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© 2019 Elsevier B.V. In 2 O 3 is one of the most important semiconducting metal oxides primarily because of its wide band gap, high electron mobility and processing versatility. To this end, high-quality thin films of In 2 O 3 can be prepared using scalable and inexpensive solution-based deposition methods, hence making it attractive for application in a number of emerging electronic applications. However, traditional solution processing often requires high temperature and lengthy annealing steps, making it impossible to use in combination with temperature-sensitive plastic substrates, which would be desired for numerous emerging flexible device applications. Here, rapid photonic curing of In 2 O 3 layers is explored as an alternative to thermal annealing. Oxide thin films are successfully prepared on a range of substrates, including glass, polyimide, and polyethylene naphthalate. The effect of substrate and post-processing treatment on the morphology, surface chemistry, and electronic properties is investigated by atomic force microscopy and X-ray photoelectron spectroscopy. Systematic trends are identified, particularly in the degree of conversion of the precursor and its influence on the electronic structure.
A number of recent studies have shown that the nonradiative voltage losses in organic solar cells can be suppressed in systems with low energetic offsets between donor and acceptor molecular states, but the physical reasons underpinning this remain unclear. Here, we present a systematic study of 18 different donor/acceptor blends to determine the effect that energetic offset has on both radiative and nonradiative recombination of the charge-transfer (CT) state. We find that, for certain blends, low offsets result in hybridization between charge-transfer and lowest donor or acceptor exciton states, which leads to a strong suppression in the nonradiative voltage loss to values as low as 0.23 V associated with an increase in the luminescence of the CT state. Further, we extend a two-state CT-state recombination model to include the interaction between CT and first excited states, which allows us to explain the low nonradiative voltage losses as an increase in the effective CT to ground state oscillator strength due to the intensity borrowing mechanism. We show that low nonradiative voltage losses can be achieved in material combinations with a strong electronic coupling between CT and first excited states and where the lower band gap material has a high oscillator strength for transitions from the excited state to the ground state. Finally, from our model we propose that achieving very low nonradiative voltage losses may come at a cost of higher overall recombination rates, which may help to explain the generally lower FF and EQE of highly hybridized systems.
© 2018 Elsevier Ltd Reduced graphene oxide (rGO) has inherited the outstanding electronic, optical, thermal and mechanical properties of graphene to a large extent, while maintaining sufficient chemically active sites. Therefore, it has attracted a great deal of research attention in the fields of energy storage, electronics, photonics, catalysis, environmental engineering, etc. Currently, the most popular way to prepare rGO is to reduce graphene oxide, which is obtained by modified Hummer methods using tedious treatments in a harsh environment, to rGO flakes. Industrial applications demand advanced preparation methods that can mass produce highly uniform rGO sheets on arbitrary substrates. In this work, a one-step growth process is introduced that utilizes cellulose acetate as a precursor, without any catalysts, to produce uniform ultrathin rGO films on various substrates and free-standing rGO powders. Systematic spectroscopic and microscopic studies on the resulting rGO are performed. Prototypes of electronic and optoelectronic devices, such as field effect transistors (FETs), photodetectors, and humidity sensors, are fabricated and tested, demonstrating the intriguing applications of our rGO materials across a wide range of fields.
© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Producing high efficiency solar cells without high-temperature processing or use of additives still remains a challenge with the two-step process. Here, the solution processing of MAPbI 3 from PbI 2 films in N,N-dimethylformamide (DMF) is investigated. In-situ grazing incidence wide-angle X-ray scattering (GIWAXS) measurements reveal a sol–gel process involving three PbI 2 -DMF solvate complexes—disordered (P 0 ) and ordered (P 1 , P 2 )—prior to PbI 2 formation. When the appropriate solvated state of PbI 2 is exposed to MAI (methylammonium Iodide), it can lead to rapid and complete room temperature conversion into MAPbI 3 with higher quality films and improved solar cell performance. Complementary in-situ optical reflectance, absorbance, and quartz crystal microbalance with dissipation (QCM-D) measurements show that dry PbI 2 can take up only one third of the MAI taken up by the solvated-crystalline P 2 phase of PbI 2 , requiring additional annealing and yet still underperforming. The perovskite solar cells fabricated from the ordered P 2 precursor show higher power conversion efficiency (PCE) and reproducibility than devices fabricated from other cases. The average PCE of the solar cells is greatly improved from 13.2(±0.53)% (from annealed PbI 2 ) to 15.7(±0.35)% (from P 2 ) reaching up to 16.2%. This work demonstrates the importance of controlling the solvation of PbI 2 as an effective strategy for the growth of high-quality perovskite films and their application in high efficiency and reproducible solar cells.
© 2019 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim The reported power conversion efficiencies (PCEs) of nonfullerene acceptor (NFA) based organic photovoltaics (OPVs) now exceed 14% and 17% for single-junction and two-terminal tandem cells, respectively. However, increasing the PCE further requires an improved understanding of the factors limiting the device efficiency. Here, the efficiency limits of single-junction and two-terminal tandem NFA-based OPV cells are examined with the aid of a numerical device simulator that takes into account the optical properties of the active material(s), charge recombination effects, and the hole and electron mobilities in the active layer of the device. The simulations reveal that single-junction NFA OPVs can potentially reach PCE values in excess of 18% with mobility values readily achievable in existing material systems. Furthermore, it is found that balanced electron and hole mobilities of >10 −3 cm 2 V −1 s −1 in combination with low nongeminate recombination rate constants of 10 −12 cm 3 s −1 could lead to PCE values in excess of 20% and 25% for single-junction and two-terminal tandem OPV cells, respectively. This analysis provides the first tangible description of the practical performance targets and useful design rules for single-junction and tandem OPVs based on NFA materials, emphasizing the need for developing new material systems that combine these desired characteristics.
© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim The impact of the gate dielectric on contact resistance in organic thin-film transistors (OTFTs) is investigated using electrical characterization, bias-stress stability measurements, and bandgap density of states (DOS) analysis. Two similar dielectric materials, namely Cytop and poly[4,5-difluoro-2,2-bis(trifluoromethyl)-1,3-dioxole-co-tetrafluoroethylene] (Teflon AF2400), are tested in top-gate bottom-contact OTFTs. The contact resistance of Cytop-based OTFTs is found to be greater than that of the AF2400-based devices, even though the metal/OSC interface remains identical in both systems. The Cytop devices are also found to perform worse in bias-stress stability tests which, along with the DOS calculations, suggests that charge trapping at the OSC/dielectric interface is more prevalent with Cytop than AF2400. This increased charge trapping at the Cytop OSC/dielectric interface appears to be associated with the higher contact resistance in Cytop OTFTs. Differences in the molecular structure between Cytop and AF2400 and the large difference in the glass transition temperature of the two polymers may be responsible for the observed difference in the transistor performance. Overall, this study highlights the importance of the gate dielectric material in the quest for better performing OTFTs and integrated circuits.
© 2018 IEEE. In this paper, Low Earth Orbit radiation and temperature conditions are mimicked to investigate the suitability of flexible Indium-Gallium-Zinc-Oxide transistors for lightweight space-wearables. Such wearable devices could be incorporated into spacesuits as unobtrusive sensors such as radiation detectors or physiological monitors. Due to the harsh environment to which these space-wearables would be exposed, they have to be able to withstand high radiation doses and low temperatures. For this reason, the impacts of high energetic electron irradiation with fluences up to 10 12 e - /cm 2 and low operating temperatures down to 78 K, are investigated. This simulates 278 h in a Low Earth Orbit. The threshold voltage and mobility of transistors that were exposed to e-irradiation are found to shift by +0.09 0.05 V and-0.6 0.5 cm 2 V -1 s -1 . Subsequent low temperature exposure resulted in additional shifts of +0.38V and-5.95 cm 2 V -1 s -1 for the same parameters. These values are larger than the ones obtained from non-irradiated reference samples. If this is considered during the systems' design, these devices can be used to unobtrusively integrate sensor systems into space-suits.
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The Hypertriglyceridemia GUIDELINES Pocket Guide is endorsed by The Endocrine Society and based on their latest guidelines. This practical quick-reference tool contains screening, detailed diagnostics with an evaluation algorithm for non-diabetics, treatment recommendations for persons with and without diabetes, drug therapy and dosing information.
Severe and very severe hypertriglyceridemia increase the risk for pancreatitis, whereas mild or moderate hypertriglyceridemia may be a risk factor for cardiovascular disease. Therefore, similar to the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP) III guideline committee's recommendations, the Endocrine Society recommends screening adults for hypertriglyceridemia as part of a lipid panel at least every 5 yr (1|⊕⊕oo).
Base the diagnosis of hypertriglyceridemia on fasting triglyceride levels and not on nonfasting triglyceride levels (1|⊕⊕⊕o).
AVOID the routine measurement of lipoprotein particle heterogeneity in patients with hypertriglyceridemia (1|⊕⊕oo). Measurement of apolipoprotein B (apoB) or lipoprotein(a) [Lp(a)] levels can be of value, whereas measurement of other apolipoprotein levels has little clinical value (2|⊕⊕oo).
Evaluate individuals found to have any elevation of fasting triglycerides for secondary causes of hyperlipidemia including endocrine conditions and medications. Focus treatment on such secondary causes (1|⊕⊕oo).
Assess patients with primary hypertriglyceridemia for other cardiovascular risk factors such as central obesity, hypertension, abnormalities of glucose metabolism, and liver dysfunction (1|⊕⊕oo).
Evaluate patients with primary hypertriglyceridemia for family history of dyslipidemia and cardiovascular disease to assess genetic causes and future cardiovascular risk (1|⊕⊕oo).
a The criteria developed for the present guidelines focus on the ability to assess risk for premature CVD vs. risk for pancreatitis. The designations of mild and moderate hypertriglyceridemia correspond to the range of levels predominant in risk assessment for premature CVD, and this range includes the vast majority of subjects with hypertriglyceridemia. Severe hypertriglyceridemia carries a susceptibility for intermittent increases in levels above 2000 mg/dL and subsequent risk of pancreatitis; very severe hypertriglyceridemia is indicative of risk for pancreatitis. In addition, these levels suggest different etiologies. Presence of mild or moderate hypertriglyceridemia is commonly due to a dominant underlying cause in each patient, whereas severe or very severe hypertriglyceridemia is more likely due to several contributing factors.
The initial treatment of mild-to-moderate hypertriglyceridemia should be lifestyle therapy, including dietary counseling to achieve appropriate diet composition, physical activity, and a program to achieve weight reduction in overweight and obese individuals (1|⊕⊕oo).
For severe and very severe hypertriglyceridemia (>1000 mg/dL), combine reduction of dietary fat and simple carbohydrate intake with drug treatment to reduce the risk of pancreatitis (1|⊕⊕⊕⊕).
The treatment goal for patients with moderate hypertriglyceridemia is a non-high-density lipoprotein (HDL) cholesterol level in agreement with NCEP ATP guidelines (1|⊕⊕oo).
Use a fibrate as a first-line agent for reduction of triglycerides in patients at risk for triglyceride-induced pancreatitis (1|⊕⊕⊕o).
Consider three drug classes (fibrates, niacin, n-3 fatty acids) alone or in combination with statins as treatment options in patients with moderate to severe triglyceride levels (2|⊕⊕oo).
DO NOT use statins as monotherapy for severe or very severe hypertriglyceridemia. However, statins may be useful for the treatment of moderate hypertriglyceridemia when indicated to modify cardiovascular risk (1|⊕⊕oo).
Fibric acid derivatives should be used with great caution in the setting of renal insufficiency because the drugs are excreted in the urine and may reversibly increase serum creatinine levels— especially fenofibrate, although the significance of this effect is unknown. Fenofibrate, which does not interfere with statin metabolism and has a lower risk of causing myopathy, is the preferred fibrate to use in combination with a statin. Due to effects on protein binding, there is a potential interaction with warfarin requiring careful monitoring.
Gemfibrozil can be considered in very severe hypertriglyceridemia beginning in the second trimester in pregnant women who are at risk of pancreatitis.
Clinical trials using niacin, alone or in combination with other lipid medications, have shown benefits in decreasing cardiovascular event rates and atherosclerosis.
The most common side effect is cutaneous flushing, which is most significant with the first few doses. The most serious complication of niacin therapy is dose dependent hepatotoxicity, and therapy should be accompanied by monitoring of liver function tests. Other side effects of niacin therapy include impairment or worsening of glucose tolerance and hyperuricemia.
Niacin is contraindicated in patients with active peptic ulcer disease.
The long-chain marine omega-3 fatty acids [eicosapentaenoic acid, C20:5n-3 (EPA) and docosahexaenoic acid, C22:6n-3 (DHA)] lower fasting and postprandial triglyceride levels in a dose-dependent fashion.
Side effects with large doses of omega-3 fatty acids include fishy taste and burping.
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Osteoporosis in CKD
Biomarker FGF23
Management of vitamin D status
Suggested algorithm for fracture risk screening and initiation of anti-fracture strategies in patients with CKD
Suggested algorithm for management of fractures
Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD-MBD). Kidney Int Suppl 2009; 76 (Suppl 113): S1–130.
Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD-MBD). Kidney Int Suppl 2009; 76 (Suppl 113): S1–130.)| false
Ketteler M, et al. KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of CKD-MBD. Kidney Int Suppl 2017; 7[Suppl 1]:1–59.
Ketteler M, KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of CKD-MBD. Kidney Int Suppl 2017; 7[Suppl 1]:1–59.10.1016/j.kisu.2017.04.001)| false
Khairallah P, Nickolas TL. Management of osteoporosis in CKD. Clin J Am Soc Nephrol 2018; 13:962–969.
Khairallah P, Nickolas TL. Management of osteoporosis in CKD. Clin J Am Soc Nephrol 2018; 13:962–969.10.2215/CJN.11031017)| false
Pimentel A, et al. Fractures in patients with CKD—diagnosis, treatment, and prevention: A review by members of the European Calcified Tissue Society and the European Renal Association—European Dialysis and Transplant Association. Kidney Int 2017; 92:1343–1355.
Pimentel A, Fractures in patients with CKD—diagnosis, treatment, and prevention: A review by members of the European Calcified Tissue Society and the European Renal Association—European Dialysis and Transplant Association. Kidney Int 2017; 92:1343–1355.10.1016/j.kint.2017.07.021)| false
Isakova T, et al. Longitudinal FGF23 trajectories and mortality in patients with CKD. J Am Soc Nephrol 2018; 29:579–590.
Isakova T, Longitudinal FGF23 trajectories and mortality in patients with CKD. J Am Soc Nephrol 2018; 29:579–590.10.1681/ASN.2017070772)| false
Ross AC, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: What clinicians need to know. J Clin Endocrinol Metab 2011; 96:53–58.
Ross AC, The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: What clinicians need to know. J Clin Endocrinol Metab 2011; 96:53–58.10.1210/jc.2010-2704)| false
Levin A, et al. Randomized controlled trial for the effect of vitamin D supplementation on vascular stiffness in CKD. Clin J Am Soc Nephrol 2017; 12:1447–1460.
Levin A, Randomized controlled trial for the effect of vitamin D supplementation on vascular stiffness in CKD. Clin J Am Soc Nephrol 2017; 12:1447–1460.10.2215/CJN.10791016)| false
Kumar V, et al. A randomized trial of vitamin D supplementation on vascular function in CKD. J Am Soc Nephrol 2017; 28:3100–3108.
Kumar V, A randomized trial of vitamin D supplementation on vascular function in CKD. J Am Soc Nephrol 2017; 28:3100–3108.10.1681/ASN.2017010003)| false
Courbebaisse M, et al. Non-skeletal and skeletal effects of high doses versus minimum recommended intake of vitamin D3 in renal transplant recipients in a prospective, multicenter, double-blind, randomized study. Late Breaking Clinical Trial Abstract, ERA-EDTA Congress 2019, Budapest.
Courbebaisse M, Non-skeletal and skeletal effects of high doses versus minimum recommended intake of vitamin D3 in renal transplant recipients in a prospective, multicenter, double-blind, randomized study. Late Breaking Clinical Trial Abstract, ERA-EDTA Congress 2019, Budapest.)| false
Sprague SM, et al. Use of extended-release calcifediol to treat secondary hyperparathyroidism in stages 3 and 4 chronic kidney disease. Am J Nephrol 2016; 44:316–325.
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Strugnell SA, et al. Rationale for raising current clinical practice guideline target for serum 25-hydroxyvitamin D in chronic kidney disease. Am J Nephrol 2019; 49:284–293.
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Scragg R, Monthly high-dose vitamin D supplementation and cancer risk: A post hoc analysis of the vitamin D assessment randomized clinical trial. JAMA Oncol 2018; 4:e182178.10.1001/jamaoncol.2018.2178)| false
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de Boer IH, Zelnick LR, Ruzinski J, et al. Effect of vitamin D and omega-3 fatty acid supplementation on kidney function in patients with type 2 diabetes: A randomized clinical Trial. JAMA. 2019; doi: 10.1001/jama.2019.17380.
de Boer IH, Zelnick LR, Ruzinski J, Effect of vitamin D and omega-3 fatty acid supplementation on kidney function in patients with type 2 diabetes: A randomized clinical Trial. JAMA. 2019; doi: 10.1001/jama.2019.17380.10.1001/jama.2019.17380)| false
Chronic Kidney Disease–Mineral and Bone Disorder: Personal Perspective after the 2017 KDIGO CKD-MBD Guideline Update
Markus Ketteler1
1 Markus Ketteler, MD, FERA, is the head of the Department of General Internal Medicine and Nephrology, Robert Bosch Hospital, Stuttgart, Germany.
The Kidney Disease: Improving Global Outcomes (KDIGO) 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD) represented a selective update of the prior CKD-MBD guideline published in 2009 (1, 2). The guideline update, along with the original 2009 publication, is intended to assist physicians, especially nephrologists, who care for CKD patients, including those using long-term dialysis therapy and individuals with a kidney transplant.
The 2017 guideline update focused on recommendations for the diagnosis of bone abnormalities in CKD-MBD; treatment of CKD-MBD by lowering serum phosphate and maintaining serum calcium; treatment of parathyroid hormone abnormalities in CKD-MBD; treatment of bone abnormalities by the use of antiresorptive agents and other osteoporosis therapies; and the evaluation and treatment of kidney transplant bone disease.
Although a reasonable number of high-quality studies were published between 2009 and 2017, significant gaps in the knowledge base about the optimized treatment approaches for patients with features of CKD-MBD still exist. Nevertheless, I would like to briefly feature three developments that were stimulated by the recent KDIGO CKD-MBD update publication that may improve the treatment of patients in the future, at least from my subjective point of view:
■ Diagnosis and management of osteoporosis in CKD patients
■ Fibroblast growth factor-23 (FGF23) as a biomarker
■ Role of nutritional vitamin D in CKD
Among the most prominent changes in the 2017 guideline update were recommendations about the clinical handling of suspected osteoporosis in patients in all stages of CKD. First, dual-energy X-ray absorptiometry for determining bone mineral density became recommended as a reasonable diagnostic test for assessing fracture risk, if the results may affect treatment decisions. Second, the caution and reservation against classic anti-osteoporosis medications (especially antiresorptive agents) was partially relieved by the accumulating evidence supporting potential clinical benefits under defined circumstances.
The KDIGO update release was consequently followed by the publication of two remarkable and well-balanced review articles that both presented clinical algorithms for two different settings:
Patients in all stages with low bone mineral density (T score ≤2.5), or with T score >2.5 plus a low-impact fracture according to the World Health Organization's definition of osteoporosis (3)
Dialysis patients (CKD G5D) with low-impact fractures (4)
The first algorithm (Figure 1) suggested using cutoff levels of bone-specific alkaline phosphatase as a pragmatic approach to more appropriately stratifying patients into high, normal, or low bone turnover groups, and it assigned treatment modalities accordingly (3). In essence, proper management of CKD-MBD phenotypes is warranted before more specific therapeutic approaches should be considered.
Abbreviations: CKD-MBD, chronic kidney disease-mineral and bone disorder; DXA, dual-energy X-ray absorptiometry; GFR, glomerular filtration rate; PTH, parathyroid hormone. Reprinted from Khairallah P et al. (3) with permission.
The second algorithm (Figure 2) for dialysis patients suggested a two-step approach, based on three groups of intact parathyroid hormone levels in accordance with the KDIGO guideline recommendations, followed again by ascertaining serum concentrations of bone-specific alkaline phosphatase (4). Both reviews also quite pragmatically discussed and considered the potential of bone biopsy in their management schemes. Although these publications obviously reflect the authors' opinions, they appear to provide rather sensible advice about issues for which the data are limited.
Abbreviations: BSAP, bone-specific alkaline phosphatase; PTH, parathyroid hormone; ULN, upper limit of normal; VRDA, vitamin D receptor activators. Reprinted from Pimentel A, et al. (4) with permission.
One of the most interesting but challenging issues in CKD-MBD is the role of FGF23 as a diagnostic biomarker or even a therapeutic target. It seems quite evident that this phosphatonin is crucial in the regulation of phosphate and vitamin D homeostasis in progressive CKD, especially in earlier stages, but it might also develop into a cardiovascular threat for patients, owing to possible myocardial toxicity.
A recent article suggested that absolute FGF23 serum levels may be of secondary importance concerning risk prediction, especially in CKD patients not receiving dialysis, in comparison with the dynamics and trends of this biomarker (so-called trajectories) (5). By far, the highest risk prediction was observed when FGF23 levels rapidly rose over time, in contrast to slowly rising or stable FGF23 serum concentrations. This observation might potentially qualify FGF23 as a longitudinal marker of CKD severity and cardiovascular consequences. In this context, further insights about the power of available medications to substantially lower FGF23 blood levels (e.g., calcimimetics, phosphate binders) may thus have an impact on treatment modalities if FGF23 lowering can be proved to associate with improved patient-meaningful outcomes in randomized controlled trials.
The current recommendations about vitamin D deficiency and insufficiency from the original KDIGO CKD-MBD 2009 guidelines remain oriented toward targets for the normal population as published by most osteoporosis societies and the Institute of Medicine (6). The latter position paper recommended a range of 25-hydroxy-vitamin D levels between 20 and 60 ng/mL as necessary to achieve, and it emphasized the importance of vitamin D for bone health while remaining cautious about the so-called pleiotropic effects on cancer and cardiovascular disease protection, infectious diseases, or autoimmunity.
Nevertheless, this unsolved issue triggered a few new study approaches that demonstrated the potentially beneficial effects of high-dose vitamin D3 supplementation with regard to endothelial function and vascular stiffness (7, 8). As reported at the recent ERA-EDTA Congress 2019 in Budapest, the VITALE study found that high-dose vitamin D3 treatment was associated with a lowered risk of symptomatic fracture (1% vs. 4% in low dose, odds ratio = 0.24, p = 0.02) in kidney transplant recipients, although other major study endpoints (cardiovacular events, diabetes incidence, cancer, death) were not reached (9). Further, the results of treatment studies in which extended-release calcifediol was used revealed that levels of 25-hydroxy-vitamin D between 50 and 80 ng/mL—even higher than those recommended by the Institute of Medicine (IOM)—are required to effectively control secondary hyperparathyroidism in CKD patients not using dialysis (10-12).
