text:
Reprod Sci. 2016 May;23(5):662-9.
A Humanized Anti-Interleukin 6 Receptor Monoclonal Antibody, Tocilizumab, for the Treatment of Endometriosis in a Rat Model.
Taskin MI1, Gungor AC2, Adali E3, Yay A4, Onder GO4, Inceboz U5.
The aim of this study was to investigate the efficacy of anti-interleukin 6 (IL-6) therapy in the treatment of endometriosis in a rat model.
STUDY DESIGN:
After the peritoneal implantation of autologous endometrial tissue, 22 Wistar female rats were divided to create 2 intervention groups: the tocilizumab group (n = 13) and the control group (n = 9). After measuring implant volume, saline was administered to the rats in the control group and 8 mg/kg tocilizumab was administered intraperitoneally to the rats in the tocilizumab-treated group every 2 weeks. After a 4-week treatment period, the volumes and histopathological properties of the implants were evaluated. A scoring system was used to evaluate the preservation of epithelia. Fibrosis score was assessed between the groups. Ectopic and eutopic endometrium were evaluated immunohistochemically for IL-6 and vascular endothelial growth factor (VEGF).
There was a significant difference between the volumes of implants before and after treatment in the tocilizumab group (P < .05). The posttreatment volumes of lesions were smaller in the tocilizumab group than in the control group. Histologic and fibrosis scores were lower in the tocilizumab group than in the control group. Immunoreactivity intensity for VEGF was significantly decreased in the tocilizumab group for ectopic and eutopic endometrium (P < .05). Interleukin 6 levels and endometrial thickness for ectopic and eutopic endometrium were similar between the groups.
Tocilizumab treatment had a regressive effect on the endometriotic implants.
Iran J Reprod Med. 2015 Aug;13(8):513-6.
An epidemiologic survey on the causes of infertility in patients referred to infertility center in Fatemieh Hospital in Hamadan.
Masoumi SZ1, Parsa P2, Darvish N3, Mokhtari S4, Yavangi M5, Roshanaei G6.
Infertility is considered as a major health care problem of different communities. The high prevalence of this issue doubled its importance. A significant proportion of infertility have been related to environmental conditions and also acquired risk factors. Different environmental conditions emphasized the need to study the different causes of infertility in each area.
The aim of this study was to determine the frequency causes of infertility in infertile couples.
In this cross sectional descriptive study 1200 infertile men and women that were referred to infertility clinic of Fatemieh Hospital during 2010 to 2011, were examined. This center is the only governmental center for infertility in Hamadan. Sampling was based on census method. Information about the patients was obtained from medical examinations and laboratory findings. To analyze the data, descriptive statistics such as frequencies and the mean were used.
The prevalence of primary and secondary infertility was 69.5% and 30.5% respectively. Among the various causes of infertility women factors (88.6%) had the highest regard. In the causes of female infertility, menstrual disorders, diseases (obesity, thyroid diseases, and diabetes), ovulation dysfunction, uterine factor, fallopian tubes and cervical factor had the highest prevalence respectively. The causes of male infertility based on their frequency included semen fluid abnormalities, genetic factors, vascular abnormalities, and anti-spermatogenesis factors, respectively.
Etiology pattern of infertility in our study is similar with the many other patterns that have been reported by the World Health Organization. However, frequency of menstrual disorders is much higher than other studies that require further consideration.
Expert Opin Pharmacother. 2015;16(16):2465-83.
Advances in pharmacotherapy for treating endometriosis.
Tafi E1,2, Leone Roberti Maggiore U1, Alessandri F1, Bogliolo S3, Gardella B3, Vellone VG4, Grillo F4, Mastracci L4, Ferrero S1,2.
Endometriosis is an estrogen-dependent chronic disease requiring long-term therapy. Therefore, the choice of medical treatment should be based on efficacy, preference of patients, incidence and severity of adverse effects and cost.
AREAS COVERED:
This review briefly summarizes the currently available medical treatment for endometriosis. The treatments most recently proposed for endometriosis will be described in detail, including gonadotropin-releasing hormone (GnRH) antagonists, aromatase inhibitors (AIs) and the flexible extended combined oral contraceptive.
EXPERT OPINION:
The oral contraceptive pill and progestogens allow for the treatment of the majority of patients with endometriosis. The flexible extended dosing regimen, containing drospirenone and ethinylestradiol, may be particularly useful in patients suffering severe dysmenorrhea and improving the adherence and compliance with treatment. GnRH agonists may be used in patients resistant to first-line therapy; up to now, limited data are available on the use of GnRH antagonist (such as elagolix) in patients with endometriosis. AIs should be regarded as experimental therapies and used only in patients with symptoms resistant to other therapies; however, the use of these drugs is limited by the possibility to administer the treatment for short-term periods only (6 months) and, similarly to GnRH antagonists, by the high incidence of adverse effects, requiring the use of add-back therapy.
Exp Clin Psychopharmacol. 2016 Feb;24(1):1-11.
Determining menstrual phase in human biobehavioral research: A review with recommendations.
Allen AM1, McRae-Clark AL2, Carlson S1, Saladin ME3, Gray KM2, Wetherington CL4, McKee SA5, Allen SS1.
Given the volume and importance of research focusing on menstrual phase, a review of the strategies being used to identify menstrual phase and recommendations that will promote methodological uniformity in the field is needed. We conducted a literature review via Ovid Medline and PsycINFO. Our goal was to review methods used to identify menstrual phase and subphases in biobehavioral research studies with women who had physiologically natural menstrual cycles. Therefore, we excluded articles that focused on any of the following: use of exogenous hormones, the postpartum period, menstrual-related problems (e.g., polycystic ovarian syndrome, endometriosis), and infertility/anovulation. We also excluded articles on either younger (<18 years old) or older (>45 years old) study samples. We initially identified a total of 1,809 articles. After our exclusionary criteria were applied, 146 articles remained, within which our review identified 6 different methods used to identify menstrual phase and subphases. The most common method used was self-report of onset of menses (145/146 articles) followed by urine luteinizing hormone testing (50/146 articles) and measurement of hormones (estradiol and/or progesterone) in blood samples (49/146 articles). Overall, we found a lack of consistency in the methodology used to determine menstrual phase and subphases. We provide several options to improve accuracy of phase identification, as well as to minimize costs and burden. Adoption of these recommendations will decrease misclassification within individual studies, facilitate cross-study comparisons, and enhance the reproducibility of results.
Oncol Rep. 2016 Feb;35(2):607-13.
ARID1A gene mutation in ovarian and endometrial cancers (Review).
Takeda T1, Banno K1, Okawa R1, Yanokura M1, Iijima M1, Irie-Kunitomi H1, Nakamura K1, Iida M1, Adachi M1, Umene K1, Nogami Y1, Masuda K1, Kobayashi Y1, Tominaga E1, Aoki D1.
The AT-rich interacting domain‑containing protein 1A gene (ARID1A) encodes ARID1A, a member of the SWI/SNF chromatin remodeling complex. Mutation of ARID1A induces changes in expression of multiple genes (CDKN1A, SMAD3, MLH1 and PIK3IP1) via chromatin remodeling dysfunction, contributes to carcinogenesis, and has been shown to cause transformation of cells in association with the PI3K/AKT pathway. Information on ARID1A has emerged from comprehensive genome‑wide analyses with next‑generation sequencers. ARID1A mutations have been found in various types of cancer and occur at high frequency in endometriosis‑associated ovarian cancer, including clear cell adenocarcinoma and endometrioid adenocarcinoma, and also occur at endometrial cancer especially in endometrioid adenocarcinoma. It has also been suggested that ARID1A mutation occurs at the early stage of canceration from endometriosis to endometriosis‑associated carcinoma in ovarian cancer and also from atypical endometrial hyperplasia to endometrioid adenocarcinoma in endometrial cancer. Therefore, development of a screening method that can detect mutations of ARID1A and activation of the PI3K/AKT pathway might enable early diagnosis of endometriosis‑associated ovarian cancers and endometrial cancers. Important results may also emerge from a current clinical trial examining a multidrug regimen of temsirolimus, a small molecule inhibitor of the PI3K/AKT pathway, for treatment of advanced ovarian clear cell adenocarcinoma with ARID1A mutation and PI3K/AKT pathway activation. Also administration of sorafenib, a multikinase inhibitor, can inhibit cancer proliferation with PIK3CA mutation and resistance to mTOR inhibitors and GSK126, a molecular‑targeted drug can inhibit proliferation of ARID1A‑mutated ovarian clear cell adenocarcinoma cells by targeting and inhibiting EZH2. Further studies are needed to determine the mechanism of chromatin remodeling dysregulation initiated by ARID1A mutation, to develop methods for early diagnosis, to investigate new cancer therapy targeting ARID1A, and to examine the involvement of ARID1A mutations in development, survival and progression of cancer cells.
Arch Gynecol Obstet. 2016 Apr;293(4):907-14.
BMI and season are associated with vitamin D deficiency in women with impaired fertility: a two-centre analysis.
Dressler N1, Chandra A2, Aguirre Dávila L3, Spineli LM3, Schippert C1, von Versen-Höynck F4.
Animal and human studies suggest that vitamin D regulates functions of the reproductive system. Vitamin D deficiency is prevalent in women of reproductive age. Vitamin D status has been associated with in vitro fertilisation outcome, features of polycystic ovarian syndrome (PCOS) and endometriosis. The aims of our study were to investigate the prevalence of vitamin D deficiency of infertile women living in central Germany, to identify risk factors for vitamin D deficiency and to specify seasonal variations of vitamin D status.
This was a retrospective cohort study at an academic tertiary care centre (N = 113) and an Outpatient Centre for Reproductive Medicine (N = 193) of women presenting for infertility treatment. The statistical evaluation was descriptive and explorative. Possible risk factors associated with an increased risk for vitamin D deficiency were assessed using multiple logistic regression models. Variables with p value less than 0.05 were further assessed in a multivariable logistic regression model.
Overall, 98.2 % of patients at centre 1 and 81.3 % of women with impaired fertility at centre 2 had deficient or insufficient vitamin D levels. Overweight BMI and limited exposure to sun (winter, spring and autumn trimester) were associated with an increased risk of vitamin D deficiency. Vitamin D levels did not vary according to age or infertility associated disorders (e.g. endometriosis, PCOS).
The rate of vitamin D deficiency among women with impaired fertility is alarming. Prospective studies are pressingly needed to confirm a causal relationship and to investigate the potential therapeutic benefits of vitamin D supplementation in this population.
Expert Opin Drug Saf. 2016 Jan;15(1):21-30.
Safety of medical treatments for endometriosis.
Berlanda N1,2, Somigliana E1,2, Viganò P3, Vercellini P1,2.
All medical treatments for endometriosis are equally effective in relieving pain. However, all of them alleviate pain symptoms for as long as they are used, but pain always relapses when medication is discontinued. Therefore, medications need to be used in the long term.
Formulations of estro-progestins that contain less than 50 µg of estrogen are associated with a low risk of venous thrombosis, myocardial infarction and stroke. When considering the neoplastic effects, data suggest that the overall risk of invasive cancer by age 60 is not increased in previous users of hormonal contraceptives. The use of progestins for contraception has never been associated with an increased risk of breast cancer, venous thromboembolism or bone fractures. Although more data on long-term therapy with progestins are needed, treatment of endometriosis with progestins may be feasible in women with metabolic or cardiovascular contraindications to estroprogestin. The other medications for the treatment of pain associated with endometriosis are less appropriate for long term administration because of side effects (danazol and GnRH analogues), costs (aromatase inhibitors and GnRH agonists) or necessity of complex regimens of associations (GnRH agonists and add back therapy or aromatase inhibitors plus progestins).
Progestins and estroprogestins are safe drugs to use in the long term. Adherence to these medications may be high because, being a contraceptive, they are perceived less as a medication for the treatment of a disease. The annual cost of therapy compares favorably with other available medications. Progestins and estroprogestins represent the first-line medications for the treatment of endometriosis associated pain.
Sci Rep. 2015 Nov 18;5:16859.
Peritoneal VEGF-A expression is regulated by TGF-β1 through an ID1 pathway in women with endometriosis.
Young VJ1, Ahmad SF1, Brown JK1, Duncan WC1, Horne AW1.
VEGF-A, an angiogenic factor, is increased in the peritoneal fluid of women with endometriosis. The cytokine TGF-β1 is thought to play a role in the establishment of endometriosis lesions. Inhibitor of DNA binding (ID) proteins are transcriptional targets of TGF-β1 and ID1 has been implicated in VEGF-A regulation during tumor angiogenesis. Herein, we determined whether peritoneal expression of VEGF-A is regulated by TGF-β1 through the ID1 pathway in women with endometriosis. VEGF-A was measured in peritoneal fluid by ELISA (n = 16). VEGF-A and ID1 expression was examined in peritoneal biopsies (n = 13), and primary peritoneal and immortalized mesothelial cells (MeT5A) by immunohistochemistry, qRT-PCR and ELISA. VEGF-A was increased in peritoneal fluid from women with endometriosis and levels correlated with TGF-β1 concentrations (P < 0.05). VEGF-A was immunolocalized to peritoneal mesothelium and TGF-β1 increased VEGFA mRNA (P < 0.05) and protein (P < 0.05) in mesothelial cells. ID1 was increased in peritoneum from women with endometriosis and TGF-β1 increased concentrations of ID1 mRNA (P < 0.05) in mesothelial cells. VEGF-A regulation through ID1 was confirmed by siRNA in MeT5A cells (P < 0.05). Our data supports role for ID1 in the pathophysiology of endometriosis, as an effector of TGFβ1 dependent upregulation of VEGF-A, and highlights a novel potential therapeutic target.
