is as much a fundamental base in toning the system, as the brass are in sustained musical harmony. It may be upon this theory that Chapman uses ice bags along the spine in so many affections where nervous symptoms predominate. " He that ice applied along the spine increases the general circulation, stops the cramp of voluntary and involuntary , proves an effective remedy in epilepsy and other convulsive affections, cures sea-sickness, restrains the sickness of pregnancy, arrests diarrhoea, recovers patients from the cold stage of , and, finally, promotes menstruation. On the other hand, heat along the spine lessens the general circulation, overcomes congestion in all parts of the body, lessens fever, restrains haemorrhage and lessens or arrests the menstrual flow." If by exciting or depressing the spinal cord, by heat or cold, such remarkable effects can be produced upon the circulatory system, we can readily see how disorders of the latter may prove to the nervous system. To work out this would be very interesting, but would require more time than I can give it. The fact is, that every thing that impedes or arrests healthy circulation, or impairs the quality or quantity of the blood, may tend to bring on convulsions, and may be ranked among the predisposing causes. The exciting causes of convulsions are very numerous, and upon them, when we can discover them; we base our immediate treatment of an attack. When arising from indigestion, how often have we cut short the spasm by an emetic or enema, when nature herself has not done the work for us, which she frequently does, and when constipation is the cause by relaxing the sphincter and evacuating the loaded intestines. But these measures often fail, and in spite of the inevitable warm bath and counter-irritation, which the child's friends have before our arrival, the convulsion goes on unabated; and if we do not arrest it, the child may die in the fit or from the supervening coma. Almost all the antispasmodics have been used for this purpose, and some of them with good effect at times, but no agent is so powerful or requires more skill in administering than chloroform. Some bear it very badly, and we discover the flagging of the pulse or the stertor of the very soon after its application, and we must desist before any *good can be done by it. In other cases its use may be kept up for a long time with no bad effects, and the convulsive action controlled. In severe cases I have seen the chloroform used freely for several hours, and the child recovered perfectly, when without it the paroxysm would have undoubtedly exhausted the nervous system, or produced cerebro-meningitis, or effusion and resulting paralysis. Such are often the results of convulsions, besides deformities from rupture of muscles, squinting, nervous excitability, epilepsy, etc., though by no means occurring in a large proportion of cases. In some children convulsions are easily excited and readily controlled, and the agent which I have found most valuable for this purpose is bromide of . There is still a good deal of skepticism on this point, but I think where it has been used and persisted in, there is no doubt of its efficacy in preventing and subduing nervous . I have given it, when the convulsive tendency was the result of impoverished blood from previous disease, in conjunction with wine and beef essence, with the happiest effect. Of the effect of ice to the spine I have no testimony of my own. Dr. Edmunds, in the Medical Times of March 12th, 1864, after relating a case of spasm in a woman which was perfectly relieved by this means, says: "I had seen Dr. Chapman's on the subject of his discovery, and also his paper in the Medical Times and Gazette, but thought the idea too pretty to be anything more than a plausible theory, until my own child, being in great danger from an obstinate laryngismus, connected witli dentition, I tried the ice bag to the cervico-dorsal portion of the spine, at the suggestion of Dr. Ramskill, and it has done more to keep off the strangling attacks than anything else. Lancing the gums when the convulsions occur during , sometimes produces immediate relief, and, if they occur during that period, it should be our first duty. Convulsions which take place at the outset of fevers, from the first impression of the poison upon the system, are not as serious as those which come on towards the close, and seldom require special treatment. It is a disputed point whether the prognosis from such is favorable or not. Worms, sunstroke, extremes of temperature, blows upon the head, sudden fright, severe burns, and local irritation of various kinds, are among the exciting causes of convulsions, and indicate the course of treatment. Calomel has been given very largely in convulsions, as a , anthelmintic and absorbent. We must bear in mind its destructive tendency, and have a distinct purpose in view, the accomplishment of which is paramount to the risk of using such a depleting agent. If we give it to promote absorption of effused serum in the brain we may obviate its injurious effects and increase its efficiency by taking especial pains to nourish and support the general system at the same time, with all the means the patient will bear. This plan was successful in my own little girl, who was two and a-half years old when she was attacked with a violent , after a day or two of gastric irritation, from which she seemed to be recovering, when, without any warning, she was seized with it, and, in spite of chloroform and everything else we could do for her, it lasted five and a-half hours. The right side 'was most effected, and, after the convulsion, remained paralyzed for several days, but recovered under the use of small doses of calomel combined with bromide of potassium, and wine, milk, and beef essence. There was a convulsive state for some weeks afterward, which seemed to be controlled by the bromide, and partial convulsions occurred without loss of consciousness, for some days after her recovery from the comatose condition which immediately followed the convulsion. The paralysis left the foot first, and she could walk well for some days before she could hold anything in her hand, but that gradually regained its use, and lastly, her tongue, which had remained silent for four weeks, began to liberate itself, in monosyllables at first, and she slowly recovered her vocabulary, as if she had never talked before. This case, which I had hoped to give more in detail, was one of intense interest and anxiety to me, and the care and responsibility of the treatment was most kindly and faithfully shared by our worthy president (Dr. Williams). She is held up in our neighborhood as a trial of medical skill, and an encouragement to parents, as well as doctors, to hope for the recovery of their little ones under the most discouraging . |
THE CHICAGO MEDICAL EXAMINER. N. S. DAVIS, M.D., Editor. VOL. IX. MARCH, 186 8. NO. 3. lynaiwai wiinnnm ARTICLE VII. THE FUNCTION OF THE SPLEEN. By Dr. H. K. JONES, Jacksonville, Ill. Read to the Morgan County Medical Society, January 9th, 1868. It must, of course, be merely tedious to attempt to bring details of experiments, observations, and various views and doctrines found in medical literature, respecting the and physiology of viscus; and mere presumption to attempt conclusions, of matters which have proven a stumbling-stone to authorities of the greatest weight and eminence. But, , the subject still lies at our door, challenging the scientific and philosophic scrutiny of this age, and to this end I would reproduce it to the attention of this Society. In part, doubtless, owing to the inherent security of the of this organ, and partly because of the demonstration of the practicability of existence without it, both in animals and in man; its importance in the animal economy, both as regards its function in health, and its pathological conditions and in the diseases of the body, is greatly underrated; and so our knowledge is abated and limited. For, if true, that its functions are vital and, therefore, its maladies absolutely and relatively grave, in that truth is to be found the stimulus to research, adequate to the erasure from medical literature of the opprobrium of this confessed superficialness and ignorance. It must be fairly illustrative of the state of our knowledge or science of this subject, no longer ago than the pupilage of some of us who, in this Society, are but junior members, to quote in brief the views of so eminent an authority as Dr. Carpenter. He introduces the spleen as an organ having "no excretory duct, nor anything glandular in its structure." * * That, "in regard to the functions of the spleen, great uncertainty exists. That the spleen performs no action essential to life, has been repeatedly proved, by the experimental removal of it in many of the lower animals, and by the accidental loss of it in man, * * for after the immediate effects of the wound were recovered from, the vital functions were performed with no perceptible interruption, and health appeared to be restored." * * That "one of the numerous theories of its operation, which have at different times been brought , the one which is most satisfactory to the author, is that which regards it as a sort of diverticulum, or reservoir, which may serve to relieve the portal venous system from undue under a great variety of circumstances." * * That, "from the observations of Mr. Dobson, it appears that the spleen has its maximum volume at the time when the process of chymification is at an end, viz., about five hours after food is taken; and that it is small and contains little blood, even hours later, when no food has been taken in the interval. Hence, he inferred that this organ is the receptacle for the increased quantity of blood which the system acquires from the food, and which cannot, without danger, be admitted into the bloodvessels generally, and that it regains its previous dimensions after the volume of the circulating fluid has been reduced by secretion." Later, and contrariwise, Dr. Dalton propounds the case thus: "The spleen is a glandular organ, analogous in its minute to the solitary and aquinated glands of the small intestine, and to the lymphatic glands throughout the body. Like them, it is a gland without an excretory duct, and resembles, also, in this respect, the thyroid and thymus glands and the supra-renal capsules. All these organs have a structure which is evidently glandular in its nature, and yet the name of glands has been refused to them, because they have, as above mentioned, no duct, and produce, apparently, no distinct secretion. We have already seen, however, that a secretion may be produced in the interior of a glandular organ, like the sugar in the substance of the liver, and yet not be discharged by its excretory duct. The veins of the gland, in this instance, perform the part of excretory ducts. * * The action of such organs is, , to modify the constitution of the blood. * * The precise alteration, however, which is effected in the blood its passage through the splenic tissue has not yet been discovered." The views of these eminent authorities in medical science and education, are here adduced for a double purpose: 1st. Of generalizing and fairly representing, as is supposed, the vagueness and contradictoriness of an accredited and literature of so modern a date; and, 2d. As affording us a convenient reduction of the matter of knowledge and to two recognized hypotheses, utterly with each other, but within which the one or the other the truth may possibly be found, namely, the "diverticulum" or reservoir theory of Dr. Carpenter, on the one hand; and the glandular theory of Dr. Dalton, on the other hand. Nor let it be supposed that Dr. Carpenter is the mere man of straw, set up for easy refutation, whilst, even at the present time, our prevailing splenic pathology and therapeutics, ideas of mere sanguineous plethora and engorgement, and consequent distension, hypertrophy, etc., are essentially grounded in the reservoir assumption. This organ has a prominent position as a member and link in the golden circle of the great blood factories, and, accordingly, receives, in common with the stomach and liver, the first blood dispensed from the abdominal aorta. And, again, no other organ of the body receives so large a stream from the arterial fountains, in proportion to its size; and it returns the largest product in proportion to what it receives, its vein having six times the capacity of its artery. Its artery is larger than both the hepatic and gastric, and in its course dispenses twigs to the stomach and pancreas, as if its organ were in some special honor and dignity among its compeers. Again, it receives and acts upon only the purest blood of the body, and has no excretory duct suggestive that its work can scarcely be subordinate or menial, neither depurating nor emunctory, but some superior service in the abdominal order and series looking primarily to a common end and use, namely, the initiation and of the blood. And, accordingly, it transmits all its through the sanguineous and lymphatic channels directly toward the fountain-head and palace and kingdom of the blood. Thus, its position among the organs related to the production of the blood, the peculiar quantity of its arterial and venous streams, the absence of depurating and emunctory apparatus, the direction and destination of all its products, are facts whose concurring import amounts to a sort of prima facie evidence that this organ may be entitled to a distinguished rank as a primary blood generating factory. But this is a mere outside view, to which the argument is by no means limited. Let us now look within, and see what we shall see. And here we will pass by its membranes, its large vessels, its trabecular meshes, etc., the framework only of the body, matters not in obscurity or dispute and enter the spaces, the chambers and workshops of the factory, in which w'e are to see the peculiar substance of the spleen at first view, a pulpy mass of "dark, reddish-brown" color, corpuscles, capillary meshes, etc., altogether the chief part of the entire bulk of this body. Now, what have we here in this mass of confusion? Is it inexplicable chaos? Or shall rational, inductive science yet illustrate and demonstrate herein the most complete order and the most beauteous and productive skill ? The foundations of the answer to this very practical question were begun to be laid two centuries ago, when the Italian, , the father of microscopic anatomy, first entered these hitherto dark chambers. Up to his time, the prevalent view's among scientific men of Europe, in common with the earlier Greeks also, were only vague notions, some of which have still found their way down to our own times and country. Such as it was a useless and superfluous part of the body, an error of nature; or, that it was for the preservation of the equilibrium of the body; or, that it attracts watery materials from the stomach; or, that it was the sewer of the humor called atra bilis; or, that it fermented a menstruum for the stomach in digestion; or that it was the origin of laughter; or that it the mucus to be secreted by the glands of the joints, etc.; and by rather more recent German and English authorities, (Schelnammer, Liston, Purcell, etc.) that it was a diverticulum for the blood in the more violent motions, etc., etc. But Malpighi taught: "In the interstitial spaces of the spleen, we observe clusters of glands, or, rather, of vesicles or sacculi, in immense numbers, dispersed throughout the organ, and closely resembling bunches of grapes. These minute glands am of an oval figure, and about the size of the glands of the kidneys. I have always found them of a white color, and although the bloodvessels of the spleen may be fully with ink, and play around the glands, yet the latter still preserve their whiteness. They appear to consist of a , but soft and very friable substance, the cavity in which is invisible by reason of its smallness, but still may be conjectured to exist, because these bodies collapse when cut. They are extremely numerous, indeed, almost innumerable, and are placed in a singular manner in the cells already described, all over the spleen, and hang from the productions of the , or from fibres arising therefrom; consequently, from the extremities of the arteries and from the ends of the nerves, moreover, the ends of the arteries wind about them like tendrils of ivy. They usually hang in bunches, each cluster consisting of seven or eight glands." Again, Winslow, the Danish anatomist, the disciple and later cotemporary, affirms: " The arteries, veins, and nerves, after entering the spleen, divide and subdivide into a great number of ramifications, and accompany each other to their very last divisions. The capillary extremities of all these ramifications, both arterial and venous, end in the small downy cells already *described. Malpighi regarded these cells as distinct capsules or follicles, each containing a small gland. The extremities of the capillary ramifications seem to swim or float in the cells and to fill their downy tissue with blood. At the ends of of these capillaries, I have observed small corpuscles like bunches of grapes; and I have seen two little tubes going out of each corpuscle, one short and open, the other long and small, which latter was lost in the sides of the spleen," etc. Other and later investigators have abundantly confirmed and amplified these discoveries into the further particulars, as, that these splenic bodies are not only covered on their exterior by a complete capillary network, but that they are also penetrated and permeated by this vascular distribution, and also that the entire splenic pulp is made up of several other varieties of bodies, suggestive of complexity of function. In brief, authority and opinion have gravitated to the conclusion above stated from Dalton, namely, that this is a glandular organ, analogous to others of the body having no excretory duct, and in some way and extent concerned in the constitution of the blood, but in what way may, , justly be said to have received no adequate scientific attempt until the very last years. Ffteen or twenty years since, Virchow propounded and certain specific doctrines concerning the origin and changes of the blood: as, that "every permanent change which takes place in the condition of the circulating juices must be derived from definite points in the body, from individual organs or tissues. * * All the morphological elements of the blood, whatever may be their nature, are to be derived from sources external to the blood * * that in the ordinary course of things, the lymphatic glands and the spleen are really intermediately concerned in the production of the formed elements of the blood; and that, in particular, the corpuscular constituents of this fluid are really descendants of the cellular bodies of the lymphatic glands and the spleen, which have been set free in their interiors and conveyed into the current of the blood." But it probably remains to our own time and countrymen to consummate the solution of this problem, and bear the of demonstrative science throughout its dark and most intricate mazes. And, already, sagacious and indefatigable explorers have reported important progress. Within the last year, Prof. Salisbury, of Cleveland, Ohio? has published a paper which may justly be admitted to be the ablest contribution ever made to medical literature upon this subject; richest in original research, and in its facts and and pertinent suggestions. Besides the arterial by capillary ramifications upon the Malpighian , he distinguishes, also, terminations in glandular structures of two other varieties, namely: 1. In tubular glandules followed by simple capillaries; and, 2. In tubular glandules followed by oval splenic bodies. In these, he discovers and traces the formation of fibrine cells, and their transformation into fibrinous cells. "These fibrin cells," says he, "during their slow, creeping passage through these thin-walled vessels, are gradually, after fully mature, spun or developed into fibrine filaments of extreme tenuity and transparency, so that by the time they have reached the veins they enter them as fibrin filaments, or as cells far advanced in filamentous metamorphosis." , "there are two sets of these cells, an internal and an external one arranged longitudinally, the other transversely. Both possess singular powers of contractility, like that of the muscular fibre," etc. And again, "when the fibrin cells are developed into , their nuclei are set at liberty, take up nerve and matter, become highly transparent and homogenous, assume a flattened shape, and form blood discs. This process can be traced through all its stages in the living spleen." "The spleen and lacteal and lymphatic glands are the main organs that organize fibrin cells and blood discs." And, "of all these glands, the spleen is the most important and the most largely engaged in this cell-forming process." Indulge me in the notice now, of one other fact claimed by this observer, namely: "In the spleen are found minute bodies containing a mesh of highly refractive cylindrical capillaries. * * They are always distended, highly refractive, and of a beautifully, pearly lustre. They resemble a meshwork of fine pearl-glass tubules. In these vessels may be noticed minute pearly drops, and on the membrane stretched across the meshes, the same kind of pearly drops aggregate into more or less spherical masses," and then, again, into larger globules, etc. And, finally: "These large globules take on a cell wall, and we have formed the genuine corpora amylacea." * * "They are the true myelin cells, or those cells which contain nerve matter." And, again: "The contents of these cells after it has escaped from the cases, become aggregated into large globular masses, and from the sides of which are beautiful, double-walled, pearly, tubular filaments, like those of nerve tissue." Now the above series of observations and facts, connected and corroborative, as landmarks indicating the progress of this inquiry through the last two centuries, are believed to embrace grounds and conclusions from which histological and science will not recede, namely: Of this organ, its duct is not in the direction of depuration or emunctory work. It more arterial blood than can be appropriated to its own nutrition, and its large venous duct conveys away larger than the residue and debris of its functions. And its products are sent exclusively towards the fountains. Also, its interstitial spaces are filled up with a variety of glandulai' bodies, unto which, as unto so many furnaces, and forges, and mills, are the ultimate ramifications and determinations of the apporting arterial streams, and from which bodies also arise the absorbent and capillary origins of the deporting venous and lymphatic trunks, which take up and bear away towards the sources of the blood materials unlike those received. So that, with the exception possibly of a minor system of anastomosing capillaries, the arterial stream, with all its vast supplies, must pass between the upper and the nether millstone of glandular structure, to be resolved into its principles and reorganized into new forms for the perpetual reproduction and reconstruction of the blood. And, lastly, one stands amid these workshops and sees the actual initiaments and progressions, first, of the fibrin cell with its ultimate development into the contractile filament, looking to the end of muscular nutrition; and then its nucleus and formed into the red-blood globule; and this, again, is here ermined and crimsoned, and sent away freighted with treasures for distant ports of the realm. And here is witnessed also the generation of the inyeline cell, with its medullary and nerve filament, looking to the end of the endowment of the blood-disc, the surrounding and protection of the axis cylinder of the nerve conduits, and the ultimate nutrition and reproduction of the essential substance of the brains and the nerves. Finally, this view is amply corroborated in the phenomena of ascertained pathological states of this organ as, 1. In the case of deficiencies of coloring matter in the blood, as also in diseases of discolorations of this fluid, confessedly phenomenal of congestions, irritations, inflammations, , hypertrophies, etc., of this viscus. Virchow, after a scrutinizing survey of the subjects of leukaemia, melanaemia, melanotic tumors, etc., concludes "that all the facts with which we are acquainted, concerning these conditions, indicate that the contamination of the blood has its rise in a definite organ, and that this organ, as in the colorless blood corpuscles, is the spleen." 2. In the case of the removal of this gland from the body, the voracity and increased ferocity of the animal until the deficiencies of the blood in the above-named materials for muscular and nervous nutrition are compensated by the vicarious functions of associated and kindred organs, afford additional corroboration. 3. Another interesting and important class of corroborative facts are the sensational, intellectual, and moral symptoms of the patient, in the functional disorders of this organ, commonly reputed, not only in popular, but also in professional parlance, to be splenetic affection of the mind, such as general irritability, particularly of the irascible dispositions, peevishness, , apprehensiveness, despondencies, anxieties, nostalgia, and, possibly, various monomanias, etc. This class of symptoms direct our attention, unmistakably, to deficiencies in the of cerebral and nervous nutriment, namely, medullary and nerve filament substances, the generation of which in the spleen has been ascertained as above mentioned. And, , Prof. Salisbury observes: " These (rnyeline cell ) are taken up by the blood-discs which transmit them to their destinations. This matter communicates a high degree of plasticity and refractive pearly lustre to the discs. * * * The rnyeline performs the office of surrounding the axis of the nerves, forming an insulating tunic between it and the nerve sheath, which prevents the nerve from escaping in its transit, save at the terminus." The relation of these matters to the nutrition and healthy and complete functions of the nervous system is so palpable, that the Professor insists "that by simply examining the blood microscopically, it can readily be determined whether a person is actively engaged in mental pursuits, under the influence of nervous exhaustion of any kind, or whether he is purely to physical undertakings, is strong and robust, and is laboring under no influence which is exhausting his nerve tissue." If now, in conclusion, it should be true, as the above chain of facts and reasonings tend to show, that in this organ as a factory not as a mere secreting gland are the generations and initiaments de novo of the fibrin cell and contractile appertaining to the support of muscular tissue, and, also, of the rnyeline cell and nervous filament appertaining to the support of nervous nutrition and function; and, also, of the red blood corpuscle as, possibly, the carrier of certain supplies to glandular ports and marts abroad; and, finally, if on the other hand, there be found, concomitant with its abnormal , muscular inanitions and debilities, mental and moral irritabilities and depressions, disturbance of the proportion of the red and white blood cells, discolorations of the blood, etc., etc., wre are, then, already on pretty fair advantage ground for the ultimate realization of a truly scientific physiology and pathology of this viscus. And this event may also possibly be hailed as the signal of deliverance for the liver and stomach and other of its neighbors that have, through the long time, endured and suffered untold indignities and penal inflictions for offenses not their own. |
THE PHILOSOPHY OF TYPHOID OR CONTINUED FEVER. A STUDY OF ITS DYNAMICS AND TREATMENT. By Z. C. McELROY, M.D., President. Read before the Muskingum County (Ohio) Medical Society, Jan. 1, 1868. In the discussion at our last meeting, on the treatment of typhoid fever, one of our fellows facetiously remarked, that "to treat a case of typhoid fever, it was a needful preliminary to have a case to treat." This remark meant, if it meant , that the diagnosis was sometimes difficult, or, if not , the name was given to patients and friends for other purposes. It occurred to me, that we could better understand a of the treatment of any disease, if we had, as a preliminary, some common understanding of its nature and pathology. It is my purpose, with the permission of the Society, to it a picture of typhoid or continued fever, as studied in the light of modern philosophy, and the empirical facts in to it, common to medical minds and literature. And, first, as to its cause or causes most likely immaterial the ordinary forces of nature acting in an ordinary way. It may, however, be accepted as certain, that it has two modes of origin, within the body, and from without the body, of those who suffer from it. These are classed as sporadic, and endemic and epidemic cases. Probably, the most of the cases met with in our locality arise from causes acting within the body of the patient; though cases from contagion contact with others suffering from it do occasionally occur. The symptomatology may be briefly summed up in the words "loss of power, or loss of force." The dynamics of the system are turned into new channels. The stomach, the citadel of the system, refuses or rejects food; or, if retained, passes it on into the bowels undigested, where it undergoes decomposition, giving rise to uneasiness, pain, tympanitis, or diarrhoea. The muscles lose pow'er, patients cannot and do not walk about with elastic step, and perform ordinary labor. The nervous system loses power; the brain cannot and does not act as in health. Every symptom may be referred to loss of power. A patient suffering from typhoid or continued fever must be regarded as in a of partial death. Coincident with loss of power, there is loss of bodily weight, whether with or without diarrhoea, , expectoration, or hemorrhage. With this loss of power and weight, we might, without patient thought, and philosophy to guide us, and the use of that tell-tale of temperature, the thermometer, conclude we either have, or ought to have, diminished heat or temperature; but not so, the "burning disease" was correctly named; the temperature is constantly higher than natural, and its above the natural standard is a tolerably accurate measure of the intensity of the disease. Now, what is the meaning of this series of phenomena, ? In endeavoring to find the solution of this inquiry, we must keep constantly before the mind the fact, that no effects of force can be manifest to our senses, except as the result of some preexisting force, and that no force is ever lost; it may be constantly changing its form, but is never destroyed. Now, why this loss of force and wasting in continued fever? Manifestly, the soft tissues of the body are burning up. And why? Because the fever poison has rendered more or less of them unsuitable for the further uses of the body. The forces of life are diverted into new channels. The of life are engaged in consuming and removing out of the body the effete or unsuitable tissues, and the phenomena can only be regarded as a conservative process, intended to save life. Boerhave's definition of fever, was, all things , the best ever given: that "fever was a mode of life resisting death." The extent of tissue made useless to the body by the cause or causes of the fever, determines its duration, intensity, and termination. If all the muscles were in a state of integrity, measured by the standard of health, they would not refuse to act. So of the various tissues of the viscera and nerves, including the commune. Just in proportion to the delirium or coma, is the quantity of brain matter unsuitable for the further uses of the organism, large or small. Nor are the tissues, or parts of tissues, thus rendered useless, if left in the body, harmless, as would be a piece of lead, gold, or silver, accidentally embedded and encysted in the body, nor yet in masses, as in sphacelus, but is deposited or exists through the muscles and organs, and perhaps enclosed in the interior, or in close proximity to the exterior of the structures, as evidenced by the aching and soreness of the bones, as patients express it. Of the nature of the changes occurring in the molecular structure of the tissues, from the action of the fever poison, it is impossible to speak, with any certainty, in the existing state of knowledge. We have no means of determining the nature of the changes in the tissues in beings killed by lightning. But the facts are known, that death does occur from shock by . In many instances, there are certainly no changes of which our senses can take cognizance. The inference then, is irresistible, that the electricity has made such changes in the molecular structure of the tissues as to cause death. And the inference is equally irresistible, that the cause or causes of fever induces analogous changes in the various textures of the body, so as to render portions of them unsuitable for the of life. Further evidence, that such must be the condition of things in continued fever, is the fact that the tissues continue to waste; first, the adipose, then, the muscular and other soft, and, , portions of the denser tissues, until the emaciation is sometimes extreme. This waste of the tissues is always a prominent feature in continued fever, commencing sometimes days and weeks prior to the patient taking to bed or seeking medical advice; and this is more especially the case in patients in whom the fever poison is generated in their own systems. Occurring from the poison being taken into the system from without, the prodrome is always shorter, the development of the symptoms more prompt and decisive, and, it may be added, with proper medical treatment, the duration shorter. It may, indeed, prove to be true, that the difference in the origin of continued fevers may constitute the difference between the types known as typhoid and typhus. Now, the human body in health, probably decays more than after death. The tissues, in fact, are perpetually renewed during life and health. The dynamics of life are due to the retrograde or destructive metamorphosis of the tissues, just as much as the phenomena of electro-magnetism are due to the oxidation of a metal. The sum of the mechanical, , emotional, sensational, psychological, and thermal work, or force, of a human body, is an exact measure of the metamorphosis or oxidation of the tissues of the body, and the maintainance of an equilibrium depends on the amount and quality of food that can be taken into the system, and to its various organs and textures. How long would any of us live without food? And what would be the extent of the waste of the body and the length of life, if compelled to work until nature was exhausted? The time is limited to days, , scarcely two weeks; and the waste, perhaps, half the weight of the body, or more. Now, in continued fever, there is a certain amount of , nervous, and vascular tissue rendered unfit for the of the most of the ordinary results of life and health. If it were not so, we would not have the weakness and waste inseparable from continued fever. The phenomena of the fever are the dynamical results of the oxidation, or destructive , of this destructive tissue. The desire for food has gone, and only those things whose action is known to facilitate destructive metamorphosis are demanded or taken by patients. Of these, water and vegetable acids, as lemon or acetic, are more acceptable than anything else the patient swallows. But no matter how treated by physicians or nurses, patients to lose weight in other words emaciate day by day, until the effete tissues, or parts of tissues, are oxidized and passed out of the body. The solid debris is found in the urine and alvine discharges; the gaseous products find exit at the lungs and from the bowels; and these gaseous products are offensive according to the amount of nitrogenized tissue transformation. Complications arise in the course of the removal of this effete tissue, according as one or several organs have an undue amount of effete matter or tissue interstitialy deposited in them. If in the lungs, it is pneumonia; in the brain, more or less delirium or coma; in the intestines, or, more broadly speaking, viscera, there will be bowel-complaint, ulcerations, or, , perforations; in the dermoid tissue, sweating and ; in the bloodvessels, pyaemia; and so on. Now, that is my understanding of continued or typhoid fever. If any of our Society can name a single phenomenon, constant or occasional, occurring in the course of the disease, which cannot be explained by this hypothesis, it will give me pleasure to have it pointed out, for a solitary example has not occurred to my mind. Viewed thus, the treatment of continued fever becomes a much more simple matter than it can be without this guide from philosophy. No coup de etats will be attempted, except in the earliest stages of the disease, originating from causes believed to be outside the body. Under such circumstances, there are very strong reasons for believing that strong do sometimes cut the disease short. Under other circumstances, they will fail to accomplish this end, but may prove very advantageous in modifying the intensity of many of the symptoms. No specifics will find much favor in the hands of any physician guided by such views as it has been my to lay before you. As you cannot safely or profitably interfere with the destructive metamorphosis going on, upon which recovery depends, and giving the products every facility to find exit from the body, attention should be principally directed to supplying the system with the means of its tissues. Remembering that the stomach, and, in fact, the whole digestive apparatus, is in a state of partial death, you would not offer it food in such forms as would be in health, for if you did, and did not wilfully misinterpret the results, you would hardly continue it. The part of supplied by the glands of the mouth are, for the most part, wholly wanting. The capacity of the stomach to assimilate or digest food is fearfully diminished in grave cases. In speaking of symptomatology, you will remember, it was stated that solid food, for the most part, was not and could not be digested, and if not rejected by vomiting, and passed into the intestines, would there add greatly to their already embarrassed and condition. Food, then, in its highest state of , and in its most easily assimilable forms, should be given in small quantities and repeated at very short intervals there should be no meals. Of food in this form, undoubtedly and milk are the most important. Eggs would no doubt occur to your minds as another; but, until the crisis has been passed, eggs are about as likely, if not more likely, to do as good; they decompose too readily, and their yields too many noxious gases and products, which can only add to the dangers and discomfort of the patient. But after the deepest depression has been reached and the stomach is resuming its tone and power, they are valuable food. articles may be given conjointly with beef-essence and milk, in fluid form, moderately, all through the disease, but the main reliance must be on meat-essence and milk. If the destructive metamorphosis of unsuitable or effete proceeds too rapidly, the patient succumbs early in the , or at whatever stage it takes place. Hence, the cautious use of agents to retard it becomes of the highest importance. The intensity of this metamorphosis is approximately measured by the thermometer, as well as by the circulation and . Hence, ice, spirits, wine, ale, tea, coflee, valerian, , opium, aconite, and veratrum viride all have their uses, and each, properly timed, confer benefits. As the life of the patient depends partly on the oxidation of the effete parts of the tissues, and the elimination of the of the destructive metamorphosis out of the body, it can easily be seen that alcohol is a dangerous remedy, improperly timed, for the reason that its action is known to retard all of the processes going on needful to recovery, viz., assimilation, destructive metamorphosis, and elimination; but exceedingly valuable in the low nervous states characterized by delirium, high temperatures, and excessive elimination It will, however, more frequently occur that destructive and elimination proceed too slowly, and, as a , digestion and assimilation are well nigh annihilated. For the relief of this condition of things, the mineral acids, especially the chlorohydric, preparations of iron, quinia, potassa, or bicarbonated alkalies, will be our best agents. The citrate of quinia and iron is a valuable agent, possessing the double property of promoting metamorphosis and elimina- . tion, though the perchloride, pyrophosphate, or iron by , are very valuable. Sometimes the simple bitters may be advantageously combined with them. Stronger wines and malt liquors are safer and better agents to modify waste than brandy or whiskey. In the management of the complications, poultices of flaxseed meal, with small proportions of mustard, are of very high value in pneumonia, continuously applied; though it may occasionally be needful to abstract small quantities of blood by leeches or cups, and sometimes apply blisters. And of the brain, blood from the temples, or blisters to the temples or sides of the , with ice to scalp. For the bowel complaint, better food, that is, food that will not be passed into the intestines undigested, with turpentine stripes, opiate injections to the rectum, opium and alcohol internally; with an occasional necessity for saturnine and astringents. Abrasions of the surface to be bathed with alcohol, and protected by artificial cuticle of gutta percha in chloroform, or lead plasters. Viewed in this way, too, the necessity for light, ventilation, cleanliness, and constant attention becomes too obvious to be mistaken or neglected. Frequent sponging or wetting the with water or soap and water, or diluted acetic acid, or alkalies, is of the utmost moment. Such are the outlines of the philosophy of typhoid or fever and its remedial management, as it appears to me, studied in the light of the persistence of force, and as cases are managed falling under my especial care. If you can pick them to pieces, do so, for if they are not true, and a safe guide in the management of cases, pray show me the more excellent way. |