Recently, however, two large randomized controlled trials (ViDa [n = 5108], VITAL [n = 25,871]) failed to demonstrate beneficial effects on cardiovascular and cancer endpoints by high-dose vitamin D3 supplementation in the normal population (13–15). Both trials potentially suffered from the fact that most patients were not in a state of vitamin D deficiency at baseline (actually levels at both baseline and the end of study were within the IOM recommended range in the two trials). A recent subgroup analysis of VITAL (VITAL-DKD) in patients with type 2 diabetes mellitus (n = 1,312) reported no significant difference in the change of estimated glomerular filtration rate with vitamin D supplementation (16). Nonetheless, follow-up periods of 3 or 5 years may still be too short to enable credible conclusions to be reached. It is hoped that further post hoc analyses of subgroups with impaired kidney function may become available from these trials, enabling an informative view on vitamin D supplementation in CKD patients.
Guideline publications are always a chance and a challenge. Unanswered questions still need to be pragmatically addressed, and if this is preliminarily done by balanced expert opinion, it will be of great help for the practitioner. When research questions are raised, knowledge gaps may be subsequently closed one by one. In about 3 years from now, the CKD-MBD field will have yet again to be reappraised concerning the accumulated evidence so that ever more sustainable advice can be generated for clinical decision-making.
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Erin R. Foster, Mayuri Bedekar, Linda Tickle-Degnen; Systematic Review of the Effectiveness of Occupational Therapy–Related Interventions for People With Parkinson's Disease. Am J Occup Ther 2014;68(1):39-49. doi: 10.5014/ajot.2014.008706.
We describe the results of a systematic review of the literature on occupational therapy–related interventions for people with Parkinson's disease (PD). Three broad categories of intervention emerged: (1) exercise or physical activity; (2) environmental cues, stimuli, and objects; and (3) self-management and cognitive–behavioral strategies. Moderate to strong evidence exists for task-specific benefits of targeted physical activity training on motor performance, postural stability, and balance. Low to moderate evidence indicates that more complex, multimodal activity training supports improvement in functional movement activities. The evidence is moderate that the use of external supports during functional mobility or other movement activities has positive effects on motor control. In addition, moderate evidence is available that individualized interventions focused on promoting participant wellness initiatives and personal control by means of cognitive–behavioral strategies can improve targeted areas of quality of life. The implications for practice, education, and research are discussed.
The objectives of this review were to systematically search the literature and critically appraise and synthesize the applicable findings to address the following focused question: What is the evidence for the effectiveness of interventions within the scope of occupational therapy practice for people living with Parkinson's disease (PD)?
Parkinson's disease is the second most common neurodegenerative disorder, affecting approximately 1 million Americans. In the United States, the prevalence of PD increases with age from approximately 554 per 100,000 in adults in their 60s to 2,949 per 100,000 in those older than age 85 (Wright Willis, Evanoff, Lian, Criswell, & Racette, 2010). With the aging of the global population, PD is now considered a world health problem and health care priority (Global Parkinson's Disease Survey Steering Committee, 2002). Although PD is typically thought of as a disease of aging, a substantial number of younger adults with the disease are active in the workforce and have small children (Knipe, Wickremaratchi, Wyatt-Haines, Morris, & Ben-Shlomo, 2011).
PD is characterized by a progressive decline in speed, flexibility, fluidity, and coordination of fine and gross motor function throughout the body, including the extremities, trunk, face, and muscles of the voice (Suchowersky et al., 2006). Postural instability creates a high risk for falls. The motor manifestations of PD, which may be mistaken for signs of incompetence, apathy, or a disagreeable personality, are stigmatizing during interpersonal interactions with others, including health care providers (Tickle-Degnen, Zebrowitz, & Ma, 2011). This stigmatization may contribute to health care disparities documented in this population (Willis, Schootman, Evanoff, Perlmutter, & Racette, 2011). PD is identified as a movement disorder; however, it is increasingly recognized that the disease itself and side effects of antiparkinsonian medications are associated with serious nonmotor problems (Park & Stacy, 2009), including cognitive impairment, such as executive dysfunction and dementia; neuropsychiatric conditions, such as depression, anxiety, and impulse control disorders; and sleep, autonomic, and sensory disturbances (e.g., visual dysfunction and pain).
Activity limitations occur early in the disease and progress over time, necessitating increasing need for support and compromising participation in valued activities and roles (Foster & Hershey, 2011; Hariz & Forsgren, 2011; Schenkman et al., 2011; Shulman et al., 2008). The training of occupational therapy practitioners in aging, normative role performance and participation, and physical and psychological adaptation to disability makes them ideally suited to lead the development and implementation of evidence-based interventions with this population in home, community, and health care settings. This systematic review of the literature describes the documented effectiveness of interventions within the scope of occupational therapy practice and suggests gaps in services, theory, and evidence that warrant continued development. It represents an update to the 2001 research synthesis of evidence about the effectiveness of occupational therapy–related interventions with PD (Murphy & Tickle-Degnen, 2001).
The articles included in this review were identified through database searches for articles published from January 2003 through May 2011. Bibliographies of selected articles were reviewed for potentially relevant articles. Articles selected for review included studies in which interventions within the scope of occupational therapy practice were administered to people with PD. The evidence from these articles was graded for quality according to the guidelines used in the American Occupational Therapy Association Evidence-Based Practice Project; strong evidence indicates consistent results from well-designed, well-conducted studies (typically two or more randomized controlled trials [RCTs]) that are unlikely to be affected by future studies; moderate evidence indicates results that are sufficient to support the effect of an intervention but with constrained confidence (because of small number or size of studies, inconsistent findings, or limited generalizability to practice) and the potential to change as more information becomes available; and low or limited evidence indicates insufficient support for the effect of an intervention on outcomes.
Physical therapy studies focused on general exercise to promote normal movement, production of dual-task gait (functional mobility), or functional fall prevention and postural control were included because these approaches are within the scope and orientation of occupational therapy. Physical therapy studies that focused on gait components, physical parameters of the lower extremities only, motor aspects without a functional performance component, or other interventions outside the scope of occupational therapy were excluded. Speech therapy research was excluded from this review because it is specialized with respect to coordination of breathing and voice in this population, which typically is not the domain of occupational therapy. Finally, although caregiver interventions for families and loved ones of people with PD are very important, studies that were directed only at caregivers were excluded. Detailed information about the methodology and a complete list of search terms can be found in the article "Methods for the Systematic Reviews of Occupational Therapy and Neurodegenerative Diseases" in this issue (Arbesman, Lieberman, & Berlanstein, 2014).
The database search yielded 4,061 abstracts, 55 of which were included in this review. Thirty-five articles were Level I RCTs, systematic reviews, or meta-analyses; 7 were Level II two-group nonrandomized studies (e.g., cohort, case control); and 13 were Level III one-group nonrandomized studies (e.g., pretest–posttest design). Supplemental Table 1 (available online at http://ajot.aotapress.net; navigate to this article, and click on "Supplemental Materials") summarizes selected articles from this review.
Three categories of interventions emerged from the studies selected for review: (1) exercise or physical activity; (2) environmental cues, stimuli, and objects, and (3) self-management and cognitive–behavioral strategies. All elements may have been present in any single study, but one or two may have been accentuated in the intervention approach or selection of outcome measures. The designs of the studies were subcategorized along a temporal dimension as synchronic or diachronic (Rosenthal & Rosnow, 2008). In the context of rehabilitation research, diachronic studies focus on changes that occur over a longer period of time, beyond a single session, to test the endurance of therapeutic effects across time. Synchronic studies focus on change elements that are active during the intervention session itself and may be responsible for short-term or long-term effects.
Interventions covered in this section involve unitask and unimodal (i.e., "simple") training, such as progressive resistance training, joint mobilization, postural stability and balance training, gait training, and aerobic fitness activities (e.g., treadmill, walking, cycling). Seven systematic reviews of predominantly diachronic outcomes provided moderate to strong Level I evidence that motor and sensory–perceptual performance skills (the latter skill subtype is related to postural stability and balance) are supported by multisession, repetitive physical exercise tasks and activity training (Crizzle & Newhouse, 2006; Dibble, Addison, & Papa, 2009; Goodwin, Richards, Taylor, Taylor, & Campbell, 2008; Keus, Bloem, Hendriks, Bredero-Cohen, & Munneke, 2007; Kwakkel, de Goede, & van Wegen, 2007; Mehrholz et al., 2010; Stewart & Crosbie, 2009). The evidence is stronger for short-term effects than for long-term effects.
In combination, the syntheses suggest that the improvement of performance skills is most responsive to task-specific compared with task-nonspecific training (Kwakkel et al., 2007). For example, muscle strength is most responsive to training that directly targets the mechanisms that strengthen muscles (e.g., progressive resistive exercise), whereas balance is most responsive to training that most directly targets the postural, kinesthetic, and vestibular mechanisms of balance. In addition, direct performance skill training does not appear to generalize as robustly to more complex occupational performance or quality of life outcomes as it does to specific performance skill outcomes. Two systematic reviews conducted meta-analyses that together suggest that simple motor performance skill training produces approximately one-half standard deviation greater improvement in motor skills in people with PD compared with control conditions (Goodwin et al., 2008; Mehrholz et al., 2010). Generalization effects to nontargeted occupational performance or quality of life outcomes, though generally in a positive direction, were about half as large as task-specific performance skill effects (Goodwin et al., 2008).
We identified 12 single primary studies with diachronic designs that addressed exercise and skill training effects on motor and sensory–perceptual performance skills that were not covered by the systematic reviews. Of these studies, 5 presented Level I evidence (Allen et al., 2010; Qutubuddin et al., 2007; Sage & Almeida, 2010; Smania et al., 2010; Yousefi, Tadibi, Khoei, & Montazeri, 2009), 3 presented Level II evidence (Dereli & Yaliman, 2010; Dibble, Hale, Marcus, Gerber, & LaStayo, 2009; Nocera, Horvat, & Ray, 2009), and 4 presented Level III evidence (Brittle et al., 2008; Gobbi et al., 2009; Jöbges et al., 2004; Rossi-Izquierdo et al., 2009). These primary studies continue to develop the evidence described in the research syntheses, providing moderate support that exercise programs improve motor performance, postural stability, and balance relative to pretest baseline scores or to no-exercise control conditions. Limited evidence indicates that postural control training has any generalized or lasting effect on fear of falling or fall reduction. Findings suggest with a low degree of evidence that specialized forms or more intense task-specific exercises are more advantageous than usual forms or less intense forms of exercise.
Two studies with synchronic designs that tested simple exercise or physical activity effects on performance skills within a single intervention session present preliminary limited evidence that single-task interventions have immediate effects conducive to performance skill development. Müller and Muhlack (2010) presented Level I evidence that positive effects of PD medication on motor performance skills (reaction time, tapping, peg insertion) were more facilitated by physical exercise than by rest. Elkis-Abuhoff, Goldblatt, Gaydos, and Corrato (2008) presented Level III evidence that simple clay manipulation tasks improved mood.
Level I research syntheses on occupational performance interventions are rare (Dixon et al., 2007; Gage & Storey, 2004; Rao, 2010) and must rely on very few and low-powered studies with diverse interventions and outcome measures that cannot easily be integrated in a cohesive manner. Consequently, it is unclear whether the task-specific effects of performance skill training interventions can be achieved from complex (dual or multitask and multimodal) occupational performance training interventions for PD. Little rigorous primary effectiveness research is available on, for example, the effect of self-care training on self-care outcomes or meal preparation training on meal preparation outcomes in people with PD (Kwakkel et al., 2007). A research synthesis on tai chi exercise outcomes provided limited evidence that tai chi enhances motor and postural performance skills in people with PD (Lee, Lam, & Ernst, 2008).
Ten single primary studies with diachronic designs that addressed complex functional training interventions were identified that were not covered by systematic reviews. These involved functional mobility and nonspecific activity of daily living (ADL) training and sports and recreational activities (primarily dance). Of these studies, 3 presented Level I evidence (Hackney & Earhart, 2009a, 2009b; Morris, Iansek, & Kirkwood, 2009), 1 presented Level II evidence (Tanaka et al., 2009), and 6 presented Level III evidence (Batson, 2010; Canning, Ada, & Woodhouse, 2008; Hackney & Earhart, 2009c; Stankovic, 2004; Tassorelli et al., 2009; van Eijkeren et al., 2008). Overall, these studies provide low to moderate evidence that complex and multimodal activity training supports short-term improvement in functional movement activities.
Dual-task activity performance, particularly related to balance, such as transporting objects while walking, is responsive to training in which both cognitive and motor performance skills are integrated within the activity performance (Morris et al., 2009). The integration of motor and interpersonal performance skill training in tango dancing, which involves tightly coordinated interpersonal movement with a partner, promises stronger functional mobility and balance outcomes than nonpartnered exercise or less tightly interpersonally coordinated dance forms (Batson, 2010; Hackney & Earhart, 2009a, 2009b, 2009c). Beginning evidence is available that multimodal physical activity intervention has positive benefits for cognition, specifically executive functioning (Tanaka et al., 2009). Long-term improvement is not yet documented with certainty, and the specificity and generality of intervention effects at this level of complex task and activity interventions are not yet documented beyond a low level of evidence.
No synchronic studies of occupational performance interventions met inclusion criteria. That few if any synchronic studies have been performed suggests that researchers may presume that more complex activity interventions require repetition or developmental progression of skills over multiple sessions, rather than a single session, to demonstrate discernible effects.
Level I research syntheses on interventions for PD that enrich or adapt the performance environment are emerging with the increased understanding of brain responsiveness to environmental stimuli and the context of action (Keus et al., 2007; Kwakkel et al., 2007; Lim et al., 2005; Rao, 2010). It is generally hypothesized that external timing of movement helps compensate for deficits in the internal motor timing mechanism associated with basal ganglia function (e.g., Ma, Trombly, Tickle-Degnen, & Wagenaar, 2004). Lim et al. (2005) conducted a synthesis of the evidence on rhythmic external cues (audio, video, and somatosensory) and concluded that auditory rhythmic cues had stronger evidence than visual, tactile, or other forms of cues for helping to regulate walking in PD and that there appeared to be instantaneous (synchronic) and multisession (diachronic) effects of these cues. At the time of the synthesis, too little evidence was available to determine whether laboratory training generalized to the home environment or whether walking outcomes transferred to more complex occupational performance outcomes.
Seven single primary studies with synchronic designs were identified that were not covered by systematic reviews. Two provided Level I evidence that investigated simple and complex rhythmic and nonrhythmic auditory cues on functional upper-extremity performance (Ma, Hwang, & Lin, 2009; Ma et al., 2004). Four presented Level II (Rochester, Burn, Woods, Godwin, & Nieuwboer, 2009; Rochester et al., 2005) or Level III evidence (Bächlin et al., 2010; Bryant, Rintala, Lai, Raines, & Protas, 2009) about effects of interventions that involve external rhythmic cuing, cuing that is paired with cognitive strategies for movement, cuing that is provided only when the person's gait freezes, or adaptive equipment that provides security against falling. One presented Level II evidence about the effect of two different types of interview question (positive vs. negative topic) on facial activity and emotional expression in people with PD (Takahashi, Tickle-Degnen, Coster, & Latham, 2010).
These studies provide a moderate level of evidence that environmental context and cue structure are important when people with PD perform simple functional tasks. Performance skills during simple and dual tasks appear to be most facilitated by contexts that are enriched by auditory rhythmic stimuli, provide a safe movement environment for focusing on the functional task, are paired with supervision in cognitive strategies for how large of a movement to make in response to the cue, or elicit positive emotions. Environmental cues that divide attention, focus attention away from the primary task, or elicit negative emotions appear to worsen performance.
Four studies with diachronic designs, all providing Level I evidence, tested whether environmental regulatory effects found in synchronic studies have lasting effects on movement performance (Elston, Honan, Powell, Gormley, & Stein, 2010; Mak & Hui-Chan, 2008; Nieuwboer et al., 2007; Rochester et al., 2010). These studies address gaps identified in the Lim et al. (2005) synthesis, and their findings provide moderate evidence that the use of client-preferred external cues during several weeks of performance of ADLs in the home have positive effects on motor control that endure for several weeks past the intervention. Still unclear are the length of time these effects are maintained, the intensity of treatment needed to produce enduring effects beyond a few weeks, and the degree to which complex ADLs and quality of life are influenced by enriched or adapted contexts of performance.
We identified 7 primary studies with diachronic designs that addressed the integration of performance patterns of self-management of health and wellness into daily life with PD. Four presented Level I evidence (Guo, Jiang, Yatsuya, Yoshida, & Sakamoto, 2009; Tickle-Degnen, Ellis, Saint-Hilaire, Thomas, & Wagenaar, 2010; Ward et al., 2004; White, Wagenaar, Ellis, & Tickle-Degnen, 2009), 1 presented Level II evidence (Ghahari & Packer, 2012), and 2 presented Level III evidence (A'Campo, Spliethoff-Kamminga, Macht, & Roos, 2010; Carne et al., 2005). In these studies, individualized interventions were focused on promoting participant wellness initiatives and personal control and helping participants modify their lifestyle and improve quality of life. The studies often used a cognitive–behavioral intervention that involved education, goal setting, performance skill training, practice, and feedback related to incorporating habits into daily life. The findings provide moderate evidence that these types of intervention can improve targeted areas of quality of life—that is, if the target is daily functioning in physical activity and participation domains, the effects are greatest in these areas. Effective outcomes occurred in studies that had at least 6- to 8-wk interventions consisting of more than 20 sessions. Limited evidence is emerging that quality of life outcomes can persist for several weeks and up to 6 mo.
No synchronic studies were identified. Self-management interventions directed at home and community participation are predicated on evidence that it takes time, personal initiative, and practice to integrate new performance patterns into daily life.
The findings of this systematic review suggest that people living with PD benefit from interventions that address physical performance skills and occupational performance through physical activity, provide environmental cues or support to regulate physical performance, and teach self-management and cognitive–behavioral strategies for integrating performance patterns into daily life.
A majority of the intervention research relevant to occupational therapy and PD addresses physical performance skills. Findings indicate that, at least in the short term, physical activity can improve or maintain physical performance skills among people with PD and that they are able to develop new performance skills through task-specific training. Task-specific training is particularly effective in environments or contexts that are enriched with external supports, such as rhythmic cues, to compensate for loss in basal ganglia functioning.
To date, the demonstrated effects of physical performance skill interventions for people with PD have been primarily task specific in that improvements in trained skills do not translate to improvements in untrained skills. For example, strength training does not improve balance. In addition, the evidence is limited as to whether simple tasks that involve physical action affect cognitive, emotional, or interpersonal performance skills. Another consistent theme from this research is the lack of transfer or generalization of performance skill effects to changes in ADLs or broader occupational performance outcomes. For example, vestibular and sensory–perceptual processing rehabilitation may help reduce balance problems, but only limited evidence indicates that it reduces falls.
Given the variety of PD-related impairments and their far-reaching effects on occupational performance and participation, interventions that address multiple factors in the context of home and community living are likely necessary to change outcomes at these higher levels of function. Syntheses have noted that well-designed, multidisciplinary, and quality of life interventions are needed to address the complex issues of living with PD (e.g., Gage & Storey, 2004; Johnston & Chu, 2010; Rao, 2010), but until recently few, if any, studies took this approach. Emerging evidence suggests that multimodal training interventions may improve multiple performance skill areas and functional activity performance in people with PD. The research on multidisciplinary self-management and cognitive–behavioral interventions, which directly target occupational performance and participation (vs. impairments), is particularly encouraging in terms of effects on quality of life.
Interventions that address cognitive and psychosocial performance skills in people with PD have been understudied, although the need for effective interventions in these areas is well documented. PD has traditionally been classified as a movement disorder, but it is now understood that movement is only one of the functional domains affected by PD. In fact, nonmotor impairments may have a greater impact on quality of life than motor impairments (Gallagher, Lees, & Schrag, 2010; Martinez-Martin, Rodriguez-Blazquez, Kurtis, & Chaudhuri, 2011; Schrag, Jahanshahi, & Quinn, 2000), with executive dysfunction and depression being particularly functionally limiting early in the disease (Foster & Hershey, 2011; Klepac, Trkulja, Relja, & Babić, 2008). Furthermore, neuropsychiatric symptoms and cognitive impairment are strong contributors to caregiver burden and nursing home placement in advanced disease stages (Aarsland, Larsen, Karlsen, Lim, & Tandberg, 1999; Aarsland, Larsen, Tandberg, & Laake, 2000).
Evidence related to the impact of nonmotor dysfunction in PD on occupational performance and participation is in the early stages compared with the evidence available for motor dysfunction. Occupational therapy researchers can make a unique contribution to rehabilitation for people with PD by generating this evidence and using it to expand the focus of intervention from motor dysfunction and its effect on basic self-care ADLs to cognitive and psychosocial issues and their potential impact on more complex areas of occupation (e.g., instrumental activities of daily living, work, social participation).
Evidence related to occupational performance and productive aging and occupational therapy interventions for other chronic neurodegenerative disorders (e.g., multiple sclerosis, Alzheimer's disease) is relevant for the population of people with PD. Interventions for populations with other diseases can be refined for PD by aligning the intervention more closely with current knowledge about the associations among pathology, body function, activity, and participation in PD. Rehabilitation research is beginning to demonstrate a more cohesive and deeper understanding of the importance of aligning activity and occupation interventions with basic and descriptive biopsychosocial research in PD. For example, partnered dancing to music is an intervention that combines current knowledge about exercise, cognitive and motor activity, interpersonal behavior, and environmental stimuli associated with neural and basal ganglia functioning. Recent work has suggested that in addition to benefiting physical function for people with PD (Duncan & Earhart, 2012), participation in a regular tango dancing class may result in increased engagement in daily life activities and roles (Foster, Golden, Duncan, & Earhart, 2013).
Rehabilitation intervention research in PD often is confounded with group intervention. Receiving intervention in a group context may be particularly healthful for this population, which is at considerable risk of daily life and health care stigmatization and social isolation (Tickle-Degnen et al., 2011). Indeed, people with PD cite social interaction and support as motivators to participate in interventions (e.g., O'Brien, Dodd, & Bilney, 2008; Ravenek & Schneider, 2009). However, evidence-based practice should be guided by an understanding of the primary mechanism of change of interventions, and a major alternative explanation for many positive findings in the PD rehabilitation literature to date is that involvement in group interventions is beneficial for people with PD regardless of the content of the groups (e.g., Tickle-Degnen et al., 2010). Intervention studies that include active social- or attention-control conditions are needed to determine the primary active change agent of interventions. Future research should also attempt to determine which intervention approaches are best implemented in a group versus individual format and whether certain outcomes are differentially responsive to group versus individual interventions.
People with PD differ substantially in their various needs, and beginning evidence indicates that baseline differences in performance or needs affect responsiveness to rehabilitation. Research is beginning to address systematic variation in the intervention outcomes of people living with PD, and future work must address this issue more clearly in the designs and measurement protocols. In addition, rehabilitation for PD would benefit from a framework for appropriately matching intervention approaches with stage of disease progression, especially in light of the chronic and degenerative nature of PD. For example, newly diagnosed people and those in early stages of disease progression may benefit greatly from interventions that promote the integration of self-management habits and other healthy performance patterns (e.g., exercise, cognitive–behavioral strategies) into daily life. Intervention in the later stages of the disease might focus more on environmental modifications and caregiver education. Longer follow-up to assess maintenance of intervention effects is also needed.