Gen Thorac Cardiovasc Surg. 2017 Mar;65(3):175-178
Resection of pulmonary endometriosis using video-assisted thoracoscopic surgery under preoperative CT-guided marking.
Furuya K1, Otsuka H1, Koezuka S1, Makino T1, Hata Y1, Wakayama M2, Shibuya K2, Iyoda A3.
Pulmonary endometriosis is a gynecological disorder in which endometrial tissue grows outside of the uterine cavity. Usually, the ectopic implants are located in the pelvis and manifest as dysmenorrhea, chronic pelvic pain, or infertility. Pulmonary endometriosis sometimes occurs in the pleurae and can result in catamenial pneumothorax; however, true pulmonary endometriosis, tissue growing in the lung itself, is rare. We report a 22-year-old patient with pulmonary endometriosis and catamenial hemoptysis. Pulmonary endometriosis was proved histologically and treated successfully by wedge resection using video-assisted thoracoscopic surgery.
J Tradit Chin Med. 2015 Oct;35(5):571-6.
Effect of warming Yang and removing blood stasis method on matrix metalloproteinases / tissue inhibitor metalloproteinases levels secreted by cultured endometrial cells from patients with endometriosis.
Huang Y, Shen L, Cai A, Xiao J.
To investigate the effect of Chinese medicines using the warming Yang and removing blood stasis method on levels of matrix metalloproteinases (MMPs)/tissue inhibitor metalloproteinases (TIMPs) secreted by cultured endometrial cells from patients with endometriosis.
Ectopic and eutopic endometrial cells obtaind from 15 endometriosis patients were cultured in vitro, and divided randomly into five groups: high dose; moderate dose; low dose; nemestran; blank control. The three dose groups were treated with a decoction prepared according to the principle of warming Yang and removing blood stasis; nemestran and 0.9% NaCl were administered to the nemestran group and balnk control group, respectively. Eutopic endometrial cells obtaind from 10 hysteromyoma patients were cultured in vitro, as the normal control group, 0.9% NaCl were administered to the normal control group. Cell culture supernatants were collected and levels of matrix metalloproteinase-1 (MMP-1), matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), tissue inhibitor metalloproteinase-1 (TIMP-1) and tissue inhibitor metalloproteinase-2 (TIMP-2) detected by enzyme-linked immuno sorbent assay (ELISA).
Compared with the normal control group, levels of MMP-1, MMP-2, and MMP-9 in eutopic and ectopic endometrium cell supernatants in the blank control group were increased, whereas levels of TIMP-1 and TIMP-2 were decreased (P < 0.05). Compared with the blank control group, levels of MMP-1 and MMP-2 in ectopic and eutopic endometrium cell supernatants cultured in low-dose, middle-dose, and high-dose groups were decreased, whereas levels of TIMP-1 and TIMP-2 were increased significantly (P < 0.05).
The warming Yang and removing blood stasis method affects expression of MMPs and TIMPs.
J Reprod Med. 2015 Sep-Oct;60(9-10):433-5.
Low-grade Endometrial Stromal Sarcoma Primarily Arising in the Vagina: A Case Report.
Rivard C, Carter JS, Downs LS Jr.
Endometrial stromal sarcoma (ESS) is a rareform of endometrial cancer, comprising < 0.2% of all uterine malignancies and 10% of all uterine sarcomas. To date, the English-language literature contains 6 reports of extrauterine ESS arising primarily in the vagina. We describe the seventh such case, and the first case in which the origin is at the introitus of the vagina.
A 43-year-old, nulligravid, Caucasian woman presented for an annual gynecologic examination and was found to have an asymptomatic 5 x 5-mm, rubbery, soft tissue mass at the 5 o'clock position of the vaginal introitus. As has been reported in several cases of low-grade ESS, this case originated at a site of endometriosis.
Based on our experience as well as a thorough review of the literature, it appears that early stage low-grade ESS arising in the vagina can be treated effectively with surgical resection followed by close observation for recurrence.
Semin Reprod Med. 2015 Nov;33(6):422-8.
The Impact of Endometriosis and Its Treatment on Ovarian Reserve.
Seyhan A1, Ata B2, Uncu G3.
Endometriosis is a chronic disease mostly affecting women at reproductive age. There is a clear association between endometriosis and infertility; however, exact mechanisms are unknown. Some evidence suggests an adverse effect on oocytes. Endometriosis and its surgical treatment can affect quantitative ovarian reserve as well. In the presence of endometriomas, serum level of anti-Müllerian hormone (AMH) seems a more reliable marker of ovarian reserve than antral follicle count. Women with endometrioma have decreased serum AMH levels as compared with healthy controls. This is further declined after surgical excision, and the decline seems permanent. Bipolar cauterization of the ovary seems to be playing a role on ovarian damage. Extraovarian endometriosis and its surgical treatment can also be associated with decreased ovarian reserve, but there is limited information. Patients with endometriosis should be informed about fertility preservation options, especially in the presence of bilateral endometriomas or prior to surgery.
Vopr Kurortol Fizioter Lech Fiz Kult. 2015 Jul-Aug;92(4):54-60.
The modern applications of radon therapy for the medical rehabilitation of the patients.
Razumov AN1, Puriga AO1, Yurova OV1.
Radon therapy is one of the methods of physiobalneotherapy the mechanism of action of which is believed to consist of the influence of the small radiation doses of radon and its daughter products on the nervous, vascular, and immune apparatuses of the skin and mucosal membranes that eventually enhances the protective and adaptive potential of the body and thereby its ability to resist pathological impacts. At present, the high effectiveness of radon therapy is universally recognized and this method is widely applied for the combined treatment of various diseases in different fields of medicine. These include (1) diseases of the musculoskeletal system and locomotor disorders in the patients presenting with recurrent rheumatic fever, reactive arthritis, ankylosing spondylitis, post-traumatic osteoarthrosis and knee joint synovitis, the sympathico-tonic course of vegetative dystonia associated with connective tissue dysplasia, etc.; (2) neurological disorders in the patients presenting with cervical dorsopathy, neurological manifedstations of degenerative lesions of the cervical and lumbar spine, etc.; (3) cardiological disorders in the patients presenting with hypertensive disease, coronary heart disease, atherosclerosis of different localization, etc.; (4) gastrointestinal disorders in the patients presenting with gastric and duodenal ulcers, irritated bowel syndrome, etc.; (5) gynecological problems in the patients presenting with primary and secondary dysmenorrhea, genital endometriosis, uterine myoma, dysregulated reproductive function, polycystic ovary – syndrome, polycystic ovary syndrome and ovulatory disorders of proinflammatory origin, etc.
Med Tr Prom Ekol. 2015;(8):14-8.
Prevalence and risk of endometriosis in industrial territories.
Alexeyev VB, Balashov SY, Dugina OY.
The study covered prevalence of endometriosis under various levels of exposure to chemical environmental factors and chemical risk factors for immune and reproductive female systems, identified as exposure markers in sanitary epidemiologic studies. Findings are that a part of inhabited area neighbouring to industrial territory is characterized by unacceptable risk of immune disorders and reproductive system diseases due to chronic exposure to formaldehyde, nickel, lead, benzene, that can result in increased prevalence of endometriosis.
Reprod Biol Endocrinol. 2015 Nov 24;13:128
Age-related trends in anti-Mullerian hormone serum level in women with unilateral and bilateral ovarian endometriomas prior to surgery.
Nieweglowska D1, Hajdyla-Banas I2, Pitynski K3, Banas T1, Grabowska O4, Juszczyk G5, Ludwin A1, Jach R6.
Endometriosis is a well-known cause of infertility, and the anti-Mullerian hormone (AMH) is an accepted biomarker of ovarian reserve and response to artificial reproductive technology procedures. The present study was a prospective analysis of age-dependent AMH serum concentration in women with bilateral and unilateral ovarian endometriomas before therapy onset compared with healthy controls.
This prospective cross-sectional study included 384 women aged 18-48 years. AMH serum concentration was assessed between days 3 and 6 of the menstrual cycle in 78 patients with bilateral and 157 patients with unilateral ovarian endometriomas and compared with 149 healthy controls. Ovarian endometriosiswas confirmed histopathologically, and data were presented as medians with interquartile range (IQR).
Stage III endometriosis was diagnosed in 53.2 %, stage IV in 18.3 %, stage V in 23.4 % and stage VI in 5.4 % of the patients. Patients with bilateral ovarian endometriomas showed the lowest median AMH levels compared with patients suffering from unilateral ovarian endometriosis (0.55; IQR: 0.59 vs. 2.00; IQR: 2.80; p < 0.001) and the control group (0.55; IQR: 0.59 vs. 2.84; IQR: 3.2; p < 0.001). Median AMH concentration values were not significantly different between patients with unilateral ovarian endometriosis and the healthy controls (2.00; IQR: 2.80 vs. 2.84; IQR: 3.2; p = 0.182). A strongly negative correlation between AMH levels and age was confirmed in healthy individuals (R = -0.834; p < 0.001) and women with unilateral ovarian endometriomas (R = -0.774; p < 0.001). Patients with bilateral ovarian endometriosis showed a significantly negative but only moderate correlation between AMH levels and age (R = -0.633; p < 0.001), which was significantly lower than in the healthy controls (R = -0.633 vs. R = -0.834; p = 0.006) but not in the patients with unilateral ovarian endometriosis (R = -0.663 vs. R-0.774; p = 0.093). Based on a multivariate regression analysis, only bilateral localization of ovarian endometrial cysts (p = 0.003) and patient age (p < 0.001), but not left/right localization of unilateral cyst or cyst volume, were negatively associated with AMH serum concentration.
According to our data, unilateral ovarian endometriosis had a moderately negative and nonsignificant effect on AMH-based ovarian reserve evaluated prior to surgery, irrespective of age. In contrast, the ovarian reserve was significantly reduced in women with bilateral ovarian endometriomas.
Gynecol Endocrinol. 2016;32(4):293-7.
Anti-Müllerian hormone levels after laparoscopic cystectomy for endometriomas as a possible predictor for pregnancy in infertility treatments.
Iwase A1,2, Nakamura T1, Kato N1, Goto M1, Takikawa S1, Kondo M1, Osuka S1, Mori M1, Kikkawa F1.
We assessed the associations between preoperative and postoperative serum anti-Müllerian hormone (AMH) levels and parameters of endometriosis and endometriomas surgery with the success of infertility treatments after cystectomy. Seventeen out of 54 patients got pregnant during the infertility treatments. In these patients, the median interval from surgery to conception was 16.3 months. The serum AMH levels 1-year postoperatively were significantly higher in the pregnant group compared to the non-pregnant group (3.44 ± 1.78 versus 2.17 ± 2.24 ng/ml, p = 0.049). The median interval from surgery to recurrence was 34.4 months, and no significant differences were found in the serum AMH levels at any time point between the recurrence and non-recurrence groups. Serum AMH levels 1 year after laparoscopic cystectomy for endometriomas may predict the success of postoperative infertility treatments, but not a recurrence of endometriomas.
Gynecol Obstet Fertil. 2015 Dec;43(12):806-9.
Endometriosis Fertility Index, or classification of the American Society of Reproductive Medicine for postoperative endometriosis patients with infertility: Which is more relevant?.
Boujenah J1, Hugues JN2, Sifer C3, Bricou A2, Cédrin-Durnerin I2, Sonigo C2, Monforte M2, Poncelet C2.
The revised American Fertility Society classification system has been most used after surgery by all consensus on endometriosis fertility. However, it does not predict pregnancy. The EFI score has been recently developed to aim at predicting clinical pregnancy after surgery. Several study performed its external validation. It may be a useful new tool to counsel couples for personalized postoperative management.
Int J Gynecol Pathol. 2016 Jan;35(1):78-81.
Seromucinous Tumors of the Ovary. What's in a Name?
Kurman RJ1, Shih IeM.
The recent 2014 World Health Organization (WHO) Classification of Tumours of the Female Reproductive Organs introduced a new category of ovarian neoplasm designated "seromucinous tumours". The recognition of this distinctive group of tumors is an important addition to the classification but the term "seromucinous" has serious flaws that obscures the nature of these neoplasms. Morphologically, seromucinous tumors in addition to serous and endocervical-type mucinous epithelium, contain endometrioid, indifferent and squamous type epithelium. Their immunoprofile is characterized by frequent expression of ER, PR, infrequent expression of WT1 and lack of expression of CK20 and CDX2, an immunostaining pattern consistent with a "müllerian" immunophenotype. Unlike serous and intestinal type mucinous tumors, seromucinous tumors are frequently associated with endometriosismaking them more analogous to endometrioid and clear cell neoplasms. Indeed, recent studies have shown that a high proportion of seromucinous tumors lost expression of ARID1A, a tumor suppressor gene, that is mutated in approximately 50% of endometrioid and clear cell tumors, in sharp contrast to serous and intestinal-type mucinous tumors which do not contain ARID1A mutations or lose its expression. Therefore, based on their clinicopathologic, immunohistochemical and molecular genetic features we believe a more appropriate designation for this group of tumors is "mixed müllerian tumors" which can be subcategorized as "mixed müllerian cystadenomas", "mixed müllerian atypical proliferative (borderline) tumors" and "mixed müllerian carcinomas".
Semin Diagn Pathol. 2016 Jan;33(1):31-42.
Non-neoplastic pancreatic lesions that may mimic malignancy.
Okun SD1, Lewin DN2.