ABSTRACT OF A CLINICAL LECTURE ON THE AND TREATMENT OF THE TYPHOID STATE IN DIFFERENT DISEASES. By CHARLES MURCHISON, M.D., F.R.S., Physician and Lecturer on the Practice of Medicine at the Middlesex Hospital. I propose in the present lecture to direct your attention to several cases of disease, widely different in their nature, but in all of which there has been a similar group of symptoms, constituting the condition ordinarily known as the " typhoid state." Case 1. William D., aged 23, admitted Oct. 26th, 1866, on the seventh day of an attack of typhus fever, with well-marked eruption ; a dry, brown tongue ; great delirium and restlessness, and signs of congestion of the lungs. Marked improvement on ^he fifteenth day. On the eighteenth day, return of the febrile symptoms ; an inflammatory swelling over the left parotid, and albumen in the urine. On the nineteenth day, frequent attacks of convulsions, which continued to recur until death by coma on the twentieth day. After Death. Blood dark and fluid; great hypostatic of lungs; spleen large and soft; kidneys presenting the characters of a recent acute nephritis. A large quantity of clear fluid, containing urea, beneath the arachnoid, and in the lateral ventricles. Case 2. John F., aged 27, admitted Dec. 3, 1866, on the ninth day of an attack of typhus, with well-marked eruption; a d*ry, brown tongue, and albumenuria. On the thirteenth day, violent delirium, followed by stupor, floccitatio, and involuntary evacuations, which continued until death on the seventeenth day. No convulsions. After Death. Blood dark and fluid. Extreme hypostatic of both lungs, the two together weighing sixty-eight ounces. Both kidneys greatly enlarged, weighing together fifteen ounces and a-half, their surfaces smooth, and capsules non-adherent, their cortices extremely congested, and the tubes gorged with granular epithelium. Much clear fluid, in which a considerable quantity of urea was detected, at the base of the brain, and in the lateral ventricles. Case 3. John S., aged 44, admitted into the London Fever Hospital, on Oct. 12th, 1863, on the seventh day of an attack of typhus, with copious eruption. On the ninth day, acute delirium, followed by stupor, complete unconsciousness, low muttering delirium, and involuntary motions. On the thirteenth day, urine very scanty and smoky, containing epithelial and blood casts. During the following night, a fit of convulsions, lasting a-quarter of an hour, and death by coma half an hour afterwards. After Death. Blood dark and fluid. Extreme hypostatic congestion of the lungs. Spleen-large and soft. The two together weighing fourteen ounces and a-half, their capsules separating readily, and their cortices quite smooth, but very friable, intensely congested, with blood dripping in large quantity from the cut surface; all the uriniferous tubes gorged with opaque granular epithelium, and many of them containing blood. Much clear fluid in the lateral ventricles and at the base of the brain, which was not examined for urea. Case J. James P., aged 73, admitted Nov. 13th, 1866, with an eruption of pemphigus over the greater part of the body. Many years before he had suffered from " typhus," and from a rheumatic attack, but he had never had dropsy. Two years before,jthe eruption had appeared on his legs, and within the last three months it had spread over his body. Two or three days after the patient's admission, he became very reslless and delirious at night; his tongue was dry and brown, and coarse moist rales could be heard over the back of the lungs ; the urine was scanty, but though examined repeatedly, contained not a trace of albumen, and there was no' dropsy. Death by coma occurred on November 21st. After Death. The blood dark and fluid. The kidneys and granular, their capsules firmly adherent, and their cortices having well-nigh disappeared. (Edema and hypostatic congestion of the lungs. Much clear fluid, containing urea, at the base of the brain, and in the lateral ventricles. Case 5. John K., aged 49, admitted Oct. 27, 1866, with a gangrenous ulcer of big toe, the result of an injury, jaundice, and albuminuria. About Nov. 15, the patient became very restless and delirious at night; the tongue was dry and brown ; there were signs of hypostatic congestion of the lungs; and the gangrene began to spread up the leg. On Nov. 20th, occurred, and, after about twenty fits, the patient died comatose on the 21st. After Death. The cause of the jaundice was ascertained to have been catarrh of the bile-ducts, from irritation of the . Both kidneys were enlarged, and presented the characters of a contracting fatty kidney. Blood dark and fluid. Marked oedema and hypostatic congestion of both lungs. The fluid in the lateral ventricles, and at the base of the brain, was found to contain urea. Case 6. James McW., aged 42, admitted Oct. 15th, 1867, with symptoms of gangrene of the bladder, succeeding those of the passage of a renal calculus. On Oct. 26th, a rigor, followed by fever, with dry, brown tongue, restlessness, and delirium at night, signs of congestion of the base of the lungs, and death, after an attack of convulsions, on Nov. 7th. After Death. Gangrene of the bladder; great dilatation of the right ureter. Sacculation of the right kidney, with complete destruction of its secreting tissue ; numerous small abscesses in the left kidney. Congestion of the lungs. A considerable quantity of clear serum, containing urea in the lateral ventricles, and at the base of the brain. Case 7. Henry P>>, aged 28, admitted Sep. 13, 1866, with all the ordinary symptoms of rheumatic fever in an intense degree, which had lasted about ten days. There was no cardiac complication. On September 17th, he became suddenly worse; he was heavy and stupid, and could scarcely be roused; the urine was loaded with lithates, but contained no albumen ; the tongue was dry and brown; there was now faint pericardial friction. On the following day he became violently delirious ; the temperature was 107deg Fahr., and at 5 P.M., he died comatose. An hour before death, the temperature was found by Dr. Murray to be 110 2deg Fahr.; indicating an unusually rapid disintegration, or combustion of tissue. After Death. Blood dark and fluid. A thin layer of recent lymph over surface of heart, but only half an ounce of fluid in pericardium. Both lungs exhibited in a marked degree the characters of hypostatic congestion, as seen after death from typhus. Spleen ten and a-half ounces, soft and pulpy, like a " typhus-spleen." Both kidneys enlarged and hyperaemic, together twelve ounces and a-half, but surfaces smooth, and capsules separated readily. No fluid in cerebral ventricles. In this case the products of tissue-metamorphosis, as indicated by the high temperature, were probably in too large quantity for healthy kidneys to eliminate. Case 8. Esther P., aged 26, admitted Nov. 5th, 1867, with febrile symptoms, a dry, brown tongue and violent delirium., She had been ill for five days before admission, and presented all the symptoms usually observed in a bad case of typhus fever; but, on examination, no eruption could be discovered on the skin, ahd though there was scarcely any cough, there were all the physical signs of pleuro-pneumonia from base to apex of the left lung, and also at the right base; the urine a considerable quantity of albumen. For four days the patient seemed to get worse; she had no sleep, was extremely delirious, and was with difficulty kept in bed ; but at the end of that time, an improvement commenced, 1 oth in the symptoms and in the physical signs of the lungs; the albumen entirely disappeared from the urine, and on the 6th of December, the patient left the hospital wrell. In the cases now submitted to your notice, the group of known as the "typhoid state" was the same, notwithstanding the varying nature of the primary maladies. These symptoms are a quick, soft pulse; a dry, brown tongue; the symptoms and physical signs of hypostatic congestion of the lungs; of the mental faculties; stupor passing into coma ;^lelirium, which at one time is acute and noisy, at another low and , and not unfrequently associated with muscular tremor; involuntary evacuations, and occasionally subsultus, carphology, or even general convulsions. The precise grouping of the will vary in different cases even of the same disease, while in diseases essentially different it may be identical. The post mortem appearances met with in such cases are a dark fluid condition of the blood ; hypostatic congestion and oedema of the lungs ; old disease or recent congestion, with epithelial engorgement of the tubes of the kidneys; and softening of the spleen, and, unless the typhoid state have been of very short duration, an accumulation of -serous fluid in the lateral ventricals and at the base of the brain, the veins and sinuses of which are usually full of dark blood. The typhoid state is developed more commonly in true typhus fever than in any other disease that we are called upon to treat in this country ; and accordingly, all diseases in which the typhoid state is apt to be developed are constantly mistaken for typhus, so that the cases registered in official returns as deaths from " typhus," furnish no reliable test of the prevalence of this epidemic fever. The cases sent as typhus to the London Fever Hospital, and in fact, to all fever hospitals, from year to year, testify unequivocally to the fact that there is scarcely an acute disease to which flesh is heir which may not in the way pointed out be mistaken for typhus. Next to true typhus, enteric, pythogenic, or the so-called " typhoid fever," is the malady in which the typhoid state is oftenest met with ; and this is one reason why it was so long, and is still so often, with typhus. In many cases of enteric fever, it is true, the typhoid state does not appear at all, or only late in the disease, and in the latter case the attack is often, though , described as " gastric fever passing into typhus." Cases of pneumonia are notuncommon where the symptoms of the local disease are completely masked by those of the general blood-, in the form of manical delirium passing into coma; and there are few medical men who have not met with examples of acute rheumatism passing into a condition indistinguishable from the typhoid state of the typhus, and presenting similar morbid appearances in the solids and fluids after death. Another class of cases very commonly mistaken for typhus is constituted by certain forms of kidney-disease, and particularly the contracted, granular, or "gouty" kidney. In this form of kidney-disease, the patient may at no period of his life have suffered from dropsy, and the urine may contain only a minute trace of albumen; or, as in Case 4, even none at all. The symptoms ordinarily with one's ideas of kidney-disease are absent, and, , when cerebral symptoms supervene, the primary disease is overlooked, and the case is regarded as one of typhus; or, if the attack be sudden or ushered in with convulsions, as one of apoplexy. The "serous apoplexy" of the pathologists of the past age cases diagnosed as apoplexy during life, but where no apoplectic clot was found in the brain after death were probably, for the most part, examples of contracted kidney. As physician to the London Fever Hospital, numerous cases of contracted kidney have come under my notice during the last six years in which the cerebral symptoms the typhoid state were from those of typhus, and where, failing in any previous history, the only points of distinguishing from typhus have been the absence of any eruption on the skin, and the fact that the temperature has been but little elevated above the healthy , except when some local inflammation has complicated the primary disease in the kidney. I shall now endeavor to explain to you why it is that a similar state of the system is so often produced in the course of diseases so widely different, and to show, in fact, that the pathology of the " typhoid state" in all diseases is probably identical, be the cause of the primary disease. To take, first, the cases of contracted kidney, it is now admitted that the cerebral symptoms are due to a poisoned condition of the blood. There may be differences of opinion as to whether the actual poison is urea or some compound of ; but for our present purpose it is immaterial to inquire which of these views is the more probable. It is sufficient to know that the blood is poisoned with the products of the metamorphosis of the nitrogenous tissues, which it is the function of the kidneys to eliminate from the body. The of tissue is not increased beyond the standard of health, but the disease of the kidneys renders them incapable of from the blood the normal quantity of the products of that metamorphosis. Take next, the class of febrile diseases. It is well known that convulsions a symptom characteristic of an extreme of the typhoid state is not uncommon in scarlatina, and it has long been acknowledged that this symptom is independent of any cerebral lesion, but is due to poisoning of the blood in of inflammation of the kidneys. Convulsions, however, are met with in many other febrile diseases besides scarlatina, I have known them occur in typhus fever a hundred times or more, and I have published evidence to prove that their in typhus is the same as in scarlet fever. The urine contains always more or less albumen; the kidneys after death exhibit traces of disease, old or recent; and in not a few (as in Case 1) I have discovered urea in the fluid of the cerebral ventricles. But convulsions, under such circumstances, are only an extreme symptom of the typhoid state. In a large proportion of cases of typhus, even where no convulsions occur, albumen is present in the urine during the second week of the disease where cerebral symptoms are most apt to appear; and in several cases where death has been preceded for some time by the typhoid state, but not by convulsions, I have found (as in Case 2) urea in the cerebral fluid. And if this be the pathology of the typhoid state in scarlet fever and typhus, it may fairly be inferred that the typhoid state in all febrile diseases, whether they be due, in the first instance, to a specific poison or to a local inflammation, admits of a similar explanation. As in the contracted kidney, the blood is with the products of tissue metamorphosis, but the cause of contamination is different. It is now well known that in all febrile disease the disintegration or combustion of the tissue is greatly increased beyond the healthy standard. To this is to be ascribed the increased temperature, which is the pathognomonic symptom of the febrile state, and the j^ipid . The products of this increased metamorphosis are mainly eliminated by the kidneys, and appear in the urine. As long as the kidneys are equal to the increased work thrown them, the blood is properly depurated, and the typhoid state is warded off. But if the kidneys be unequal to the task, either from the large amount of effete material to be eliminated, from previous disease in the secreting tissue, or from congestion (as it often does) from their increased work, then the blood becomes contaminated, and convulsions or the typhoid state supervene. This explains why albumen so commonly in the urine in the course of all acute diseases of a severe form, and why it is so justly regarded as an unfavorable symptom. It also explains why albuminuria is looked upon as a contraindication to any serious surgical operation. The fever which follows an operation is attended by an increased metamorphosis of tissue; and if the kidneys be diseased, the products of the metamorphosis will be retained in the blood, and induce the typhoid state with all its dangers. If the views now submitted to you as to the pathology of the typhoid state be correct, they furnish material for reflection as to its appropriate treatment. This ought to be directed towards depuration of the blood of the products of tissue metamorphosis, avoiding, at the same time all measures which will irritate the kidneys, and interfere still more with their secreting functions. At the present day, existence of the typhoid state is usually regarded as in itself an indication for liberal administration of alcoholic stimulants. Considerable experience of the typhoid state in all diseases lias induced me to doubt the wisdom of the practice, and from an experimental inquiry at the London Fever Hospital, in which the patients admitted with typhus fever on alternate days have been treated with and without alcoholic stimulants, 1 am satisfied that the benefits of late years ascribed to alcohol in the typhoid state have, to say the least, been greatly overrated. Before drawing conclusions as to the good effects of alcohol in typhus, it is necessary to watch the course of the disease where no alcohol has been given, and this precaution has too often been overlooked. At the same time you must not go away with the impression that stimulants, in moderation, are injurious in all cases where the typhoid state is present. Not unfrequently this condition is accompanied by great impairment of the heart's action, indicated by extreme weakness or of the radial pulse, a diminution of the cardiac impulse, and weakness with shortening of the first sound. Under such circumstances, stimulants in moderate quantity are of use. It is the indiscriminate administration of large quantities of brandy in all cases of the typhoid state that I am induced to condemn, both from theory and from practical . Such a practice, it appears to me, is calculated to prove injurious by irritating the kidneys, and thus impeding the of the products of tissue-metamorphosis with which the blood is contaminated. The administration of stimulants must be regulated by the condition of the pulse and heart, and not by the mere existence of the typhoid-state. Brit. Med. Jour. Jan. 4-> 1868. Med. News $ Library. |