The systematic reviews and primary studies included in this review have several limitations. Most of the systematic reviews did not use methods to determine effect sizes of the interventions that were included, and primary studies rarely provide this information. As a result, it is very difficult to determine the percentage of people who might benefit from the interventions. Most of the primary studies, including those indicated as Level I studies by the classification scheme, have low statistical validity because of low statistical power. This low power is created by sample sizes that are too small to measure the effect of the intervention, measurement tools that may not directly test the underlying mechanism of change in the intervention, and intervention designs that are of insufficient intensity to produce the desired change.
Most intervention research relevant to occupational therapy and PD is being conducted by physical therapy researchers and is focused on improving or maintaining physical performance skills. Although the results thus far are positive and encouraging, these studies provide limited evidence that the beneficial effects of these interventions are lasting or generalize to improved function at the activity and participation levels. Interventions with an occupational performance or community living perspective are beginning to emerge and are promising in terms of addressing the complex needs of people with PD.
Occupational therapy researchers can make valuable contributions to rehabilitation for people with PD by developing interventions that build on an emerging understanding of PD as a multifaceted and heterogeneous chronic condition with motor and nonmotor effects. These interventions should address physical, cognitive, and psychosocial issues in the context of meaningful occupations in the home and community. Recently, occupational therapy researchers have conducted preliminary work for appropriately powered and large-scale Level I RCTs of occupational therapy intervention for PD (Clarke et al., 2009; Sturkenboom et al., 2013). This work will help establish occupational therapy as an integral part of care for people with PD.
Occupational therapy practitioners should encourage their clients with PD to engage in regular physical activity and can help them find appropriate and meaningful forms of physical activity to ensure continued engagement. More complex, multimodal forms of exercise with an interpersonal component may confer the broadest benefits.
Practitioners can recommend a system of targeted external cues or supports that people with PD and their caregivers can implement to regulate physical performance during daily activities. A substantial amount of training and practice on the use of these supports would likely be necessary, and the long-term effects should be monitored because they are currently unknown.
Practitioners should consider the impact of PD-related nonmotor dysfunction (e.g., cognitive impairment, depression) on occupational performance and participation.
Practitioners should incorporate client-centered self-management strategies into intervention with clients with PD to enhance self-efficacy and maintain participation in valued activities and roles, thus mitigating the negative effects of PD on health and quality of life.
Practitioners can refine interventions from the aging or chronic neurological disease literature for people with PD. Examples of intervention approaches that seem particularly relevant are home modifications and fatigue management programs.
Although individually tailored treatments in clients' natural environments are important for addressing daily function and independence, social support gained from being in a group setting with other people living with PD is likely beneficial for social participation and overall quality of life. Practitioners can guide their clients with PD toward community resources for this type of social interaction (e.g., programs provided by the American Parkinson Disease Association).
We thank Deborah Lieberman and Marian Arbesman for their guidance and support throughout the review process. Individual author contributions are as follows: initial retrieval of articles and inclusion and exclusion decision making, Mayuri Bedekar, Linda Tickle-Degnen; summarization of evidence into tables, Draft 1—Mayuri Bedekar, Draft 2—Linda Tickle-Degnen, final draft—Erin R. Foster; writing of Critically Appraised Topic, Linda Tickle-Degnen; and writing and coordination of final article, Erin R. Foster.
*Batson, G. (2010). Feasibility of an intensive trial of modern dance for adults with Parkinson disease. Complementary Health Practice Review, 15, 65–83.
Rosenthal, R., & Rosnow, R. L. (2008). Essentials of behavioral research: Methods and data analysis (3rd ed.). New York: McGraw-Hill.
*Stewart, A., & Crosbie, J. (2009). Aerobic fitness in people with Parkinson's disease: A review of the evidence. Physiotherapy Ireland, 30, 21–26.
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A new study by investigators from Brigham and Women's Hospital provides a biophysical and structural assessment of a critical immune regulating protein called human T-cell immunoglobulin and mucin domain containing protein-3 (hTIM-3). Understanding the atomic structure of hTIM-3 provides new insights for targeting this protein for numerous cancer and autoimmune therapeutics currently under clinical development. The findings of this study were published online in Scientific Reports on Nov. 30.
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Sugar is the harm to human health is greater. The body needs glucose, but the right foods and the correct amount for consumption should be considered.
Sugar has a big place in our lives, but this situation is not very encouraging. The consumption of sugar is gradually increasing and reaches different heights. Almost every food we consume in beverages and candy. Even natural sugar in fruits and vegetables containing certain proportions, but ready-sugar foods and drinks we consume can be the result of. Excessive consumption of sugar is a recipe for many diseases. It even has a negative impact on future generations. So take precautions for consumption should be considered.Is seen to increase the risk of heart diseases and can trigger a heart attack.Excessive sugar consumption lead to obesity.
For drinks with a fructose content as a result of maturation of the fat I accumulated. This is frequently the beverages we drink, and the next generation of individuals who caught the disease because of obesity, excessive weight gain cause. Sugar, and especially belly fat around the waist increases the rate of. The regional leads to this amorphous body types and lubrication.Sugar is named as the silent killer. Causing diseases without showing no signs or symptoms leads. By damaging the immune system, bacteria, viruses, reduces the resistance against microorganisms. The body needs sugar, but sugar taken in excess it has toxic effects.
Created by the liver creates the effect of alcohol. Pregnancy and nursing mothers the excess sugar in the baby if you are loading may have negative consequences in the development of Nov. Women may be caused by ovarian cancer. Causes premature aging. The impact of sugar on eye health is enormous. Vision problems, and can cause cataracts. Vitamin E in the blood reduces. Alcohol addiction can do. Excessive sugar consumption in children moodiness, anxiety, and hyperactivity. So, it should be noted that the consumption of sugar.The solution is non-caused diseases should not be.For future generations to have healthy and robust and reduce the consumption of sugar for a structure to be considered should be given importance.
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The cave fauna of the Brazil is poorly documented, and among the insects those live or frequent caves and their adjacent environments phlebotomine sand flies call for special attention because several species are vectors of pathogens among vertebrates hosts. A new species of sand fly from Minas Gerais is described based in females and males collected in a cave of the municipality of Lassance.
The morphological characters of the new species permit to include in the Evandromyia genus, cortelezzii complex. This complex consists of three species: Evandromyia corumbaensis (Galati, Nunes, Oshiro & Rego, 1989), Evandromyia cortelezzii (Brethes, 1923) and Evandromyia sallesi (Galvao & Coutinho, 1940).
The new species can be separate from the others of the cortelezzii complex through morphological characters of the male terminalia and female spermathecae.
Sand flies are responsible for transmission of the genus Leishmania among vertebrates hosts and study of this insect group is of great importance in attempts to control of leishmaniasis . In Brazil, the cave fauna of insects is poorly documented, and among the insects that live or frequent caves and their adjacent environments, phlebotomine sand flies call for special attention because several species are vectors of arboviruses and protozoa, among other parasites.
The geographical distribution of the sand flies species depends on their ability to adapt to different ecological niches. Thus, by its development in the immature stages and their feeding habits when adults, the species of sand flies are found where both larvae and adults can find appropriate environments for their development, including blood supply for females. In this way, the geographical distribution of species can be restricted to their access to a specific environment and vertebrate host. Already the occurrence of leishmaniasis is basically determined by the presence of both a susceptible vector and a host/reservoir equally susceptible to the infection .
The growing of tourism, involving a search for natural attractions such as cave exploration, demands a better knowledge of the threats to health that people may face in those new areas.
In the present investigation a new species of sand fly from Minas Gerais is described based on both genders collected in a cave in the Lassance municipality.
Sand flies were collected using CDC light traps (HP model), conducted between June 2008 to May 2010, in the cave named "Gruta Rebenta Bombas" city of Lassance, Minas Gerais state. Sand flies were mounted in Canada balsam (males) and Berlese liquid (females), measured with a binocular Olympus CH-2 microscope with the aid of a micrometer ocular and the drawings were done with the help of a camera lucida. All the measurements presented in this paper are given in micrometers. The nomenclature and classification is that proposed by Galati and the abbreviation of the names for phlebotomine genera by Marcondes . The new species is described based on 10 females and 10 males, which were associated by their capture in the same place at the same time as well as by the association of the morphological characteristics (antennal and palpal formulas; length association of the genital filaments; pigmentation of the thorax; and other structures) that include all the specimens of both sexes in the same genus and group.
In accordance with section 8.6 of the ICZN's International Code of Zoological Nomenclature, copies of this article are deposited at the following five publicly accessible libraries: Natural History Museum, London, UK; American Museum of Natural History, New York, USA; Museum National d'Histoire Naturelle, Paris, France; Russian Academy of Sciences, Moscow, Russia; Academia Sinica, Taipei, Taiwan.
sand fly of medium size, measurement ca. 2,677 (2,609 ± 125.4; n = 10) in length, general colour light brown.
Evandromyia spelunca sp. nov. (Holotype male). Head, frontal view. Bar = 100 μm.
(370 ± 13.9; n = 10) long and 262 (261 ± 10.0; n = 10) wide. Head length/head width ratio 1.47: 1 (1.42 ± 0.08; n = 10). Clypeus 133 (129 ± 7.1; n = 10) long; clypeus length/head length ratio 0.34: 1 (0.35: 1 ± 0.02; n = 10). Eye 126 (132 ± 16.9; n = 10) long and 75 (83 ± 10.7; n = 10) wide; eye length/head length 0.33: 1 (0.36: 1 ± 0.04; n = 10). Interocular distance 119 (114 ± 6.8; n = 10). Labrum-epipharynx (LE) 218 (215 ± 5.8; n = 10). LE/head length 0.56: 1 (0.58 ± 0.01; n = 10). Labial suture forming a fork. Antenna with simple and short ascoid, not reaching the next flagellomere. Antennal formula AIII-AXV: 2 Antennomere lengths: AIII 304 (297 ± 10.0; n = 10); AIV 166 (155 ± 8.4; n = 10); AV 166 (157 ± 7.5; n = 10); AXV > AXVI (AXV > AXVI; n = 7). AIII, AIV, AV, AXII, AXIII, AXIV, AXV, AXVI with papilla; ratios: AIII/head length 0.79: 1 (0.80: 1 ± 0.04; n = 10); AIII/LE 1.39: 1 (1.38: 1 ± 0.06; n = 10). Palpal formula 1.4.2.3.5 (1.4.2.3.5; n = 10). Palpomere lengths: P1 37 (36 ± 3.3; n = 10); P2 146 (139 ± 4.1; n = 10); P3 173 (167 ± 6.0; n = 10); P4 122 (113 ± 5.7; n = 10); P5 400 (367 ± 43.6; n = 10). Newstead's spines inserted medially on palpomere 3, also present on its apical third portion.
Proepimeral setae present, 4-4 [(4-4; n = 2), (3-4; n = 3), (4-5; n = 2), (3-5; n = 1), (3-3; n = 1)] and anepisternal superior setae present, 9-9 [(12-12; n = 2), (13-13; n = 2), (9-10; n = 2), (13-14; n = 1), (10-12; n = 1), (10-10; n = 1)]; setae on the anterior region of the katepisternum present. Wing (Figure 2) measurement 1,973 (1,907 ± 50.7; n = 10) long and 483 (471 ± 59.7; n = 10) at maximum width. Length/width ratio 4.08: 1 (4.05: 1 ± 0.37; n = 10). Length of the vein sections: R5 1,242 (1,213 ± 29.5; n = 10); alpha 359 (336 ± 37.0; n = 10); beta 276 (258 ± 14.7; n = 10); gamma 649 (625 ± 25.4; n = 10); delta 41 (59 ± 25.3; n = 10). Legs: anterior, median and posterior, respectively: femur 731 (727 ± 15.2; n = 9), 662 (690 ± 23.6; n = 10) and 787 (764 ± 25.7; n = 9); tibia 952 (924 ± 35.3; n = 9), 1,090 (1,047 ± 68.0; n = 10) and 1,256 (1,267 ± 17.9; n = 9); tarsomere I 580 (560 ± 22.1; n = 9), 635 (621 ± 18.7; n = 10) and 690 (698 ± 24.1; n = 9); tarsomeres II+III+IV+V 676 (635 ± 33.1; n = 9), 690 (661 ± 21.9; n = 10) and 745 (718 ± 24.4; n = 8).
Evandromyia spelunca sp. nov. (holotype male). Wing. Bar = 250 μm.
terminalia (Figure 3): gonostyle 133 (133 ± 3.5; n = 10) long, with four spines: one apical, one upper external, inserted in a tubercle near the outer lower, which is thinner than that, and an internal implanted below the outside and with the same caliber of this. Sub terminal seta present. Gonocoxite 245 (231 ± 13.7; n = 10) long and 92 (89 ± 7.7; n = 10) wide, with a tuft containing four long and slender setae, inserted in a small tubercle, and two smaller setae, inserted beside this others. The base of the tuft presents a small pigmented area. Paramere thickened at the base, which narrows in the middle region, and widens again, taking the shape of a bird's head with the nozzle facing down. This paramere presents a suture that divides the inside and follows almost the entire length of the same. Accompanying this suture, are found setae implanted in the dorsal region. Lateral lobe 286 (277 ± 7.3; n = 10) long and 24 (25 ± 2.9; n = 10) wide. Lateral lobe/gonocoxite ratio 1.17: 1 (1.20 ± 0.07; n = 10). Conical and pigmented aedeagus. Genital filament (Figure 4) 435 (425 ± 30.1; n = 10) long and 3.0 (3.0; n = 10) wide and genital pump 153 (150 ± 4.5; n = 10). Genital filament/genital pump ratio 2.84: 1 (2.83 ± 0.22; n = 10). Type of genital filaments slender and beak-shaped.
Evandromyia spelunca sp. nov. (holotype male). Terminalia. Bar = 100 μm.
Evandromyia spelunca sp. nov. (holotype male). Genital pump and filaments. Bar = 100 μm.
sand fly of medium size, measuring ca. 2,567 (2,574 ± 260.6; n = 10) in length. Coloration as in the males holotype and paratypes.
(422 ± 30.6; n = 10) long and 290 (301 ± 18.0; n = 10) wide. Head length/head width ratio 1.43: 1 (1.40 ± 0.10; n = 10). Clypeus 153 (168 ± 14.0; n = 10) long; clypeus length/head length ratio 0.37: 1 (0.40: 1 ± 0.01; n = 10). Eye 133 (142 ± 10.4; n = 10) long and 92 (85 ± 9.7; n = 10) wide; eye length/head length 0.32 (0.34: 1 ± 0.03; n = 10). Interocular distance 143 (146 ± 17.0; n = 10). Labrum-epipharynx (LE) 292 (306 ± 18.4; n = 10). LE/head length 0.71: 1 (0.73 ± 0.06; n = 10). Labial suture forming a fork. Antenna with simple and long ascoid and reaching the next flagellomere. Antennal formula AIII-AXV: 2 Antennomere lengths: AIII 235 (264 ± 18.8; n = 10); AIV 122 (128 ± 7.4; n = 10); AV 122 (128 ± 7.4; n = 10); AXV > AXVI (AXV > AXVI; n = 10). AIII, AIV, AXIV, AXV and AXVI with papilla; ratios: AIII/head length 0.57: 1 (0.63: 1 ± 0.05; n = 10); AIII/LE 0.80: 1 (0.86: 1 ± 0.06; n = 10). Palpal formula 1.4.3.2.5 (1.4.3.2.5; n = 10). Palpomere lengths: P1 51 (48 ± 4.6; n = 10); P2 153 (158 ± 8.1; n = 10); P3 173 (177 ± 10.8; n = 10); P4 112 (120 ± 8.4; n = 10); P5 442 (446 ± 20.5; n = 10). The Newstead spines implanted in the median region of the third palpomere. Cibarium with four posterior (horizontal) teeth developed and individualized, not fused in their base. The anterior (vertical) teeth are present in greater number in the regions lateral of the cibarium, starting from the two sides of the cibarium, and forming an arch with about four teeth larger vertical, situated below the posterior teeth (Figure 6). Sclerotized area is well defined and the sclerotized arch is complete. Unarmed pharynx. Lacinia of the maxilla with 7-9 external teeth in a single longitudinal row.
Evandromyia spelunca sp. nov. (Alotype female). Head, frontal view. Bar = 100 μm.
Evandromyia spelunca sp. nov. (paratype female). Pharynx and cibarium. Bar = 100 μm.
Proepimeral setae present, 3-4 [(3-4; n = 2) (5-6; n = 3), (5-5; n = 2), (4-5; n = 1), (4-4; n = 1)] and anepisternal superior setae present, 10-11 [(15-15; n = 1), (20-20 n = 1), (13-14; n = 1); (14-15; n = 1), (17-18; n = 1), (11-13; n = 1), (16-17; n = 2)]; setae on the anterior region of the katepisternum present. Wing (Figure 7) measurement 2,029 (2,040 ± 141.9; n = 10) long and 442 (558 ± 69.1; n = 10) at maximum width. Length/width ratio 4.59:1 (3.66: 1 ± 0.37). Length of the vein sections: R5 1,311 (1,324 ± 103.4; n = 10); alpha 414 (439 ± 69.9; n = 10); beta 262 (266 ± 28.3; n = 10); gamma 759 (755 ± 55.5; n = 10); delta 110 (145 ± 38.2; n = 10). Legs, anterior, median and posterior, respectively: femur 773 (796 ± 59.0; n = 9), 718 (783 ± 70.6; n = 10) and 828 (886.6 ± 79.2; n = 8); tibia 842 (891 ± 74.4; n = 9), 994 (1,048 ± 80.8; n = 4) and 1,229 (1,273 ± 100.7; n = 8); tarsomere I 511 (570 ± 61.5; n = 9), 593 (625 ± 38.4; n = 10) and 690 (716 ± 33.3; n = 7); tarsomeres II+III+IV+V 662 (652 ± 56.7; n = 9), 649 (687 ± 56.2; n = 10) and 690 (735 ± 49.6; n = 7).
Evandromyia spelunca sp. nov. (paratype female). Wing. Bar = 250 μm.
spermathecae (Figure 8): 20 (20 ± 1.7; n = 10) long by 17 (17; n = 10) at maximum width. The body of the spermatheca is globular with diameters approximately equals to the others of group. The head of the spermathecae present some fine bristles inserted in the apex. The individual and common sperm ducts are smooth-walled, the latter being short compared to the first. The individual duct is 197 (199 ± 12.4; n = 8) in length and the common duct 47 (48 ± 2.7; n = 8). Cercus 119 (125 ± 15.7; n = 10) long.
Evandromyia spelunca sp. nov. (paratypes female). Spermathecae. Bar = 100 μm.
Hotype male (N. 89,458) and allotype female (N. 87,358) collected respectively on 30th September 2009 and 26th June 2008 with CDC light traps, model HP, in a limestone cave named "Gruta Rebenta Bombas", municipal district of Lassance, Minas Gerais state, Brazil (Carvalho, G.M.L. and colleagues), together with nine male paratypes (N. 87,715 collected on 28/08/2008; N. 89,459 to N.89,464 collected on 30 09 2009;N.89,465 collected on 26/05/2009 and 89,466 collected on 10/03/2010) and nine female paratypes (N. 86,800 collected on 17/04/2008; 86,970; and 87,011 collected on 21/05/2009; 87,158; 87,233;87,367; 87,368 collected on 26/06/2008; 87,403 and 87,405 collected on 26/05/2008). The type-material is deposited in the "Coleção de Flebotomíneos" of the "Instituto René Rachou/FIOCRUZ", Belo Horizonte, Brazil.
The name Evandromyia spelunca sp. nov. has been given in regards to the meaning of cave in Latin.
The morphological characters of the new species permit included in the Evandromyia genus, in the cortelezzii complex. This complex consists of three species: Evandromyia corumbaensis (Galati, Nunes, Oshiro & Rego, 1989), Evandromyia cortelezzii (Brethes, 1923) and Evandromyia sallesi (Galvão & Coutinho, 1940). These species are morphologically close and often confused, causing errors in its specific identification .
The males of the genus Evandromyia present the gonocoxite with a tuft of bristles, basal and compact; the paramere is simple or branched; the lateral lobe apex is thin and the females present the relationship between the lengths: clypeus/head wider than 1/3; eye/head less than 1/2; and spermathecae, with variable body. The cortelezzii complex belongs to the cortelezzi series of the Barretomyia subgenus. This series presents as main morphological characteristics: males, with the paramere and aedeagus simple; the gonostyle with upper external spine implanted in his middle, and lower spine, inserted in the basal third. Females with the globular spermathecae's body and the individual ducts are tubular . Evandromyia edwardsi (Mangabeira, 1941) also belong to this series.
The new species can be separated from others of the cortelezzii complex through morphological characters. All the males of the complex are very close being separated by the following characteristics: paramere, which provides more similar aspect to Ev. cortelezzii and Ev. sallesi, however, with the internal suture, the curvature and the shape of the paramere, being enough to separate the new species from the other two closer (see Figures 3, 9 and 10). Ev. sallesi presents the paramere with the most consistent shape compared to all other species, so being the most robust (Figure 9). The suture that divides the inside of the paramere is more central and follows almost the entire length of paramere in the new species. This is more evident in the parameres of the Ev. cortelezzii and Ev. corumbaensis, the latter being the thinnest and convex paramere of all species of the complex (Figure 11). The lateral lobe is slightly longer than all other species of the complex. The base of the tuft presents a small pigmented area, being this characteristic common to the three other species of the cortelezzii complex. But with the tuft of the gonocoxite in the new species being slightly different from the others three species of the complex, which provides a more similar aspect to Ev. corumbaensis, both separated by the aspect of the bristles, more thinner in Ev. corumbaensis, and the tubercle that presents less setae in the new species.
Evandromyia sallesi - Paramere. Bar = 100 μm.
Evandromyia cortelezzii - Paramere. Bar = 100 μm.
Evandromyia corumbaensis - Paramere. Bar = 100 μm.
The separation of the females from the others of the complex is more confused, and was not always possible, usually when the spermathecae are not present or totally visible. However, the new species can be separated from the Ev. cortelezzii and Ev. sallesi (Figure 12) by spermathecae and characteristics of their ducts: individual and common, which are noticeably longer in the new species (Figure 8) and more similar to Ev. corumbaensis. Only characteristics of the cibarium were not enough to separate the females of the complex. We can utilize characteristics of the cibarium to separate the species of the complex, observing the distance between the vertical teeth implantation, and position of the arch that form the horizontal teeth, this distance being greater in the new species. Added to this, it is important to check the layout of vertical teeth in the new species, which appears in the form of an arc, starting at the sides of cibarium, from top to bottom, which usually causes the distance between the deployments mentioned above, higher in Ev. spelunca sp. nov.
Evandromyia sallesi - Spermathecae. Bar = 100 μm.
Due to the difficulty of identifying the species of this complex, it became routine, with rare exceptions , to use geographic distribution for identify them in Brazilian regions. However, it was recently demonstrated that the three species of the complex occur in all states of the Center-west Region, and only Ev. corumbaensis is restricted to that region. The species of this complex that present the greater distribution in the country is Ev. cortelezzii, demonstrating its omission from the lists of species in several states due Ev. sallesi, which has more restricted distribution than the one quoted in the literature . Thus, we do not suggest the use of geographic distribution to identify the species of this complex, but we can suggest the observation of its occurrence in caves, beyond the morphological characteristics, since the new species had their captures practically restricted to inside the cave studied, showing preference for this environment.