The widespread use of abdominal ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI) has resulted in an increased identification of asymptomatic pancreatic lesions. Preoperative diagnoses of pancreatic lesions can be difficult. Solid and cystic lesions and anatomic variants of normal can all mimic tumor clinically and radiologically. Newer imaging modalities have increased the likelihood of the accurate diagnosis of non-neoplastic pancreatic disease, however, despite the many advances; it still remains a challenge to differentiate rarer non-neoplastic entities and inflammatory masses from adenocarcinoma, preoperatively. Adding to the challenge is the fact that a variety of inflammatory, solid and cystic non-neoplastic lesions have significant clinical and radiological overlap with malignancies. About 5-10% of pancreatectomies performed with the primary clinical diagnosis of pancreatic carcinoma are later proved to be essentially non-neoplastic lesions. It is vital to include these non-neoplastic entities in the differential diagnosis while working up abnormal clinical and radiological pancreatic findings because it may drastically alter therapeutic options for the patients. The significance of recognizing these lesions preoperatively is to help to guide the clinical decision-making process and the avoidance of an unnecessary pancreatectomy. Examples of such entities include chronic pancreatitis, sarcoidosis, intrapancreatic accessory spleen (IPAS), lymphoid hyperplasia, lipomatous pseudohypertrophy (LPH), lymphangioma, lymphoepithelial cyst (LEC) and endometriosis.
Mol Cell Endocrinol. 2016 Feb 15;422:74-83.
Triclosan and bisphenol a affect decidualization of human endometrial stromal cells.
Forte M1, Mita L1, Cobellis L2, Merafina V3, Specchio R3, Rossi S3, Mita DG4, Mosca L2, Castaldi MA2, De Falco M5, Laforgia V5, Crispi S6.
In recent years, impaired fertility and endometrium related diseases are increased. Many evidences suggest that environmental pollution might be considered a risk factor for endometrial physiopathology. Among environmental pollutants, endocrine disrupting chemicals (EDCs) act on endocrine system, causing hormonal imbalance which, in turn, leads to female and male reproductive dysfunctions. In this work, we studied the effects of triclosan (TCL) and bisphenol A (BPA), two widespread EDCs, on human endometrial stromal cells (ESCs), derived from endometrial biopsies from woman not affected by endometriosis. Cell proliferation, cell cycle, migration and decidualization mechanisms were investigated. Treatments have been performed with both the EDCs separately or in presence and in absence of progesterone used as decidualization stimulus. Both TCL and BPA did not affect cell proliferation, but they arrested ESCs at G2/M phase of cell cycle enhancing cell migration. TCL and BPA also increased gene expression and protein levels of some decidualization markers, such as insulin growth factor binding protein 1 (IGFBP1) and prolactin (PRL), amplifying the effect of progesterone alone. All together, our data strongly suggest that TCL and BPA might alter human endometrium physiology so affecting fertility and pregnancy outcome.
Fertil Steril. 2016 Feb;105(2):435-43.
Expression of microtubule associated protein 2 and synaptophysin in endometrium: high levels in deep infiltrating endometriosis lesions.
Gori M1, Luddi A1, Belmonte G1, Piomboni P1, Tosti C1, Funghi L1, Zupi E1, Lazzeri L1, Petraglia F2.
To assess whether healthy endometrium, eutopic endometrium, and endometriotic lesions express nerve growth factor (NGF), microtubule-associated protein 2 (MAP-2), and synaptophysin (SYP).
Molecular study in tissue extracts.
A group of women (n = 70), divided as [1] healthy controls (n = 30) and [2] with endometriosis (n = 40), was included.
From the healthy control group an endometrial specimen was collected by hysteroscopy (proliferative phase, n = 16; secretive phase, n = 14). Endometriotic and endometrial specimens were collected from women undergoing laparoscopic surgery for endometriosis, endometrioma (OMA) (n = 20), or deep infiltrating endometriosis (DIE) (n = 20).
To assess expression of NGF, MAP-2, and SYP messenger RNA (mRNA) levels in endometrium and in endometriosis by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and protein localization by immunofluorescence. Cultures of human endometrial stromal cells were used to evaluate the effect of tumor necrosis factor (TNF)-α on NGF and SYP.
Endometrial tissue from control expressed mRNA for NGF, MAP-2, and SYP, without any difference between proliferative and secretive phase. The DIE and OMA lesions showed the highest NGF mRNA expression, significantly higher than in eutopic endometrium and control. In DIE lesions SYP mRNA expression was higher than in OMA or in eutopic endometrium or controls. Immunofluorescence analysis of NGF, MAP-2, and SYP showed a slightly more intense positive signal in endometriotic lesions. Exposure to TNF-α increased NGF and SYP mRNA expression in endometrial culture cells.
The present study revealed the presence of two selected neuronal markers, MAP-2 and SYP mRNAs and protein expression, in eutopic endometrium and in endometriotic lesions.
Avicenna J Med Biotechnol. 2015 Oct-Dec;7(4):173-8.
Association between Serum Paraoxonase 1 Activities (PONase/AREase) and L55M Polymorphism in Risk of Female Infertility.
Motovali-Bashi M1, Sedaghat S1, Dehghanian F1.
The risk of developing female infertility has been associated with gene polymorphisms that decrease the activity of enzymes involved in systemic Oxidative Stress (OS). In this study, PON1 L55M polymorphism for association with susceptibility to infertility was investigated among Iranian female population.
Samples from 120 Iranian females [20 endometriosis; 30 Polycystic Ovary Syndrome (PCO); 70 controls] were analyzed and PCR-RFLP assay was used to determine the PON1 rs854560 (L55M) frequencies. The paraoxonase (PONase) and arilesterase (AREase) activities of PON1 enzyme were also assessed in order to investigate the association between serum PON1 activities, female infertility, and PON1 L55M polymorphism.
The women with a MM genotype (p=0.021; OR=2.55) showed more possibilities of experiencing infertility than those with a LM genotype (p=0.039; OR=1.91). According to LSD test, endometriosis subjects had significantly lower paraoxonase enzyme activity compared to control group (p=0.0024; CI=95%). No significant difference was found in women with PCOS for both PONase and AREase activity in comparison with control group (p=0.469; CI=95%). Furthermore, PON1 activities were the highest in LL genotype followed by LM and then MM genotype (MM<LM<LL) in both patients and controls.
PON1 L55M polymorphism may be associated with serum PON1 activity and the risk of developing female infertility.
Adv Biomed Res. 2015 Aug 31;4:182
Evaluation of antimullerian hormone levels before and after laparoscopic management of endometriosis.
Mostaejeran F1, Hamoush Z1, Rouholamin S1.
Serum antimullerian hormone (AMH) proposed to be a reliable marker of ovarian reserve; the aim of this study was to evaluate the influence and value of laparoscopic management in endometriosis as measured by serum AMH levels.
In this cross-sectional study, 33 infertile patients who referred to fertility – Infertility Center of Isfahan – with different stages of endometriosis managed by diagnostic operative laparoscopy and serum AMH levels were measured pre and one month postoperative laparoscopy. Main outcome measures were serum AMH levels in correlation with the type of infertility, stage of endometriosis, and type of surgery in infertile patients.
33 infertile patients enrolled in the study with mean age 28.9 ± 5 years, and thus did not show a significant difference. Mean serum AMH levels was 4.23 ± 3.75 ng/ml and 2.2 ± 2.47 ng/ml, respectively, in primary and secondary infertility groups before and one month after laparoscopy, which shows a significant difference (P < 0.001). Median AMH level changes in Cauterization (0.67 ± 0.76 ng/ml), endometrioma excision 2 ± 0.6 ng/ml, both 2.18 ± 0.81 ng/ml and shows no significant differences. Mean serum AMH levels were definitely decreased in minimal/mild and severe stage endometriosis before and 1 month after laparoscopy, (1.84 ± 2.06 ng/ml and 2.18 ± 3.45 ng/ml), respectively. Also serum AMH according to ovarian appearance and evolvement showed no significant differences after laparoscopy: (5.5 ± 1.4 ng/ml and 2.76 ± 0.96 ng/ml) and (3.37 ± 2.2 ng/ml and 1.84 ± 1.5 ng/ml).
Serum AMH levels clearly decreased 1 month after operative laparoscopy.
J Obstet Gynaecol Can. 2015 Sep;37(9):804-809.
An Evaluation Model for a Multidisciplinary Chronic Pelvic Pain Clinic: Application of the RE-AIM Framework.
Chen I1, Money D2, Yong P2, Williams C2, Allaire C2.
Chronic pelvic pain (CPP) is a prevalent, debilitating, and costly condition. Although national guidelines and empiric evidence support the use of a multidisciplinary model of care for such patients, such clinics are uncommon in Canada. The BC Women's Centre for Pelvic Pain and Endometriosis was created to respond to this need, and there is interest in this model of care's impact on the burden of disease in British Columbia. We sought to create an approach to its evaluation using the RE-AIM (Reach, Efficacy, Adoption, Implementation, Maintenance) evaluation framework to assess the impact of the care model and to guide clinical decision-making and policy.
The RE-AIM evaluation framework was applied to consider the different dimensions of impact of the BC Centre. The proposed measures, data sources, and data management strategies for this mixed-methods approach were identified.
The five dimensions of impact were considered at individual and organizational levels, and corresponding indicators were proposed to enable integration into existing data infrastructure to facilitate collection and early program evaluation.
The RE-AIM framework can be applied to the evaluation of a multidisciplinary chronic pelvic pain clinic. This will allow better assessment of the impact of innovative models of care for women with chronic pelvic pain.
PLoS One. 2015 Nov 25;10(11)
Associations between Medical Conditions and Breast Cancer Risk in Asians: A Nationwide Population-Based Study in Taiwan.
Chuang SC1, Wu GJ1, Lu YS2,3, Lin CH2, Hsiung CA1.
The breast cancer incidence in Asia is rising. To explore whether the etiology of breast cancer is different from the known risk factors from studies in Western countries, we conducted a nested case-control study using data from the Taiwan National Health Insurance Research Database (NHIRD).
All medical conditions based on the first three digits of the ICD-9 and a list of medical conditions based on literature review were retrieved for each case and control. The odds ratios (OR) and 95% confidence intervals (CI) of the associations between medical conditions and breast cancer risks were estimated using conditional logistic regression and adjusted for occupation, number of breast cancer screening, and the average number of outpatient visits prior the diagnosis. The associations were also estimated for younger (<50 years old) and older subjects separately.
The analyses included 4,884 breast cancer cases and 19,536 age-matched controls. Prior breast diseases (OR, 95% CI: 2.47, 2.26-2.71), obesity (1.43, 1.04-1.96), endometriosis (1.44, 1.15-1.80), uterine leiomyoma (1.20, 1.03-1.40), hypertensive diseases (1.14, 1.05-1.25), and disorders in lipid metabolism (1.13, 1.04-1.24) were associated with increased breast cancer risk. No heterogeneity was observed between age groups (<50 and ≥50 years old).
In addition to benign breast diseases, obesity, endometriosis, uterine leiomyoma, hypertensive diseases, and disorders of lipid metabolism were associated with a subsequent breast cancer risk.
IMPACTS:
Our results suggest that estrogen related factors may play an important role in breast cancer risks in the Taiwanese female population.
Int J Health Sci (Qassim). 2015 Jul;9(3):273-81
Prevalence of endometriosis among adolescent school girls with severe dysmenorrhea: A cross sectional prospective study.
Ragab A1, Shams M2, Badawy A2, Alsammani MA3.
To determine the prevalence of endometriosis among adolescent school girls with severe dysmenorrhea.
Data was collected via interviewed questionnaire. Patients with symptoms and signs suggestive of endometriosis were further evaluated by abdominal ultrasonography (AUS), serum cancer antigen 125 (CA125). Laparoscopy was done for confirmation in those who agreed. Those who declined laparoscopy were offered magnetic resonance imaging (MRI).
A total number of 654 adolescents were interviewed. Their mean age was 15.2 ± 3.53 SD years. The mean duration of cycles and flow days was 29 ± 8.4 SD and 4 ± 2.8 SD respectively. The age of menarche in years was 13 ± 1.2 SD. Cycles were regular in 77.4 % (n=506) while irregular in 22.6 % (n=148). Of all studied girls, 48.9% (n=320) had menstrual pain of varying degree of severity. Severe dysmenorrhea was reported in 68.8 % (n=220/320) of them. Fifty six of these cases (25.5 %) had ultrasound findings suggestive of endometriosis. CA125 was elevated in 41.5 % (n= 27/56) of them. Patients accepted laparoscopic confirmations were 34, of them 79.4%, (n=27) had positive histo-pathological evidence of endometriosis. MRI was offered to those declined laparoscopy (n=22). Endometriosis was suggested in 77.3% of them.
The study concluded the prevalence of endometriosis in adolescents with severe dysmenorrhea was 12.3 % despite some declined laparoscopy. The unacceptability of laparoscopy and unfeasibility of local examination and trans-vaginal ultrasound add more to the difficulty of diagnosis.
J Pediatr Adolesc Gynecol. 2017 Apr;30(2):228-233.
Recurrence of Ovarian Endometrioma in Adolescents after Conservative, Laparoscopic Cyst Enucleation.
Lee SY1, Kim ML2, Seong SJ2, Bae JW3, Cho YJ4.
STUDY OBJECTIVE:
To evaluate the cumulative recurrence rate of endometriomas after a laparoscopic endometriotic cyst enucleation in adolescents and to find the factors associated with recurrence.
A multicenter retrospective cohort study.
Three university hospitals.
One hundred five patients surgically treated with laparoscopic enucleation of endometriotic cysts younger than 20 years of age were selected.
INTERVENTIONS:
MAIN OUTCOME MEASURES:
Endometrioma recurrence was considered when transvaginal or transrectal sonography indicated a cystic mass with a diameter of 20 mm or greater. Recurrence rate of endometrioma and median time to recurrence were evaluated.
In total, 105 patients were followed for 47.3 (±44.3) months (range, 3-161 months). Seventeen patients (16.2%) experienced recurrence after the first-line surgery and 8 patients (7%) underwent a second surgery. The median time to recurrence was 53.0 (±8.5) months (range, 8-111 months). Using Kaplan-Meier method, the cumulative recurrence rates of endometrioma per patient at 24, 36, 60, and 96 months after the first-line surgery were 6.4%, 10%, 19.9% and 30.9%, respectively. Surgical characteristics, such as the diameter of the cyst, revised American Society for Reproductive Medicine stage, unilateral or bilateral involvement, and coexistence of deep endometriosis were not associated with recurrence in this age group.
Although the short-term recurrence rate in adolescents after first-line surgery is relatively low, the recurrence rate appears to be higher according to the follow-up duration. Long-term and continuous follow-up is needed for patients who have undergone surgical treatment for endometriosis in the adolescent period.