(r) 0 r r t $ p o p d c n r c. AN EVENING AT THE MEETING OF THE LONDON PATHOLOGICAL SOCIETY. * ______ X The London Pathological Society numbers among its many of the most valuable men in the medical in that city. Many in attendance upon its meetings are gray-haired and venerable, but the larger number are yet young men, who have risen by industry and talent to positions where they have abundant opportunities to pursue the study of under the most favorable circumstances. Holding as house-physicians and surgeons in the various hospitals, they are constantly coming upon cases whose , with verifications by autopsy, render them of intense to the profession. The aggregate of these labors furnishes abundant material to occupy the members at the stated of the Society, and the only trouble is to find time to do justice to the cases presented. Men learn there the necessity of condensation in the statement of cases and the presentation of opinions; and the way the members manifest their desire to terminate a voluble harangue is so decided, that the bravest cannot long resist the pressure. A statement is always in the hands of the President, of just what is to be presented at that meeting; and the moment a case is called, the person having it in hand steps forward and claims attention. If brief, terse, and lucid, the more is he acceptable; if it has special merit, it receives most careful hearing; if trivial or trite, it is not wise for a young man to weary their patience long. So, too, the pet theories of old men are frequently cut short in the midst of their expression by the merciless little bell. If their presence is secured it is for a purpose, and there must be no abuse. The effect is good every way. If a man has nothing worth saying, he soon learns to keep still; if his subject has merit, he strives to set it forth in brief, but enjoying, manner; and so, in a single evening, matters are brought under consideration and referred for publication in their Transactions,' which a physician in private practice might only reach during long years of patient observation. The regular sessions of the Society occur every two weeks. They are held in the rooms owned by the Medico-Chirurgical Society, from which they are rented for use upon these evenings. The London Obstetrical Society make use of the same rooms on other evenings in the same way. The rooms impress one as the theatre of action, where many of the best men that have lived, and most talented, have labored for the amelioration of misery; for the benefit of the race. The living are there in all the vigor of manhood; the memories of the dead are there also. The room in which the sessions are held is about 40 feet square, with high walls, covered on every side by cases of books. The lighting by day is accomplished entirely from the ceiling. On every side among the cases, on brackets, are placed marble busts, in memory of the venerable dead who once were members and officers of these societies. I made note of some of these, and of the years when they were presidents of the Medico- Society. I give a few of them as they were noted, but not in the order of their election. The likenesses are said, in most instances, to be very striking, and I could but think that our British brethren would do the world a favor if they would cause these busts to be photographed, that the profession in every land, who have admired these men while living, might now the better perpetuate their memories, by placing side by side their works and likenesses. Among these, where all are chief, are the names of John Abernethy, President of the Society in 1823; of Benjamin , in 1827; of William Laurence, in 1831; of Sir Astley Cooper, in 1819; of Sir Henry Halford, in 1810; of Gilbert Blain, in 1813; of William Babington, in 1817; of Thomas Addison, in 1849; of Sir Benj. Brodie, in 1839; of James M. Arnott, in 1847; of Sir Charles Locock, in 1857; of Caesar II. Hawkins, in 1855; and other names, which space forbids me to write, to perpetuate the memory of whom receives the sanction of the world. But I must come to the meeting of the Society, which I attended on the bth of May last. The Society convened at 8 o'clock. Its President is John Simon, known to many Americans, and now holding the as Chief of the Medical Department of the Privy Council, 4 and having a general surveillance of epidemics, etc., as they occur in the kingdom, and giving direction as governmental attention is demanded in medical matters. I noticed that he attained the Astley Cooper prize in Guy's Hospital, in 1844, his subject being the "Thymus Gland." His preparations are carefully preserved in that museum, in accordance with the rules of the hospital. He makes a good presiding officer, and the utmost decorum was manifest. About 60 members were present, all very promptly in their seats, as though they came for a purpose and had business to transact. I give the minutes of some 20 of the 27 cases which had been enrolled in the order of their presentation. I am unable to give the names of the persons offering them. First, Second, and Third, were specimens of morbid growths of the femur. Fourth. Granular disease of the kidney. Capsule ; renal artery terminates in a cul-de-sac; weight 6 grains. Fifth. Disease of the parietal bones, with specimens and history of the case. Skull thickened; brain covered with lymph; patient sometimes violent in temper; no other disease manifest. Sixth. Endocarditis. Specimen presented, case described; lymph shown on the tricuspid valves. Seventh. Deformities of the chest Pigeon-breast. Motion of heart discoverable through the thin walls at the fifth left costal interspace; alternates with recession of spaces on the right side. Eighth. Perforation of chest Pneumo-thorax. Ninth. Four specimens of disease of the supra-renal . The bronzing proportionate to the slowness, but not to the severity of the capsular disease. Tenth. Multilocular ovarian tumor. Removed the previous day; description of its diagnosis and of operation; blood found in cysts; woman still living. Eleventh. Tuberculated liver. Description of case; with remarks upon entozoa in the gall-bladder. Twelfth. Follicular tumors upon parietal bone, with . Semblance to malignant tumors; vascular; remarks on arrest of hemorrhage. Thirteenth. Abdominal and thoracic aneurismal rupture, with description of sac. Difficulty of diagnosis in this case. Fourteenth. Colloid cancer of stomach. Specimen ; reasons for diagnosis. Referred to Cancer Committee. Fifteenth. Ulceration of the larynx, with obstruction of the oesophagus. Sixteenth. Epithelial cancer of the oesophagus and lung. Interest from deposit in the lung. Seventeenth. Microscopic specimens, delineating of the mesentery of the frog. Stages of inflammation and the appearance of corpuscles; passage of white corpuscles through the veins; passage of a red corpuscle through thick vessel wall. Here occurred a lively discussion on the passage of corpuscles. Eighteenth. Fracture of femur. Injury of vessels; following. Nineteenth. Case of swallowing of date-stones, with of hernia, and passages of these from artificial opening in one month; gradual closure of intestinal opening. Twentieth. Case of curious deposit in the lungs, liver, and kidneys. These, with seven cases additional, were passed in rapid , only those points which were unusual being seized upon and discussed briefly, as the cases suggested them. The adjourned at 10 o'clock, when a cold collation was served, according to custom, in the front parlor, or reception-room; the audience-room being on the first floor also, and in the rear of the former. An informal and spirited discussion was held among a few of the members after adjournment, having to the subjects presented with case Seventeen. Prof. Lionel Beale, to whose courtesy and invitation I was indebted for the pleasure of attendance at the meeting, entered heartily into the discussion, as to the precise seat of the of pus corpuscles. His views, as given in his work on the growth of tissues, are being received with great favor, so far as I can judge, by those who have given them candid and careful study. Such extended opportunities for study as these united efforts afford, are of untold value; and they account, in part, for the attainments of those men who have had to do very largely in shaping the medical literature and opinions of the world. America, young in everything else, is yet in the infancy of such labors; but the facilities for improvement are more and more at hand, as our cities increase and our hospitals multiply. We may confidently anticipate that, as all eyes are now turned to a much more thorough and improved system of medical , societies for medical improvement will also be multiplied, and that these, being wisely conducted, will enlist the best and talents of the profession, and secure for us an position and a just respect by all who appreciate the value of medical attainment, both at home and in other lands. The labors of the London Pathological Society are well worthy of emulation. It is in the power of our Chicago and surgeons to institute a favorable comparison of efforts if they will. J. H. H. Hastings, Minn., June 12, 1868. Professor Davis, Dear Sir: At the meeting of the Morgan County Medical Society, in February last, in your State, the case of placenta praevia reported, led Dr. Prince to say that "he believed in this presentation, the profession would eventually adopt the maxim, 'the most speedy delivery possible.'" With the highest respect for Dr. Prince, as a practitioner and a writer, I feel strongly impressed with the duty I owe to my fellow-beings, to give "mine opinion" and show a better way. Speedy delivery has two important objections: it is dangerous, and in my opinion unnecessary. To many this will appear paradoxical; but it is, nevertheless, perfectly true. I am satisfied that a general resort to speedy delivery, as a main dependence, will result in the death of many women. My preceptor, in the State of New York, lost two cases, by that practice, out of three. My first was saved by that , but required very assiduous nursing and stimulating for many hours. Last fall we had two cases in this city, to both of which I was called in counsel. One was "delivered " by another physician, of the most consummate skill, and proved fatal in half an hour. In the other case, we loosened the placenta and waited, and she delivered herself in three hours with entire safety the hemorrhage ceasing upon the detachment of the placenta, and she gradually reviving from the state of depression to which she had been brought by the hemorrhage. I think the article on this subject in Professor Simpson's Works, Vol. I., p. 599, one of the most complete pieces of good reasoning that I have ever seen; and that it should be in the hands of every practitioner of midwifery. I am an entire to his doctrine, and believe that his practice will save almost every case. An anxious study of this subject, and a practice of forty years, have led me firmly to this conclusion, It would be quite improper to lengthen this paper, by to give even a synopsis of Prof. Simpson's statements and arguments on this subject. I greatly hope that many of the readers of the Examiner will be led to possess themselves of a copy of his obstetrical works, and read it for themselves. One of his positions is, that complete detachment of the stops the hemorrhage which partial detachment produces. This looks inconsistent. To judge correctly of it, we must read his article and weigh his reasoning and facts. He says the uterine vessels collapse as far as detachment takes place; and that the hemorrhage connected with partial detachment is through the placenta, and not directly from the uterine vessels. This I believe to be so. To deliver a woman exhausted with hemorrhage, whilst we leave her still to bleed through a partially detached placenta, is one of the most dangerous operations that we can possibly subject her to. Is it not like amputating a thigh without a tourniquet? Or, after an accident, before reaction? It looks to me very much like these. Let me warn my brethren of the profession, therefore, how they proceed to "the most speedy possible delivery" in cases of placenta praevia, for it is often fraught with the most awful danger! Save the blood of your patient with the tampon, cold, and rest, till you find delivery necessary. Then loosen the , and wait for her to revive if depressed, and deliver if she can. If not, after reaction has taken place, so as to render it safe, deliver, and never before. The danger is from loss of blood. That, by detachment, is under our control. Immediate delivery can be but seldom necessary. It should not be resorted to to stop hemorrhage. If it be, it will often be followed by speedy death. Mr. Editor, please excuse my plainness of speech, and assure my brethren of the continued esteem of an old man in the . Respectfully yours, F. B. ETHERIDGE. |
ARTICLE XXVIII. IMPROVED FORM OF THE ENDOSCOPE. By E. ANDREWS, M.D., Prof, of Principles and Practice of Surgery, Chicago Medical College. [Read to the Illinois State Medical Society, May 20, 18G8.J The object of the endoscope is the examination of cavities of the body not accessible to ordinary vision. The form best known in this country is the one invented by Desormeaux, of Paris. It consists essentially of three parts, viz.: the , the perforated mirror, and the tube. The lantern is an enclosed lamp, filled with burning fluid, having on one side a concave reflector (R Fig. 4), whose function is to send back the rays which fall upon it, so as to increase the light thrown in the opposite direction. The light, thus re-enforced, falls upon a lens (L, Fig. 4), which condenses it upon the perforated plane mirror (M, Fig. 4). The latter being set at an angle of forty-five degrees, throws the light in a condensed beam into the tube (C, Fig. 4), and strongly illuminates the interior of any cavity into which the tube is inserted, rendering it visible to the eye placed at E, Fig. 4, where it looks through the of the mirror directly into the tube. The principle is plain, but the practical difficulty is, that unless the apparatus be in perfect order, the light fails to reach the bottom of such a deep, narrow tube in sufficient strength to illuminate and render visible the membranes at its extremity. So great is this difficulty that I apprehend that the iustrument, in the form devised by the European inventors, will never come into extensive practical use. In order to overcome this evil, and produce an instrument which will display its objects when under such management as it would be likely to get in ordinary hands, it is necessary to have a more intense light than can be obtained by any common lamp. I have, therefore, devised an apparatus for burning a magnesium wire in the flame of the lamp, which gives an illumination of such intensity that it can only be compared to the blaze of the noonday sun. This is very simple, and is represented in the sectional view, Fig. 3, in which L is the lamp, and F the flame. S is a revolving metallic spool, on which the wire is wound; and P represents an inclined plane, along which the wire passes. Through an opening in the side of the lantern the wire enters the tube T, which conducts it to the flame of the lamp. If, now, the thumb be pressed upon the inclined plane, and then moved upward, it will slide the wire forward, and cause it to enter the flame, where it burns with a brilliancy far superior to that of the best lamp. I at first intended to have the wire to the flame by means of springs and wheels, but a little experimentation convinced me that this would complicate the apparatus too much, and that it was better to simply slide forward the wire by the pressure of the thumb. The spool may be dispensd with, without inconvenience, the observer simply taking a piece of the wire and inserting it without winding it upon anything. The endoscope is adapted to the inspection of all deep and mucous passages into which a straight tube may be passed. It may be used for examining the ear, the rectum, and the bladder, as well as the interior of abscesses. It may be passed into the track of bullet wounds, to distinguish broken bones from impacted balls, and to detect pieces of cloth and other foreign bodies. It has been even inserted through into ovarian tumors, to examine their interior. Calculi in the bladder have also been detected by it. Its principal practical use, however, is the examination of the interior of the urethra, as a means of diagnosing its different diseases, and of ascertaining the progress of the cure. In order to understand its usefulness for this purpose, a few remarks on the pathology of the urethra are necessary. The healthy urethra is lined with a smooth membrane, of a light pink hue, like that of most other mucous canals. When , its walls fall together in five or six longitudinal folds, so that, seen through the endoscope, the folds, prolapsed over the end of the tube, present a radiated form, as shown in Figs. 1 and 2. If the membrane be inflamed or congested, it presents a deeper red; and if anaemic, it is seen to be abnormally pale. The most important revelation of the endoscope is the establishment of the fact that the mucous membrane of the urethra, like the conjunctiva oculi, is subject to a granular inflammation, and that this disease constitutes the true lesion in many chronic gonorrhoeas. Some years ago this idea was broached in Europe, and experiments were made on abandoned women, hired for that purpose, which showed that granular ophthalmia might be inoculated into the urethra, and there a perfectly similar disease, which could not be from chronic gonorrhoea. The want of a proper for inspection, however, rendered the demonstration rather difficult and unsatisfactory, and this important discovery fell into obscurity. Desormeaux's instrument has brought this fact again into notice, and given good reasons to believe in the propositions: 1. True chronic gonorrhoea, is a granular inflammation, in nature with the granular inflammations of the eyelids, of the cervix uteri and of the larynx; and one may be produced from the other by inoculation. 2. When this disease exists, it has no tendency to recovery, but will last indefinite years unless treated, and will communicate contagion as long as it continues. This disease often persists long after the patient believes himself or herself free from the clap, and hence the frequency with which men contract gonorrhoea from females whom they believe, and who believe themselves, to be free from disease. The chief use of the endoscope is the diagnosis and treatment of this disease. In order to employ it to advantage, a variety of tubes are required, but the smallest should at least equal a No. 10 catheter. The tube is first detached from the lamp, oiled, and a core is placed in it, which projects in a rounded extremity beyond the tip, to facilitate the entrance. If the urethra is too contracted, it must first be dilated. The tube should be passed pretty nearly to the prostate gland, when the core is withdrawn and a pledget of cotton pushed through it into the urethra beyond, to prevent the flow' of mucus or other fluids into the tube. This pledget may be left there, to be expelled by the next passage of urine. Attaching the lamp, and applying the eye to the instrument, the tube should be gradually withdrawn, so that every part of the canal prolapses over the extremity of the tube. At the same time the magnesium wire is kept burning, and thus the whole interior of the urethra is inspected. The appearance of the granular disease thus seen is represented in Fig. 2; while the healthy urethra is represented by Fig. 1. The applications to be used here are precisely those found most useful in granular conjunctivitis, viz., nitrate of silver, sulphate of copper, tannin, alum, acetate of lead, subnitrate of bismuth, carbolic acid, etc. An injection of one part of acid, dissolved in three parts of linseed oil, frequently has a powerful effect in arresting the suppurative discharge, though it is rather severe treatment. In Paris, at the present time, great advantage is claimed for the use of powders blown in through the tube and dusting the interior of the urethra. In my own practice, I commonly carry in the powders on a pledget of cotton wound on the end of a wire. For this purpose, nitrate of silver, sulphate of copper, and various other medicaments, may be finely pulverized, along with subnitrate of bismuth, using a greater or lesser proportion, according to the strength required. Granular inflammation of the urethra, like the same disease on the eyelids and in the cervix uteri, is extremely slow and obstinate several months, and often a year or more, being in the cure. As long as the endoscope shows any of the granulations remaining, so long the disease exists, and its continues. During all this time the discharge may be scarcely worthy of notice, and not at all purulent, but a slight irritation serves to rouse the granulations into activity, so that the patient, without being subjected to any new , may have all the symptoms of a new attack of acute gonorrhoea. Chronic urethretis and metritis, like granular , may be communicated in a quiescent form, the granulations springing up gradually, accompanied by a slight irritation, without the patient ever passing through the of ordinary acute clap. Hence, many persons will give gonorrhoea to others who are utterly unaware that they have ever had the disease themselves. This is one reason why the weekly medical examinations of strumpets, under the license systems of France and Prussia, have proved so worthless for restraining the spread of venereal disease. The quiescent form of the disease escapes the notice of the examiner, who never