It is still important to emphasize that the new species is sympatric with Ev. sallesi inside or outside the cave, however the latter one are always captured inside the cave in less number than outside the cave (data not shown).
The present study adds a new species, namely Ev. spelunca sp. nov., to the Brazilian phlebotomine sand fly fauna, presenting characters for its separation from members of the cortelezzii complex, to which it belongs With the description of the new species, now the cortelezzii complex contains 4 species, belonging to the cortelezzii series of the Barretomyia subgenus, Evandromyia genus.
GMLC, RPB, CCS and JDAF participated in morphological analysis and taxonomic discussion of the specimens. GMLC and CCS did drawing and measurements of the new species. GMLC, JDAF and RPB drafted the manuscript. All authors read and approved the final version of the manuscript.
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While patients with gliomas characterized by mutations in the isocitrate dehydrogenase (IDH) enzyme tend to live three to five times longer, with better response to chemo- and radiation therapy, than do patients whose tumors do not carry IDH mutations, the mutations themselves may initiate and drive the growth of the tumor. IDH mutant tumors produce elevated levels of 2-hydroxyglutarate (2HG), which is believed to contribute to tumor initiation by interfering with gene expression control. While it is unclear whether reducing 2HG level would reverse the process in patients, it could be used as a biomarker for diagnosis and monitoring of IDH mutant tumors.
The MGH and Dana-Farber Cancer Institute are one of the sites for a Phase 1 clinical trial of the IDH1 inhibitor IDH305 for IDH1-mutated glioma treatment. Of eight patients who had enrolled in the trial at the time of the current study, MR imaging data collected before and a week after treatment began was available for five. Three-dimensional MRS imaging of the data found that 2HG levels dropped around 70 percent after treatment initiation. Levels of additional metabolites connected with the mutant IDH1 pathway – including glutamine and glutamate – were altered in response to IDH305 treatment, indicating a potential metabolic reprogramming of the tumor.
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Question: I can't breathe well 10 years post-op Rhinoplasty, what to do?
ANSWER: Rhinoplasty should balance form as well as function. A nose that looks good but doesn't breathe well is not acceptable. Sometimes rhinoplasty techniques can decrease breathing if proper attention to the airway wasn't taken at the time of surgery. However, sometimes breathing difficulty can be a result of nasal allergies, and no surgery can do away with allergies. With your post-operative description of air being real tight to get through your nasal passage, sniffing and use of a neti pot 2 times a day, dryness inside nose and worsening of allergic symptoms suggests allergy issues. First stop for you is a board certified otolaryngologist (ENT) or a facial plastic surgeon that is also board certified in otolaryngology because they have extensive training in both nasal anatomy, as well as aesthetics. You need a thorough evaluation of your airway and sinuses to see what the inside problem could be. It could be sinus disease, polyps, an empty nose syndrome, a deviated septum, a septal perforation, just plain allergy, etc. Also it could be a valve problem that will require grafting. Most insurance companies recognize nasal airway problems as medical in nature and not cosmetic if you and your surgeon determine that revision nasal surgery is required.
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Serological diagnosis of lung cystic hydatid disease using the synthetic p176 peptide
Saul J. Santivañez, Patricia Arias, Milagrytos Portocarrero, Silvia Rodriguez, Armando E. Gonzalez, Robert H. Gilman, Cesar M. Gavidia, Hector H. Garcia
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Cystic hydatid disease (CHD) is a worldwide zoonosis caused by the larval stage of the dog tapeworm Echinococcus granulosus. Diagnosis is based on imagenological tools (abdominal ultrasound, chest X-rays, or computed tomography [CT] scan). Serological antibody-detecting assays, using diverse native antigens, have been used as a supportive diagnostic tool, but their sensitivities and specificities differ greatly. The use of synthetic peptides as antigens should provide more reliability and allow better assessment and comparison of test formats and case series. The synthetic peptide p176, corresponding to the N-terminal extreme of the subunit of antigen B (AgB8/1), has shown promising performances for diagnosis of CHD. We evaluated the performance of the synthetic peptide p176 for the diagnosis of pulmonary hydatid disease in an enzyme-linked immunosorbent assay (ELISA) format. Sixty-one serum samples from patients with a diagnosis of pulmonary hydatidosis confirmed by surgery and 128 from healthy volunteers were tested. The overall sensitivity and specificity of the p176 ELISA for lung CHD were 78.69% and 96.88%, respectively. On bivariate analysis, positive serum antibody reactions were associated with the presence of complications and with the number of cysts (single/multiple). Only the presence of persistent complications significantly associated with seropositivity on multivariate logistic regression analysis (odds ratio [OR], 9.58; 95% confidence interval [CI], 2.15 to 42.6; P = 0.003). The p176 ELISA performs well for the diagnosis of lung CHD and adds an easily reproducible diagnostic assay to the existing diagnostic tools. Copyright © 2012, American Society for Microbiology. All Rights Reserved.
Clinical and Vaccine Immunology
https://doi.org/10.1128/CVI.05540-11
10.1128/CVI.05540-11
Dive into the research topics of 'Serological diagnosis of lung cystic hydatid disease using the synthetic p176 peptide'. Together they form a unique fingerprint.
Echinococcosis Medicine & Life Sciences 100%
Antigen Chemical Compounds 70%
Peptides Medicine & Life Sciences 53%
Lung Medicine & Life Sciences 45%
Enzyme-Linked Immunosorbent Assay Medicine & Life Sciences 35%
Antigens Medicine & Life Sciences 32%
Pulmonary Echinococcosis Medicine & Life Sciences 27%
Santivañez, S. J., Arias, P., Portocarrero, M., Rodriguez, S., Gonzalez, A. E., Gilman, R. H., Gavidia, C. M., & Garcia, H. H. (2012). Serological diagnosis of lung cystic hydatid disease using the synthetic p176 peptide. Clinical and Vaccine Immunology, 944-947. https://doi.org/10.1128/CVI.05540-11
Santivañez, Saul J. ; Arias, Patricia ; Portocarrero, Milagrytos ; Rodriguez, Silvia ; Gonzalez, Armando E. ; Gilman, Robert H. ; Gavidia, Cesar M. ; Garcia, Hector H. / Serological diagnosis of lung cystic hydatid disease using the synthetic p176 peptide. In: Clinical and Vaccine Immunology. 2012 ; pp. 944-947.
@article{0fa1581208634f2a85ab6143c74d8204,
title = "Serological diagnosis of lung cystic hydatid disease using the synthetic p176 peptide",
abstract = "Cystic hydatid disease (CHD) is a worldwide zoonosis caused by the larval stage of the dog tapeworm Echinococcus granulosus. Diagnosis is based on imagenological tools (abdominal ultrasound, chest X-rays, or computed tomography [CT] scan). Serological antibody-detecting assays, using diverse native antigens, have been used as a supportive diagnostic tool, but their sensitivities and specificities differ greatly. The use of synthetic peptides as antigens should provide more reliability and allow better assessment and comparison of test formats and case series. The synthetic peptide p176, corresponding to the N-terminal extreme of the subunit of antigen B (AgB8/1), has shown promising performances for diagnosis of CHD. We evaluated the performance of the synthetic peptide p176 for the diagnosis of pulmonary hydatid disease in an enzyme-linked immunosorbent assay (ELISA) format. Sixty-one serum samples from patients with a diagnosis of pulmonary hydatidosis confirmed by surgery and 128 from healthy volunteers were tested. The overall sensitivity and specificity of the p176 ELISA for lung CHD were 78.69% and 96.88%, respectively. On bivariate analysis, positive serum antibody reactions were associated with the presence of complications and with the number of cysts (single/multiple). Only the presence of persistent complications significantly associated with seropositivity on multivariate logistic regression analysis (odds ratio [OR], 9.58; 95% confidence interval [CI], 2.15 to 42.6; P = 0.003). The p176 ELISA performs well for the diagnosis of lung CHD and adds an easily reproducible diagnostic assay to the existing diagnostic tools. Copyright {\textcopyright} 2012, American Society for Microbiology. All Rights Reserved.",
author = "Santiva{\~n}ez, {Saul J.} and Patricia Arias and Milagrytos Portocarrero and Silvia Rodriguez and Gonzalez, {Armando E.} and Gilman, {Robert H.} and Gavidia, {Cesar M.} and Garcia, {Hector H.}",
doi = "10.1128/CVI.05540-11",
journal = "Clinical and Diagnostic Laboratory Immunology",
Santivañez, SJ, Arias, P, Portocarrero, M, Rodriguez, S, Gonzalez, AE, Gilman, RH, Gavidia, CM & Garcia, HH 2012, 'Serological diagnosis of lung cystic hydatid disease using the synthetic p176 peptide', Clinical and Vaccine Immunology, pp. 944-947. https://doi.org/10.1128/CVI.05540-11
Serological diagnosis of lung cystic hydatid disease using the synthetic p176 peptide. / Santivañez, Saul J.; Arias, Patricia; Portocarrero, Milagrytos; Rodriguez, Silvia; Gonzalez, Armando E.; Gilman, Robert H.; Gavidia, Cesar M.; Garcia, Hector H.
In: Clinical and Vaccine Immunology, 01.06.2012, p. 944-947.
T1 - Serological diagnosis of lung cystic hydatid disease using the synthetic p176 peptide
AU - Santivañez, Saul J.
AU - Arias, Patricia
AU - Portocarrero, Milagrytos
AU - Rodriguez, Silvia
AU - Gonzalez, Armando E.
AU - Gilman, Robert H.
AU - Gavidia, Cesar M.
AU - Garcia, Hector H.
N2 - Cystic hydatid disease (CHD) is a worldwide zoonosis caused by the larval stage of the dog tapeworm Echinococcus granulosus. Diagnosis is based on imagenological tools (abdominal ultrasound, chest X-rays, or computed tomography [CT] scan). Serological antibody-detecting assays, using diverse native antigens, have been used as a supportive diagnostic tool, but their sensitivities and specificities differ greatly. The use of synthetic peptides as antigens should provide more reliability and allow better assessment and comparison of test formats and case series. The synthetic peptide p176, corresponding to the N-terminal extreme of the subunit of antigen B (AgB8/1), has shown promising performances for diagnosis of CHD. We evaluated the performance of the synthetic peptide p176 for the diagnosis of pulmonary hydatid disease in an enzyme-linked immunosorbent assay (ELISA) format. Sixty-one serum samples from patients with a diagnosis of pulmonary hydatidosis confirmed by surgery and 128 from healthy volunteers were tested. The overall sensitivity and specificity of the p176 ELISA for lung CHD were 78.69% and 96.88%, respectively. On bivariate analysis, positive serum antibody reactions were associated with the presence of complications and with the number of cysts (single/multiple). Only the presence of persistent complications significantly associated with seropositivity on multivariate logistic regression analysis (odds ratio [OR], 9.58; 95% confidence interval [CI], 2.15 to 42.6; P = 0.003). The p176 ELISA performs well for the diagnosis of lung CHD and adds an easily reproducible diagnostic assay to the existing diagnostic tools. Copyright © 2012, American Society for Microbiology. All Rights Reserved.
AB - Cystic hydatid disease (CHD) is a worldwide zoonosis caused by the larval stage of the dog tapeworm Echinococcus granulosus. Diagnosis is based on imagenological tools (abdominal ultrasound, chest X-rays, or computed tomography [CT] scan). Serological antibody-detecting assays, using diverse native antigens, have been used as a supportive diagnostic tool, but their sensitivities and specificities differ greatly. The use of synthetic peptides as antigens should provide more reliability and allow better assessment and comparison of test formats and case series. The synthetic peptide p176, corresponding to the N-terminal extreme of the subunit of antigen B (AgB8/1), has shown promising performances for diagnosis of CHD. We evaluated the performance of the synthetic peptide p176 for the diagnosis of pulmonary hydatid disease in an enzyme-linked immunosorbent assay (ELISA) format. Sixty-one serum samples from patients with a diagnosis of pulmonary hydatidosis confirmed by surgery and 128 from healthy volunteers were tested. The overall sensitivity and specificity of the p176 ELISA for lung CHD were 78.69% and 96.88%, respectively. On bivariate analysis, positive serum antibody reactions were associated with the presence of complications and with the number of cysts (single/multiple). Only the presence of persistent complications significantly associated with seropositivity on multivariate logistic regression analysis (odds ratio [OR], 9.58; 95% confidence interval [CI], 2.15 to 42.6; P = 0.003). The p176 ELISA performs well for the diagnosis of lung CHD and adds an easily reproducible diagnostic assay to the existing diagnostic tools. Copyright © 2012, American Society for Microbiology. All Rights Reserved.
U2 - 10.1128/CVI.05540-11
DO - 10.1128/CVI.05540-11
JO - Clinical and Diagnostic Laboratory Immunology
JF - Clinical and Diagnostic Laboratory Immunology
Santivañez SJ, Arias P, Portocarrero M, Rodriguez S, Gonzalez AE, Gilman RH et al. Serological diagnosis of lung cystic hydatid disease using the synthetic p176 peptide. Clinical and Vaccine Immunology. 2012 Jun 1;944-947. https://doi.org/10.1128/CVI.05540-11
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September - October 2016 A comparison of acute kidney injury classification systems in sepsis
Nefrología al Día
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Nefrología (English Edition)
Nefrología is the official publication of the Spanish Society of Nephrology. The Journal publishes articles on basic or clinical research relating to nephrology, arterial hypertension, dialysis and kidney transplants. It is governed by the peer review system and all original papers are subject to internal assessment and external reviews. The journal accepts submissions of articles in English and in Spanish languages. Nefrología follows the publication requirements of the International Committee of Medical Journal Editors (ICMJE) and the Committee on Publication Ethics (COPE).
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Vol. 36. Issue. 5.September - October 2016
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DOI: 10.1016/j.nefroe.2016.11.007
A comparison of acute kidney injury classification systems in sepsis
Comparación de los sistemas de clasificación del fracaso renal agudo en la sepsis
Emilio Rodrigoa,
[email protected]
Corresponding author.
, Borja Suberviolab, Zoila Albinesa, Álvaro Castellanosb, Milagros Herasa, Juan Carlos Rodriguez-Borregánb, Celestino Piñeraa, Mara Serranoa, Manuel Ariasa
a Servicio de Nefrología, Hospital Universitario Marqués de Valdecilla, Santander (Cantabria), Spain
b Unidad de Cuidados Intensivos, Hospital Universitario Marqués de Valdecilla, Santander (Cantabria), Spain
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(Daily data update)
Table 1. Main patient characteristics.
Table 2. Stages of acute kidney injury according to each classification.
Table 3. Percentage of in-hospital death with each stage of AKI.
Since 2004, various criteria have been proposed to define and grade acute kidney injury (AKI). Nevertheless, fixed criteria for assessing severe sepsis-related AKI have not yet been established.
To assess the power of the different methods of AKI classification to predict mortality in a cohort of patients with sepsis.
A prospective study of patients>18 years with septic shock admitted to the intensive care unit (ICU) of our hospital from April 2008 to September 2010 was conducted. Plasma creatinine levels were measured daily. Patients were classified retrospectively according to RIFLE, AKIN, KDIGO and creatinine kinetics (CK) criteria.
The percent of AKI rate according to the different criteria was 74.3% for RIFLE, 81.7% for AKIN, 81.7% for KDIGO and 77.5% for CK. AKI staging by RIFLE (OR 1.452, p=0.003), AKIN (OR 1.349, p=0.028) and KDIGO criteria (OR 1.452, p=0.006), but not CK criteria (OR 1.188, p=0.148) were independently related to in-hospital mortality.
A high rate of patients with severe sepsis developed AKI, which can be classified according to different criteria. Each stage defined by RIFLE, AKIN and KDIGO related to a higher risk of in-hospital mortality. In contrast, the new CK criteria did not relate to higher mortality in patients with severe sepsis and this classification should not be used in these patients without having validated its suitability with further studies.
Acute kidney injury
Desde 2004 se han propuesto diversos criterios para definir y estadiar el fracaso renal agudo (FRA), sin embargo, no se conoce cuál de ellos debe ser empleado cuando se desarrolla FRA en el contexto de la sepsis grave.
Valorar la capacidad predictiva de mortalidad en una cohorte de pacientes con sepsis de los distintos métodos de clasificación del FRA.
Estudio prospectivo de los pacientes>18 años ingresados en la Unidad de Cuidados Intensivos (UCI) de nuestro hospital desde abril de 2008 hasta septiembre de 2010 con shock séptico. La creatinina plasmática se determinó diariamente en UCI. Los pacientes se clasificaron de forma retrospectiva según las clasificaciones RIFLE, AKIN, KDIGO y cinética de la creatinina (CK).
El porcentaje de pacientes que desarrolló FRA según cada clasificación fue: 74,3% RIFLE; 81,7% AKIN; 81,7% KDIGO y 77,5% CK. Cada estadio de FRA por RIFLE (OR 1,452; p=0,003), por AKIN (OR 1,349; p=0,028) y por KDIGO (OR 1,452; p=0,006) se relacionaba de forma independiente con la mortalidad intrahospitalaria, pero no por CK (OR 1,188; p=0,148).
Un porcentaje elevado de pacientes con sepsis grave desarrolla FRA que se puede clasificar según los distintos métodos propuestos. Los estadios de las clasificaciones RIFLE, AKIN y KDIGO se relacionan con un mayor riesgo de muerte intrahospitalaria. Por el contrario, la nueva definición de CK no se relaciona con una mayor mortalidad y no se debería usar en estos pacientes con sepsis grave sin confirmar su utilidad en estudios posteriores.
Fracaso renal agudo
Acute kidney injury (AKI) is one of the most serious complications in hospitalised patients. AKI patients are at increased risk of death, both short and long term, at increased risk of developing chronic kidney disease, and they consume a substantial amount of healthcare resources.1–9 Close to half of all cases of AKI in critically ill patients are caused by sepsis.10,11 The high mortality rates in sepsis patients are largely due to the development of AKI which occur in 1/3 to 2/3 of cases, depending on the series.12–15
Different classifications have traditionally been used to define and grade AKI. However, it was eventually recognised that standardised definitions of AKI were required so it could be easily applied in routine practice; also, there was a need for epidemiological and research studies to be carried out.16 As a result, since 2004, four systems for defining and staging AKI have been proposed.17–20 The various studies that have compared the validity of these classification modalities to predict outcomes of AKI have not found any one method to offer substantial advantages over the others.21 The classification system based on creatinine kinetics (CK) seems to offer some advantages, especially in patients with previous chronic kidney disease.22,23 However, in patients with sepsis, creatinine synthesis is profoundly diminished24 and patients are often haemodiluted, which would alter the utility of using a classification system based on absolute changes in the creatinine values. The aim of our study was to assess the degree of agreement in the diagnosis and classification of AKI and the predictive power for mortality in a cohort of patients with sepsis between different AKI classification methods.
We prospectively included all patients over 18 years admitted to the Intensive Care Unit (ICU) at Marqués de Valdecilla University Hospital from April 2008 to September 2010 with septic shock according to the definitions proposed by the SCCM/ESICM/ACCP/ATS/SIS Consensus Conference, i.e. the presence of severe sepsis with hypotension or signs of persistent tissue hypoperfusion that do not respond to intravenous administration of 20ml/kg of fluids and require infusion of vasoactive drugs.25 Patients with renal impairment on renal replacement therapy and kidney transplant recipients were excluded from the study.
Demographic and analytical variables (leukocytes, lactate, base excess, CRP, procalcitonin), use of vasopressors and APACHE-II and SOFA patient classification scores calculated at the time of admission to ICU were all recorded from the medical records. Plasma creatinine was determined daily during the patient's admission to the ICU. Baseline creatinine was considered as the last available creatinine value obtained 7–365 days before admission.26,27 For the 4% of patients who did not have previous values in that period, baseline creatinine was considered as that calculated for a glomerular filtration rate of 75ml/min/1.73m2 estimated using the MDRD-4 equation, following the ADQI group recommendation.28 Patients were retrospectively classified according to the RIFLE, AKIN, KDIGO and CK classifications according to the definitions previously proposed.20,26
The continuous variables were expressed as mean±standard deviation and the qualitative variables as their absolute values or percentages. Proportions were compared using the chi-squared test. The degree of agreement to classify patients by stages between the different classification methods was estimated using Cohen's weighted kappa. The ability to discriminate for the in-hospital mortality risk for each classification method was measured by the area under the ROC curve (AUC-ROC). Logistic regression analysis was performed to estimate the risk of death in the hospital according to each AKI classification method, unadjusted and adjusted, for APACHE-II and SOFA.
The main characteristics of the patients (n=405) are described in Table 1. The percentage of patients who developed AKI according to each classification method was as follows: 74.3% RIFLE; 81.7% AKIN; 81.7% KDIGO and 77.5% CK. The number of patients in each stage according to the different classifications is shown in Table 2 and Fig. 1. The degree of agreement between RIFLE and AKIN was 95.7% (kappa index 0.895; p<0.001), between RIFLE and KDIGO 97.1% (kappa index 0.929; p<0.001), between RIFLE and CK 85.4% (kappa index 0.666; p<0.001), between AKIN and KDIGO 98.3% (kappa index 0.956; p<0.001), between AKIN and CK 85.7% (kappa index 0.664; p<0.001) and between KDIGO and CK 85.5% (kappa index 0.658; p<0.001).
Main patient characteristics.
Age (years) 65±16
Gender (male) 68.9%
Hypertension 47.7%
Diabetes mellitus 18.3%
Leukocytes 15,413±13,093
Lactate 30.7±24.5
Base excess −4.3±5.4
Vasopressors 84.3%
APACHE 20.7±6.8
SOFA 8.5±2.9
CRP 20.1±12.4
Procalcitonin 24.1±38.7
Basal creatinine 1.02±0.37
Mean stay in ICU 9.7±23.4
Mean hospital stay 11.9±26.6
Stages of acute kidney injury according to each classification.
n (%)
KDIGO
0 104 (25.7) 74 (18.3) 74 (18.3) 91 (22.5)
1 66 (16.3) 104 (25.7) 100 (24.7) 37 (9.1)
2 124 (30.6) 130 (32.1) 121 (29.9) 100 (24.7)
3 111 (27.4) 97 (24.0) 110 (27.2) 177 (43.7)
Diagnosis and classification of acute kidney injury by RIFLE, AKIN, KDIGO and CK.
(0.06MB).
The number of patients who died during hospitalisation was 101 (24.9%) and at three months there were 109 deaths (26.9%). The percentage of patients who died in the hospital was significantly higher in more advance stages of AKI in any of the classification methods (Table 3 and Figure 2). The AUC-ROC for in-hospital mortality for RIFLE was 0.673 (95% CI: 0.612–0.734), AKIN 0.649 (95% CI: 0.588–0.711), KDIGO 0.667 (95% CI: 0.606–0.729), CK 0.600 (95% CI: 0.539–0.661), with no significant differences in the ability to discriminate. Adjusted for the APACHE-II severity rating system, each stage of AKI measured by RIFLE (OR 1.452; 95% CI 1.137–1.854; p=0.003), AKIN (OR 1.349; 95% CI: 1.033–1.761; p=0.028) and KDIGO (OR 1.452; 95% CI: 1.115–1.892; p=0.006) was independently associated with in-hospital mortality. By contrast, although the classification by CK was associated with increased in-hospital mortality in each stage (OR 1.421, 95% CI: 1.151–1.755; p=0.001), the association was not sustained after adjustment by APACHE-II (OR 1.188; 95% CI: 0.941–1.499; p=0.148). The adjustment by SOFA produced similar results.