Fertil Steril. 2016 Feb;105(2):430-4.e26
Mapping of bowel occult microscopic endometriosis implants surrounding deep endometriosis nodules infiltrating the bowel.
Badescu A1, Roman H2, Aziz M3, Puscasiu L4, Molnar C4, Huet E5, Sabourin JC6, Stolnicu S7.
To provide a mapping of bowel occult microscopic endometriosis implants from colorectal specimens removed from patients who had undergone colorectal resection for deep endometriosis infiltrating the rectum.
A series of consecutive patients with deep endometriosis infiltrating the rectum or/and sigmoid colon, between January 2013 and December 2013.
University tertiary referral center.
Twenty-six patients with deep endometriosis infiltrating the rectum or/and sigmoid colon.
Surgical management by colorectal resection.
Twenty-six patients with prospective recording of data (age, clinical history, symptoms, preoperative assessment, and intraoperative findings) underwent colorectal resection for bowel endometriosis. Mapping of occult microscopic endometriosis implants from specimens was established by histologic examination of 1,051 microsection slides taken from transversal macrosections of 3-mm thickness (40 microsections per patient on average).
The mean (SD) length of colorectal specimens was 110 (42) mm. Microimplants were found at varying distances up to 54 mm from macronodule limits. Multiple macroscopic nodules were identified in five patients (19.2%). In 18 specimens (69%) diffusion of endometriosis microimplants was longitudinal, whereas in 8 specimens (31%) diffusion was concentrated around the macroscopic nodule. Respectively, 31%, 19%, 8%, and 4% of patients presented with endometriosis microimplants at 2, 3, 4, and 5 cm from macroscopic nodules.
The present data suggest that in patients presenting with deep colorectal endometriosis, microscopically complete excision of rectal endometriosis may be unachievable because of bowel occult microscopic endometriosis implants located far from macroscopic nodules.
Minerva Ginecol. 2016 Apr;68(2):211-8.
Should we diagnose and treat minimal and mild endometriosis before medically assisted reproduction?
The treatment of minimal or mild endometriosis prior to assisted reproduction (ranging from intrauterine insemination to in vitro fertilization [IVF]) to improve the likelihood of success is controversial. Ovulation suppression is commonly used in endometriosis to decrease pain, however, there is little evidence to suggest improvements in fertility associated with this technique. Moreover, current evidence is sparse and does not support ovarian suppression prior to intrauterine insemination with or without ovulation induction, while there is some evidence favoring ovarian suppression with gonadotropin releasing hormone agonists prior to IVF to improve pregnancy rates. However, the majority of studies were performed in women with moderate to severe endometriosis. There is currently conflicting evidence regarding surgical ablation or removal of endometriomas prior to IVF, and its outcome on pregnancy rates. This review highlights the paucity of data in the management of endometriosis prior to assisted reproductive technologies and suggests that further studies are needed.
Cell Physiol Biochem. 2015;37(6):2231-45
Genome-Wide Microarray Analysis of Long Non-Coding RNAs in Eutopic Secretory Endometrium with Endometriosis.
Wang Y, Li Y, Yang Z, Liu K, Wang D.
BACKGROUND/AIMS:
Dysregulated long non-coding RNAs (lncRNAs) can lead to the occurrence of various diseases; however, reports of the function of lncRNAs in endometriosis and related studies are scarce. The pathogenesis of endometriosis is still poorly understood.
Dysregulated lncRNAs and mRNAs between eutopic and normal endometrium (both are late secretory) were analyzed by lncRNA microarray. Eight lncRNAs and mRNA CDK6 were validated using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Bioinformatics prediction was used to investigate the potential function of these differentially expressed lncRNAs.
Microarray expression profiling suggests 1277 lncRNAs (488 up- and 789 down-regulated) and 1216 mRNAs (578 up- and 638 down-regulated) were expressed differentially between eutopic and normal endometrium. Pathway analysis and gene ontology (GO) analysis found differently expressed lncRNAs associated with the cell cycle and immune regulation. The relative level of expression of CDK6 and AC002454.1 were obtained by qRT-PCR and the Pearson correlation coefficient was 0.747 (p<0.0001). A coding-noncoding gene co-expression (CNC) network was constructed for these validated lncRNAs.
These dysregulated lncRNAs might provide information for new biomarkers or novel therapeutic targets of endometriosis. AC002454.1 might induce cell cycle disorder by regulating CDK6 to participate in the pathogenesis of endometriosis.
Expert Opin Investig Drugs. 2016;25(2):227-47.
An overview of early drug development for endometriosis.
Leone Roberti Maggiore U1,2, Ferrero S1,2.
Endometriosis is an estrogen-dependent chronic disease of women of fertile age requiring chronic therapy. Although available drugs have good efficacy and safety profiles, some patients experience partial or no improvement of pain with conventional treatment and recurrence of symptoms after discontinuation of the therapies. For these reasons, many new compounds are currently under investigation for the treatment of endometriosis.
This review offers the reader a complete and updated overview on emerging therapies for the treatment of endometriosis. The authors describe, in detail, the laboratory and clinical studies on these therapies and highlight the potential advantages and limitations associated with the administration of these new agents.
Gonadotropin-releasing hormone antagonists are the most intriguing emerging agents for the treatment of patients with endometriosis. It should be noted that while there are a number of drugs under investigation, a large majority of these new compounds have only been investigated in laboratory studies with more extensive research required to better elucidate their efficacy and safety profiles.
Arch Iran Med. 2015 Dec;18(12):844-8
Prevalence of Endometriosis in Malignant Epithelial Ovarian Tumor.
Akbarzadeh-Jahromi M1, Shekarkhar G2, Sari Aslani F2, Azarpira N3, Heidari Esfahani M2, Momtahan M4.
The present study aims to assess the prevalence and histological characteristics of endometriosis in different types of ovarian surface epithelial tumors.
Microscopic slides of 110 ovarian tumors (89 malignant and 21 borderlines) were reviewed from 2008 to 2013 in two major gynecological centers affiliated with the Shiraz University of Medical Sciences, Shiraz, Iran. The presence or absence of endometriosis and transitions from atypical endometriosis to carcinoma were also histologically evaluated. Chi-square and t-test were used to compare the study groups.
The mean age of the patients was 49.93 ± 9.36 years in the Endometriosis-Associated Ovarian Carcinomas (EAOC) group and 50.18 ± 12.8 years in the non-EAOC group. Among the 110 patients, 28 (25.4%) had endometriosis. According to ovarian cancer subtype 67% (4/6) of clear cell adenocarcinoma, 65% (11/17) of endometrioid adenocarcinoma, 28% (7/25) of low grade serous adenocarcinoma, 4% (1/25) of high grade serous adenocarcinoma, 30% (4/13) of borderline serous tumor, and 25% (1/4) of mixed carcinoma had endometriosis. None of the mucinous borderline tumors and mucinous adenocarcinoma cases had endometriosis. Moreover, 23 cases had typical endometriosis, while 14 had atypical endometriosis. On the other hand, 19 cases had both typical and atypical endometriosis. Furthermore, transition from atypical endometriosis to carcinoma was seen in 11 cases.
Clear cell and endometrioid carcinoma are the most common types of EACO. Atypical endometriosis was more commonly seen in endometrioid and clear cell carcinomas which are included in type I ovarian cancer. Thus, it can be concluded that atypical endometriosis is a precursor for type I ovarian cancer.
J Res Med Sci. 2015 Jul;20(7):668-74.
Serum anti-inflammatory cytokines for the evaluation of inflammatory status in endometriosis.
Măluţan AM1, Drugan T2, Ciortea R1, Mocan-Hognogi RF1, Bucuri C1, Rada MP1, Mihu D1.
Endometriosis is a frequent gynecologic disease with a severe impact on the quality of life in the affected women; its pathogenesis is yet to be fully understood, with an altered immunity as a possible key factor. The present study aimed to investigate the serum anti-inflammatory cytokine profile in the patients with endometriosis compared with the healthy controls.
One hundred and sixty women were included, divided into two study groups (Group I – endometriosis; Group 2 – healthy women). We evaluated the serum levels of interleukin-1 receptor antagonist (IL-1Ra), IL-2, IL-2R, IL-4, IL-10, IL-13, and IL-15 with the use of Human multiplex cytokine panels. Statistical analyses (normality distribution analysis, independent t-test, Mann-Whitney U-test) were performed using IBM SPSS software (version 22.0) and GraphPad Prism (version 5.00); receiver operating characteristic curve were used to demonstrate the diagnostic performance of the studied markers.
The mean serum level of IL-1Ra, IL-4, and IL-10 were significantly higher in women with endometriosiscompared to women free of disease from the control group (30.155, 138.459, and 1.489, respectively, compared to 14.109, 84.710, and 0.688, respectively; P < 0.001, P < 0.001, and P = 0.002, respectively.). No significant differences in the mean serum levels of IL-2, IL-13, and IL-15 were observed between the studied groups and IL-2R had a very low detection rate.
Endometriosis is associated with elevated levels of anti-inflammatory cytokines, IL-1Ra, IL-4, and IL-10, markers that have a potential role as a prognostic factor for endometriosis.
Exp Ther Med. 2015 Aug;10(2):787-791.
Association between macrophage migration inhibitory factor in the endometrium and estrogen in endometriosis.
Zhang X1, Mu L2.
Recent studies have shown that macrophage migration inhibitory factor (MIF) has a possible role in endometriosis-related pain and infertility, yet it has not been explored whether the mRNA level of MIF is altered in endometrial tissues from patients with endometriosis. The aim of the present study was to compare the expression of MIF in endometrial tissues from women with and without endometriosis, and to analyze the association between endometrial MIF expression and 17β-estradiol (E2). The protein and mRNA expression of MIF in the human endometrial tissue was assessed by western blotting and reverse transcription-polymerase chain reaction analysis, respectively. The MIF expression of women with endometriosis was found to be significantly higher than that of the controls. A positive correlation was noted between the serum E2 level and MIF expression. In endometrial cells from women with endometriosis, the level of E2-induced MIF upregulation was significantly higher than that in cells from women without endometriosis. In conclusion, this study demonstrated a significant increase in MIF expression in the endometrial tissues of women with endometriosis and an association between MIF expression and E2 level. MIF expression in endometrial cells from patients with endometriosisshowed an increased sensitivity to stimulation by E2.
Oncol Lett. 2015 Aug;10(2):571-576.
Checkpoint kinase 1 inhibitors as targeted molecular agents for clear cell carcinoma of the ovary.
Kobayashi H1, Shigetomi H1, Yoshimoto C1.
In clear cell carcinoma of the ovary, chemoresistance frequently results in treatment failure. The present study aimed to review the potential association of transcription factor hepatocyte nuclear factor (HNF)-1β with cell cycle checkpoint machinery, as a mechanism for chemoresistance. The English-language literature on the subject was reviewed to identify genomic alterations and aberrant molecular pathways interacting with chemoresistance in clear cell carcinoma. Oxidative stress induced by repeated hemorrhage induces greater susceptibility of endometriotic cells to DNA damage, and subsequent malignant transformation results in endometriosis-associated ovarian cancer. Molecular changes, including those in HNF-1β and checkpoint kinase 1 (Chk1), may be a manifestation of essential alterations in cell cycle regulation, detoxification and chemoresistance in clear cell carcinoma. Chk1 is a critical signal transducer in the cell cycle checkpoint machinery. DNA damage, in turn, increases persistent phosphorylation of Chk1 and induction of G2/M phase cell cycle arrest in cells overexpressing HNF-1β. HNF-1β deletion induces apoptosis, suggesting that enhanced levels of HNF-1β may be associated with chemoresistance. Targeted therapy with Chk1 inhibitors may be explored as a potential treatment modality for patients with clear cell carcinoma. This provides a novel direction for combination therapy, including targeting of Chk1, which may overcome drug resistance and improve treatment efficacy.
Novel biomarker candidates for the diagnosis of ovarian clear cell carcinoma.
Kobayashi H1, Sugimoto H1, Onishi S1, Nakano K1.
Ovarian clear cell carcinoma can arise from endometriosis; however, it is distinct from other types of epithelial ovarian carcinoma in terms of its clinicopathological and molecular features. Cancer antigen 125 lacks the sensitivity and specificity required for accurate clinical diagnosis of clear cell carcinoma. Therefore, the aim of the current review was to identify novel biomarker candidates for the immunohistochemical and serological diagnosis of clear cell carcinoma. A search of the relevant English language literature published between 1966 and 2014 was conducted using the PubMed MEDLINE online database. High-throughput tissue microarray technology and proteomic screening combined with mass spectrometry may provide additional information regarding diagnostic biomarker candidates for ovarian clear cell carcinoma. The present review summarizes the characteristics of potential genomic alterations that activate cancer signaling pathways and, thus, contribute to carcinogenesis. The major signaling pathways activated in clear cell carcinoma are associated with cell cycle regulation (hepatitis A virus cellular receptor 1 and tumor protein D52), growth factor signaling (insulin-like growth factor binding protein 1; KiSS-1 metastasis-suppressor; erb-b2 receptor tyrosine kinase 2; and fibroblast growth factor receptor 2), anti-apoptosis and survival pathways [sialidase 3 (membrane sialidase)], metabolism (γ-glutamyltransferase 1), chemoresistance (napsin A aspartic peptidase, glutathione peroxidase 3; and aldehyde dehydrogenase 1 family, member A1), coagulation [coagulation factor III (thromboplastin, tissue factor); and tissue factor pathway inhibitor 2], signaling (lectin, galactoside-binding and soluble, 3), and adhesion and the extracellular matrix [cadherin 1, type 1, E-cadherin (epithelial); versican; and laminin, α 5]. The present review of the relevant literature may provide a basis for additional clinical investigation of the ovarian clear cell carcinoma serum biomarker candidate proteins identified herein.