looks for granulations, but only for the more noticeable of ordinary gonorrhoea and syphilis. Hence, a large of the prostitutes, who weekly receive their certificate of health, are really diseased, and become chronic centres of , as many a verdant Englishman and American has found out to his cost, who, trusting to the fancied security of the governmental inspections, has indulged in Parisian . I stated above that granulur urethretis has scarcely any to spontaneous cure. I have seen cases of 20 years' standing which were still in full activity. There is, however, at length, a sort of natural termination, which is reached by some patients in a few years, but by others not in a lifetime. The tendency of the granular disease is to gradually infiltrate the mucous membrane with permanently organized plastic lymph. This, like all other new tissue, undergoes contraction, which gradually compresses the contained bloodvessels, and at length obliterates them to such an extent as to atrophy and destroy the granulations themselves. The mucous membrane is now found to be paler than is natural, and to be hard and gristly, like the tissue of a cicatrix. The contractile tendency here is doubtless the same which we see in granulation of the eyelids, where it produces similar results; and, in addition, by diminishing the area of the conjunctive, draws in the edges of the lids until the ciliae rub on the eye. Hence why so often follows granular conjunctivitis. A perfectly analogous phenomenon is observed in granular urethritis. In every case, according to Desormeaux, there is present some contraction of the calibre of the urethra, which, even when slight, may be detected by a practised hand in introducing a sound, and in more aggravated cases constitutes stricture. Hence, the opinion that this trouble is usually due either to the acuteness of the first inflammation, or to the injudicious use of nitrate of silver by the surgeon, must be considered erroneous. Granular urethretis tends towards stricture in all cases, though the narrowing is not always great enough to trouble the patient in urination. The same contraction, when it is considerable in amount, shortens the urethra so much as to be an obstacle to erection, constituting the chronic form of chordee. The granular disease, situated in the cervix uteri, is probably the cause of the well-known barrenness of strumpets, and of women whose husbands have been of loose habits. In the latter case, the woman produces perhaps one or two children, but by this time gets from her husband a granular' metritis, which obstructs the os uteri, and effectually prevents further conceptions. It is in this way that licentiousness operates to restrict the growth of population, and correspondingly the progress and power of nations. In conclusion, I would state, that I think the endoscope is a valuable addition to our resources in urethral diseases; but that examinations, by means of it, into the interior of the , the cavities of tumors, and the tracks of fistulas, will be found rather matters of curiosity than of usefulness. I think, also, that in consequence of the dimming of the reflectors, by time and other deteriorations, it will only be satisfactory in ordinary hands when used with the addition of the magnesian light. |
Mnrrinu u nrrcsnoiuinirc Paris, March 3d, 1868. Dear Doctor: Since my last visit to this great medical centre, the old masters have mostly disappeared. In surgery, Malgaigne, Velpeau, Civiale, and Jobert (de Lamballe) are dead; Ndlaton, full of honors and riches, has retired from the hospitals and the school, and men comparatively new are their places. In medicine, Trousseau, justly regarded as the first among his equals in France and, perhaps, in the world, at the end of a long and useful life, the practical results of which are given to the profession in his last and best work, the Clinique Medicale, also sleeps the sleep that knows no waking. Death has also taken away many others of lesser note, so that at the Academy of Medicine, the Society of Surgery, and in the hospitals, the changes are very apparent. In the Academy, the subject of tuberculosis which has, the last year, occupied so much of its time, was brought up again last week by the presentation of a letter from Professor Lebert (of Breslau). It is very generally admitted, I believe, that inoculation with tuberculous matter is followed by the development of morbid elements having a strong resemblance to, if not identical with, those of tubercle; but there is quite a difference in the views entertained by pathologists as to the modus operandi of the inoculated matter. Villemin and others who have experimented upon animals, think that the disease is a specific one, as much so as small-pox or syphilis, and that the introduction into the system of a portion of tuberculous matter, however small, by a process of incubation, results in the development of tubercular masses. On the other side, the specific nature of the disease is denied, and the mode of production of the morbid matter questioned. Prof. Chauffard, at previous meetings of the Academy, had attempted to show that the same results follow from inoculation with any morbid non-specific matter, and that, consequently, there is no incubation, no such relation between the ultimate disease and the inoculated matter as exists, for instance, the syphilitic disease and the syphilitic virus. The has raised the old question, which was supposed to be settled, as to the inflammatory nature of tuberculosis, and the question is asked whether this introduction of morbid matter into the blood does not set up a kind of inflammatory action, resulting in an unhealthy exudation. Such seems to be the opinion of Lebert. In connection with this question, the histology of tubercle has again become the subject of discussion. The question as to what constitutes tubercle, whether it is simply granular or whether it is more or less cellular, whether there is any definiteness of size and form or whether these qualities are incidental, determined by location and clinical history; whether there are two varieties, or whether the so-called crude yellow tubercle is only the product of a chronic pneumonia; these are so many questions that seem to be, in the minds of many of the best thinkers, yet unsolved. So far as the treatment of tuberculosis is concerned, there seems to be but little, even in the way of suggestion, that is new. M. Moutard Martin presented to the Academy of Medicine a memoir upon the value of arsenic in the treatment of phthisis pulmonalis. The conclusions of the memoir are as follows: 1st. The arsenical medication has a very positive effect upon the tubercular disease. 2d. Its action is more efficacious in those cases where the progress is slow, with but little constitutional disturbance. 3d. Acute phthisis is in no respect modified by the arsenical treatment. 4th. In a large number of cases, even in advanced stages with hectic fever, the general condition of the patients is, for a time at least, favorably affected by the treatment. 5th. The change in the local lesions is accomplished slowly. 6th. A certain number of cures ought to be attributed to the arsenical medication, the success would be more certain if the patients did not too soon consider themselves out of danger. 7th. To be efficacious, the treatment must be continued a long time. Sth. The drug should be administered in doses extremely minute. 9th. The doses should not be more than | of a grain daily. 10th. Contrary to the opinion of some authorities, arsenic is better tolerated in the early than in the advanced stage of the disease. 11th. When not more than 4 to | of a grain is given daily, the tolerance is indefinite. 12th. The most evident action of arsenic is manifested in the reestablishment of the general strength, the improvement in the local pulmonary lesion being secondary. Nevertheless, certain facts go to show that arsenic produces a direct effect upon the function of respiration, and suggests that it may act directly upon the pulmonary tissue and upon the tubercular deposits. I had the pleasure of again seeing Fauvel, who devotes entirely to the diseases of the throat and nares. I saw him operate in several cases of laryngeal polypus. He has a good deal of dexterity, and is thoroughly enthusiastic in his specialty. He is about publishing a work on the diseases of the throat and larynx, illustrated with drawings of cases in his practice. Many of these drawings I had the of seeing. Moura Bourouillou, Mandi, and Fourni^ are also engaged in the treatment of affections of this portion of the respiratory apparatus. Prof. Tourdes, of Strasbourg, and Hepp, pharmacien en chef of the civil hospitals of Strasbourg, have been conducting a series of experiments with a new anaesthetic, the bichloride of methyline. The conclusions to which they arrive are, that its action is very much like that of chloroform, probably in no respect better or safer. So far as I can learn, the sanitary condition of Europe is good. I hear of no epidemics and no tendencies to any. The hospitals of Paris remain as they have been. The demolitions for the new Hotel Dieu are going on, but it must be a long time before the structure will be completed. Three years ago, the Emperor expressed the hope that this work of mercy would be achieved before the completion of the great temple of pleasure on the Boulevard, but the Grand Opera House is nearly ready and will soon be filled with music and beauty, while years must elapse before this structure, so appropriately named, will be ready to open its doors to the suffering poor who so much need the shelter and aid it is destined to furnish. H. A. J. London, Feb. 28, 1868. To the student of orthopaedic surgery, London offers a large field for observation. The number of cases of deformity , and constantly occurring in a city of its size, has the surgeon to more thoroughly investigate the means of preventing and correcting them. The result is, that London now has three hospitals devoted to this specialty which are open for clinical instruction three days in the week. The material thus collected for study has greatly advanced the pathology and, consequently, the rational and successful treatment of joint diseases and all deformities. The control of skilful , willing to construct whatever the surgeon desires, renders the mechanical treatment a much easier task than is in Chicago or our eastern cities. "The Royal Orthopaedic Hospital" contains the largest of cases of talipes and spinal curvatures. Its statistics report the treatment of over two thousand cases of deformities of the feet. The division of tendons is not as frequently to as formerly, although by no means abandoned. is frequently performed when the location will permit; as muscles make better union and regain their function more perfectly than tendons. The foot is seldom retained in the shoe by means of bandages, but, enclosed in an elastic stocking, it is secured by means of bands passing over the points where pressure acts to the greatest mechanical advantage. The stocking prevents swelling, which would occur were the bands alone used. By this mode, the force is more localized and not diffused over the foot, as is the case when the bandage is used. In the first part of the process, but little tension is made, allowing union to begin in the divided tendons or ; in the latter, all the force that the patient can tolerate without producing pain. The compound forms of talipes are treated by removing one element of the deformity at a time. For instance, (in talipes) equion-varus, the varus is first corrected and the case reduced to a simple talipes-equinus, which is overcome by subsequent treatment. The cure is more rapid and more perfect when this course is pursued, than when the old method is followed. The tendency to toe in, so frequently met with after the plantar surface is restored, is also entirely obviated. In Potts' disease, or the backward curvature of the spine, the relief of the inflamed vertebrae from pressure and general tonic treatment, is the course pursued. Recent cases of lateral curvature are corrected without great difficulty; but those of long standing, especially when with rotation of the vertebrae, are among the most deformities to remove. Exercise of special spinal muscles, accompanied with moderate lateral pressure, together with such constitutional treatment as each particulai' case may require, are the means . The surgery of deformities is, in London, receiving the which it merits, and those cases which a few years ago fell into the hands of "quacks" and "wonderful liniment menf are now receiving skilful and efficient treatment. J. S. SHERMAN. Paris, March %8d, 1868. The medical and surgical departments of Paris have, within a few years, undergone great changes. Within the last four years many of the most prominent men of the medical schools have died. The death of such as Velpeau, Trousseau, and is not yet forgotten in our own country, much less in Paris. Ricord and Nelaton have both passed the age of service, and no longer appear at the clinic. The bad ventilation of the hospitals and the consequent produced by the impure air, are the most objectionable features in Paris. These buildings were erected years ago, when the importance of ventilation was not known. The has refused to build sufficient new ones, and this the use of the old ones. Some improvements are, , being made. The "Hotel Dieu" is being rebuilt with all the modern improvements in ventilation, and it is the hope of the medical faculty that a similar course will be taken with the remainder. The large number of patients brought to the exceeds their accommodations, and leads to disastrous overcrowding in their wards. The use of sutures after amputations is almost abandoned, the cut surfaces being held in apposition by a simple compress. When the circular operation is performed, the compress is omitted, the limb being placed in a position to favor drainage, without any dressing whatever. The irritation of stitches is thus prevented, and better results claimed than by the ordinary method. Prof. Syme, of Edinburgh, frequently omits the of arteries, hemorrhage being controlled by torsion, in vessels both large and small. There is no more interesting clinic here than that of M. Mallez, who gives his attention specially to diseases of the -urinary organs. Gonorrhoea and gleet, the latter of which is here known as "Za goutte inilitaire" or "military drop," on account of its frequent occurrence in the army, is treated by insufflations of various remedies. The remedies are thus directly to the diseased part. It is painless in its , and can be applied to portions of the urethra which be reached by injections. For the purpose of making these insufflations, he has an instrument consisting'of a small flexible tube, one end of which terminates in a hollow rubber ball. This tube, near its attachment, has a small hopper connecting with its interior, into which the powder to be blown into the urethra is placed. In using it, a silver tube is first introduced into the urethra, large enough to easily admit the elastic one; the space between them furnishes a return for air. By the rubber ball, the powder is carried directly to the membrane, and by gradually withdrawing the tube, the whole surface of the urethra may be covered with the remedy. All substances thus used should be finely powdered. Those most in use are bismuth subnit., acid tannic, alum, potas. , any others may, however, be used, according to the in the case. The usual duration of treatment is from eight to twelve days; many cases yield in less time; old and obstinate cases of chronic urethritis, which have lasted for years, have been cured by this mode of treatment when all others have failed. Applications to the bladder may be made by means of the same instrument. M. Mallez treats paralysis of the bladder by exercise of its muscular coat. To accomplish this, he first injects it with warm water, sufficient to well distend it. This produces a slight , and expulsion of the fluid. Water of a lower is then injected, which causes a still greater contraction. This is repeated several times, the temperature being lowered in each injection, until the limit of contraction is reached. The excitor of muscular action being cold and the principle the same that we apply in paralysis of other parts of the body. Strictures of the urethra he divides by means of the galvanic cautery, and claims that wounds when produced by this agent do not contract when healing; hence, there is less liability to a return of the stricture than when the knife is used. Sufficient time has not elapsed to absolutely determine the truth of this theory, yet the numerous cases operated upon have progressed most favorably. Many of the most obstinate cases are found in his specialty, and he has certainly developed much in their pathology and successful treatment. J, S. SHERMAN. |
THE CHICAGO MEDICAL EXAMINER. N. S. DAVIS, M.D., Editor.- VOL. IX. MAY, 186 8. NO. 5. intrttnaL (rotttri n nttfliis ARTICLE XIV. REPORT ON THE SANITARY CONDITION OF THE CITY OF CHICAGO, AND THE PREVALENCE OF DISEASES FROM OCTOBER 1st, 1867, TO APRIL 1st, 1868. By N. S. DAVIS, M.D., Member of Sanitary Committee. Since the date of my last report to this Society, no diseases of a strictly epidemic character have been prevalent in this city. The meteorological conditions have been less variable, the extremes of heat and cold less, and the wet or rainy days less than the average of winter and spring months in this locality. The small-pox has continued to find victims amongst our heterogeneous population, in numbers sufficient to materially increase the aggregate mortality. The deaths from this were, in October, 20; November, 18; January, 39; , 33; March, 37. In the efforts made by those acting under the direction of the Board of Health and others, to stop the further prevalence of this disease by vaccination, two errors appear to have been committed in some instances. The first was, in not exercising due care in the selection and preservation of the vaccine used. It is certain that an unusually large number of cases have been followed by bad results, such as large phagadaenic ulcers, abscesses, and persistent eruptions, both pustular and . In two children who came under my care, the vaccine pustules had been accompanied by the most intense , ending in gangrene, and the formation of foul ulcers extending half the circumference of the arm, with a very degree of constitutional disturbance. Four others that I saw, had very extensive ulcerations, but without gangrene. A few days since, a gentleman, past the middle period of life, called at my office to consult me about his arm. He had been vaccinated in early life, the cicatrix of which was still visible. Five or six weeks since, he had been re-vaccinated. It a moderate-sized pustule, which matured in the usual time and cicatrized, leaving nothing unusual in the scar. In about one week after the vaccine sore had healed, an eruption began to appear on the arm, in the vicinity of the vaccine scar, and has continued to the present time. The eruption presents two forms: one is pustular, presenting much the shape and size of the larger pustules of acne, and very painful; the other is vesicular, of the size of pemphigus, filled with a sero- fluid. Nearly all the eruptions had a dark purple color at the base, reminding one of syphilide. New pustules and had continued to appear from time to time, but were all located on the vaccinated arm between the shoulder and the elbow, except a single pustule which had appeared on the arm. This patient denied ever having had syphilis in any form; neither had he been subject to cutaneous eruptions. None of the patients to whom I have alluded here, were by myself, and I know nothing of the history of the vaccine matter used. From the reports and rumors on this subject, I think the bad results here alluded to have been numerous to materially increase the prejudices against vaccination, in the minds of many of our citizens. Such results can only be accounted for in three ways: First, by supposing the vaccine virus to have been taken from persons who were previously infected with syphilis or some other disease. Second, by supposing that the vaccine virus, though from pure and healthy subjects, had been so used as to undergo a putrefactive change, by which it had acquired the properties of a purulent infection. Might not this occur either from allowing the scab to be put up too moist, or still more by repeatedly, at different times, wetting