Percentage of in-hospital death with each stage of AKI.
RIFLE*
AKIN*
KDIGO*
CK**
0 11.7 11.0 11.0 13.3
p<0.001.
p=0.011.
In the context of severe sepsis, a majority of patients develop AKI. Depending on the definition used, 74–82% of the cohort of ICU patients with sepsis developed AKI. The most sensitive definitions were AKIN and KDIGO while, according to the RIFLE criteria, fewer patients had AKI. The lack of a standardised reference method makes it difficult to estimate the diagnostic accuracy of each classification.16 Most studies comparing RIFLE and AKIN find a higher percentage of patients with AKI if the AKIN criteria are used, both in hospitalised patients in general and patients in ICU or cardiac surgery,16 although this has not been confirmed in all studies.26,27,29 The definition by CK was more sensitive than RIFLE for diagnosing AKI in one study,23 but less sensitive than KDIGO in another.22 Differences in the characteristics of the populations studied, in whether or not to include diuresis in the definition of AKI, in the definition of baseline renal function and in the number of days monitoring creatinine can cause the percentages of patients defined as AKI for each criterion to vary.
Although there are differences in the percentage of diagnoses of AKI, in general, the degree of agreement between the definitions is acceptable. In our study, the degree of agreement was "very high" (kappa>0.8) between RIFLE, AKIN and KDIGO and "good" (kappa 0.6–0.8) between CK and the other classification methods. In previous studies comparing RIFLE and KDIGO, the kappa index was always good or very good; it varied from 0.682 to 0.849.29–32 In the only previous study that analyses the degree of agreement between CK and RIFLE, the values obtained were similar to those reported here (0.67).23 Despite the degree of agreement, it is interesting to note that with the CK classification, most patients with AKI are classified within the maximum degree of severity: 3. Similarly, Liborio et al. found that most patients classified as stage 2 by KDIGO passed to stage 3 using CK22.
It is very common for patients with sepsis to develop AKI and it contributes to an increased risk of death.15 The AKI risk can be reduced, at least partially, by early, goal-directed resuscitation,15 although this last point has not been verified in all studies.33 The increase in mortality is related not only to the diagnosis of AKI but also to its severity.34 Thus, the discrimination ability measured by AUC-ROC was always significant with each of the classifications we analysed and has also been demonstrated in previous studies, with higher values in less heterogeneous clinical settings than sepsis (AUC-ROC for mortality 0.731 for KDIGO and 0.687 for CK after myocardial infarction and 0.852 for RIFLE and 0.887 for CK after cardiac surgery).22,23 Significant differences between the different definitions in their ability to discriminate the risk of death were not found in these studies or in ours.22,23
A recent multicentre, epidemiological study involving 1802 patients in ICUs shows the relationship between the severity of AKI in each of the stages of KDIGO and increased risk of death.34 The quality of the previous studies only provides us with a low-to-moderate level of evidence on the relationship between each RIFLE and AKIN stage and the risk of death.21 In our prospective cohort of patients with sepsis, classifications by RIFLE, AKIN and KDIGO were independently associated with the risk of in-hospital death. The minimal difference in mortality detected between stages 1 and 2 with the three classifications has been previously reported using the AKIN criteria.16,21
In contrast, the stages of severity defined by CK were not independently associated with the risk of death in our population. Only two previous studies have analysed the association between AKI classified by CK and the risk of death. In patients with myocardial infarction, the risk for each stage of CK was significant (OR 5.607, 95% CI: 1.915–16.421, adjusted for APACHE-II) and the findings were similar in a group of patients who had undergone cardiac surgery.22,23 It has been shown in experimental models that sepsis reduces creatinine production and this can lead to kidney damage being underestimated in sepsis more than in other forms of AKI24, especially with a classification that does not include a previous "normal" baseline creatinine value. Similarly, the haemodilution presented by critically ill patients in ICU may vary the effectiveness of each classification. The CK model described by Waikar and Bonventre is based on an "ideal" mathematical simulation that does not take in the whole complexity of severe sepsis.20
In conclusion, a percentage of patients with severe sepsis will develop AKI, which can be diagnosed and classified according to the different proposed methods: RIFLE, AKIN, KDIGO and CK. They all have a high or very high degree of agreement with each other. Using the RIFLE, AKIN and KDIGO classification methods, each stage of greater severity of AKI is associated with an increased risk of in-hospital death, with no significant differences between them. In contrast, the new definition of CK was not associated with increased mortality in our cohort of patients with severe sepsis and should not be used in these patients without being confirmed in future studies.
The authors have no conflicts of interest.
This work has been supported by a grant from the Sociedad Española de Nefrología (S.E.N.) [Spanish Society of Nephrology] 2013–2015.
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Please cite this article as: Rodrigo E, Suberviola B, Albines Z, Castellanos A, Heras M, Rodriguez-Borregán JC, et al. Comparación de los sistemas de clasificación del fracaso renal agudo en la sepsis. Nefrologia. 2016;36:530–534.
Copyright © 2016. Sociedad Española de Nefrología
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Emergency Medical Services Intervals and Survival in Trauma: Assessment of the "Golden Hour" in a North American Prospective Cohort
Craig Newgard, Robert H. Schmicker, Jerris R. Hedges, John P. Trickett, Daniel P. Davis, Eileen M. Bulger, Tom P. Aufderheide, Joseph P. Minei, J. Steven Hata, K. Dean Gubler, Todd B. Brown, Jean Denis Yelle, Berit Bardarson, Graham Nichol
Study objective: The first hour after the onset of out-of-hospital traumatic injury is referred to as the "golden hour," yet the relationship between time and outcome remains unclear. We evaluate the association between emergency medical services (EMS) intervals and mortality among trauma patients with field-based physiologic abnormality. Methods: This was a secondary analysis of an out-of-hospital, prospective cohort registry of adult (aged ≥15 years) trauma patients transported by 146 EMS agencies to 51 Level I and II trauma hospitals in 10 sites across North America from December 1, 2005, through March 31, 2007. Inclusion criteria were systolic blood pressure less than or equal to 90 mm Hg, respiratory rate less than 10 or greater than 29 breaths/min, Glasgow Coma Scale score less than or equal to 12, or advanced airway intervention. The outcome was inhospital mortality. We evaluated EMS intervals (activation, response, on-scene, transport, and total time) with logistic regression and 2-step instrumental variable models, adjusted for field-based confounders. Results: There were 3,656 trauma patients available for analysis, of whom 806 (22.0%) died. In multivariable analyses, there was no significant association between time and mortality for any EMS interval: activation (odds ratio [OR] 1.00; 95% confidence interval [CI] 0.95 to 1.05), response (OR 1.00; 95% CI 9.97 to 1.04), on-scene (OR 1.00; 95% CI 0.99 to 1.01), transport (OR 1.00; 95% CI 0.98 to 1.01), or total EMS time (OR 1.00; 95% CI 0.99 to 1.01). Subgroup and instrumental variable analyses did not qualitatively change these findings. Conclusion: In this North American sample, there was no association between EMS intervals and mortality among injured patients with physiologic abnormality in the field.
https://doi.org/10.1016/j.annemergmed.2009.07.024
Respiratory Rate
Newgard, C., Schmicker, R. H., Hedges, J. R., Trickett, J. P., Davis, D. P., Bulger, E. M., ... Nichol, G. (2010). Emergency Medical Services Intervals and Survival in Trauma: Assessment of the "Golden Hour" in a North American Prospective Cohort. Annals of Emergency Medicine, 55(3). https://doi.org/10.1016/j.annemergmed.2009.07.024
Emergency Medical Services Intervals and Survival in Trauma : Assessment of the "Golden Hour" in a North American Prospective Cohort. / Newgard, Craig; Schmicker, Robert H.; Hedges, Jerris R.; Trickett, John P.; Davis, Daniel P.; Bulger, Eileen M.; Aufderheide, Tom P.; Minei, Joseph P.; Hata, J. Steven; Gubler, K. Dean; Brown, Todd B.; Yelle, Jean Denis; Bardarson, Berit; Nichol, Graham.
In: Annals of Emergency Medicine, Vol. 55, No. 3, 03.2010.
Newgard, C, Schmicker, RH, Hedges, JR, Trickett, JP, Davis, DP, Bulger, EM, Aufderheide, TP, Minei, JP, Hata, JS, Gubler, KD, Brown, TB, Yelle, JD, Bardarson, B & Nichol, G 2010, 'Emergency Medical Services Intervals and Survival in Trauma: Assessment of the "Golden Hour" in a North American Prospective Cohort', Annals of Emergency Medicine, vol. 55, no. 3. https://doi.org/10.1016/j.annemergmed.2009.07.024
Newgard C, Schmicker RH, Hedges JR, Trickett JP, Davis DP, Bulger EM et al. Emergency Medical Services Intervals and Survival in Trauma: Assessment of the "Golden Hour" in a North American Prospective Cohort. Annals of Emergency Medicine. 2010 Mar;55(3). https://doi.org/10.1016/j.annemergmed.2009.07.024
Newgard, Craig ; Schmicker, Robert H. ; Hedges, Jerris R. ; Trickett, John P. ; Davis, Daniel P. ; Bulger, Eileen M. ; Aufderheide, Tom P. ; Minei, Joseph P. ; Hata, J. Steven ; Gubler, K. Dean ; Brown, Todd B. ; Yelle, Jean Denis ; Bardarson, Berit ; Nichol, Graham. / Emergency Medical Services Intervals and Survival in Trauma : Assessment of the "Golden Hour" in a North American Prospective Cohort. In: Annals of Emergency Medicine. 2010 ; Vol. 55, No. 3.
@article{c4e52e17e5d742ff93924c283a31b8b4,
title = "Emergency Medical Services Intervals and Survival in Trauma: Assessment of the {"}Golden Hour{"} in a North American Prospective Cohort",
abstract = "Study objective: The first hour after the onset of out-of-hospital traumatic injury is referred to as the {"}golden hour,{"} yet the relationship between time and outcome remains unclear. We evaluate the association between emergency medical services (EMS) intervals and mortality among trauma patients with field-based physiologic abnormality. Methods: This was a secondary analysis of an out-of-hospital, prospective cohort registry of adult (aged ≥15 years) trauma patients transported by 146 EMS agencies to 51 Level I and II trauma hospitals in 10 sites across North America from December 1, 2005, through March 31, 2007. Inclusion criteria were systolic blood pressure less than or equal to 90 mm Hg, respiratory rate less than 10 or greater than 29 breaths/min, Glasgow Coma Scale score less than or equal to 12, or advanced airway intervention. The outcome was inhospital mortality. We evaluated EMS intervals (activation, response, on-scene, transport, and total time) with logistic regression and 2-step instrumental variable models, adjusted for field-based confounders. Results: There were 3,656 trauma patients available for analysis, of whom 806 (22.0{\%}) died. In multivariable analyses, there was no significant association between time and mortality for any EMS interval: activation (odds ratio [OR] 1.00; 95{\%} confidence interval [CI] 0.95 to 1.05), response (OR 1.00; 95{\%} CI 9.97 to 1.04), on-scene (OR 1.00; 95{\%} CI 0.99 to 1.01), transport (OR 1.00; 95{\%} CI 0.98 to 1.01), or total EMS time (OR 1.00; 95{\%} CI 0.99 to 1.01). Subgroup and instrumental variable analyses did not qualitatively change these findings. Conclusion: In this North American sample, there was no association between EMS intervals and mortality among injured patients with physiologic abnormality in the field.",
author = "Craig Newgard and Schmicker, {Robert H.} and Hedges, {Jerris R.} and Trickett, {John P.} and Davis, {Daniel P.} and Bulger, {Eileen M.} and Aufderheide, {Tom P.} and Minei, {Joseph P.} and Hata, {J. Steven} and Gubler, {K. Dean} and Brown, {Todd B.} and Yelle, {Jean Denis} and Berit Bardarson and Graham Nichol",
doi = "10.1016/j.annemergmed.2009.07.024",
journal = "Annals of Emergency Medicine",
T1 - Emergency Medical Services Intervals and Survival in Trauma
T2 - Assessment of the "Golden Hour" in a North American Prospective Cohort
AU - Newgard, Craig
AU - Schmicker, Robert H.
AU - Hedges, Jerris R.
AU - Trickett, John P.
AU - Davis, Daniel P.
AU - Bulger, Eileen M.
AU - Aufderheide, Tom P.
AU - Minei, Joseph P.
AU - Hata, J. Steven
AU - Gubler, K. Dean
AU - Brown, Todd B.
AU - Yelle, Jean Denis
AU - Bardarson, Berit
AU - Nichol, Graham
N2 - Study objective: The first hour after the onset of out-of-hospital traumatic injury is referred to as the "golden hour," yet the relationship between time and outcome remains unclear. We evaluate the association between emergency medical services (EMS) intervals and mortality among trauma patients with field-based physiologic abnormality. Methods: This was a secondary analysis of an out-of-hospital, prospective cohort registry of adult (aged ≥15 years) trauma patients transported by 146 EMS agencies to 51 Level I and II trauma hospitals in 10 sites across North America from December 1, 2005, through March 31, 2007. Inclusion criteria were systolic blood pressure less than or equal to 90 mm Hg, respiratory rate less than 10 or greater than 29 breaths/min, Glasgow Coma Scale score less than or equal to 12, or advanced airway intervention. The outcome was inhospital mortality. We evaluated EMS intervals (activation, response, on-scene, transport, and total time) with logistic regression and 2-step instrumental variable models, adjusted for field-based confounders. Results: There were 3,656 trauma patients available for analysis, of whom 806 (22.0%) died. In multivariable analyses, there was no significant association between time and mortality for any EMS interval: activation (odds ratio [OR] 1.00; 95% confidence interval [CI] 0.95 to 1.05), response (OR 1.00; 95% CI 9.97 to 1.04), on-scene (OR 1.00; 95% CI 0.99 to 1.01), transport (OR 1.00; 95% CI 0.98 to 1.01), or total EMS time (OR 1.00; 95% CI 0.99 to 1.01). Subgroup and instrumental variable analyses did not qualitatively change these findings. Conclusion: In this North American sample, there was no association between EMS intervals and mortality among injured patients with physiologic abnormality in the field.
AB - Study objective: The first hour after the onset of out-of-hospital traumatic injury is referred to as the "golden hour," yet the relationship between time and outcome remains unclear. We evaluate the association between emergency medical services (EMS) intervals and mortality among trauma patients with field-based physiologic abnormality. Methods: This was a secondary analysis of an out-of-hospital, prospective cohort registry of adult (aged ≥15 years) trauma patients transported by 146 EMS agencies to 51 Level I and II trauma hospitals in 10 sites across North America from December 1, 2005, through March 31, 2007. Inclusion criteria were systolic blood pressure less than or equal to 90 mm Hg, respiratory rate less than 10 or greater than 29 breaths/min, Glasgow Coma Scale score less than or equal to 12, or advanced airway intervention. The outcome was inhospital mortality. We evaluated EMS intervals (activation, response, on-scene, transport, and total time) with logistic regression and 2-step instrumental variable models, adjusted for field-based confounders. Results: There were 3,656 trauma patients available for analysis, of whom 806 (22.0%) died. In multivariable analyses, there was no significant association between time and mortality for any EMS interval: activation (odds ratio [OR] 1.00; 95% confidence interval [CI] 0.95 to 1.05), response (OR 1.00; 95% CI 9.97 to 1.04), on-scene (OR 1.00; 95% CI 0.99 to 1.01), transport (OR 1.00; 95% CI 0.98 to 1.01), or total EMS time (OR 1.00; 95% CI 0.99 to 1.01). Subgroup and instrumental variable analyses did not qualitatively change these findings. Conclusion: In this North American sample, there was no association between EMS intervals and mortality among injured patients with physiologic abnormality in the field.
U2 - 10.1016/j.annemergmed.2009.07.024
DO - 10.1016/j.annemergmed.2009.07.024
JO - Annals of Emergency Medicine
JF - Annals of Emergency Medicine
10.1016/j.annemergmed.2009.07.024
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Module 3 / Iron deficiency anaemia
Individuals with iron deficiency anaemia are anaemic (based on low haemoglobin) and iron deficient (based on one of the recommended indicators of iron status). Fig. 3.1. shows two examples of the relationship between iron deficiency, iron deficiency anaemia and anaemia in populations with the same prevalence of anaemia. The level of overlap between these three conditions will vary between populations, and within a given population. In setting A, the prevalence of iron deficiency in the population is high, as is the prevalence of iron deficiency anaemia, while non-iron deficiency causes of anaemia are infrequent. In setting B, the prevalence of iron deficiency and iron deficiency anaemia are lower than in setting A, indicating that other factors, such as malaria, hookworm, and/or genetic blood disorders (for example, haemoglobinopathies) may be the main causes of anaemia.
Fig. 3.1. Visual representation of the overlap between iron deficiency, iron deficiency anaemia and anaemia
Adapted from: reference 1.
WHO, UNICEF, UNU. Iron deficiency anaemia: assessment, prevention and control, a guide for programme managers. Geneva: World Health Organization; 2001. ↩
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External validation of vaginal birth after cesarean delivery calculator in Israeli cohort of parturients and construction of an improved model
Noa Haggiag, Shani Eitan, Esther Maor-Sagie, Mordechai Hallak, Rinat Gabbay-Benziv
Objective: To validate the Maternal Fetal Medicine Unit's (MFMU) vaginal birth after cesarean delivery (VBAC) calculator in an Israeli cohort, and to detect other variables associated with VBAC and construct an improved VBAC calculator. Methods: A retrospective cohort study was performed at a single university-affiliated medical center. Women carrying a singleton, term, cephalic-presenting fetus, with previous one low transverse cesarean delivery who opted for trial of VBAC were included. Demographic and obstetric characteristics were incorporated into the MFMU's calculator, to predict probabilities of VBAC and compare prediction performance with the original publication utilizing receiver operating characteristic (ROC) statistics. Logistic regression analysis was used to investigate other variables and construct an improved model for success of VBAC. Results: Of 490 parturients, 396 (80.8%) had a successful vaginal delivery. Compared to the original publication, the MFMU's calculator underperformed: area under the ROC curve (AUC) was 0.709 (95% confidence interval [CI] 0.652–0.766, P < 0.001). Sensitivity, specificity, positive and negative predictive values, and overall accuracy were 67.42%, 65.96%, 89.30%, 32.46%, and 32.46%, respectively. An improved model that included previous VBAC, prior vaginal delivery, spontaneous onset of delivery, and maternal diabetes resulted in improved prediction performance with an AUC of 0.771 (95% CI 0.723–0.82, P < 0.001). Conclusion: MFMU's VBAC calculator needs to be validated in different populations before implementation.
International Journal of Gynecology and Obstetrics
https://doi.org/10.1002/ijgo.14439
Accepted/In press - 1 Jan 2022
Maternal-Fetal Medicine Unit's vaginal birth after cesarean delivery calculator
cesarean delivery
maternal diabetes
trial of labor after cesarean delivery
vaginal birth after cesarean delivery
10.1002/ijgo.14439
Dive into the research topics of 'External validation of vaginal birth after cesarean delivery calculator in Israeli cohort of parturients and construction of an improved model'. Together they form a unique fingerprint.
Vaginal Birth after Cesarean Medicine & Life Sciences 100%
Publications Medicine & Life Sciences 13%
Mothers Medicine & Life Sciences 10%
Obstetrics Medicine & Life Sciences 7%
Area Under Curve Medicine & Life Sciences 6%
Haggiag, N., Eitan, S., Maor-Sagie, E., Hallak, M., & Gabbay-Benziv, R. (Accepted/In press). External validation of vaginal birth after cesarean delivery calculator in Israeli cohort of parturients and construction of an improved model. International Journal of Gynecology and Obstetrics. https://doi.org/10.1002/ijgo.14439
Haggiag, Noa ; Eitan, Shani ; Maor-Sagie, Esther et al. / External validation of vaginal birth after cesarean delivery calculator in Israeli cohort of parturients and construction of an improved model. In: International Journal of Gynecology and Obstetrics. 2022.
@article{ea8f691b1fbf4c2a9249af36b5621c5f,
title = "External validation of vaginal birth after cesarean delivery calculator in Israeli cohort of parturients and construction of an improved model",
abstract = "Objective: To validate the Maternal Fetal Medicine Unit's (MFMU) vaginal birth after cesarean delivery (VBAC) calculator in an Israeli cohort, and to detect other variables associated with VBAC and construct an improved VBAC calculator. Methods: A retrospective cohort study was performed at a single university-affiliated medical center. Women carrying a singleton, term, cephalic-presenting fetus, with previous one low transverse cesarean delivery who opted for trial of VBAC were included. Demographic and obstetric characteristics were incorporated into the MFMU's calculator, to predict probabilities of VBAC and compare prediction performance with the original publication utilizing receiver operating characteristic (ROC) statistics. Logistic regression analysis was used to investigate other variables and construct an improved model for success of VBAC. Results: Of 490 parturients, 396 (80.8%) had a successful vaginal delivery. Compared to the original publication, the MFMU's calculator underperformed: area under the ROC curve (AUC) was 0.709 (95% confidence interval [CI] 0.652–0.766, P < 0.001). Sensitivity, specificity, positive and negative predictive values, and overall accuracy were 67.42%, 65.96%, 89.30%, 32.46%, and 32.46%, respectively. An improved model that included previous VBAC, prior vaginal delivery, spontaneous onset of delivery, and maternal diabetes resulted in improved prediction performance with an AUC of 0.771 (95% CI 0.723–0.82, P < 0.001). Conclusion: MFMU's VBAC calculator needs to be validated in different populations before implementation.",
keywords = "Maternal-Fetal Medicine Unit's vaginal birth after cesarean delivery calculator, cesarean delivery, maternal diabetes, trial of labor after cesarean delivery, vaginal birth after cesarean delivery",
author = "Noa Haggiag and Shani Eitan and Esther Maor-Sagie and Mordechai Hallak and Rinat Gabbay-Benziv",
note = "Publisher Copyright: {\textcopyright} 2022 International Federation of Gynecology and Obstetrics.",
doi = "10.1002/ijgo.14439",
journal = "International Journal of Gynecology and Obstetrics",
Haggiag, N, Eitan, S, Maor-Sagie, E, Hallak, M & Gabbay-Benziv, R 2022, 'External validation of vaginal birth after cesarean delivery calculator in Israeli cohort of parturients and construction of an improved model', International Journal of Gynecology and Obstetrics. https://doi.org/10.1002/ijgo.14439
External validation of vaginal birth after cesarean delivery calculator in Israeli cohort of parturients and construction of an improved model. / Haggiag, Noa; Eitan, Shani; Maor-Sagie, Esther et al.
In: International Journal of Gynecology and Obstetrics, 01.01.2022.
T1 - External validation of vaginal birth after cesarean delivery calculator in Israeli cohort of parturients and construction of an improved model
AU - Haggiag, Noa
AU - Eitan, Shani
AU - Maor-Sagie, Esther
AU - Hallak, Mordechai
AU - Gabbay-Benziv, Rinat
N1 - Publisher Copyright: © 2022 International Federation of Gynecology and Obstetrics.