Biomed Rep. 2015 Nov;3(6):874-878.
Association between nm23 gene polymorphisms and the risk of endometriosis.
Huang XI1, Zhao W2, Li Y1, Kang S2.
The first tumor metastasis-suppressor gene, nm23, may have an important role in the pathogenesis of endometriosis (EM). The present study aimed to evaluate whether nm23 gene polymorphisms are correlated with the risk of the development of EM in North Chinese women, as a preliminary study. The case-control study was conducted with 379 EM patients and 384 unrelated healthy controls. Genotyping of two polymorphisms within the nm23 gene promoter region (rs16949649 T/C and rs2302254 C/T) were performed using polymerase chain reaction-restriction fragment length polymorphism. The data showed that the rs16949649 and rs2302254 polymorphisms within the nm23 gene were not associated with the risk of developing EM. There were no statistical differences in the distribution of nm23 genotypes between patients with EM and the control group (P=0.490 and P=0.440, respectively). For the rs16949649 T/C, compared with the C/T + T/T genotype, the C/C genotype did not increase the risk of EM [odds ratio (OR)=0.81; 95% confidence interval (CI), 0.57-1.17]. For the rs2302254 C/T, compared with the C/T + C/C genotype, the T/T genotype did not increase the risk of EM (OR=1.46; 95% CI, 0.81-2.64). In conclusion, the findings in the present pilot study suggest that nm23 polymorphisms do not contribute to EM susceptibility. However, more studies in larger populations are required to confirm these results.
Obstet Gynecol Sci. 2015 Nov;58(6):481-6.
Effect of second-line surgery on in vitro fertilization outcome in infertile women with ovarian endometrioma recurrence after primary conservative surgery for moderate to severe endometriosis.
Park H1, Kim CH1, Kim EY1, Moon JW1, Kim SH1, Chae HD1, Kang BM1.
To evaluate the effect of second-line conservative surgery on in vitro fertilization (IVF) outcome in comparison with IVF without second-line surgery in infertile women with ovarian endometrioma recurrence after primary conservative surgery.
In this retrospective cohort study, 121 consecutive IVF/intracytoplasmic sperm injection cycles that were performed after second-line surgery (n=53) or without second-line surgery (control group, n=68) between January 2006 and December 2011 in 121 infertile women with ovarian endometrioma(s) recurrence after primary conservative surgery for moderate to severe endometriosis were included. The two groups were compared in terms of controlled ovarian stimulation and IVF outcomes.
There were no differences in patients' characteristics between the two groups. Total dose and days of gonadotropins administered were significantly higher in the second-line surgery group than in the control group (P<0.001, P=0.008). The numbers of oocytes retrieved, mature oocytes and grade 1 or 2 embryos were significantly lower in the second-line surgery group (P=0.007, P=0.001, P<0.001, respectively). Clinical pregnancy rate per cycle and embryo implantation rate were also significantly lower in the second-line surgery group of 24.5% and 11.8% compared with 48.5% and 25.3% in the control group (P=0.008, P=0.005, respectively).
Ovarian response to controlled ovarian stimulation and IVF outcome after second-line surgery is worse than those in IVF cycles without second-line surgery in infertile women with ovarian endometrioma recurrence after primary surgery for moderate or severe endometriosis.
Gig Sanit. 2015 Sep-Oct;94(5):86-91.
NIGHT SHIFT WORK AND HEALTH DISORDER RISK IN FEMALE WORKERS.
Kukhtina EG, Solionova LG, Fedichkina TP, Zykova IE.
There was evaluated the risk to health in females employed in shift work, including night shifts. According to the data of periodical medical examinations health indices of 403 females employed in shift work, including night shifts, were compared with indices of 205 females–workers of administrative units of the same enterprise. Overall relative risk (RR) for the health disorder associated with the night shift was 1.2 (95%; confidence interval (CI): 1.09-1.28). A statistically significant increase in risk was observed in relation to uterine fibroids (OR 1.3; 95% CI: 1.06-1.54), mastopathy (OR 1.4; 95% CI: 1.2-1.6), inorganic sleep disorders (OR 8.8; 95% CI 2.6-29.8). At the boundary of the statistical significance there was the increase in the risk for obesity (OR 1.2; 95% C: 0.97-1.39), hypertension (OR 1.2; 95% CI, 0.9-1.5) and endometriosis (OR 1.5; 95% CI: 0.98-2.16). There was revealed an adverse effect of night shifts on the gestation course: ectopic pregnancy in the experimental group occurred 6.6 times more frequently than in the control group (95% CI: 0.87-50.2), and spontaneous abortion–1.7 times (95% CI: 0.95-3.22). The performed study has once again confirmed the negative impact of smoking on women's reproductive health: smoking women in the experimental group compared with the control group smokers had 2.7 times increased risk of uterine fibroids (within 1.06-7.0), the risk in non-smokers was significantly lower–1.2 (0.98-1.4). The findings suggest about a wide range of health problems related to employment on shift work, including night shifts, which indicates to the need for adoption of regulatory and preventive measures aimed to this professional group.
Kobe J Med Sci. 2015 May 25;61(2):E40-6.
A Case of Bilateral Decidualized Endometriomas during Pregnancy: Radiologic-pathologic Correlation.
Nakai G1, Kitano R1, Yoshimizu N1, Yamamoto K1, Higashiyama A1, Juri H1, Nakamoto A1, Yamamoto K1, Yamada T2, Hirose Y2, Ohmichi M3, Narumi Y1.
Clinical differentiation between decidualized endometrioma and malignant transformation still poses difficulties as both are intracystic vascularized excrescences of an endometrial cyst and exhibit similar characteristics on color-flow Doppler sonography. This is a characteristic sonographic finding associated with ovarian cancer, but MRI can provide further information about mural excrescences that can aid in their differential diagnosis; for example, the signal of decidualized endometriomas is isointense with the placenta within the uterus on all sequences and the apparent diffusion coefficient is higher than that of malignant mural nodules. Thus, MRI should be an aid in deciding whether to intervene during pregnancy. However, considering that it is not yet possible to clearly differentiate decidualized endometriomas from ovarian cancer, surgery or watchful observation may still be needed to exclude the possibility of malignancy.
J Obstet Gynaecol Can. 2015 Nov;37(11):1006-15.
A Systematic Review of the Association Between Psychiatric Disturbances and Endometriosis.
Pope CJ1, Sharma V2, Sharma S3, Mazmanian D1.
An association between endometriosis and psychiatric disturbances has been identified by some researchers. The purpose of this systematic review was to consolidate existing empirical findings to clarify the association between endometriosis and psychiatric conditions.
We searched three electronic databases (Medline/PubMed, PsychInfo, and ClinicalTrials.gov) using the following search items: "endometriosis" combined with "mood," "bipolar disorder," "major depressive disorder," "anxiety," "psychiatric," "psychosocial," "antidepressants," "antianxiety," "pharmacotherapy," or "psychotherapy."
STUDY SELECTION:
We included all relevant articles published in English. We identified 18 original research studies examining the association between endometriosis and psychiatric symptoms, with a combined total of 999 endometriosis patients being examined.
DATA EXTRACTION AND SYNTHESIS:
Of the 18 studies examined, 14 reported that endometriosis was associated with at least some aspect of reduced psychological functioning or mental health quality of life. Tabulation of raw frequencies of the studies using clinical diagnostic criteria and a comparison group revealed that at least 56.4% of women (44/78) with a diagnosis of endometriosis and 43.6% of women (48/110) without such a diagnosis met the criteria for a psychiatric disorder.
The limited research suggests that women presenting with endometriosis are at risk for psychosocial disturbances or psychiatric distress. Whether such disruptions are a consequence of endometriosis, the associated chronic gynaecological pain, or another factor such as inflammation remains to be delineated. In the interim, women presenting with symptoms of endometriosis should also be screened for psychosocial and psychiatric disturbances.
J Assist Reprod Genet. 2016 Jan;33(1):101-10
Downregulation of adiponectin system in granulosa cells and low levels of HMW adiponectin in PCOS.
Artimani T1,2, Saidijam M3, Aflatoonian R4, Ashrafi M4, Amiri I2, Yavangi M2, SoleimaniAsl S2, Shabab N3, Karimi J5, Mehdizadeh M6,7.
The purpose of the study was to investigate changes in adiponectin system expression in granulosa cells (GCs) and high molecular weight adiponectin levels in serum and follicular fluid (FF) of 40 women with polycystic ovary syndrome (PCOS) compared to those in 40 women with normal ovary function.
Adiponectin (Adipo), adiponectin receptor 1 (AdipoR1), and adiponectin receptor 2 (AdipoR2) messenger RNA (mRNA) expression levels were measured using quantitative real-time polymerase chain reaction (qRT-PCR). High molecular weight (HMW) adiponectin protein concentration was evaluated by ELISA method. Data were analyzed using Student's t test and one-way ANOVA in SPSS 21 software. At oocyte retrieval, FF was aspirated and GCs were obtained from a pooled collection of FF per each patient.
PCR results showed expression of adiponectin, AdipoR1, AdipoR2, follicle-stimulating hormone receptor (FSHR), and luteinizing hormone receptor (LHR) in GCs. After controlling body mass index (BMI) values, qRT-PCR demonstrated a decreased expression of adiponectin system in GCs of PCOS patients compared to those in controls (p = 0.001). There was a strong positive correlation among AdipoR1 and AdipoR2 expression and also among FSH and LH receptor expression. (Both r = 0.8, p = 0.001). There were low levels of high molecular weight adiponectin in the serum of PCOS patients with controlled ovarian hyperstimulation (30.19 ± 4.3 ng/ml) compared to the controls (48.47 ± 5.9 ng/ml) and in the FF of PCOS patients with controlled ovarian hyperstimulation (7.86 ± 1.44 ng/ml) compared to the controls (14.22 ± 2.01 ng/ml; p = 0.02).
Lower expression of adiponectin and its receptors in GCs might be an important manifestation in gonadotropin-stimulated PCOS patients which could influence the physiologic adiponectin roles such as interaction with insulin and LH in induction of GC gene expression.
Dermatol Online J. 2015 Nov 18;21(11).
Painful nodule in the caesarean section scar of a young woman.
Russo VA1, Alikhan A.
Endometriosis is the presence of ectopic endometrial tissue outside the uterus and cutaneous endometriosis is a rare manifestation of this disease that may be found at the sites of surgical scars as a result of iatrogenic implantation. Herein we present a case of scar endometriosis in a 35-year-old woman. The scar was sustained following a remote caesarean section.
Mass Spectrom Rev. 2017 May;36(3):450-470.
A mass spectrometric insight into the origins of benign gynecological disorders.
Yang H1,2, Lau WB3, Lau B4, Xuan Y5, Zhou S1, Zhao L5, Luo Z6, Lin Q6, Ren N6, Zhao X1, Wei Y5.
Applications of mass spectrometry (MS) are rapidly expanding and encompass molecular and cellular biology. MS aids in the analysis of in vivo global molecular alterations, identifying potential biomarkers which may improve diagnosis and treatment of various pathologies. MS has added new dimensionality to medical research. Pioneering gynecologists now study molecular mechanisms underlying female reproductive pathology with MS-based tools. Although benign gynecologic disorders including endometriosis, adenomyosis, leiomyoma, and polycystic ovarian syndrome (PCOS) carry low mortality rates, they cause significant physical, mental, and social detriments. Additionally, some benign disorders are unfortunately associated with malignancies. MS-based technology can detect malignant changes in formerly benign proteomes and metabolomes with distinct advantages of speed, sensitivity, and specificity. We present the use of MS in proteomics and metabolomics, and summarize the current understanding of the molecular pathways concerning female reproductive anatomy. Highlight discoveries of novel protein and metabolite biomarkers via MS-based technology, we underscore the clinical application of these techniques in the diagnosis and management of benign gynecological disorders.
Nutrients. 2015 Dec 2;7(12):9972-84.
High Prevalence of Vitamin D Deficiency in Infertile Women Referring for Assisted Reproduction.
Pagliardini L1, Vigano' P2, Molgora M3, Persico P4, Salonia A5, Vailati SH6, Paffoni A7, Somigliana E8, Papaleo E9, Candiani M10.
A comprehensive analysis of the vitamin D status of infertile women is the first step in understanding hypovitaminosis impact on reproductive potential. We sought to determine vitamin D profiles of women attending an infertility center and to investigate non-dietary determinants of vitamin D status in this population. In this cross-sectional analysis, a cohort of 1072 women (mean age ± standard deviation 36.3 ± 4.4 years) attending an academic infertility center was used to examine serum 25-hydroxy-vitamin D (25(OH)D) levels in relation to demographic characteristics, seasons and general health risk factors. Both unadjusted and adjusted levels of serum 25(OH)D were examined. Median 25(OH)D concentration was below 30 ng/mL for 89% of the entire year. Over the whole year, 6.5% of patients had 25(OH)D levels ≤10 ng/mL, 40.1% ≤20 ng/mL, and 77.4% ≤30 ng/mL. Global solar radiation was weakly correlated with 25(OH)D levels. At multivariable analysis, 25(OH)D levels were inversely associated with BMI; conversely, 25(OH)D levels were positively associated with height and endometriosis history. Serum 25(OH)D levels are highly deficient in women seeking medical help for couple's infertility. Levels are significantly associated with body composition, seasonal modifications and causes of infertility. Importantly, this deficiency status may last during pregnancy with more severe consequences.
Fertil Steril. 2016 Aug;106(2):410-5. Risks of tubo-ovarian abscess in cases of endometrioma and assisted reproductive technologies…
Pag. 15 Obstet Gynecol. 2011 May;117(5):1042-50. Assessing ovarian cancer risk when considering elective oophorectomy at…
Int J Gynaecol Obstet. 2010 Sep;110(3):203-207. Epub 2010 May 23.Prevalence of newly diagnosed endometriosis in women attending the general practitioner.Ferrero S, Arena E, Morando A, Remorgida V.Department of Obstetrics and Gynecology, San Martino Hospital and University of Genoa, Genoa, Italy; Cairosalute, Cairo Montenotte, Italy.OBJECTIVE: To investigate the prevalence of newly ...