and using from the same virus kept between two plates of glass. In this way, virus that had been productive of perfect results with many of the past cases vaccinated, might, in subsequent ones, prove bad. Third, by supposing the existence, in the individual vaccinated, of some latent constitutional disease, which the vaccine only serves to excite into activity. This is, doubtless, the true of a large number of the cases. The second error to which I have alluded, consists in a neglect to examine the cases vaccinated at suitable during the progress of the vaccine. Hundreds of those vaccinated are never examined after the operation is performed. If all the profession would make it a rule to examine the vesicular stage of the vaccine sores, very many cases would be detected and remedied, and some bad results, by a little treatment, would be greatly mitigated. Everything relating to vaccination should receive more attention from the profession than is usually given to it. Rubeola, or measles, has also continued unusually prevalent during the last four months. And, among the poorer classes especially, pneumonia has been a very frequent complication or sequel. In young children, the pneumonia has supervened insidiously in the lobular form, and proved fatal in a large of the cases. From my own observations, I think the fatality has been greatly increased from the two following causes: First, a large proportion of the community no sooner suppose the child to have measles than they wrap it in thick blankets, keep the room inordinately hot, stop all ventilation, and industriously ply it with hot stimulating drinks, for the purpose of getting out and keeping out the eruption. A more cruel or injurious practice could not readily be devised. , during the active progress of the measles, the pneumonic or broncho-pneumonic symptoms are not distinguished from the ordinary catarrhal symptoms that belong to the eruptive fever, and hence no danger is apprehended, and in many instances no physician is called until the latter has completed its course and the patient is found still becoming worse instead of recovering. The physician now finds the lungs hepatized and the vitality of the little sufferer so far exhausted that no remedies will avail. An examination of the monthly bills of mortality shows the following results: from measles, in October, 4; November, 8; January, 21; February, 24; March, 21. From pneumonia, in October, 11; November, 19; January, 49; February, 54; March, 28. These figures are much above the average from these diseases. Thus in the same months of 1866 and 1867, the returns were as follows: from measles, in October, 6; , 1; January, 0; February, 0; March, 1. From , in October, 3; November, 13; January, 11; February, 20; March, 12. In relation to .the prevalence of other diseases, we have observed nothing requiring special mention. There have been occasional cases of scarlet fever and diphtheria, and the usual prevalence of catarrhal and rheumatic affections. During the latter part of the continuous cold weather of January, attacks of meningitis, convulsions, and croup were more frequent. During the months of February and March, I have met with cases of diarrhoea and dysentery more frequently than is usual in those months. These, together with the peculiarly qualities of the atmosphere during the two or three warm days that occurred in the first starting of'the frost and ice in the last of February, have caused me to look with some anxiety in reference to a return of epidemic cholera the coming summer. The weekly and monthly reports of the Board of Health have led many to suppose that the past year has been unusually healthy in this city. This has been done by comparing the mortality of each month in 1867 with the corresponding month in 1866. The year 1866, as is well known, was characterized by a special epidemic of cholera, which added nearly 1000 to the gross mortality of that year, and hence does not afford a proper standard of comparison in reference to the ordinary ratio of mortality. If we compare the ratio of mortality in 1867 with that of 1865, when no special epidemic was , it will afford a much better test and show very different results. Thus, the aggregate mortality for 1865 was 3663, the population 185,000, making the ratio 1 death to 50 of the . The aggregate mortality of 1867 was 4604, the 230,000, making the ratio 1 death to 49 of the population. This will be found fully up to the average ratio for the last 10 years. In respect to the sanitary condition of the South Division of the city, which I represent, and, indeed, of all the Divisions of the city, there arc visible simply the following improvements over past years, namely: fewer heaps of ashes and garbage, especially in the central parts of the city, and a somewhat less number of heaps of stable manure. The institution of a system, imperfect and irregular as it is, has materially lessened the winter accumulations of the kind just named; still manure heaps of respectable age are abundant in all parts of the city. Full out-door privies are still more abundant; and even ditches obstructed by both ashes and garbage are not wanting. The point of vital importance to the sanitary welfare of our city, however, seems to be almost overlooked or neglected. I allude to the overflow and thorough saturation of the soil during the spring, with water holding in solution all the derived from macerating manure heaps, contents of , etc., and disappearing chiefly by evaporation so as to leave in the soil all the animal and vegetable matter previously held in solution, in a condition admirably adapted to undergo and evolve into the air a variety of actively products so soon as the higher temperature of summer is brought to bear on it. Were it not for this source of , our wide streets swept freely by the winds from the lake and the prairie, would render Chicago one of the healthiest cities in our country. There are, however, at this time (April 1st), notwithstanding all the improvements made during the past year, whole sections of the city, closely inhabited, the soil of which is completely saturated and partially covered with standing water, and over which are scattered a sufficient of manure heaps and open privies to thoroughly impregnate the whole with both animal and vegetable matter. During the succeeding two months of cool weather, the excess of water will evaporate, leaving the animal and vegetable residue in such a condition as is most favorable for the evolution of miasms, sporules, and fungi under the high temperature of July and August. It is in vain to expect any marked or permanent in the health of the city while such a state of things exists. The removal of ashes and garbage, and the sweeping of a few central streets, is all proper and necessary; but it has comparatively little effect on the health of the citizens. There may be some who think the great evil of stagnant surface , in large parts of the city, is unavoidable, on account of the low and level character of the surface. This is true, however, only to a limited extent; for the larger number of the very worst places are fully accessible to surface drainage into good permanent sewers already constructed. Take, for instance, that part of the North Division lying between North Market Street and the North Branch of the river, and south of Street, large portions of which are now either overflowed or fully saturated with standing water. The middle and rear part of the lots fronting directly on sewered streets are, in very many instances, so covered with water that the stable and the privy are like islands, accessible only by planks or boards. And yet nothing is wanting, to relieve the whole, except one or two hours of labor in opening suitable channels to the street gutter. In visiting some patients on Townsend, Bremer, and Wesson Streets two or three days since, I found the rear part of nearly all the lots fronting on these streets saturated with stagnant water and thoroughly impregnated with the contents of privies and stable refuse, and the street gutters full. On further , I found nearly all the inlets of the Chicago Avenue and other sewers in that region more or less obstructed. Six good laborers armed with hoe, spade, and axe, under the of a man of intelligence and common-sense, could have relieved the whole of that territory of its surface water in two days, and left it in such a condition that the subsequent showers of spring would have washed and aided in purifying the instead of macerating it for weeks, and returning into the air loaded with miasms. In visiting a patient yesterday, at 605 West Lake Street, a few rods west of Union Park, I to pass the rear end of the lot. I found, not only the rear end of that lot, but the alley, and as far as I could see along the adjoining lots, more or less covered with standing water well impregnated with animal and vegetable matters. Yet, in the centre of Lake Street, directly in front of the whole block, was a good brick sewer, on such a level as to be capable of draining the whole, if there had been any side gutters leading into it. Scores of similar instances might be pointed out in the south and parts of the city, but these are sufficient for illustration. My principal object in calling the attention of the Society to this subject, is to urge the exertion of its entire influence in accomplishing the two following items: First. The adoption by the Boards of Health and of Public Works, of proper ordinances requiring the owner or occupant of every lot in the city, to so connect its surface with the street gutters that all water falling upon any part of such surface shall have an unobstructed access to such street gutters. Second. The adoption and rigid enforcement of a rule, that on the first breaking up of winter, which is generally the last week in February or the first in March, a sufficient force of laborers, under the direction of a suitable number of intelligent overseers, shall be employed to clear all obstructions, of kind, from the entrances to the sewers, and from the street and alley and lot gutters. By having the work done promptly, at the time indicated, it would not only prevent the long retention of the water to the first spring freshet, impregnated with the of winter, but it would render every subsequent spring shower a cleansing and purifying agent. It would cost no more to employ a sufficient number of men to do all the work in ten days, at the exact season when it is of the highest degree of sanitary importance, than it would to keep a small number at work during the whole season, and have of the work done so late in the season as to lose nearly all its value, in a sanitary aspect. If our Board of Health shall continue much longer to keep a large number of sub-officials employed in making sanitary , and gathering statistics to cumber the shelves of its office, and leave the most important part of all its sanitary work undone, or done so late in the season as to be of little practical value, it is. certain that the great mass of tax-payers will soon begin to regard the whole machinery as a useless pecuniary burden. Every practising physician should feel an interest in maintaining an efficient system of sanitary , and the accurate registry of statistics of births, , and deaths. And it is from no desire to find fault with the present Board of Health, that I have called your attention to the foregoing topics, but from an ardent desire to aid in rendering its work more efficient and timely in the prevention of sickness and death. |
>> F1T T 11 B n H ON THE CONVEYANCE OF ASIATIC CHOLERA FROM HINDOOSTAN, THROUGH CENTRAL ASIA AND PERSIA, TO RUSSIA AND ENGLAND, FROM 1817 TO 1831. ______ By JOHN C. PETERS, M. D., of New York. Asiatic, or Hindoostanee cholera, has always originated in India or Hindoostan, and has been conveyed from thence repeatedly to almost all parts of the world. The cholera of 1817 originated at or near the mouth of the Ganges, followed up the course of that river to the northwest, towards its source in the Himalaya Mountains, then pursued the great trunk road of trade and traveled through the cities of Delhi and Lahore, to the Punjaub, or extreme northwestern province of ; passed through the Himalaya Mountains along the line of the Cabul river to the city of Cabul; thence followed the course of the caravan trade between Russia and Asia, through the great cities of Central Asia and Independent Tartary, viz.: Balk, Bokhara, and Khiva, to the towns of Astrakhan and Orenburg, in European Russia. Another great route of cholera was from Bombay, in 1821, to Muscat, at the foot of the Persian Gulf; thence up the Gulf to Bushire; from there through Central Persia to Ispahan and Teheran, and up the Caspian Sea till it reached Astrakhan, in Russia, near the mouth of the Volga, in 1823, when 216 cases, and 144 deaths occurred. The Russian Government a most rigid quarantine against Astrakhan, and saved the rest of Europe. From Teheran, to Persia, near the foot of the Caspian Sea, it also followed the line of travel up between the Black and Caspian Seas, to Tabrez and Tiflis, in the , and reached Astrakhan from this (third) direction. But the precautions of the Russian authorities again prevented this, and from' 1823 to 1829, we find European medical writers speaking of cholera as an epidemic which had passed away, and expressing the hope that it would never return. But in 1827, cholera received a fresh impulse in Ilindoostan, and was again carried by caravans from Lahore, in the Punjaub, through the Himalaya Mountains, by way of Attock and Peshawar, to Cabul, Balk, Bokhara, and Khiva, and reached Orenburg, in Russia, on the 29th of August, 1829. About the same time, it was again carried from Bombay up the Persian Gulf, and again arrived at Teheran, in the part of Persia, in 1829, whence it was forwarded up the Caspian Sea to Astrakhan, by the 19th of July 1830. Thus Astrakhan and Orenburg, in Russia, were the first towns in Europe ever attacked by cholera,-and if it is asked why this should be, the answer is very easy. Orenburg is situated on the Ural river, some distance above its mouth, by which it empties into the northern end of the Caspian Sea. The Ural river forms part of the boundary line 'between Russia and Asia, and Orenburg is built on both sides of this stream, with two separate bazaars one European, the other Asiatic each located on the side of the river belonging to their respective countries. The European bazaar has 180 shops; the Asiatic 492. In fact, Orenburg is the chief of the Russian trade with Central Asia, large caravans arriving yearly from Bokhara and Khiva, with jewels, gold, silk, cotton, cashmere shawls, indigo, tea, and other goods, to the value of over <PS1,500,000. Russia sends back the same amount of iron, cutlery, and other manufactures. More than 3,000 camels are employed in the transport of cast iron articles alone, consisting mainly of pots, kettles, and water cans. , there is no house, and even no tent, in all Central Asia, where there is not some article of Russian manufacture. The most active trade and correspondence is also kept up between the two countries, for many wealthy Asiatic merchants make constant trips to the Russian Fair of Nishni Novgorod, and frequently travel on to Moscow and St. Petersburg. is also the principal Russian military station for against Central Asia, for in 1829, the town had only 11,000 inhabitants, of which number 6,000 were soldiers, and in 1839, no less than 20,000 men and 10,000 camels, set out from this city on a campaign against Khiva. Hence we are not surprised to find that cholera first declared itself in the Russian garrison at Orenburg. It prevailed from the 26th of August, 1829, to the 20th of November, and about 1,000 had the disease, out of a population of 11,000, but several hundreds only succumbed. It was checked by the cold weather, and by the middle of February, Russia was free of the disease. Astrakhan is the great rival of Orenburg for the Asiatic trade. Its population is composed of Russians, Armenians, Cossacks, Tartars, Calmucks, Hindoos, and the Asiatic tribes. In fact, it consists of almost all nations of Europe, Asia, and of all creeds. It has mosques for the Mahommedans, temples for the Hindoos, as well as churches for the Christians. It has over 100 large manufacturing establishments, extensive salt works, and flourishing fisheries on the Volga and Caspian Sea. It is likewise one of the principal naval depots, not only for the Caspian and Aral Seas, but also for many lakes and rivers of Central Asia. Numerous sailing vessels and steamers are constructed and armed at Astrakhan for the lakes and rivers of Central Asia. Cholera was introduced into Orenburg by merchants, , caravans and soldiers, but it came to Astrakhan by vessels, especially from the port of Bakon, on the side of the Caspian Sea. In ten days, 1,290 persons were seized with cholera in Astrakhan, of wrhom 430 died. From Astrakhan it extended up the river Volga the distance of 420 miles, in less than a month, and is supposed to have traveled nearly 1,500 miles from Persia, in three and a-half months, in order to reach Nishni Novgorod and Moscow. It is said that many persons fled from Astrakhan, along the course of the Volga, and carried the disease with them; for in ten different towns along this stream, the first victims were navigators of the Volga, or others arriving from places where the disease already raged. Some distance above its mouth the Volga bends abruptly to the West, and approaches the river Don, which makes an equally marked elbow towards the East, and affords a facile and favorite place of trade for the on the two rivers. Don Cossacks visited the Volga for the purpose of trade, contracted the disease, returned to the Don, where some of them died in September, and the cholera commenced to travel down the river Don towards its mouth in the Sea of Azof, and thus spread to the Black Sea, at the same time that it was ascending the Volga to Nishni Novgorod and Moscow. No less than 54,000 Don Cossacks contracted the disease in 1830, and 31,000 of them died. Other Cossacks were drafted in the Russian army, which was going to the Polish war, and with this army, cholera entered the southeast corner of Poland, and was carried northwest to Warsaw, from thence into Prussia. It is very significant that the little town of Sarepta is situated on the great elbow of the Volga, in the very midst of the Don Cossack district, and has never contracted the cholera. The inhabitants are always very cleanly, and always institute a most rigid quarantine against cholera. By the 27th of August, the pestilence reached Nishni , high up on the Volga. Some say it came from , in the East; others from Astrakhan, in the South. It probably arrived almost simultaneously from both places. The chief importance of Nishni Novgorod, is derived from the fair which is held there annually, and continues during the whole of July and August. It is visited by from 300,000 to 400,000 traders, and the value of the goods exhibited averages $50,000,000, of which more than one-tenth part comes from China, Persia, Central Asia, and India. In fact, Indian, Persian, and Chinese silks, teas, and furs, form some of the principal-articles of Russian foreign trade, most of which reach it from Orenburg and Astrakhan. The vessels engaged in taking cargoes in and out are so numerous that the waters of the Oka and Volga rivers, at the confluence of which Nishni Novgorod is situated, are literally crowded and choked with the mass of shipping. The number of Asiatic visitors is also so great that Mahommedan mosques and Hindoo temples are placed in company with the Russian churches within the of the fair. By the 15th of September, 1830, the cholera reached , due west of Nishni Novgorod and Orenburg, 50,000 fled the city. But up to January, 1831, 9,000 of those who were left were attacked, and more than one-half of them died. Moscow is the seat of the principal Russian , of which not less than 484 are in active operation. It is also a great centre of internal commerce with Riga, on the Baltic. From Moscow it was conveyed, early in May, 1831, to Riga, and it is distinctly stated that it was brought to the headwaters of the river Duna, at the mouth of which Riga is situated, and was carried up the stream to that city. Immense alarm arose, and on June 3d, no less than 60 vessels fled in haste from Riga, four of which were destined for England, especially for Sunderland, on the east coast. By October 26th, 1831, an official English report declared that 306 cases and 94 deaths had already occurred in Sunderland, and the first case of cholera in London occurred in the person of a man from Sunderland. From London it was carried to Dover, and over to Calais and Paris, in France. From England it was carried to Ireland, and in the spring of 1832, vessels from Dublin and Cork, conveyed the disease over the Atlantic to Quebec, in the manner stated in the October number of your journal. From Moscow it was also carried to St. Petersburg, on the 26th of June, 1831, and Drs. Russell and Barry, of the Indian service, who had been familiar with cholera in Hindoostan, were sent by the English Government to observe the disease. A triple cordon of troops were placed around St. Petersburg to keep out the cholera; but Drs. Russell and Barry stated that the first case occurred in a person who came down the river Neva, in a bark with goods from Moscow; the second in an individual who had been on board the bark upon its arrival; and the third in a soldier who had mounted guard on the boat to prevent any intercourse with the shore. From St. it was carried down to Cronstadt, on the Baltic, and a new current of the disease was then let loose to visit Hamburg, Bremen, Denmark, Norway, Sweden, and England. It is well to add that Sunderland, which is only 20 miles from Newcastle, had over 500 vessels engaged in the coal trade, with ports in the Baltic, in 1831; that Riga has the largest commerce of any other port in Russia, except St. Petersburg, and that Drs. Russell and Barry also state that the disease was propagated in St. Petersburg, immediately upon the arrival of several thousand passengers and boatmen, who had come from infected places in the interior of Russia, or had been exposed to infection on the passage on board these . |