N2 - Objective: To validate the Maternal Fetal Medicine Unit's (MFMU) vaginal birth after cesarean delivery (VBAC) calculator in an Israeli cohort, and to detect other variables associated with VBAC and construct an improved VBAC calculator. Methods: A retrospective cohort study was performed at a single university-affiliated medical center. Women carrying a singleton, term, cephalic-presenting fetus, with previous one low transverse cesarean delivery who opted for trial of VBAC were included. Demographic and obstetric characteristics were incorporated into the MFMU's calculator, to predict probabilities of VBAC and compare prediction performance with the original publication utilizing receiver operating characteristic (ROC) statistics. Logistic regression analysis was used to investigate other variables and construct an improved model for success of VBAC. Results: Of 490 parturients, 396 (80.8%) had a successful vaginal delivery. Compared to the original publication, the MFMU's calculator underperformed: area under the ROC curve (AUC) was 0.709 (95% confidence interval [CI] 0.652–0.766, P < 0.001). Sensitivity, specificity, positive and negative predictive values, and overall accuracy were 67.42%, 65.96%, 89.30%, 32.46%, and 32.46%, respectively. An improved model that included previous VBAC, prior vaginal delivery, spontaneous onset of delivery, and maternal diabetes resulted in improved prediction performance with an AUC of 0.771 (95% CI 0.723–0.82, P < 0.001). Conclusion: MFMU's VBAC calculator needs to be validated in different populations before implementation.
AB - Objective: To validate the Maternal Fetal Medicine Unit's (MFMU) vaginal birth after cesarean delivery (VBAC) calculator in an Israeli cohort, and to detect other variables associated with VBAC and construct an improved VBAC calculator. Methods: A retrospective cohort study was performed at a single university-affiliated medical center. Women carrying a singleton, term, cephalic-presenting fetus, with previous one low transverse cesarean delivery who opted for trial of VBAC were included. Demographic and obstetric characteristics were incorporated into the MFMU's calculator, to predict probabilities of VBAC and compare prediction performance with the original publication utilizing receiver operating characteristic (ROC) statistics. Logistic regression analysis was used to investigate other variables and construct an improved model for success of VBAC. Results: Of 490 parturients, 396 (80.8%) had a successful vaginal delivery. Compared to the original publication, the MFMU's calculator underperformed: area under the ROC curve (AUC) was 0.709 (95% confidence interval [CI] 0.652–0.766, P < 0.001). Sensitivity, specificity, positive and negative predictive values, and overall accuracy were 67.42%, 65.96%, 89.30%, 32.46%, and 32.46%, respectively. An improved model that included previous VBAC, prior vaginal delivery, spontaneous onset of delivery, and maternal diabetes resulted in improved prediction performance with an AUC of 0.771 (95% CI 0.723–0.82, P < 0.001). Conclusion: MFMU's VBAC calculator needs to be validated in different populations before implementation.
KW - Maternal-Fetal Medicine Unit's vaginal birth after cesarean delivery calculator
KW - cesarean delivery
KW - maternal diabetes
KW - trial of labor after cesarean delivery
KW - vaginal birth after cesarean delivery
U2 - 10.1002/ijgo.14439
DO - 10.1002/ijgo.14439
JO - International Journal of Gynecology and Obstetrics
JF - International Journal of Gynecology and Obstetrics
Haggiag N, Eitan S, Maor-Sagie E, Hallak M, Gabbay-Benziv R. External validation of vaginal birth after cesarean delivery calculator in Israeli cohort of parturients and construction of an improved model. International Journal of Gynecology and Obstetrics. 2022 Jan 1. doi: 10.1002/ijgo.14439
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OB-GYN Treating Pregnant Women With Zika Virus: 'This Is What It's Like'
By emily | November 17, 2018
As a medical student, I remember reading books about the early days of the HIV epidemic and wondering what it was like for doctors to take care of patients who had a new, unknown disease. It seemed to me like it would be frightening for both patients and doctors alike. I didn't expect that early in my career as an OB-GYN, I would be caught in the middle of another new disease outbreak — Zika.
Most people who catch this virus feel fine. Some will end up with a fever, rash, aches and pains and red eyes (conjuntivitis), or rarely, a serious nerve disorder called Guillain-Barre. But in pregnancy there can be very serious consequences to the baby. As of July 28, the World Health Organization reports that nearly 2,000 babies are affected with microcephaly or central nervous system malformations associated with Zika worldwide.
I teach and practice obstetrics and gynecology at the University of Miami Hospital and Jackson Memorial Hospital, and I treat pregnant women who have been infected with Zika: so far over a dozen women. We began preparing to care for infected women in January. Now, it is part of the daily care we provide. And with first known cases of local mosquito-borne transmission in the continental U.S. reported in Wynwood, a neighborhood in Miami, the risk has become even more real.
How am I, and other doctors who care for pregnant women, dealing with this new disease?
Confirming the diagnosis
When I talk to patients these days, I ask them where they or family members have traveled recently. These are questions OB-GYNs across the country may ask pregnant patients. And since I practice in Miami, I might also ask patients if they have been in Wynwood, the neighborhood where local mosquito transmission has occurred. Since Zika is primarily spread by mosquitoes, I also talk with patients about avoiding mosquito bites and using bug repellent. Sexual transmission is also possible, and we talk about that, too.
The patients I worry about the most now are those who live or work in Wynwood and those who've traveled to countries where Zika is more widespread, or those who show the symptoms of Zika infection. We are being vigilant for evidence of spread to other parts of the Miami area.
If I am worried that a pregnant patient has been infected with Zika, I order tests to confirm the diagnosis. The state of Florida has announced that starting next week there will be free Zika testing for all pregnant women through the Department of Health.
If a Zika infection is confirmed, we then have to talk about the risks that she is willing to accept in her pregnancy. If a patient infected with Zika is in her first or second trimester, then we can talk about staying pregnant or having an abortion.
While we think that the first trimester is the time of greatest risk, we still don't know if there is ever a safe point in pregnancy. So how much risk is she willing to accept? What would it mean to have a sick baby in her family? How would she get support no matter what options she chooses? Those answers will be different for everyone.
And these conversations are difficult, because there is still so much we don't know about Zika.
For instance, we don't know how many pregnant women who are infected with Zika will have babies with brain problems — there is no perfect percentage I can give her so she can weigh her options.
One study from Brazil found that of the women who were pregnant, had symptoms of Zika and had blood tests confirming infection, a startling 29 percent of the pregnancies had some sort of issue, such as microcephaly or abnormal brain structure, for instance. But other computer modeling studies have put the risk for the general population of pregnant women who are infected in the first trimester at about 1 percent. It's these wide ranges in outcomes that makes counseling patients so difficult.
And that's not the only unknown about Zika.
How does the virus get into the fetus? Researchers are still figuring that out. In which trimester does infection pose the highest risk? As with other infections in pregnancy, it seems that the first trimester is the most at risk, but there are still plenty of unknowns. And do complications for the fetus vary by time of infection? It is going to take time to understand all of the risks.
To answer these questions, countries are creating registries of pregnant women with Zika to gather data about what happens to their pregnancies and the babies after birth. Departments of health in each state keep anonymized data on all pregnant women with Zika. This data gets fed into the Centers for Disease Control and Prevention's (CDC) surveillance system, the U.S. Zika Pregnancy Registry.
As of July 28, the CDC was monitoring over 900 pregnant women in the U.S. and its territories with laboratory evidence of Zika infection based on blood testing. Researchers want to know if these babies have the same mental development and meet the same milestones as other infants, or if they have eye or ear problems that cannot be seen on ultrasound or immediately after birth. The CDC also reports 15 babies with birth defects from pregnancies with laboratory evidence of Zika infection and six pregnancy losses in the United States and District of Columbia, as of July 28.
Planning for birth
If a woman is in her third trimester and has been infected with Zika, at each visit we focus on planning for birth, monitoring the baby by ultrasound and reviewing the latest research together.
Since this is such a fast-moving and public epidemic, we are sharing the research with our patients to keep them involved and help them understand why it is so important to collect as much information as possible.
We might also plan for monthly ultrasounds. It is possible that a baby that looks normal on one ultrasound may show problems on a later ultrasound. Some problems can develop over time and become obvious later. However, ultrasounds can't detect every problem, and microcephaly isn't the only problem Zika can cause. So, we plan her delivery at a hospital with pediatricians who know about Zika and can be prepared to care for the newborn, and look at the baby's eyes and ears and in some cases do brain imaging tests after birth.
Even with planning, there are still many questions we can't answer for our patients. For instance, if a baby is born with microcephaly, we don't know the exact issues that the baby might have. This means the mother won't know right away if her child will lead a normal life or will always need medical care.
A dose of humility
Physicians like me are learning about Zika along with our patients. This takes a dose of humility on our part and an understanding from our patients that we learn something new every single day.
With daily news and internet updates, patients are able to stay just as up-to-date as the doctors. I will have patients print out a news article or a research finding and bring it to their appointment, highlighted and with questions in the margins.
But this barrage of media can also lead to confusion and concern when the information is constantly changing. For this reason, it is so important to have open lines of communication with our patients, and be honest about the uncertainties.
Christine Curry, assistant professor of obstetrics and gynecology, University of Miami
Zika Virus: How Long Does It Stay In Your System?
Zika Virus Miami Beach 2016: CDC Warns Community, Pregnant Women
Baby Born With Birth Defect In New Jersey To Mother Infected With Zika: Media
Zika Virus And Birth Defects: How Babies Contract Microcephaly, Other Severe Complications
Zika Epidemic: Florida Travel Warning Issued For Pregnant Women After More Zika Cases
Florida Reports Evidence Of Local Zika Transmission
Zika Sexual Transmission And Pregnancy Risks Update: How Long Should Infected Men Abstain?
Zika Virus Mother-To-Child Transmission Likely Much Higher Than Previously Believed, Study Says
Zika Virus Brain Infection May Also Affect Adults, Study Finds
Zika Virus In Adult Human Eyes, New Study Discovers
WHO Says $122M Needed For Global Response To Zika Virus
Zika Symptoms And Risks As 49 Pregnant Women Are Diagnosed In New York; What You Should Know
CDC Says 157 Pregnant Women In U.S. Test Positive For Zika
Zika Infection Risks 2016: 3 Ways The Virus Can Be Transmitted And What We Still Don't Know
Zika Virus Update: Woman Carried Virus In Vagina For Two Weeks
New Research Finds Low Risk Of Zika Virus At Olympics
Zika Early Symptoms 2016: Warning Signs That You're Infected And What To Do
Limiting Travel, Controlling Mosquitoes Reduces Zika Risk
Zika Virus Can Infect And Replicate In Cells Without Killing Them; It's Also Unique In Its Ability To Cross Placental Barrier
Where Zika Virus Goes, Abortion Rates Grow — Even In Countries Where It's Illegal
Malaria Drug May Block Zika Virus Infection In Mother From Passing To Unborn Child
Zika Virus Update: How Long Does It Stay In Your Body?
Zika Virus 2017: Just Because It's Winter Doesn't Mean Outbreak Is Over Yet
US Public Health Agencies Issue New Guidelines To Protect Workers From Zika Virus
As Work On Experimental Zika Vaccine Begins, So Does New Generation Of Conspiracy Theories Spread Via Social Media
Spain Records First Case Of Sexually Transmitted Zika Virus
Hologic Wins Emergency US Authorization For Zika Virus Test
Zika Effects In Babies Update: Virus May Cause Deafness As Well As Microcephaly
Zika Virus: Where Did It Come From And How Did It Spread?
Zika Virus May Spread To Europe In Coming Months, WHO Warns
Category: Conditions Tags: Zika, Zika Virus
← How Zika Virus Attacks The Body And What Happens After Infection: Everything You Need To Know, Watch For Is Zika Contagious? Facts And Myths About How It Spreads →
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An estimate of amyotrophic lateral sclerosis heritability using twin data
Jump to comment:
Re:Possibility of epigenetic events in the pathogenesis of ALS
Ammar Al-Chalabi
Possibility of epigenetic events in the pathogenesis of ALS
Heikki Savolainen
Ammar Al-Chalabi, Neurology and Genetics
<?xml version="1.0" encoding="UTF-8"??>
We agree that genetic studies have so far explained only a small fraction of the heritability of ALS (1,2), and this is true in many other diseases as well (3). Epigenetic factors are almost certainly part of the answer, but there are also several other possibilities. We are only just developing the tools to look for disease-associated rare variants on a large scale. In addition, we do not understa...
We agree that genetic studies have so far explained only a small fraction of the heritability of ALS (1,2), and this is true in many other diseases as well (3). Epigenetic factors are almost certainly part of the answer, but there are also several other possibilities. We are only just developing the tools to look for disease-associated rare variants on a large scale. In addition, we do not understand the genetic code for most of the genome since we can only reliably translate the 1% that is exonic sequence (4). This means much variation cannot be interpreted even though it is very likely to contribute to disease and the associated genetic variants may be weak correlates of the larger effect true causal variant. We do not routinely search for interaction between genes or genes and environment and there is no easy method to interpret the actions of multiple gene variants acting in concert. Furthermore, the three dimensional nature of the genome is not considered but may have a role to play in disease if variants in physical proximity interact through protein binding or other mechanisms.
As genetic, statistical and computing technologies advance, we expect our current linear and simple view of the genome to be transformed and far more of the so-called missing heritability explained.
(1) Al-Chalabi A, Fang F, Leigh PN, et al. An estimate of amytotrophic lateral sclerosis heritability using twin data. J Neurol Neurosurg Psychiatry 2010;81:1324-1326
(2) Shatunov A, Mok K, Newhouse S, et al. Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries: a genome-wide association study. Lancet Neurol 2010;9,986-994
(3) Manolio TA, Collins FS, Cox NJ, et al. Finding the missing heritability of complex diseases. Nature 2009;461,747-753
(4) Taft RJ, Pheasant M, and Mattick JS. The relationship between non -protein-coding DNA and eukaryotic complexity. Bioessays 2007;29:288-299
Conflict of Interest:
None declared
Heikki Savolainen, Prof.
The twin studies show conclusively the limits of classical genetics in the studies of the etiology and pathogenesis of the ALS (1).
It has been suggested that a susceptibility or familial factor could play a role. In this case, they may be mediated by epigenetic mechanisms which control the activity and expression of the genome (2).
The incorrectly coded polypeptides could lead to...
The incorrectly coded polypeptides could lead to a gain of function of an enzyme or to aberrant tertiary structures of protein species (3).
This sequence of events could also shed light on familial cases as family members often are exposed to similar environment or other exogenous factors.
1 Al-Chalabi A, Fang F, Leigh PN, et al. An estimate of amytotrophic lateral sclerosis heritability using twin data. J Neurol Neurosurg Psychiatry 2010; 81: 1324-1326
2 Stauffer BL, DeSouza CA. Epigenetics: an emerging player in health and disease. J appl Physiol 2010; 109: 230-231
3 Palo J, Savolainen H, Kivalo E. Comparison between the proteins of human brain myelin in subacute sclerosing panencephalitis, amyotrophic lateral sclerosis and malignant diseases. J neurol Sci 1973; 18: 175-181
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What is the state doing to ensure equitable distribution for the safe delivery of vaccines for children ages 5 to 11?
California will administer vaccines with the strategies laid out in the state's COVID-19 Vaccine Action Plan (PDF). The state will be leveraging existing infrastructure and partnerships currently used to administer vaccines for 12 and up. This includes working closely with local health departments, schools, community partners and others to administer vaccines safely and equitably through mobile clinics and vaccine pop-ups in hardest-hit communities across the state.
1. Is the COVID-19 vaccine safe for children?
Yes. Comprehensive clinical trials in more than 4,500 children ages 5 to 11 demonstrate the COVID-19 vaccine is safe and effective in this age group, resulting in a strong antibody response in children who received the vaccines.
Clinical trials began in June for 5 to 11 year-olds in which a lower dose Pfizer-BioNTech vaccine was tested. Pfizer announced in late September that their data demonstrated the vaccine is safe and produces a significant immune response. After this thorough study and the clinical trials, the Food and Drug Administration (FDA) authorized the Pfizer-BioNTech vaccine for emergency use. The Centers for Disease Control and Prevention (CDC) and Western States Scientific Review Group reviewed all data and recommended the vaccine for all children ages 5 to 11.
There's consistent and real-world evidence of the vaccine's safety and effectiveness. The vaccine has been given safely to millions of youth since it was authorized for ages 16 and up last December and for ages 12 and up in May.
2. Where and how will the youth vaccine be administered?
California was allocated 1.2 million pediatric doses with additional supply from the federal government becoming available in the coming weeks. Distribution of these vaccines will be the same as throughout the vaccination effort with direct shipments to local health jurisdictions and providers.
3. Is this a different vaccine and what is the dosage?
The COVID-19 vaccine for children ages 5 to 11 contains a smaller amount of the same mRNA material that has been given safely to millions of youth since it was authorized for ages 16 and up last December and for ages 12 and up in May.
The dosage of Pfizer's ages 5 to 11 vaccine is in two, 10-micrograms (mcg) doses administered 21 days apart. This dosage is one-third of the adolescent and adult dose of two, 30-mcg doses.
The clinical trials demonstrated a robust antibody response and favorable safety outcomes in kids ages 5 to 11 who received the two-dose regimen.
4. Will younger kids experience the same symptoms as adolescents and adults?
After COVID-19 vaccination, some children - like adults - may have some mild side effects like soreness, headache, fever, chills. These are normal signs that your body is building immunity and, while they may affect your child's ability to do daily activities, they should go away in a few days.
Some people have no side effects at all. The risks from COVID-19 far outweigh the possible mild side effects from the vaccine.
5. Why is it important to get kids vaccinated?
Children are susceptible to serious complications from the virus and will benefit from the protection given by the vaccine. COVID-19 is the 8th leading cause of death for children ages 5 to 11. Children can also experience "long COVID" and in some instances, the virus has caused Multisystem Inflammatory Syndrome in Children (MIS-C), in which a hyperactive immune system attacks the child's body.
6. What is the state doing to ensure equitable distribution for the safe delivery of vaccines for children ages 5 to 11?
7. How do I get my child vaccinated?
There are many ways to get your eligible children vaccinated by either making an appointment or visiting a walk-in clinic. You can call your pediatrician or local health clinic to schedule your child's vaccination appointment. You can also visit the MyTurn website or call 833-422-4255 to find a vaccine near you.
8. If my child already had COVID-19, do they still need to get the vaccine?
Scientists and doctors recommend that children and adolescents ages 5 and up get the vaccine, even if they've had COVID-19. We don't know how long someone is protected from getting sick after recovering from the virus. And we don't know whether the immunity developed against one strain provides enough protections against new variants.
Here's what we know: These free, safe, and effective vaccines will help kids fend off the worst outcomes of this infectious virus, including the highly contagious Delta variant.
9. Where can I find more information?
Centers for Disease Control and Prevention (CDC) COVID-19 Vaccines for Children and Teens
Pfizer BioNTech Fact Sheets
California's Safe Schools for All Hub
CDC Vaccination Recommendation for 5 to 11 Year Old Children
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Daily drinking of lemon water in the mornings on an empty stomach, it paves the way for reducing fat in your body, promoting multiple benefits, extraordinary. It contains therapeutic properties, that helps to maintain a healthy heart and improving your skin, lemon tea which helps eliminate toxins from the body.
A glass of water with lemon in morning will release toxins that stimulates and enhances the activity of the urinary tract, thanks to its diuretic properties. Also, lemon with warm water will fight against infections and will improve the healthy liver function.
Get ready to say goodbye to stomach ache, indigestion, constipation and diarrhea, By daily consumption of lemon water in the morning. In addition, helps to maintain healthy liver to improve your bile flow: American Cancer Society, they advised patients to consume this drink daily, For proper digestion that can reduce heartburn and constipation.
Daily drinking of lemon water will bring more tenderness in your life, lemon juice in a big glass of water will clean mouth also it will stimulate saliva production and remove the white pith and unpleasant on the tongue. In addition, it helps to get rid of teeth pain and gums, although you have to be cautious, brush your teeth before drinking lemon water in the morning.
Vitamin C and antioxidants in the lemon help to illuminate the skin and helps to fight free radicals and slow down the process of aging.
This time, our hero is potassium, which help you have a restful sleep, a healthy mind and a resistance to stress, essential factors for high blood pressure control. Additionally, lemon water helps cleanse and moisturize morning lymphatic system.
It's time to remember and about the extraordinary benefit of daily consumption of lemon water in the morning. Lemon contains citric acid and ascorbic acid properties, whichmetabolized very quickly in the body. This is extremely important because studies have shown that diseases are often associated with increased levels of acidity in the body. Moreover, this miraculous beverage and which neutralizes acids like uric acid in the joints. The benefits of lemon water are endless.
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1156525_Sarker,S_2021.pdf (1.67 MB)
Genomic Characterisation of a Novel Avipoxvirus Isolated from an Endangered Yellow-Eyed Penguin (Megadyptes antipodes)
posted on 2021-03-18, 02:35 authored by Subir SarkerSubir Sarker, Athukorala Vidanalage Ajani Priyadarshan AthukoralaAthukorala Vidanalage Ajani Priyadarshan Athukorala, TR Bowden, DB Boyle
Emerging viral diseases have become a significant concern due to their potential consequences for animal and environmental health. Over the past few decades, it has become clear that viruses emerging in wildlife may pose a major threat to vulnerable or endangered species. Diphtheritic stomatitis, likely to be caused by an avipoxvirus, has been recognised as a significant cause of mortality for the endangered yellow-eyed penguin (Megadyptes antipodes) in New Zealand. However, the avipoxvirus that infects yellow-eyed penguins has remained uncharacterised. Here, we report the complete genome of a novel avipoxvirus, penguinpox virus 2 (PEPV2), which was derived from a virus isolate obtained from a skin lesion of a yellow-eyed penguin. The PEPV2 genome is 349.8 kbp in length and contains 327 predicted genes; five of these genes were found to be unique, while a further two genes were absent compared to shearwaterpox virus 2 (SWPV2). In comparison with penguinpox virus (PEPV) isolated from an African penguin, there was a lack of conservation within the central region of the genome. Subsequent phylogenetic analyses of the PEPV2 genome positioned it within a distinct subclade comprising the recently isolated avipoxvirus genome sequences from shearwater, canary, and magpie bird species, and demonstrated a high degree of sequence similarity with SWPV2 (96.27%). This is the first reported genome sequence of PEPV2 from a yellow-eyed penguin and will help to track the evolution of avipoxvirus infections in this rare and endangered species.