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Deloitte Fined for Audit of Malawi Leaf Company
The Institute of Chartered Accountants in Malawi (ICAM) has fined Deloitte Malawi after finding the auditing firm guilty in cases involving its audits of Malawi Leaf Company.
ICAM conducted investigations through the Ethics and Investigations Committee and convened disciplinary hearings through the Disciplinary Committee on cases of its members, according to Malawi24.
In one case, ICAM says Deloitte did not give due diligence to the procedures in auditing Malawi Leaf Company (MLC) , a subsidiary of Auction Holdings Limited. Deloitte assured that AHL Group had complied with the applicable International Financial Reporting Standards.
The company was found guilty for this and the ICAM council has imposed on Deloitte a maximum penalty of a severe reprimand and a fine of 1.5 million Kwacha.
Between 2014 and 2016, ICAM says Deloitte did not give due diligence to the procedures in auditing and assured financial statements for the years in question that had errors and misstatements because they included fictitious sales made to Eastern Tobacco Company for $1.2 million.
The company was found guilty for this and the council has imposed on Deloitte a maximum penalty of severe reprimand and a fine of 1.5 million Kwacha.
However, Deloitte was found not guilty on a third charge related to overvaluing stocks in financial statements for 2014, 2015 and 2016.
Tags: Africa Malawi Malawi Leaf Company