ON THE USE OF STRYCHNINE IN EPILEPSY. By WALTER TYRRELL, Esq., Malvern. [Mr. Tyrrell published a paper on this subject in May, 1867.] I stated at the end of my former paper, my belief that "in strychnine we possess a drug which will always control the excitability of the medulla oblongata, and restrain the attacks of convulsion." This opinion will, I think, be found to be remarkably strengthened by a perusal of the following cases. One most important fact is to be gathered from them, viz., that large doses of the drug must be given to produce the favorable results. In some of the cases the doses may appear formidable, but I feel confident that with care and watchfulness no ill need follow their administration to the epileptic. In such cases the system appears to lose its susceptibility; and the drug, even in large doses, produces none of the ordinary signs of disagreement. In no case have I seen it produce any excitement or irritation; and I may state that in one very severe case, still under treatment, I have carried the dose as high as one-fifth of a grain, taken twice daily, and this for nearly three weeks together, not only without its producing the slightest sign of irritation, but, on the contrary, the most marked diminution in the frequency and violence of the attacks. The following case, although the attacks had but recently come on, is interesting, as showing how rapidly the beneficial effect of strychnine is often gained, no attacks having supervened after two doses (each of one-twelfth of a grain) had been taken. H. R., aged 29, has been of late years much exposed to heat in China, Singapore, and Japan; had congestion of the liver in March, 1865; was invalided home in June, 1865; since which time he has been living at home, under treatment for of the liver, using iodide of potassium and iodine locally. On May 22, of this year a very cold, snowy day he imprudently stayed out all day fishing, and at dinner that evening was seized with a violent epileptic fit, accompanied with great convulsion; this was followed by other attacks at the following intervals: May 25, three fits, at intervals of one hour and a-half; May 30, a fit in the evening; June 1, two fits, with six hours' interval; June 2, one fit in the evening. On June 5, he arrived in Malvern, and I prescribed for him of a grain of strychnia twice daily, allowing him to continue his potash in rather increased quantity. On the morning of the 6th, he had three fits, during the first of which I was present; they were very convulsive, and produced an extremely prostrating effect on his mind so much so, that even after the ordinary stupor had passed off, he was unable to answer the simplest question without consideration and great hesitation. It is needless to give a daily report of this case. I increased the dose of the strychnine to one-eighth of a grain; he had no further attacks; and his return to health, both and mental, although gradual, was most perfect. He is now at the seaside, and may be considered, to all intents and purposes, convalescent. In this case, it was curious to observe how the inclination to an attack (which occurred several times during the early treatment of the case) yielded at once to a slight increase in the strength of the dose. I may say that in this case I found the use of ice to the nape very useful, insuring quiet sleep, and also allaying a frequent tendency to irritability. In the following case, where the attacks were dependent on menstrual irregularity, the utility of combining the strychnine with remedies directed to the removal of the exciting cause will be apparent. L. A., aged 17, a not unhealthy looking girl, has never properly; has been subject to epilepsy for four years, the interval never having been longer than one week; the vary in intensity, a slight one being sooner followed by others. In this case, I commenced with one-sixteenth of a grain of strychnia twice daily, gradually carried up to the tenth, at the same time giving her aloes and myrrh, and assafoetida in pills twice daily. In this case, a perfect imtnunity from attacks commenced with the treatment, and has continued up to the present day, a period of nearly three months. Although the menstrual irregularity has not entirely ceased, it is very much ameliorated. 1 used, also, in this case, the cold effusion to the nape, coupling it at times with the application of warmth to the feet. This case, although not severe, is a type of a very form of the disorder, and shows how amenable such cases are to treatment. In another case, somewhat similar, which is \ still under treatment, I have the greatest benefit from the use of the bromide of potassium in combination with strychnia. E. II., aged 14, a fair girl, partially paralyzed on the left side. When two years old had what was called brain fever, during which she was insensible for a length of time; , but had a return about two years ago. Since the first attack she lias been subject to continued attacks of petit mal., sometimes five and six in the day. She turns slightly to the right; is slightly convulsed; sometimes is partially conscious during them, and tries to talk; sometimes she bites her tongue; her manner is silly, being fond of repeating lines of poetry, for which her memory is good. She has slight tenderness on over the upper cervical vertebrae, and on percussing the atlas with the finger points she complains of pain at the . The attacks sometimes come on during sleep. I will give here an extract from the diary kept by the parents. The patient came under my care in May, and I prescribed for her: 1^. Tinct. nucis vomicae 3iij, syr. aurantii SSj. M., cap. 5j bis in die ex aqua. The following is a diary from May 29 up to the stoppage of the attacks: May 29. Four fits in the day; two in the night. 30th. No fits in the day, but eight in the night, two of them being severe. 31st. One fit in the morning; eight again at night, but less severe. June 1. No fit in the day; four at night. 2d. No fit in the day; five at night. 3d. No fit in the day; four at night. 4th. No fit in the day; three at night. 5th. No fit in the day; three slight ones at night. 6th. No fit in the day, and if any at night very slight. 7th. No fit in the day; only one observed at night. 8th. No fits day or night. 9th. No fits day or night. 10th. No fit. 11th. No fit. 12th. No fit. And so on. Since this date she has continued almost entirely* free from attacks, but few having occurred, and those of an altered and much slighter character, which yield readily to a slightly increased dose of the strychnine. Although the following case is still under treatment, yet I think a slight sketch of it cannot fail to be interesting as the effects of strychnine in very severe convulsive , and as also showing what large doses of the drug may be given with impunity. This patient who has suffered for some years, is one of the severest cases of the disorder I have ever seen. I commenced treating him on the 15th June last, and as the case is still under treatment, I will merely give a comparative table of the number of his attacks during May of the present year and July. During the former month, he was under no treatment of any kind. During July, he was taking strychnine in the doses appended to the table. The attacks, which occurred almost exclusively at night, were most violently convulsive. They were much influenced by atmospheric changes, heavy thundery weather invariably increasing both their number and severity. Thus July would, under ordinary circumstances, be his most unfavorable month. In addition to the strychnine, during part of the month, he was using cold affusion to the nape and ice to the occiput during the night. Ao Treatment. May 1, 1867, 2 fits << 2 " 1 << 3' " 2 May 17, 1867, 1 fit " 18, " 0 " 19, " 0 " 4, " 3 " 5, " _______________2 " 6, << 3 " 7, " 2 " 8, " 2 a q <( i " 10,' " ______________0 " 11, " 2 " 12, " 2 " 13, " 4 " 14, " 3 " 15, " 3 << 16, " 3 20, " _______________0 " 21, " _____________1 " 22, " _____________0 " 23, " 2 " 24, " 2 " 25, " 3 " 26, " 3 " 27, " 2 " 28, " _____________1 " 29, " 2 " 30, " 0 " 31, " 0 Under Strychnine. Fits. July 1, 1867, 0 | gr. " 2, " 1 very slight 44 q 44 i f very slight ( no con. " 4, " 0 " 5, " 0 " 6, " 0 44 7, 44 ! " 8, " 2 " 9, " 0 | gr. " 10, " 0 " 11, " 0 " 12, " 0 " 13, " 0 " 14, " 1 A gr. " 15, " 0 Fits. July 16, 1867, 3 " IL " 0 1 gr. " 18, " 0 " 19, " 0 " 20, " 0 " 21, " 0 " 22, " 0 " 23, " 0 44 24, " 0 " 25, " 0 " 26, " 0 " 27, " 1 " 28, " 1 " 29, " 0 " 30, " 0 " 31, " 0 On July 14, owing to a misunderstanding, he only had of a grain instead of |. It will be seen that four fits followed in rapid succession. I think this table shows the power which strychnine possesses in restraining the epileptic attacks. I may add that, although so remarkably lessened in number, they were not at all increased in severity, but, on the contrary, were less convulsive. The above table gives the following results: May. July. No. of attacks. Nights free. No. of attacks. Nights free. 51 7 11 23 It will be observed that during the latter half of the month, the dose of strychnine was as high as | of a grain, taken twice daily, and this without its producing the slightest sign of or irritation. In combination with the strychnine, the patient is taking the infusion of digitalis. In conclusion, I would reiterate the summing up of my last paper: "That in strychnine we possess a drug which will control the excitability of the medulla oblongata and convulsions, but that to cure the disease we must also the exciting cause. Medical Times $ Grazette, Aug. 1867, p. 201. Braithwaite s Retrospect. |
d i t o f i a I The record of Proceedings of the Illinois State Medical occupy so much more space than we expected, that we are obliged to omit from the present number both the clinical and some book notices.. They will appear in our next issue. Chicago Medical College. We have received the Tenth Annual Announcement of this Institution, by which the public are informed of some important changes. The two important chairs of Chemistry have been filled by the appointment of Prof. Wheeler, a gentleman of the highest order of attainments in that department of science. He has promptly established a laboratory for instruction in practical chemistry, which will give to the medical students advantages equal to those enjoyed only at Ann Arbor and Cambridge. The clinical advantages have also been made more extensive by the appointment of Professors Johnson, Byford, and Bevan in the active staff of attendants in the County Hospital. This, added to the previous clinical advantages of Mercy Hospital, renders the means for bedside instruction equal to any in this or other countries. But the item to which we wish to call the attention of our readers most particularly, is the full provision for the system of Medical College Instruction recommended by the Convention of Delegates from Medical Colleges, held at Cincinnati, in May, 1867. Nearly all the State Medical in the North-West, as well as the profession at large, have emphatically endorsed this plan, and called earnestly on the colleges for its adoption in practice. They have now an to show the sincerity of their recommendations, by properly directing the students under their charge or influence. Money Receipts to June 29th. Drs. A. D. Andrews, $5; James , 3; Stacy Hemenway, 5; H. C. Newkirk, 1.50; Thos. W. Howes, 3; . Sterling, 3; B. Wilson, 3; F. K. Bailey, 2; James W. Mill, 1; George A. Bardwell, 3; H. P. Oggell, 3; J. B. Newman, 3; V. H. Coffman, 5; G P. Martin, 3; Wm. Dougall, 1.50. A Hint for Women. Mrs. Caroline H. Dall says: "I have looked in women's faces to see what marks their lives have left, and I tell you that it is a simple fact that women who habitually prevent impregnation grow cold, debased, in their expression; and that those who resort to become sharp, irritable, and ungenial, everything in short that we mean by unmotherly." Mortality Report for the Month of May: CAUSES OF DEATH. Accident, drowned, 4 " railroad,_1 " machinery, 1 " revolver,_1 Angina 1 Apoplexy 6 Asphyxia 1 Birth, premature 13 " still 28 " tedious 1 Brain, compres. at birth 1 " congestion of 4 " disease of 1 " dropsy of 1 " inflammation _ 7 " injury by blow, 1 " softening of, 1 Bright's disease 2 Bronchitis 5 " capillary _ 1 " chronic 2 Bowels, inflammation^ 3 " " & old age 1 Cancer 1 " of uterus, 1 " of breast,_____ 2 " of neck & throat, 1 Convulsions 36 " puerperal,- 1 Compound comminuted fracture of right femur 1 Chlorosis 1 Cholera infantum 1 Croup 4 " membranous, 2 Cyanosis 1 Debility 5 Delirium tremens 1 Deficient nutrition, 1 Diphtheria___________ 4 Diarrhoea 6 " chronic, 1 Dropsy 3 Dysentery, 2 Eczema, congenital,__1 Enteritis, chronic 1 Erysipelas, 1 " phlegmonous 1 Exastisis of 2d. cervical vertebra resulting in hemiplegia, 1 Fever, puerperal 1 " scarlet__________13 " typhoid__________ 5 " typhus 1 Gastritis__________ 1 chronic 1 Heart, disease of_. 1 " organic disease 1 Hemorrhage, internal, 1 Hydrothorax,__________ 1 " fol'ing pulmonalis,____ 1 Hydrocephalus________ 9 " acute, 3 Intestines, and ulceration, _ 1 Invagination ileus, 1 Infanticide, by mother, 1 Inanition____________ 13 Indigestion and old age, 1 Inflammation caused by constipation of bow'ls, 1 Insufficiency of aortic semilunar valves, 1 Insanity,____________ 1 " resulting from epilepsy, 1 Intemperance_________ 1 Jaundice_____________ 1 Laryngitis, tubercular, 2 Liver, cirrhosis of__ 1 Lungs, congestion of _ 3 " abscess of_______ 1 Manslaughter,_________ 1 Measles_______________ 5 Metritis, puerperal, 1 Meningitis____________ 2 " cerebro-spinal, 4 " tuberculosis, 1 Myelitis 1 Nephritis acuto, in uraemic , _______________ 1 Old Age_______________ 2 " and dropsy,______ 1 Paraphlegia, traumatic, 1 Paralysis_____________ 1 " general, 1 Peritonitis___________ 2 Phthisis " " and chorea, 1 " laryngeal,____ 1 Phrenitis, 3 Pneumonia, 18 and with hypertrophy of left and fatty of right ventricle 1 Rheumatism, inflam'ory 1 " .back & spine, 1 Skull, fracture of, 1 Small-pox_____________12 " complicated with pneumonia 1 Stomach, inflammation 2 Suicide 3 Scrofula 1 Tabes mesenterica,____ 7 Tetanus traumaticus,- 1 Teething 10 " and convulsions, 1 Unknown_______________ 1 Uterus, rupture of____ 1 Total__________ 321 Deaths in May, 1868, 321 | Deaths in May, 1867, 241 | Increase, 80 Deaths in April, 1868, 305 | Increase,________________________ 16 AGES. Under 5______________167 5 to 10_______________ 22 10 to 20______________ 16 20 to 30______________ 29 30 to 40______________ 27 Males,____________178 Single, . 238 White,_____________310 | 40 to 50_____________ 23 50 to 60_____________ 17 60 to 70_____________ 7 70 to 80_____________ 9 80 to 90_____________ 3 Females, 143 Married,____________ 83 Colored,____________11 90 to 100___________ 0 100 to 110__________ 0 Unknown 1 Total_________ 321 Total,___________321 Total____________321 Total____________321 NATIVITY. Chicago 126 Other parts U. S._ 62 Bohemia 8 Canada____________ 3 Denmark___________ 0 France____________ 2 England____________ 7 Germany___________ 47 Holland 3 Italy______________ 1 Ireland 38 Norway_____________ 7 Scotland___________ 1 Sweden____________ 11 Switzerland.:_______ 2 Unknown 3 Total________ 321 DEATHS BY SMALL-POX. For the Month of May, 1868. 6th Ward_________________ 1 7th Ward_________________ 1 11th Ward 1 12th Ward__________________ 3 13th Ward 4 15th Ward_________________________2 * Lake Hospital 1 Total,_______________________13 MORTALITY BY WARDS FOR THE MONTH. Ward. Mortality. Pon. in 1866. One death in Ward. Mortality. Pon. in 1866. One death in 1 3 9,648 3,216 2 * 15 12,985 865 2-3 3 16 15,738 983 5-8 4 19 10,884 572 4-5 5 23 9,610 409 1-8 6 19 10,680 556 8-10 7 21 18,755 893 1-10 8 16 10,429 651 6-8 9 21 13,940 663 1-5 10 11 11,416 1,037 9-11 11 13 12,924 994 2-13 12 28 12,695 453 3-7 13 20 8,188 409 2-5 14 19 12,108 637 1-4 15 32 15,766 491 1-8 16 11 14,912 1,355 7-11 County hosp.14 Unknown, 1 Alexian Bros. 1 Home of the Friendless, 2 Soldier's horn. 1 Mercy hos., 4 St.Luke's hos.2 Orphan asyl. 8 Lake Hosp., 1 Total________________________________________321 The Late Dr. R. T. Richards. At the annual meeting of the DeWitt County Medical Society, held on the 11th day of May, 1868, Dr. C. Goodbrake, from the committee appointed to draft resolutions expressive of the sense of this Society on the death of our late colleague, Dr. Richards, reported the preamble and resolutions, which were unanimously adopted: Whereas, It has pleased God, in Ilis wise Providence, to from our midst and from a field of great professional , our highly esteemed friend and co-laborer in the science and practice of medicine, Dr. Rolla T. Richards, who died at Santa Anna, on the 12th day of March, 1868; be it therefore Resolved, That we deeply feel the loss of our deceased friend and brother, who, by his upright, moral conduct, and deportment, had endeared himself to all with whom he associated. Resolved, That, in his death, the profession is deprived of one of its most zealous and devoted members, and the community of a good physician, and one of her best and most patriotic citizens. Resolved, That we feel a sincere sympathy for his widow in her great affliction, and can only refer her, with unfeigned , to Him who has promised to be the widow's God. Resolved, That the foregoing preamble and resolutions^be spread upon the records of the Society; an attested copy sent to the widow of the deceased, and one to each of the medical journals published in Chicago, for publication. C. GOODBRAKE,) J. WRIGHT, > Committee. Z. H. MADDEN. J J. A. EDMISTON, M.D., Prest. C. Goodbrake, M.D., Secy. \ 1504 Walnut Street, Philadelphia, Afay 1868. Dear Sir: I am instructed by the Committee of Publication of the American Medical Association to call your attention to the following amendment to the "Plan of Organization^" at the late meeting held in Washington City, and to request you to forward the amount named to the Treasurer, 1303 Arch Street, on or before the 1st day of July, proximo, in order that the requisite number of copies of the forthcoming edition may be printed without delay. Very respectfully yours, FRANCIS G. SMITH, Jr., Chairman. "The sum of $5 shall be assessed annually upon each to the sessions of the Association, as well as upon each of its Permanent Members, whether attending or not, for the of raising a fund to defray the necessary expenses of the Association, and for printing the Transactions. The payment of this sum shall be required of the delegates and members in attendance upon the sessions of the Association previously to their taking seats and participating in the business of the . Permanent Members not attending shall forward their yearly dues to the Treasurer, and thereby shall be entitled to receive a copy of the Transactions, the same as delegates." O'REILLY PRIZE. Dr. John O'Reilly, of New York, having offered, through the N.Y. Academy of Medicine, a Prize of Six Hundred for an Essay on the Physiology and Pathology of the or Ganglionic Nervous System, the Committee of Award, appointed by the Council of the Academy, have adopted, with the concurrence of the Council, the following regulations: I. The competing essays shall be sent in to the Chairman of the Committee, Prof. J. C. Dalton, M.D., No. 101 East Twenty-Third Street, New York, on or before the First day of March, 1869. II. Each Essay shall be marked with some distinguishing device or motto, and accompanied by a sealed envelope bearing the same device or motto, and containing the name and address of the writer. III. The Essay selected by the Committee shall be by them, together with its accompanying envelope, to the Council of the N.Y. Academy of Medicine, under whose direction the envelope shall be opened and the name of the writer announced at the first meeting of the Academy in May, 1869. IV. This Prize is open for universal competition. V. The Committee have a right to reject whatever does not come up to a proper standard of merit. ALFRED C. POST, M.D., Prest of the Acad'y, On behalf of the Council. Committee of Awards. J. C. Dalton, M.D., Professor of Physiology in the College of Physicians and Surgeons, New York; A. Flint, Jr., M.D., Professor of Physiology in Bellevue Hospital Medical College, New York; Alfred L. Loomis, of the Institutes and Practice of Medicine in University Medical College, New York. New York, December, 1867. |