(p. 194-194)
MDPI AG
https://doi.org/10.3390/v13020194
avipoxviruscomplete genomeendangered yellow-eyed penguinevolutionpenguinpox virus 2
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Key Primary Research 76
Ongoing clinical trials 11,070
Hematology 1,831
Surgery 1,429
Endocrinology 1,276
Urology 1,073
Hospice and palliative care 2
1. Loss of Life Expectancy by 10 Years or More From Elevated Aspartate Aminotransferase: Finding Aspartate Aminotransferase a Better Mortality Predictor for All-Cause and Liver-Related than Alanine Aminotransferase. (PubMed)
Loss of Life Expectancy by 10 Years or More From Elevated Aspartate Aminotransferase: Finding Aspartate Aminotransferase a Better Mortality Predictor for All-Cause and Liver-Related than Alanine Aminotransferase. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are 2 commonly ordered liver function tests, and ALT has long been considered more liver-specific than AST. Between the 2, the one which is better in predicting liver or non-liver-related mortality remains (...) ), other than just liver disease. All-cause mortality remained significantly increased, when high risk groups were excluded, such as frequent drinkers, hepatitis carriers, those died from nonmedical conditions, those died in the first 3 years, or advanced fibrosis index based on 4 factors or aspartate transaminase-to-platelet ratio index. Results were consistent between those returned for second visits and those analyzed in initial visits.Those with elevated AST (≥40 IU/L) had life expectancy cut short
2019 American Journal of Gastroenterology
2. Hepatitis C Virus Clearance by Direct-acting Antiviral Results in Rapid Resolution of Hepatocytic Injury as Indicated by Both Alanine Aminotransferase and Aspartate Aminotransferase Normalization (PubMed)
Hepatitis C Virus Clearance by Direct-acting Antiviral Results in Rapid Resolution of Hepatocytic Injury as Indicated by Both Alanine Aminotransferase and Aspartate Aminotransferase Normalization Background and Aims: Hepatitis C virus (HCV) infection results in hepatocytic injury with elevation of both alanine aminotransferase (ALT) and aspartate aminotransferase (AST). It remains to be determined if direct-acting antiviral treatment can terminate hepatocytic injury following virologic response
2018 Journal of clinical and translational hepatology
3. Association between De Ritis ratio (aspartate aminotransferase/alanine aminotransferase) and oncological outcomes in bladder cancer patients after radical cystectomy. (PubMed)
Association between De Ritis ratio (aspartate aminotransferase/alanine aminotransferase) and oncological outcomes in bladder cancer patients after radical cystectomy. New biological prognostic predictors have been studied; however, some factors have limited clinical application due to tissue-specific expression and high cost. There is the need for a promising predictive factor that is simple to detect and that is closely linked to oncological outcomes in patients with urothelial bladder cancer (...) (BC) who have undergone radical cystectomy (RC). Therefore, we investigated the clinical prognostic value of the preoperative De Ritis ratio (aspartate aminotransferase/alanine aminotransferase) on oncological outcomes in patients with urothelial BC after RC.We retrospectively evaluated clinicopathological data of 118 patients with non-metastatic urothelial BC after RC between 2008 and 2013 at a single center. The association between the De Ritis ratio and clinicopathological findings was assessed
2019 BMC Urology
4. Diagnostic Accuracy of Aspartate Aminotransferase to Platelet Ratio Index and Fibrosis 4 Scores in Predicting Advanced Liver Fibrosis in Patients with End-stage Renal Disease and Chronic Viral Hepatitis: Experience from Pakistan (PubMed)
Diagnostic Accuracy of Aspartate Aminotransferase to Platelet Ratio Index and Fibrosis 4 Scores in Predicting Advanced Liver Fibrosis in Patients with End-stage Renal Disease and Chronic Viral Hepatitis: Experience from Pakistan The aim was to assess the diagnostic accuracy of APRI and FIB-4 in assessing the stage of liver fibrosis in end stage renal disease (ESRD) patients with chronic viral hepatitis and to compare the two tests with standard tru-cut liver biopsy.The study was conducted (...) %) patients had both infections. The mean Ishak fibrosis score was 1.95 ± 2. Advanced fibrosis was noted in 37 (34%) patients. Univariate analysis showed that advanced liver fibrosis was associated with lower platelets counts (P=0.001) and higher aspartate aminotransferase (AST) (P=0.001), alanine aminotransferase (ALT) (P=0.022), APRI score (P=0.001) and FIB-4 score (P=0.001). On logistic regression analysis, only APRI score (P < 0.001) was found to be the independent variable associated with advanced
2018 Journal of translational internal medicine
5. Salivary and Serum Aspartate Aminotransferases and Alanine Aminotransferases in Insulin-Dependent Diabetes Mellitus and Normal Children: A Comparative Study (PubMed)
Salivary and Serum Aspartate Aminotransferases and Alanine Aminotransferases in Insulin-Dependent Diabetes Mellitus and Normal Children: A Comparative Study The aim of the study was to estimate and compare aspartate aminotransferases (AST) and alanine aminotransferases (ALT) levels in saliva and serum of insulin-dependent diabetes mellitus (IDDM) and normal children, and the objective was to evaluate the significance of these enzymes in assessing the salivary gland injury in IDDM children.The
2018 Journal of International Society of Preventive & Community Dentistry
6. The Effects of Extra Virgin Olive Oil on Alanine Aminotransferase, Aspartate Aminotransferase, and Ultrasonographic Indices of Hepatic Steatosis in Nonalcoholic Fatty Liver Disease Patients Undergoing Low Calorie Diet (PubMed)
The Effects of Extra Virgin Olive Oil on Alanine Aminotransferase, Aspartate Aminotransferase, and Ultrasonographic Indices of Hepatic Steatosis in Nonalcoholic Fatty Liver Disease Patients Undergoing Low Calorie Diet Coronary artery disease is the most common cause of death in the patients with nonalcoholic fatty liver disease (NAFLD). Studies have shown that there is a strong relation between the increase in the aminotransferase levels and fat accumulation in the liver with cardiovascular (...) complications, independent of all aspects of the metabolic syndrome. This study aimed to examine the effect of virgin olive oil on alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and the severity of steatosis in the NAFLD patients undergoing a weight-loss diet.This clinical trial was carried out on 50 patients with nonalcoholic fatty liver (mean age of 45.91 ± 9.61 years, mean BMI of 29.7 ± 0.58 Kg/m2) and the subjects were randomly assigned to the olive oil group (receiving
2018 Canadian journal of gastroenterology & hepatology Controlled trial quality: uncertain
7. Appropriateness phase 1 OHTAC recommendations: Annual health exams, aspartate aminotransferase testing, chloride testing, creatine kinase testing, ferritin testing, folate testing, and vitamin B12 testing
Appropriateness phase 1 OHTAC recommendations: Annual health exams, aspartate aminotransferase testing, chloride testing, creatine kinase testing, ferritin testing, folate testing, and vitamin B12 testing Appropriateness phase 1 OHTAC recommendations: annual health exams, aspartate aminotransferase testing, chloride testing, creatine kinase testing, ferritin testing, folate testing, and vitamin B12 testing Appropriateness phase 1 OHTAC recommendations: annual health exams, aspartate (...) , aspartate aminotransferase testing, chloride testing, creatine kinase testing, ferritin testing, folate testing, and vitamin B12 testing. Toronto: Health Quality Ontario (HQO). OHTAC recommendation. 2013 Final publication URL Indexing Status Subject indexing assigned by CRD MeSH Health Services Misuse; Health Services Needs and Demand; Humans; Methods Language Published English Country of organisation Canada Province or state Ontario English summary An English language summary is available. Address
2014 Health Technology Assessment (HTA) Database.
8. Essential roles of aspartate aminotransferase 1 and vesicular glutamate transporters in β-cell glutamate signaling for incretin-induced insulin secretion. (PubMed)
Essential roles of aspartate aminotransferase 1 and vesicular glutamate transporters in β-cell glutamate signaling for incretin-induced insulin secretion. Incretins (GLP-1 and GIP) potentiate insulin secretion through cAMP signaling in pancreatic β-cells in a glucose-dependent manner. We recently proposed a mechanistic model of incretin-induced insulin secretion (IIIS) that requires two critical processes: 1) generation of cytosolic glutamate through the malate-aspartate (MA) shuttle in glucose (...) metabolism and 2) glutamate transport into insulin granules by cAMP signaling to promote insulin granule exocytosis. To directly prove the model, we have established and characterized CRISPR/Cas9-engineered clonal mouse β-cell lines deficient for the genes critical in these two processes: aspartate aminotransferase 1 (AST1, gene symbol Got1), a key enzyme in the MA shuttle, which generates cytosolic glutamate, and the vesicular glutamate transporters (VGLUT1, VGLUT2, and VGLUT3, gene symbol Slc17a7
9. Metabolic effects of an aspartate aminotransferase-inhibitor on two T-cell lines. (PubMed)
Metabolic effects of an aspartate aminotransferase-inhibitor on two T-cell lines. An emerging method to help elucidate the mode of action of experimental drugs is to use untargeted metabolomics of cell-systems. The interpretations of such screens are however complex and more examples with inhibitors of known targets are needed. Here two T-cell lines were treated with an inhibitor of aspartate aminotransferase and analyzed with untargeted GC-MS. The interpretation of the data was enhanced (...) by the use of two different cell-lines and supports aspartate aminotransferase as a target. In addition, the data suggest an unexpected off-target effect on glutamate decarboxylase. The results exemplify the potency of metabolomics to provide insight into both mode of action and off-target effects of drug candidates.
10. Aspartate-aminotransferase to platelet ratio index score for predicting HELLP syndrome. (PubMed)
Aspartate-aminotransferase to platelet ratio index score for predicting HELLP syndrome. HELLP (hemolysis, elevated liver enzyme levels, low platelet counts)-syndrome is a rare but dramatic pregnancy-related illness. The difficult part of this syndrome is the lack of standardised diagnostic criterias and tests to be used to predict it. The aim of this study is determining the role of APRI score in the diagnosis of HELLP syndrome.In this cross sectional, retrospective study, patients with HELLP
11. Predictive value of the aspartate aminotransferase to platelet ratio index for parenteral nutrition associated cholestasis in extremely low birth weight infants. (PubMed)
Predictive value of the aspartate aminotransferase to platelet ratio index for parenteral nutrition associated cholestasis in extremely low birth weight infants. Parenteral nutrition (PN) improves the survival of premature infants. However, prolonged PN increases the risk of PN-associated cholestasis (PNAC).We aimed to evaluate the predictive value of aspartate aminotransferase (AST)-to-platelet ratio index (APRI) for PNAC in infants with extremely low birth weight (ELBW, birth weight < 1000 g (...) ) infants.We retrospectively reviewed the medical records of ELBW infants from March 2010 to February 2017. Clinical data and the serial APRI, AST, alanine aminotransferase (ALT), AST-to-ALT ratio, and direct bilirubin (DB) were analyzed. PNAC was diagnosed in infants with a history of PN for at least 2 weeks and direct bilirubin concentrations > 2 mg/dL after other causes of neonatal cholestasis were excluded.Among the 179 eligible ELBW infants, 56 (31.3%) were diagnosed with PNAC. APRI significantly
2019 BMC Pediatrics
12. Serum alanine aminotransferase/aspartate aminotransferase ratio is one of the best markers of insulin resistance in the Chinese population (PubMed)
Serum alanine aminotransferase/aspartate aminotransferase ratio is one of the best markers of insulin resistance in the Chinese population The alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ratio is reportedly associated with insulin resistance (IR). However, few studies have explored the relationship between the ALT/AST ratio and IR in the Chinese population. Here, we aimed to explore whether the ALT/AST ratio is associated and, if so, to what extent, with IR in the Chinese
2017 Nutrition & metabolism
13. Effects of Carbamazepine and Valproate on Serum Aspartate Aminotransferase, Alanine Aminotransferase and Gamma - Glutamyltransferase in Children (PubMed)
Effects of Carbamazepine and Valproate on Serum Aspartate Aminotransferase, Alanine Aminotransferase and Gamma - Glutamyltransferase in Children Epilepsy is one of the most common neurological diseases in childhood and adolescence. Carbamazepine (CBZ) and valproate (VPA) have been widely used as the first generation of antiepileptic drugs (AED).The aim of the study has been to evaluate and compare the effect of CBZ and VPA monotherapy on aspartate aminotransferase (AST), alanine (...) aminotransferase (ALT) and gamma-glutamyltransferase (GGT) serum levels in children.The study has included 100 patients (boys 57/girls 43, age range 1 to 18 years), who have been treated with CBZ or VPA, as initial monotherapy, for at least 12 months. Patients with liver lesions or patients who have been treated with other drugs have been excluded from the study. The initial serum enzyme levels (AST, ALT and GGT) and after 12 months of treatment have been compared.53/100 (53%) patients have been treated
2017 Medical Archives
14. Diagnostic value of FIB-4, aspartate aminotransferase-to-platelet ratio index and liver stiffness measurement in hepatitis B virus-infected patients with persistently normal alanine aminotransferase (PubMed)
Diagnostic value of FIB-4, aspartate aminotransferase-to-platelet ratio index and liver stiffness measurement in hepatitis B virus-infected patients with persistently normal alanine aminotransferase To assess the diagnostic value of FIB-4, aspartate aminotransferase-to-platelet ratio index (APRI), and liver stiffness measurement (LSM) in patients with hepatitis B virus infection who have persistently normal alanine transaminase (PNALT).We enrolled 245 patients with chronic hepatitis B: 95
2017 World Journal of Gastroenterology
15. Prognostic value of pretreatment serum alanine aminotransferase/aspartate aminotransferase (ALT/AST) ratio and gamma glutamyltransferase (GGT) in patients with esophageal squamous cell carcinoma. (PubMed)
Prognostic value of pretreatment serum alanine aminotransferase/aspartate aminotransferase (ALT/AST) ratio and gamma glutamyltransferase (GGT) in patients with esophageal squamous cell carcinoma. The levels of liver function tests (LFTs) are often used to assess liver injury and non-liver disease-related mortality. In our study, the relationship between pretreatment serum LFTs and overall survival (OS) was evaluated in esophageal squamous cell carcinoma (ESCC) patients.Our purpose (...) was to investigate the prognostic value of the preoperative alanine aminotransferase/aspartate aminotransferase (ALT/AST) ratio and gamma glutamyltransferase (GGT) in ESCC patients. A retrospective study was performed in 447 patients with ESCC, and follow-up period was at least 60 months until death. The prognostic significance of serum LFTs were determined by univariate and multivariate Cox hazard models.LFTs including ALT, AST, LSR, GGT, TBA and LDH were analyzed. Serum LSR (HR: 0.592, 95% CI = 0.457-0.768, p
2017 BMC Cancer
16. Usefulness of aspartate aminotransferase to platelet ratio index as a prognostic factor following hepatic resection for hepatocellular carcinoma (PubMed)
Usefulness of aspartate aminotransferase to platelet ratio index as a prognostic factor following hepatic resection for hepatocellular carcinoma Liver function is a major prognostic factor following hepatic resection for hepatocellular carcinoma (HCC), which is well correlated with the degree of fibrosis. On the other hand, the presence of liver cirrhosis itself leads to a higher incidence of HCC than chronic hepatitis. Therefore, preoperative noninvasive markers of fibrosis are important (...) for the assessment of prognosis for treatment of HCC. The present study aimed to analyze whether aspartate aminotransferase to platelet ratio index (APRI) could predict prognosis following hepatic resection for HCC. The subjects were 162 patients who underwent hepatic resection for HCC between January 2000 and December 2011. The relationship between APRI and disease-free and overall survival were retrospectively investigated. In multivariate analysis, indocyanine green at 15 min (ICG-R15) ≥15% (P=0.0306), APRI
2018 Molecular and clinical oncology
17. Immunological Measurement of Aspartate/Alanine Aminotransferase
Immunological Measurement of Aspartate/Alanine Aminotransferase Immunological Measurement of Aspartate/Alanine Aminotransferase - Full Text View - ClinicalTrials.gov Hide glossary Glossary Study record managers: refer to the if submitting registration or results information. Search for terms x × Study Record Detail Saved Studies Save this study Warning You have reached the maximum number of saved studies (100). Please remove one or more studies before adding more. Immunological Measurement (...) of Aspartate/Alanine Aminotransferase The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our for details. ClinicalTrials.gov Identifier: NCT03562585 Recruitment Status : Completed First Posted : June 19, 2018 Last Update Posted : June 19, 2018 Sponsor: Chuncheon Sacred Heart Hospital Information provided by (Responsible Party): Ki Tae Suk, Chuncheon Sacred
18. Prognostic role of aspartate aminotransferase-lymphocyte ratio index in patients with metastatic colorectal cancer: results from the randomized ITACa trial (PubMed)
Prognostic role of aspartate aminotransferase-lymphocyte ratio index in patients with metastatic colorectal cancer: results from the randomized ITACa trial The aim of this study was to investigate the role of pre-treatment aspartate aminotransferase-lynphocyte ratio (ALRI) as a predictor of prognosis and treatment efficacy in patients with metastatic colorectal cancer (mCRC) enrolled in the prospective multicenter randomized ITACa (Italian Trial in Advanced Colorectal Cancer) trial to receive
2018 OncoTargets and therapy Controlled trial quality: uncertain
19. Prognostic value of aspartate aminotransferase to platelet ratio index as a noninvasive biomarker in patients with hepatocellular carcinoma: a meta-analysis (PubMed)
Prognostic value of aspartate aminotransferase to platelet ratio index as a noninvasive biomarker in patients with hepatocellular carcinoma: a meta-analysis The aspartate aminotransferase-to-platelet ratio index (APRI) has been correlated with clinical outcome in patients with hepatocellular carcinoma (HCC), but controversial results were obtained with previous studies. This study was aimed to evaluate the prognostic value of the APRI in patients with HCC.A literature survey was conducted
2018 Cancer management and research
20. FibroScan, aspartate aminotransferase and alanine aminotransferase ratio (AAR), aspartate aminotransferase to platelet ratio index (APRI), fibrosis index based on the 4 factor (FIB-4), and their combinations in the assessment of liver fibrosis in patients (PubMed)
FibroScan, aspartate aminotransferase and alanine aminotransferase ratio (AAR), aspartate aminotransferase to platelet ratio index (APRI), fibrosis index based on the 4 factor (FIB-4), and their combinations in the assessment of liver fibrosis in patients The aim of this study was to assess the effects of FibroScan, aspartate aminotransferase and alanine aminotransferase ratio (AAR), aspartate aminotransferase to platelet ratio index (APRI), fibrosis index based on the 4 factor (FIB-4
2015 International journal of clinical and experimental medicine
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CRP Testing to Guide Antibiotic Prescribing for COPD
In this randomized trial, C-reactive protein testing was used as a point-of-care aid in determining whether antibiotic therapy was warranted in patients with an acute exacerbation of COPD. Among 653 outpatients, there was significantly less use of antibiotics with CRP guidance, with no evidence of any worse outcome.
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A 60-year-old man presented to the otolaryngology clinic with a 2-month history of a firm, painless mass on the right side of his neck. He had no history of smoking or heavy alcohol use and denied any changes in voice or difficulty swallowing. Physical examination showed unilateral enlargement of the right tonsil. What is the correct diagnosis?
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In the 1940s, scientist Linus Pauling discovered the abnormality in the hemoglobin protein molecule that caused sickle cell disease. When deoxygenated, this abnormal hemoglobin protein (sickle hemoglobin or HbS) polymerizes and causes red blood cell sickling that leads to hemolysis, chronic anemia, inflammation, and vascular occlusion...
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The liver has a range of responses to drug-induced injury, with a number of phenotypes. In addition, idiosyncratic reactions may occur as a consequence of both direct drug action and indirect drug effects. Antibiotics are the most common cause of drug-induced liver injury.
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Less-Taxing Spontaneous Breathing Trial Was Better for Liberating Patients from the Ventilator
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The Power and Limits of Classification — A 32-Year-Old Man with Abdominal Pain
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Risk Stratification and D-Dimer Can Safely Exclude Pulmonary Embolism in Pregnant Patients
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Acanthamoeba Keratitis
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The cluster supports proposals that make use of the tools of systems and synthetic biology to generate a comprehensive understanding of complex interactions within biological systems across different scales. Proposals using experimental and computational approaches in a synergistic fashion are a high priority. The cluster seeks proposals using tractable established or emerging model systems that focus on: regulatory and metabolic network dynamics; fundamental rules governing complex behavior; and microbial communities and their interactions.
Mechanistic modeling of regulatory, signaling, and metabolic networks and the interactions among networks.
The origins of life, the minimal cell and emerging behaviors of complex interactions.
Novel experimental and computational tool development including those that facilitate the exploration and discovery of fundamental molecular scale mechanisms.
Molecular to system-wide scale rules of assembly and function in natural or synthetic microbial communities and symbiotic partnerships.
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Chemical Imbalance Causing Depression Nhs 2019
July 14, 2018 by Richard
Chemical Imbalance Causing Depression Nhs 2019 3.5 out of 5 based on 130 ratings.
Bipolar disorder is a mental illness characterised by episodes of mania ('highs') and depression. Previously known as manic depression, the condition is the sixth leading cause of disability in the world, according to the World Health organisation.
Honey. Honey is known to possess a sticky texture, which helps in pulling out the dirt that might be present in the pores of your skin. Honey is known to play the role of an antimicrobial and helps to destroy bacteria, which is a major cause for developing acne.
MTHFR gene mutations can cause absolutely no symptoms at all. They can also cause severe irreversible health conditions such as Down's syndrome.
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The exact cause of bipolar disorder is unknown. Chemical imbalance in the brain. and episodes of depression may be the result of noradrenaline levels becoming.
Dec 30, 2010. The chemical dopamine is produced naturally in the body and functions. and the habitual use of antidepressants, symptoms such as depression, syndrome may be caused by an imbalance in the brain of dopamine since.
NHS Direct Wales is a health advice and information service available 24 hours a day, every day. You can call us on 0845 46 47 if you are feeling ill and are unsure what to do, or for health information on a wide range of conditions, treatments and.
She did an evaluation and then told me this story: "The problem with you," she explained, "is that you have a chemical imbalance. though serotonin plays a role in depression, low serotonin is likel.
Is Depression Just Bad Chemistry?. and his colleagues found that 84.7 percent of participants found it "likely" that chemical imbalances cause depression.
What chemical imbalance causes bipolar disorder? Quora. Finally, in the cases of each anxiety, depression and manic depression, scientists are learning impor.
Moving Beyond 'Chemical Imbalance' Theory of Depression. Unfortunately, the alleviation of depression's symptoms with these treatments remains elusive;.
Discover the symptoms of PMDD, include mood swings, breast tenderness, headache, with the neurotransmitters (chemicals that serve as messengers) in the brain. Further, mood changes and depression that may accompany PMDD can be. Women with hormone imbalances can seek treatment from medications like.
The Chemical Imbalance Explanation for Depression: Origins, Lay Endorsement, and Clinical Implications Christopher M. France Cleveland State University
This is a list of registered systematic reviews that are currently under-way. Protocols for these reviews may already be published or in preparation for publication within 6 months of initial registration.
Hormones are chemical messengers that help regulate different processes in the body. From feeling hungry. depression and anxiety • feeling tired. Available from: https://www.nhs.uk/conditions/menopause/#symptoms-of-the-menopause 5.
Feb 5, 2018. Doctors can help users detox while limiting withdrawal symptoms. people with depression, these drugs can correct a chemical imbalance.
Overview of liver disease, including various types, and related laboratory tests
HL7 Version 3 Standard: Structured Product Labeling, Release 4 DESCRIPTION. The HL7 Version 3 Structured Product Labeling (SPL) specification is a document markup standard that specifies the structure and semantics of the content of authorized published information that accompanies any medicine licensed by a medicines licensing authority.
Scientific studies have found that numerous brain areas show altered activity in patients suffering from depression, and this has encouraged advocates of various theories that seek to identify a biochemical origin of the disease, as opposed to theories that emphasize psychological or situational causes.
Related: Depression Support Groups Delaware County Pa
Quite what triggers off this chemical imbalance is the subject of hot debate by scientists, In the past, people with symptoms of depression or anxiety were often. been able to refer patients on the NHS, but waiting times for nonurgent cases.
Read about what causes depression. There's no single cause and many possible risk factors.