redpajama_set_name: RedPajamaCommonCrawl


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Paul Tuennerman
Tales of the Cocktail
Chief Business Office & Co-Owner
talesofthecocktail.com
Paul Tuennerman is Chief Business Officer and Co-Owner of Tales of the Cocktail, the world's must-attend cocktail festival held annually in New Orleans. Since its inception, it has attracted more than 100,000 drinks experts and libations enthusiasts from as far away as China, Kenya and New Zealand and has injected an estimated $100 million into the local economy. Working closely with his wife, Ann Tuennerman, its Founder, Tales of the Cocktail has emerged as a global cultural phenomenon that has helped nurture the Cocktail Renaissance surging across the U.S. and worldwide that has elevated the tippling habits of millions.
Paul, a 39-year veteran of the hospitality industry, is responsible for Tales of the Cocktail's business administration and management. In addition to overseeing all financial and legal aspects of the organization, he works closely with Ann on the development and implementation of growth strategies for the festival and its expanding businesses in the U.S. and abroad.
While now full-time with Tales of the Cocktail, since 2006, Paul has played an instrumental role in the festival. It began by not hesitating to lend Ann $15,000 when its sole sponsor backed out in the wake of Hurricane Katrina. He also helped her fundamentally reimagine and relaunch Tales of the Cocktail on its trajectory of success ever since. Paul was pivotal in establishing the New Orleans Culinary & Cultural Preservation Society (NOCCPS), a non-profit 501(c)(3) dedicated to supporting the hospitality industry, for which Tales of the Cocktail became its funding mechanism.
Previously, Paul was Senior Vice President, Business Development, Raising Cane's, a $740 million chain of fast casual restaurants that is the fourth fastest-growing in the nation. Paul conceptualized and implemented business development strategies, expanding the Brand into Non-Traditional Venues, such as colleges, universities, retail centers, and airports and spearheaded the chain's successful entry into, and launch throughout the Middle East. He was also responsible for the overseeing the franchise business, which he grew by 130 percent over thirty-six months.
Prior to Raising Cane's, Paul was Vice President at Piccadilly Restaurants, a $260 million chain of family dining restaurants. In this position, he was tasked with launching their Food Service Division, targeting colleges, universities, secondary schools, healthcare, business and industry and generated $10 million in sales in its first 36 months.
Paul's first job in hospitality was frying fish at Arthur Treacher's Fish & Chips in Blacksburg, Virginia, at the age of 15. By the time he left, he ran the night shift and came to relish the rush of working in a restaurant, the camaraderie it engendered and the life-long friendships and bonds of trust that were forged.
A U.S. Navy veteran, Paul was assigned to three Carrier Group deployments to the Indian Ocean. In addition to numerous accolades and scholarships, Paul earned a Presidential Citation and the Navy Achievement Medal. Since 2013, Paul has been a mentor at the Jonas Project, which helps veterans transition from military to civilian life and supports "Warrior Entrepreneurs" establish themselves in business.
Continuing his passion for the seas, Paul enjoys sailing in the Caribbean, especially the British Virgin Islands, as well as photography and discovering new things. While he loves a great bottle of Champagne, Paul is known to hoist a Negroni or a Daiquiri. A native of Garfield Heights, Ohio, Paul lives with Ann in New Orleans, along with the unofficial Tales of the Cocktail mascot, Delta Dawg.
Tales of the Cocktail AUA (Ask Us Anything) Queen Anne Ballroom at the Hotel Monteleonems. franky marshall • Philip Duff • Simon Ford • Don Lee • Ann Tuennerman • Paul Tuennerman
Toast to Tales: Tales is headed in new directions. Find out where. Front Steps of the Hotel MonteleoneAnn Tuennerman • Paul Tuennerman


My visit to Ingolstadt was a voyage I had been dreaming of for years. I am a huge fan of Audi and the brand has been popular in urban culture since the Audi 5000 debuted in the United States in the early eighties. I have been fascinated by the heritage of the brand and the origins of the Auto Union for as far as I can remember. The four rings in the Audi logo represent four companies: Audi, Horch, DKW, and Wanderer, that each had their own heritage and united to form the Auto Union in 1932.
For my pilgrimage, I took a combined approach of fast intercity express trains (ICE) and regional trains on the DB (Deutsche Bahn). I voyaged through Baden and Zurich in Switzerland and Basel in Germany. The countryside was breathtaking and travel on the DB was easy and efficient. I made a stop at Kinding and stayed at a small hotel to get a pulse of the area. I dined with friendly locals and found out that there were universities nearby, including ones in the nearby cities of Ingolstadt, Regensburg, and München also known as Munich (home of BMW). It took about 18 to 20 minutes on the ICE to get from Kinding to Ingolstadt and I was as giddy as one could be to arrive at the station and then take a bus to the Audi Forum Ingolstadt, which serves as a global headquarters, a museum and a main factory for the brand.
Almost 44,000 employees work at the Ingolstadt site. Around 8,000 work in the assembly shop where about 2,400 vehicles are made daily with the aid of robots through human-robot collaboration (HRC). The site is where several models are manufactured including the Audi Q2, Audi A3, Audi A4, Audi A3 Sportback e-tron, and the Audi A3 Sportback g-tron. Around 1,800 employees at this facility are apprentices or are in a dual study program.
Audi also held its second Smart Factory Hackathon out of the Ingolstadt factory last October (2017), which is something we can appreciate, having run several hackathons out of our base at Carnegie Mellon University over the past few years. Participants hailed from all over the world to competitively create solutions to real-life challenges in production and logistics in a 25-hour timeframe. It is another opportunity for Audi to connect with potential future employees.
ually, taking delivery in Ingolstadt or any of Audi factories worldwide would be my preferred choice and I was informed that the most recent factory in Mexico is actually the newest and is also home of the Q5.
What I saw in the factory was a technological marvel that reminded me of the Transformers movie and the fictional home planet of Cybertron. Robots moved and operated with breathtaking precision and accuracy and in some instances, without the aid of humans. Doors were fastened, metal was stamped, and windshields were affixed with up to 5 different model variations on the same assembly line. Each vehicle had its own black box with details of the owner's order, allowing the robots to relay the data into their assembly. In the earlier stages of manufacturing, humans were less involved, other than to provide the materials for the robots to utilize in the stamping, painting, assembly and other processes of manufacturing. Human worked closely with the robots, but the functionality and efficiency displayed by the robots was amazing. In the later stages, I saw teams refasten doors, work on fit and finish, fasten wheels, work on electronics, and other functions to ensure the build quality of the vehicles. There are several options customers can choose from, including 30 standard paint colors or the option to customize their own colors. Around 2500 employees work in the paint shop alone at the Ingolstadt plant. This all serves to enhance the products Audi can make at the factory. Regarding the final product, Audi now has a new 3D configurator for customers, where they can virtually enter their vehicles and get a more representative visual experience of what they are purchasing.
forward to visiting other Audi factories to see how other products in the lineup get made, including brands like Lamborghini and Ducati. For more information, visit Audi Forum here.