, ARTICLE XXIII. N S0D2E SULPHIS AND HYPOSULPHIS IN THE TREATMENT OF VARIOLA AND VARIOLOID. By WILLIAM H. PRICE, M.D., Danby, Ill. Since Prof. Polli's admirable treatise upon tlie use of the and hyposulphites in the treatment of zymotic diseases has been laid before the profession, I have been fully determined to test the value of these remedies in the treatment of small-pox, as soon as an opportunity should occur; and since that opportunity has already presented itself, in which my expectations of those remedies have'been fully realized, I thought a brief description of the following cases might not prove uninteresting to the many readers of your valuable journal: Case I. Jan. 17, 1868, was called to see Patrick B., aged 25, by occupation a daily laborer, and who, as I was informed by the messenger, had been bleeding furiously all the previous night from the right nostril. On my arrival, and after having been introduced to my patient, I immediately recognized the case as being one of discrete variola, which was just entering the stage of suppuration, notwithstanding the patient had been vaccinated while a youth. On questioning the patient closely, I soon learned that he had been exposed to small-pox in Chicago, and had already passed through the febrile and eruptive stages. The symptoms of the case were as follows: The whole system was in a state of profuse perspiration; the eruption had itself pretty thoroughly over the whole body and , some of these pustules on the chest and neck measuring nearly half an inch in diameter; pulse ranging from 80 to 100; bowels rather constipated; tongue coated; appetite poor; urine natural, though passed in unusual quantities. The epistaxis, which amounted to three or four quarts during the previous night, arrested itself towards morning by a plug of coagulated blood, which I ordered not to be disturbed until the following day, when it came away while the patient was being washed, without any further loss of blood. The fearful epistaxis, together with the extensive eruption and suppuration, gave the patient a rather deplorable aspect. I immediately prescribed a saturated solution of equal parts of sulphite and hyposulphite of soda, to be taken in teaspoonful doses every three hours until the bowels were freely opened, when the hyposulphite should be discontinued and the sulphite continued, ad libitum, until my next visit. In addition, I a generous diet, with strict cleanliness and free ventilation. Jan. 18. Found the patient very much improved, both and mentally. Rest good; head clear; no return of the epistaxis; urine not secreted in such large quantities; pulse 70; bowels open; appetite rather better; with some tendency to perspiration still remaining. I omitted the hyposulphite, but continued the sulphite in the usual large doses. Jan. 19. Patient improving rapidly, with a decided in all the symptoms. The stage of desiccation is now fully inaugurated. The appetite and sleep is now good, and the patient's spirits very much elated. Ordered the sulphite of soda to be continued in large doses. I informed the patient that I would again visit him in three days. On the second day after my last visit, the patient despatched a messenger to inform me that my services were no longer , for the reason that he (the patient) was able to be about the house, and was feeling quite well. He, however, continued to take the medicine for several days, after which he called at my office, stating that he was as well as ever, having made a perfect recovery without being marked in the slightest degree. Case II. Was called, Jan. 30, 1868, to see Mr. Charles P., aged 30, and a lawyer by profession, who was complaining of a severe pain in the head and spinal column, accompanied with slight chills and fever. On questioning this patient closely concerning his previous history, I was informed that he had been during the years 1865 and 1866 very much exposed to the malarial regions of Kansas and Oregon, and had suffered at that time from a severe attack of ague, from which he thought he had never entirely recovered. On further inquiry, he stated that he had been exposed during the week to severe cold, and more especially during the night of the great fire in Chicago, which, taking into consideration the existing symptoms, was sufficient cause in my mind to give rise to a renewed attack of the old complaint. Having previously used the hyposulphites in cases presenting these symptoms, I accordingly ordered the hyposulphite of soda in 10 gr. doses, in solution, every four or six hours. Jan. 31. Found the patient very much improved, relieved entirely of the chills and the pain in the back and head. At this visit, a very slight eruption w'as noticed upon the forehead, which the patient stated he had noticed on occasions after having been attacked by ague. The same treatment was continued. Feb. 3. Found the eruption more fully developed upon the ' forehead and face, and just making its appearance upon the body and extremities, and presenting all the characteristics of the eruption of varioloid. The patient's bow'els being now rather loose, the hyposulphite of soda was discontinued and the sulphite ordered, in large doses, every four hours, together with liberal diet and well-ventilated apartments. Feb. J. Found the eruption more fully developed upon the body and extremities, with a slight appearance of the stage of . suppuration on the forehead and face. The symptoms present at this visit confirmed my diagnosis. All the functions seemed to be regular, and the patient was able to sit up and walk about his room. The sulphite was continued. Feb. 6. Found the patient passing rapidly through the stage of suppuration, and on some portions of the face verging upon the stage of desiccation, without any unfavorable symptoms whatever. The sulphite was continued in the usual large doses. From this time forward, the patient made a rapid recovery, and in a few days made his appearance, without a mark of the disease to be seen. Case III. Feb. 16, was called to see Mrs. B., aged 38, the mother of five children, was suffering somewhat from pain in the head and back, and nausea and vomiting, during the of the 14th. Feb. 15th. Severe pains in the head and back continued, together with high fever and quick pulse. Feb. 16th, the day on which I first saw the patient, I did not make a positive diagnosis, although there was a slight eruption to be seen on the forehead and arms. Pulse was very quick; bowels rather loose; tongue coated; urine natural in quality and ; pain in the back and head very severe. I immediately prescribed sodae hyposulphis, in from 5 to 10 gr. doses, every three hours. On the evening of the 16th, the bowels were very loose; fever quite high; pulse 110; pains severe in the loins, back, and head. An anodyne was ordered, to relieve pain and to produce sleep, as well as check the bowels, which were now quite loose. The hyposulphite was continued. Feb. 17. The previous night was passed without sleep, and without any amelioration of those severe symptoms already described. Pulse was 120. The hyposulphite was then to be discontinued, and potass, bromide, in saturated solution, to be given in teaspoonful doses every three hours, until the pain should be somewhat relieved and sleep produced. During the evening of the 17th, the patient expressed herself very much better, those severe symptoms being, in a great measure, relieved. Ordered the potass, bro'Tnidi to be continued all night. Feb. 18. Patient entirely relieved of pain, after having had a good night's rest. The stage of eruption was now fully inaugurated, and I then was positive that I had a case of small-pox to deal with, and informed the patient and friends accordingly. The potass, bromidi was discontinued, and the sulphite of soda ordered to be given in 9 doses, every two or three hours. The body to be sponged with tepid or cold water; room to be well ventilated; together with generous diet and plenty of ripe fruits. I must now add that the menses made their appearance, which contributed largely to weaken the patient. Feb. 19. The stage of eruption is fast progressing, being on the face and forehead of the confluent, and on the body of the discrete variety. Appetite is very fair, and patient rests well; pulse 80; bowels regular; very little perspiration. Ordered an infusion of prunus Virginiana to be given with the sulphite. Feb. PS0. Stage of eruption seems to be nearly completed. Patient passed a good night; bowels regular; tongue not coated; appetite very good; head a little confused; throat somewhat sore; feet and hands a little swollen; pulse 70. Patient complains to-day of excessive salivation, although she has taken no medicine which would produce such symptoms since the invasion of the disease. The same treatment was ordered to be continued. Feb. 21. Patient seems to be as comfortable as yesterday, excepting the difficulty of deglutition, which is somewhat . Pulse 75; bowels regular; tinnitus aurium not quite so bad to-day; face considerably more swollen to-day than ; appetite is very fair. Patient's face and forehead is now one solid mass of eruption. The stage of suppuration seems to be now setting in, accompanied with intense fever, and a sensation over the surface of the face and head. still continues, although not accompanied with so large a flow of menstrual fluid as yesterday. Feb. 22. Stage of suppuration is progressing slowly on some parts of the body, while the eruptive stage does not seem to be quite completed on other parts. The swelling on the face, forehead, hands, and feet seems now to be at its height. Pulse and bowels regular, appetite good, and rest at night better than heretofore. In addition to the sulphite and infusion of wild cherry, which has constituted the principal treatment since the invasion of the disease, a pill of from 3 to 5 grs. of assafoetida is ordered to be taken ter die. The patient is allowed to be sponged with whatever fluid substance seems to afford her the most relief; sometimes with cold water, but oftener with sour milk. The menses have now ceased to flow. Feb. S3. Patient is in good spirits. Stage of suppuration is now progressing rapidly, especially upon the body and limbs. The itching and burning sensation upon the face, forehead, and head, which has so much annoyed the patient, is now to the body and limbs. The appetite is good, bowels regular, etc., etc. The same treatment is continued. Feb. SJf,. Stage of suppuration is now being rapidly . The stage of desiccation is making a very slight on the forehead. There is considerable hoarseness, caused by laryngeal and bronchial irritation. The appetite is very good. The patient has not, as yet, shown any symptoms of depression and exhaustion, either in mind or body, but, on the contrary, manifests considerable vitality. The mucous membranes are now very much involved: those of the nose, mouth, larynx, and trachea being the seat of an eruption. The tongue and palate have' become covered with vesicles. The throat is quite sore, there being considerable hoarseness and some difficulty of deglutition. Feb. S5. Patient presents symptoms of drowsiness; appears to be doing well. The urine was examined, and found to contain albumen in a moderate quantity. The of the parotids, face, and eyelids is somewhat subsiding. The lingual, laryngeal, and bronchial irritation is not so great as it was yesterday and the day before. The stage of is showing itself more clearly upon the forehead and head. Pulse 80, bowels regular, and the urine is passed in the usual quantity. Feb. S6. The patient is apparently doing well. The of the face, eyes, and parotid glands is rapidly subsiding. All of the organic functions seem to be performed as well as they can under the circumstances. The appetite is quite good, and the bowels are open. The patient is allowed to partake freely of ripe fruits and well-cooked vegetables. The stage of desiccation has not set in upon the body and limbs, but is pretty well established upon the face and head. The treatment is now equal parts of the sulphite and hyposulphite of soda, the latter being given in conjunction with the former for the double of keeping the bowels in a soluble condition, and to the blood a powerful catalytic. The assafoetida pill is continued ter die, together with the infusion of the prunus Virginiana. Feb. 28. Patient improving rapidly. The stage of is pretty well advanced upon the face and head, but just commencing upon the body and limbs. The patient has not, as yet, the slightest symptoms of delirium or convulsions. The appetite is very good; the bowels are very regular; the urine is passed freely and normally, although still containing slight traces of albumen. The hyposulphite is continued, but the sulphite discontinued, in order to insure regularity of the bowels. Feb. 29. Found the patient doing remarkably well. All the functions are regular, and there is every appearance of a tolerable amount of strength and vitality in the system. The stage of desiccation is rapidly progressing. The same is continued. March 1. Found the patient doing well in every respect. The stage of desiccation is pretty well advanced; the crusts are falling off rapidly; the appetite and sleep are good. The urine was to-day examined, and found to contain no albumen. The patient appears to be convalescing without any unfavorable sequelae whatever. The same treatment continued. March 6. Patient has been doing well since last visit. The crusts have nearly all fallen off, except those upon the arms and lower extremities. All the functions seem to be quite ; sleep and appetite very fair. The patient complains of weakness in the back and joints, and some general depression, in consequence of which the hyposulphite is discontinued, and tonics are ordered in its stead, together with generous diet. March 10. Patient able to sit up most of the day in a chair. Appetite is very good. Patient complains of being very weak in the joints, especially of the lower extremities. The tonic treatment is continued. March 15. Patient improving very rapidly. From this time forward, the patient continued to improve in strength under the tonic treatment, and in a few days was able to attend to her household duties with as much vigor and energy as ever. Case IV. Eugene B., aged 4 years, son of Mrs. B., was complaining March 1st, 1868, of sore throat, with intense pain in the back and head, together with high fever. The of soda was prescribed. March 2. The pain and fever was somewhat relieved. The hyposulphite was continued. March 3. Noticed a slight eruption upon the face and , very much resembling the eruption of measles. The bowels were constipated and pulse very quick. Ordered and milk diet. March J. Found the eruption more fully developed, and all the symptoms of a genuine case of discrete variola. The of soda was continued in 5 gr. doses, every two or three hours, and a liberal diet of milk was ordered. March 5. Found the stage of eruption nearly completed. Bowels were somewhat constipated; urine passed freely; and sleep very fair. March 6. The stage of suppuration is now making its upon the body and limbs, as well as upon the head and face. There is one thing remarkable in this case, however, that is worthy of mention, viz.: During the first two days of this patient's illness, there was considerable difficulty of and respiration, as has been already stated, and for the relief of which a narrow strip of flannel, well saturated with kerosene oil, was placed around his throat. At my next visit, these symptoms were very much relieved. After the stage of eruption had been nearly completed, it was noticed by myself and attendants that there was no eruption anywhere to be seen upon the throat, on which the saturated flannel had been* placed. Now, whether the application of the kerosene had anything to do with preventing the appearance of the eruption upon the throat and neck, or not, is a question I am unable to decide without further experience. The theory looks rather plausible, however, for the reason that well-formed small-pox pustules are now to be seen scattered over the whole body, except around the patient's neck. March 8. The stage of suppuration is rapidly being . All the symptoms at present seem to be very favorable. The hyposulphite of soda is continued. March 10. Patient sleeps well, and has a good appetite. Stage of suppuration is nearly completed. Urine was and found to contain no albumen. The same treatment continued. March ll^. Patient doing well. The stage of desiccation is now rapidly advancing, without any unfavorable symptoms; has good appetite, and sleeps well; bowels rather constipated, in consequence of partaking too freely of boiled milk. Ordered laxatives. Hyposulphite is continued. March 25. Our little patient has, without any unfavorable or distressing sequelae, made a rapid and perfect recovery. Case I, as has already been stated, was contracted in , and came home to be sick in a family of five in number, viz.: the father, mother, and three children. The patient had passed through the first and second stages of the disease, and nearly through the third, before these children, who had been daily exposed, were vaccinated; and yet they escaped from the dreadful malady. From this one case in this family, in a thrifty neighborhood, no other cases originated. Case II was exposed in Chicago, and came home to expose a loving wife and three little children, who had never been until within two days of the father's arrival; and yet these little ones, together with the mother and attendants, entirely escaped from the disease. Case III, whose family of four children, together with her- #self, nurse, and husband, had been vaccinated fourteen days previous to the invasion of the disease, was contracted by the clothes of Case II. During this patient's illness, the family, cooked, ate, drank, and slept in the same room with the patient; and, strange to say, not one of them took the except the little boy, who represents Case IV. The three children, together with the nurse and father were vaccinated at the same time the mother and boy were, and with the same virus. With these four cases, this small epidemic of variola in Danby and vicinity terminated. Before closing this article, I will add that it is my humble opinion that the sulphites and hyposulphites, as a basis in the treatment of small-pox and zymotic diseases generally, if and judiciously used, are superior to any other remedies now known in the profession. As Prof. Polli says: The sulphites and hyposulphites not only destroy the deteriorating power of the materies morbi upon the cerebro-spinal and organic nervous centres; not only the amount of albumen and increase the amount of urea in the urine; but directly destroy the fermento-reproductive power of the poison in the blood, so that the system, if aided by proper nutriment and sustaining treatment, will ultimately eliminate the morbid material, and, in due time, speedily convalescence. |
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