A steady stream of new rooftop bars, patios and beer gardens have opened this summer, though the beastly weather probably has kept people from making a first visit. With the humidity finally beginning to subside, it's time to get out and enjoy happy hour outside. Here are 10 new outdoor bars to check out this week.
There are three levels at this Florida Avenue bar, opened by the team behind Shaw's Tavern and the Front Page, but you should go straight to the rooftop deck to enjoy a beach-worthy Orange Crush or a Moscow Mule big enough for a group to share.
After a lengthy fight with neighbors over permitting, this cozy Shaw bar finally opened its sidewalk patio in June. It's the perfect place to sip a #19 cocktail: Tanqueray gin, Capitoline rosé vermouth, orange juice and bitters.
D.C.'s only cidery has a lovely yard filled with picnic tables and newly planted apple trees, which will someday provide juice for the bar's cider.
At the southern end of Barracks Row, the Brig offers a large family-friendly and dog-friendly beer garden. Grab a giant mug of German lager or a local craft beer and settle in at an umbrella-shaded table.
The Hyatt Place hotel's rooftop bar has become an attraction near L'Enfant Plaza, thanks to its sweeping views, good cocktails and happy hour tap takeovers with RAR, DC Brau and other local breweries.
Hazel's gem of a patio features wicker lounge furniture, flowering pots hanging on the walls and bright green artificial turf underfoot.
While Mason and Rook's ground-floor Radiator bar is worth a visit, you'll want to linger at the rooftop's poolside bar and enjoy the views with a tiki drink or glass of rosé in hand.
This beer garden, located a block west of Union Market, comes from the team behind the market's outdoor bar, Suburbia. Beers and cocktails are on tap, and bocce and darts are available.
The back patio behind Clarendon staple Spider Kelly's has room for 300 people at tables, benches and around fire pits. Happy hour, which lasts until 8 p.m. on weekdays, includes $4 beers, sangria and wines by the glass.
After weeks of delays, Wunder Garten finally opened in its new location in NoMa on Friday, Aug. 19. The large beer garden features picnic tables and long German-style benches on carpets of artificial turf, a fire pit with a make-your-own-S'mores station and a bar pouring German and American beers. Dogs are welcome on Tuesday for Doggy Happy Hour, which runs from 4 until 7 p.m.


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Episode 1 Episode 2 Episode 3 Episode 4 Episode 5 Episode 6 Episode 7 Episode 8 Episode 9
Watch Money Heist Online
Watch Money Heist Full Series Online. La Casa de Papel with English Subtitle FREE. To carry out the biggest heist in history, a mysterious man called The Professor recruits a band of eight robbers who have a single characteristic: none of them has anything to lose. Five months of seclusion – memorizing every step, every detail, every probability – culminate in eleven days locked up in the National Coinage and Stamp Factory of Spain, surrounded by police forces and with dozens of hostages in their power, to find out whether their suicide wager will lead to everything or nothing.
Director: Álex Pina
Actors: Alba Flores, Álvaro Morte, Antonio Cuellar Rodriguez, Daniel Oliveira, Darko Peric, Enrique Arce, Esther Acebo, Hovik Keuchkerian, Itziar Ituño, Jaime Lorente, Miguel Herrán, Najwa Nimri, Pedro Alonso, Rodrigo de la Serna, Úrsula Corberó
Studio: Vancouver Media
Duration: 70,47 min
Networks: Antena 3, Netflix
Tags:EN Subbed Foreign Language Popular Returning Series 2017
Watch Digimon Adventure Full Series Online. The new anime will take place in 2020 and will feature an all-new story centering on Taichi Yagami when he is in his fifth…
Genre: Action & Adventure, Animation, Comedy, Sci-Fi & Fantasy
Fraggle Rock: Rock On!
Watch Fraggle Rock: Rock On Full Series Online. The Fraggles might be apart in separate caves, but they can still find ways to have fun together! Join Gobo, Red, Boober,…
Genre: Kids
Watch The Romanoffs Full Series Online. An anthology series centered around people who believe themselves to be the modern-day descendants of the Romanov family.
Watch The Detour Full Series Online. A what-in-the-living-hell-is-wrong-with-this-family comedy created by comic super-couple Jason Jones & Samantha Bee and inspired by their own experiences with family trips. Unfiltered dad Nate…
The Twelve
Watch The Twelve Full Series Online. Twelve ordinary people are called for jury duty for a murder case as traumatizing as it is controversial: the respected headmistress Fri Palmers stands…
59,45,42,55 min
Watch The Killing Full Series Online. The Killing is an American crime drama television series based upon the Danish television series Forbrydelsen. Set in Seattle, Washington, the series follows the…
Watch Chicago Med Full Series Online. An emotional thrill ride through the day-to-day chaos of the city's most explosive hospital and the courageous team of doctors who hold it together….
Watch White Famous Full Series Online. Floyd Mooney is a young African-American comedian whose star is on the rise. But the path to stardom is a minefield that Floyd must…
Watch Wolfblood Full Series Online. Being a teenager is hard enough. Being a Wolfblood teenager is ten times more complicated. 14 year old Maddy loves her abilities – heightened senses,…
Watch Forbidden History Full Series Online. Jamie Theakston uncovers the startling truth behind great myths, historical legends, conspiracy theories, ancient treasures, lost civilisations and war time secrets.
Watch Dietland Full Series Online. Plum Kettle, ghost-writer for the editor of one of New York's hottest fashion magazines, struggles with self-image and sets out on a wildly complicated road…
The L.A. Complex
Watch The LA Complex Full Series Online. Six young performers having been dubbed "most likely to succeed" in their hometowns now face the challenges and opportunities of a lifetime in the…
Genre: Drama, Soap
Trailer: Money Heist


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Phoenix Tour Armenia / Blog (Page 11)
Armenian Tonir BBQ: The Sun In The Ground
Everyone knows, that the Sun was an ancient symbol of Armenians. But not many people know that the Armenians also have the Sun symbol in the ground. That is the Armenian Tonir - from time immemorial the tonir was worshiped by Armenians like other...
Charles Aznavour (1924-2018)
Arguably, the most famous Armenian of his time, Charles Aznavour was a French-Armenian singer, lyricist, actor and diplomat. In a career as a composer, singer and songwriter, spanning over 70 years, he recorded more than 1,200 songs interpreted in 9 languages. Moreover, he wrote or...
Armenian Duduk
The Armenian duduk is a double reed woodwind instrument made of apricot wood, and it is indigenous to Armenia. Born in the early eons of Armenian history, the duduk is considered the most "Armenian" of all folk instruments, because of its origins and its ability...
Lake Sevan Crayfish Kebab: An Armenian Delicacy
Broaden your gastronomic horizons, and go beyond the traditional meat or chicken kebab. Try kebab made of crayfish! A visit to Armenia is not complete without you trying a Crayfish Kebab. The blue crayfish found in Lake Sevan and surrounding rivers is absolutely delicious. So,...
Quba Mere Diwane - World's Largest Yazidi Temple In Armenia
Quba Mere Diwane is the biggest Yazidi Temple in the world, which serves a robust Yazidi community in the heart of the South Caucasus. The temple is dedicated to the Angel Melek Taus and the Seven Angels of Yazidi theology. The highest dome and the...
Matnakash - The Ultimate Armenian Bread
The golden brown crust from the outside and the softness on the inside will make you devour this delicious bread, especially when it's fresh out of the oven. Have the bread with cheese, tomatoes, cucumbers, fresh greens & herbs, along with your general meal, or...
Bezoar Goats: A "Red Book" Animal
Would you be interested to see the graceful endangered Bezoar goats grazing and jumping over the red cliffs in the Vayotz Dzor Province of Armenia? Then pack your bags, come down to our amazing country and join any of our tours featuring Bezoar goats sights!...
Armenian Dried Fruits
Armenia has a centuries old tradition of producing high-quality dried fruits and berries. Armenian dried fruits are especially delicious, because they are made from local fruits, which are noted for their sweetness and richness of the taste. They are cholesterol free, low in sodium and...
Molokans - Adding Ethnic Color To A Homogeneous Armenia
Molokans are a Russian Christian sect, which split from Russia's Orthodox Church in the 16th century, and were persecuted under the Russian tsars. By the early 19h century, the Molokans sought refuge in Armenia and in other South Caucasus countries. Currently they number about 3,000...
Vank Cathedral: A Gorgeous Fusion Of Islamic & Armenian Architecture
The Armenian Holy Savior Cathedral (Surb Amenaprkich Vank), also known the Church of the Saintly Sisters, is a cathedral located in the New Julfa district of Isfahan, Iran (UNESCO World Heritage Site). The delicately blue and gold painted central dome depicts the Biblical story of...
Armenian Heritage
Notable Armenians
What to buy in Armenia?


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Il Palaeopropithecus ingens era un grosso lemure estinto vissuto in Madagascar.

Descrizione
Le zampe anteriori di ques'animale erano più lunghe di quelle posteriori, al contrario di altri indridi estinti, nei quali avveniva il contrario; sulle mani, i pollici erano scarsamente sviluppati, mentre le altre dita avevano falangi allungate ed erano incurvate ad uncino, per potersi appendere agli alberi a testa in giù come i bradipi.

Il cranio era piuttosto robusto, con un muso piuttosto allungato, con una grossa mandibola sulla quale gli incisivi inferiori erano piccoli ed a forma di spatola, inoltre erano verticali rispetto alla mandibola, mentre i molari erano larghi e muniti di creste; queste caratteristiche dentarie lasciano supporre che il Palaeopropithecus ingens fosse un mangiatore di foglie.

Estinzione

La data della sua estinzione non è certa, tuttavia si ipotizza che questi animali siano scomparsi completamente dopo il 1500, poco prima dell'arrivo degli europei in Madagascar, probabilmente a causa della caccia e della distruzione del loro habitat da parte dei primi colonizzatori malgasci.

Note

Bibliografia
 Fleagle, J.G. 1988. Primate Adaptation and Evolution. Academic Press: New York.
 Martin, R.D. 1990. Primate Origins and Evolution: A Phylogenetic Reconstruction. Princeton University Press: Princeton, New Jersey.

Voci correlate
 Gigantismo insulare

Altri progetti

Indridi
Mammiferi estinti

en:Palaeopropithecus ingens

redpajama_set_name: RedPajamaWikipedia


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5034d1601684adbf218c3238176f5916
2023 New Focus on the Website
We would like to thank all of our customers for their business over the 25+ years that Phil's Coins has been in business. At the beginning of 2023 our company will be changing ownership and will now be run by the first employee of Phil's Coins. With this change you will see several changes in our company which we hope will improve our online experience. We will have a new focus on our website and you will see a much larger inventory of the coins that we have in stock. We are already preparing for this change and you will see some changes in the coming months. But be reassured that you will receive the same great service and products that you have always received from Phil's Coins. We hope you enjoy the changes coming in the future and we will be here to serve you for years to come.