Apr 21, 2015. September 2016. http://content.digital.nhs.uk/searchcatalogue?productid=. Even before the concept of chemical imbalance was first formally. The treatment of this disease followed pathways where symptoms were to be.
Shooting The Odds: Dr. Shipko is a psychiatrist in private practice in Pasadena, CA and author of Surviving Panic Disorder and Xanax Withdrawal.Drawn from his clinical experience, his blog concerns adverse effects of SSRI antidepressants, particularly withdrawal related effects.
The Terms on a Food Label to Ignore, and the Ones to Watch For. Food labels are meant to be easy to read, but some terms on those labels are marketing lingo or mean something different than you may think.
Signs and Symptoms of Male Hormone Imbalance. Many of the symptoms of male hormonal imbalances come on very gradually. Depression or anxiety;
a recurring pain or discomfort in the chest that happens when some part of the heart does not receive enough blood. It is a common symptom of coronary heart disease, which occurs when vessels that carry blood to the heart become narrowed and blocked due to atherosclerosis.Angina feels like a pressing or squeezing pain, usually in the chest.
Jul 28, 2015. Anxiety and depression could be linked to the presence of bacteria in the intestines, scientists have found.
What causes gallstones? Gallstones are thought to develop because of an imbalance in the chemical make-up of bile inside the gallbladder. In most cases the levels of cholesterol in bile become too high and the excess cholesterol forms into stones.
What Causes Depression? Myths About Chemical Imbalances A closer look at physicians, drug companies, and the medicalizing of depression. Posted Mar 13, 2014
Ménière's disease is a rare disorder that can cause vertigo, tinnitus, hearing loss, and a feeling of pressure inside the ear. Learn about its symptoms and treatments.
This section will focus mainly on Major Depressive Disorder (MDD), commonly referred to as "Major Depression" or simply, "Depression." Other mood-related conditions will be explored, including Bipolar Disorders, Dysthymic Disorder, Anxiety Disorders, Seasonal Affective Disorder, Mood Disorder Due.
Many things are quoted as 'medical causes' of depression, including the good old 'chemical imbalance'. Which are really causes, and which symptoms?
By Dr. Joseph Mercola Contributing writer for Wake Up World Do you know what causes depression? Many people would respond that it's due to a chemical imbalance in the brain.
According to some statistical websites I was reading on the internet, suicide is the eighth leading cause. and depression.
However, the most common symptoms of depression to look out for include:. chemicals in the brain, known as endorphins, which causes an improvement in.
It's often said that depression results from a chemical imbalance, but that figure of speech doesn't capture how complex the disease is. Research suggests…
Aug 9, 2017. An imbalance of the neurotransmitters is thought to play a part in. The role these chemicals have in causing, or treating, depression is unclear.
Related: Dating Someone With Depression And Social Anxiety
Breast implant symptoms are from silicone which is a known adjuvant (catalyst) for auto-immune symptoms and because silicone is a toxic soup of chemicals
The prevalence of depression presents economic problems as well — it's one of the most common causes of disability. in the way things are supposed to work in the brain — chemical imbalances that ca.
Mother And Daughter Camp For Depression Mother-Daughter Retreat is offered to current Camp DeSoto campers who are in the 8th, 9th, and 10th grades and their mothers. This weekend is a fun chance. When Maggie Wolf began struggling with depression and an eating disorder, nobody understood her pain. Including her mother, getting help for her daughter, She was the mother to
Emotional and mental symptoms of depression can include:. There is still speculation, however, as to whether this chemical imbalance is a cause or. The NHS – an alternate to a private practice in the UK is seeing your GP and asking for a.
For over three decades, scientists have attributed a chemical imbalance in the brain as the source of major depression. Now, a new study provides an explanation
Major depressive disorder (MDD), also known simply as depression, is a mental disorder characterized by at least two weeks of low mood that is present across most situations. It is often accompanied by low self-esteem, loss of interest in normally enjoyable activities, low energy, and pain without a clear cause. People may also.
While chemical imbalance is one of the causes of depression, it can be caused by several other factors such as genes, stressful events, and seasons.
There are many symptoms of hormone imbalance including: Premenstrual syndrome (PMS); Weight gain; Depression or mood swings; Sleep problems; Fatigue.
Evidence-based information on depression chemical imbalance from hundreds of trustworthy sources for health and social care. Make better, quicker, evidence based decisions.
The cause of depression is still unknown, but most current research points to a chemical imbalance in the brain, making it a physical disease that someone cannot simply "snap out of." Though there is.
Are Anxiety Disorders Caused By a Chemical Imbalance?. Assuming a chemical imbalance is what causes your anxiety and not the other way. depression and mental.
Sep 28, 2015. Many women suffer with hormonal symptoms thanks to an imbalance in the primary female hormone 'Oestrogen'. Oestrogen controls the first part of the menstrual cycle, causes changes in the. Irritability or depression.
How treatment helped me to live with depression and anxiety. By causing a change to your brain chemistry, antidepressants may lift your mood. and there is no scientific evidence that depression is caused by a chemical imbalance which.
But for over 16 million American adults, depression is a daily struggle. Depression is a chemical imbalance in the brain. It could be thyroid issues or other imbalances that are causing the symptom.
Depression has a wide range of physical and psychological symptoms, but the. even biological factors, including your family history or a chemical imbalance in.
Atypical Depression Bipolar Spectrum Bipolar spectrum disorder may affect. In the Mood Spectrum model depression and bipolar disorder are seen as the. Atypical symptoms of depression such as. Bipolar & Bipolar Spectrum Practical Clinical tips for the GP. Atypical depression- Hypersomnia, hyperphagia, leaden paralysis, reactive mood to stresses Key words: Affective disorder spectrum, bipolar I, bipolar II, long-term course,
Related: History Of Depression As A Disorder
It is not electroconvulsive therapy. While the exact cause of depression is not known, the leading scientific theory is that it is caused by an imbalance of the brain's neurotransmitters, which are ch.
Apr 13, 2018. GAD is a long-term condition that causes you to feel anxious about a wide. an imbalance of the brain chemicals serotonin and noradrenaline, which. to distinguish from other mental health conditions, such as depression.
Sleep Disordered Breathing Icd Code Newest Otc Sleep Aid with Sleep Aids Music and Insomnia When Coming Off Period Sleep Deprivation Meditation Tylenol Pm Sleep Aid.
Often there is more than one cause of depression. Causes of depression. Chemical imbalance. People with depression have an imbalance of chemicals in the brain.
A hiccup occurs as a result of a rush of air into the lungs. Everyone gets hiccups from time to time, but a long-lasting attack of hiccups may require investigation. This article looks at the causes of hiccups, which can include lifestyle factors or medical conditions. Pick up some tips on how to get rid of hiccups.
Feb 12, 2016. These effects can interact with the symptoms of mental distress. symptoms, not the targeted reversal of underlying chemical imbalances. College London and also works as a consultant psychiatrist in the NHS in London. of 40+ books, among them The Future of Mental Health, Rethinking Depression,
According to a Korean study recently presented at the annual meeting of the Radiological Society of North America (RSNA), researchers have identified a chemical imbalance in the. imbalanced ratio i.
Aug 17, 2011. Nicotine is the ingredient that causes physical addiction to tobacco. A variety of different brain chemicals are altered each time you. Some suggest it's the long- term effect of nicotine on the brain that causes depression,
Bipolar disorder is widely believed to be the result of chemical imbalances in the. between periods of elevated or 'high' moods (mania) and depressed or 'low'.
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FGF-1 possess broad mitogenic and cell survival activities, and is involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. Very important part in FGF-1 functioning is connected with its translocation within a cell - from cytoplasm to nucleus. There are several proteins discovered to be binding partners for FGF-1, helping it in its activities. It has been shown that FGF-1 for sure interacts specifically with intracellular proteins, such as FIBP, p34 and CK2 but it has been also initially described that there are new potential binding partners: nucleolin, nucleophosmin and major vault protein (MVP).
Major vault protein, nucleolin and nucleophosmin are potential binding partners for FGF-1. It was shown by means of mass spectrometry that these proteins, among some others, were present after performing fishing experiments using streptavidin tag attached to FGF-1 and streptavidin dynabeads. However, it is not clear if these three proteins interact with FGF-1 directly or if they just exist in a complex of a few proteins interacting with FGF-1. As MVP, nucleolin and nucleophosmin are very interesting intracelular proteins we decided to study these probable interactions as well as the colocalization in the cell and the fates of these partner proteins.
Major vault protein is a main protein of vault particles which are present in large numbers (10.000 - 1.000.000 vaults per cell) in the cytoplasm of most eukaryotic cells. MVP is thought to be present in 96 copies per vault, based on the observed symmetry of the particle and the fact that MVP accounts for 75% of the total protein mass of the particle.
MVP takes part in transport mechanisms, signal transmission and immune responses and is overexpressed in multi-drug resistance cells.
Nucleolin is DNA and RNA binding protein involved in regulation of gene transcription, chromatin remodeling, RNA metabolism and ribosomal RNA synthesis. Nucleolin contains several functional domains that mediate its functions. The N-terminal part contains multiple phosphorylation sites and is rich in acidic amino acids. The central part of nucleolin includes four RNA binding domains (RBD) and the C-terminal part contains glycine and arginine rich domain (termed RGG or GAR domain).
Nucleophosmin is a protein that is involved in regulation of cell growth, proliferation, apoptotic response to stress, oncogenic stimuli (such as DNA damage and hypoxia), and it can modulate the activity and stability of crucial tumour suppressor proteins such as p53.
Fig. Model of vaults. MVP structural repeats 2, 5, 6, and 7 (gray) were modeled based on the 3-4 domain structure (color) and placed to form a continuous wall comprising the widest part of the vault particle. (Kozlov G. et al. (2006). Solution Structure of a Two-repeat Fragment of Major Vault Protein. J. Mol. Biol. 356, 444-452).
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There are so many ways to enhance your vision, and the team at GW Eye Associates Inc is happy to answer any and all questions that you may have about them. This willingness to listen and to educate has made our team one of the leading eye care and vision correction centers in the San Diego area.
Many patients ask us, "How does LASIK surgery compare to contact lenses?" Let's look into this issue right now.
LASIK is a laser vision correction option that is designed to treat refractive errors. Using a safe surgical laser, an eye surgeon is able to reshape the corneal contour. By doing this, light that passes through the eyes will properly focus on the retina, which is the light-sensitive tissue located at the back of the eyes.
Good candidates for LASIK are people who are at least 18 years old, not pregnant or nursing, and who suffer from a refractive error. It's important that LASIK candidates have had a stable vision prescription for at least a year leading into surgery, and that they have not experienced an injury or eye infection within the last year as well. Patients with thin corneas and patients who experience dry eye syndrome are not good candidates for LASIK.
There are numerous advantages to LASIK surgery. For one, the results are long-lasting, allowing patients to see clearly without the aid of corrective lenses for years and years to come. In addition, the procedure is quick and the recovery period is brief as well.
LASIK can also help prevent issues with eye allergies when compared to contact lenses. Sometimes people with eye allergies experience worse issues with symptoms because pollen and other irritants get trapped under or on a contact lens. This is not an issue with LASIK.
Contact lenses are a reliable option for correcting vision. These lenses are worn in the eye and help improve clarity and quality of vision. There are different kinds of contact lenses that may be used depending on the needs of the patient.
Good candidates for contact lenses are patients who may not be ideal candidates for LASIK or other refractive procedures and would prefer to not wear glasses. Since there are different kinds of contact lenses available, the vast majority of people who require vision correction of some form will be able to wear contact lenses of some kind.
Compared to LASIK, contact lenses are more affordable up front. (Though some studies and number crunchers suggest a lifetime of contacts may be just as much as a LASIK surgery.) Contact lenses are a non-surgical eye care solution, which means no risk of severe side effects or complications.
Weighing all pros and cons is crucial for good vision care. During your consultation with our team, we will be more than happy to answer all of your questions and address your concerns so that you can make a confident decision about your vision options.
If you would like to learn more about your options for enhancing your vision and improving the overall health of your eyes, be sure to contact our team of eye care specialists today. The entire team here at GW Eye Associates Inc looks forward to your visit and helping you make the best possible choices when it comes to advanced eye care.
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Research article | Open | Open Peer Review | Published: 07 February 2017
Musculoskeletal pain and co-morbid insomnia in adults; a population study of the prevalence and impact on restricted social participation
Shula Baker ORCID: orcid.org/0000-0003-2222-24911,
John McBeth1,2,
Carolyn A. Chew-Graham1,3 &
Ross Wilkie1
BMC Family Practicevolume 18, Article number: 17 (2017) | Download Citation
Comorbidity is common in patients consulting in primary care. Musculoskeletal pain and insomnia each increase the risk of the other. Co-occurrence may pose an increased burden on well-being. However, the prevalence and impact of co-existing pain and insomnia in adults living in the community who may present to primary care is unclear. The aim of this study was to report the prevalence of pain and insomnia in adults registered with primary care, and to examine the impact of co-occurrence on social activities.
This population-based prospective cohort study of adults aged ≥18 years (n = 1181) used health survey data collected via baseline and 12 month follow-up questionnaires. Baseline data on pain, insomnia (4 symptoms: delayed sleep onset, difficulty maintaining sleep, early waking and non-restorative sleep) and putative confounders and social activity restriction at follow up was collected. Associations between baseline pain, insomnia and restricted social activities (RSA) at 12 months were examined using logistic regression, with adjustment for confounders. Interaction terms between pain and each insomnia symptom were examined in final models.
Mean respondent age was 49.6 (SD ± 15.2) years, 55.7% were female. At baseline, 880 (74.5%) reported pain, 122 (10.3%) delayed sleep onset, 298 (25.2%) difficulty maintaining sleep, 188 (15.9%) early wakening, and 215 (18.2%) reported non-restorative sleep. At follow-up 200 (16.9%) reported RSA. Pain and each insomnia symptom were associated with RSA at 12 month follow-up; pain [unadjusted odds ratio (OR:2.3;95%CI:1.5,3.5), delayed sleep onset (OR:6.1;95%CI:4.0,9.1), difficulty maintaining sleep (OR:3.2;95%CI:2.3,4.4), early wakening (OR:4.1;95%CI:2.9,5.9), and non-restorative sleep (OR:4.0; 95%CI:2.8,5.8). Only delayed sleep onset (OR:2.6;95%C:1.5,4.5) remained significantly associated with restricted social activities in the fully adjusted model. There was a significant interaction between pain and delayed sleep onset (OR:0.3;95%CI:0.1,0.99; p = .049) and restricted social activity at 12 months in the final multivariable model.
Pain and insomnia commonly co-occur, resulting in greater impact upon subsequent functional ability. Delayed sleep onset is the insomnia symptom most strongly associated with reduced functional ability. Clinicians should be aware of the common co-occurrence of insomnia symptoms, inquire about sleep in patients consulting with pain, and offer interventions that target both sleep and pain.
Musculoskeletal pain is common in adults and is a frequent reason for consultation to primary health care [1]. One quarter to one third of the general population report low back, hip or shoulder pain and one in five experience chronic pain (i.e. pain that lasts for three months or more) [2, 3]. Musculoskeletal pain impacts on physical and mental health, and mortality risk [4, 5]. Thirty percent of adults in the general population report significant sleep disturbance and 6% to 10% meet diagnostic criteria for insomnia [6], defined as difficulty initiating or maintaining sleep, or nonrestorative sleep, for at least 1 month [7]. Left untreated, insomnia is associated with an increased incidence of depression, anxiety [8] and worse physical health [9]. Insomnia frequently occurs in patients with chronic pain with the prevalence of co-occurrence ranges between 50% and 88% [10, 11]. However, the prevalence and impact of co-existing musculoskeletal pain and insomnia in adults living in the community who may present to primary care is unclear.
Musculoskeletal pain and insomnia have a reciprocal relationship, with each condition increasing the risk of the other which may augment the burden on health and well-being [12]. The mechanisms underlying the association appear to be complex and multi-factoral. Sleep disruption may be attributed to musculoskeletal pain arising from painful stimuli during sleep, which can induce microarousal and increase wakefulness [11]. There is also evidence to suggest that recurrent sleep deprivation and disruption (especially disruption of slow wave sleep) for three consecutive nights or more can decrease an individual's pain threshold, amplify negative mood and produce somatic symptoms [10, 11].
Social participation involves taking part in social activities and hobbies as well as fulfilling social roles such as being a worker, carer or community member [13]. Maintaining social participation is a clinically important outcome, potentially modifiable by intervention, and a target for intervention in primary care [14]. Restricted social activity is associated with higher rates of morbidity and mortality and lower life satisfaction and health-related quality of life [15, 16]. The aim of this prospective cohort study was to report the prevalence of co-morbid pain and insomnia in community-dwelling adults registered with primary care and its association with restricted social activities.
Study design and procedure
The study was a population-based prospective cohort study exploring headache prevalence in the general adult population. Five general practices were selected from 15 practices constituting the North Staffordshire GP Research Network, to contain a mix of urban and rural settings, and a spread of social class. The practice age/sex registers were downloaded with unique identifiers and sampling was conducted by obtaining randomly generated samples of 1000 persons, aged 18 and over, from each of 5 general practices in North Staffordshire (total sample of 5000). The sample size was determined based upon expected headache prevalence. As this study was concerned with pain in any body part, so included many additional pain sites, the sample size was also sufficient for the purpose of this research question. After excluding those individuals who had recently moved, died or were unable to participate due to ill health (N = 243,4.9%) a total of 4757 persons were invited to take part in the study. In the UK over 95% of the population are registered with a general practice and provide representative samples of the general population [17]. Ethical approval was obtained from the North Staffordshire Local Research Ethics Committee. All participants provided informed consent to participate in the study.
Potential participants were mailed a baseline questionnaire that collected data on pain, insomnia and putative confounders.
Assessment of musculoskeletal pain
To assess musculoskeletal pain participants were asked to indicate the site of any pain lasting one day or longer that they had experienced during the last month on a blank body manikin (front and back views). Pain manikins are valid and reliable tools for recording pain prevalence in self-administered questionnaires [18, 19]. Using their reports of pain, participants were classified into 'any pain' (any shading of pain on the manikin) or 'no pain' (no shading) groups.
Identification of insomnia
The four-item Estimation of Sleep Problems Scale [20] was used to examine sleep quality and identify insomnia. The scale asks about recent problems with sleep and contains items on the most commonly occurring symptoms of poor sleep quality: delayed sleep onset ('During the past four weeks did you have trouble falling asleep?'); sleep maintenance ('During the past four weeks did you wake up several times per night?'); early wakening ('During the past four weeks did you have trouble staying asleep, including waking up far too early?'); and non-restorative sleep ('During the past four weeks did you wake up after your usual amount of sleep feeling tired and worn out?'). Participants indicate the frequency in the past month that they have experienced difficulties in each of the four sleep components on a 3-point scale ranging from 0 to 2 (0 = not at all; 1 = on some nights; 2 = on most nights). For this analysis "on most nights" was used to define the presence of each respective sleep problem. This method of determining those with insomnia has been validated for use both in individuals with pain [21] and the general population [22].
Putative confounders
Putative confounders were demographics (age, gender), and socio-economic status (occupational class: manual (skilled manual, partly-skilled or unskilled roles professional/managerial, semi-routine, routine) / non-manual (professional, managerial or skilled non-manual roles)), anxiety, depression and physical health related quality of life. Levels of anxiety and depression were measured using the Hospital Anxiety and Depression Scale (HADS) [23]. The HADS performs well in assessing severity and identifies cases of anxiety and depression in hospital practice, for which it was first designed, primary care and in the general population [24]. The sensitivity and specificity of each scale to detect cases when clinical diagnosis is considered as the gold standard ranges between 70 and 80% [24, 25]. The HADS, along with the Geriatric Depression Scale, have been identified as the best instruments to measure mood and behaviour in older adults in observational studies and trials, scoring highly for practicality, feasibility, psychometric properties and relevant content [26]. The HADS scale consists of 14 items scored on a Likert scale of 0–3: 7 items ask about symptoms of anxiety and give a total score of 0–21, and 7 items ask about symptoms of depression, giving a total score of 0–21. Higher scores represent more frequent symptoms of depression/anxiety. For both scales scores of 0–7 were classified as a non-case, 8–21 a probable case using guidelines by the original authors [23]. Scores of ≤7 are considered 'normal' in the general adult population, while those of 8 or more are suggestive of a disorder [24]. HADS has been shown to have good sensitivity and specificity when a cut-off of ≤7 is used to identify probably cases of depression and anxiety in samples of primary care patients [24].
Physical health related quality of life was measured using the Medical Outcomes Short-Form 12 (SF-12) physical component summary score [27]. Computation of the PCS component was achieved by multiplying each indicator variable by a respective physical regression weights provided as part of the SF-12 scoring algorithm [27]. As in other studies [28], PCS score tertiles were then used in the analyses for the ease of interpretation, with the highest third used as the referent group.
Identifying restricted social activity at follow-up
Participants who returned a baseline questionnaire, and who agreed to further contact, were mailed a follow-up questionnaire 12 months later. A single item from the SF-12 was used to measure RSA at 12 month review; 'Has your health limited your social activities (like visiting friends or close relatives)?' RSA was defined as responses of 'All'/'Most'/'A good bit'/'Some of the time', and those responding 'A little bit of the time' or 'None of the time' were defined as not having RSA. This point was chosen based upon the extent of restriction reported being judged as likely to reduce functional ability, and the total number reporting RSA exceeding 10% of the overall sample. Baseline RSA was included as a putative confounder, and was measured and categorised using the same method.
A complete-case analysis was conducted that included only those participants with complete data at baseline and follow-up. First, the distribution of baseline variables were examined by pain and insomnia status with differences tested for significance using Chi-square or Kruskal Wallis tests where appropriate. Bootstrapped (n = 1000) 95% confidence intervals were calculated for the prevalence of pain and each insomnia symptom to provide an estimation for the study population. Univariate logistic regression models examined the relationship between pain and insomnia, and RSA at 12 month follow-up, adjusting for age, gender, and occupational class. Pain and insomnia were then included in the same multivariate model which was cumulatively adjusted for: i) putative confounders age, gender and occupational class (model 1), ii) anxiety, depression and physical health related quality of life (model 2), iii) baseline social participation (model 3). Finally, to determine whether the association between pain and RSA at 12 month follow-up was moderated by insomnia, an interaction term between pain and each insomnia symptom was included separately adjusting for all confounders (model 4), and then all interaction terms were included in the same model. Outliers were tested for by looking at for studentized residuals larger than 3 for all variables in the model. None were found.
Continuous covariates were standardised prior to entry into the regression analysis. Results are reported as odds ratios (OR) with 95% confidence intervals (95%CI). Model goodness of fit was examined for each model using the area under the Receiver Operating Characteristic curve (AUROC) to examine predictive power, and the Hosmer-Lemeshow test to highlight the goodness-of-fit to the data. AUROC values are measures of a model's ability to discriminate between those with RSA at 12 months and those without. Traditionally values of 0.7 or more represent moderate accuracy/discrimination [29]. Analysis was performed using SPSS 19.0 and Stata 13.0 for Windows
Of 4757 participants who were eligible to take part, 2662 (56.0%) returned a completed questionnaire at baseline. Compared to participants, non-participants were younger (mean age: 47 years cf. 51 years; p < 0.001) and more likely to be male (52 cf. 42%; p < 0.001). After excluding those who refused further contact (n = 247), decedents (n = 84), those who did not respond at follow-up (n = 340), or had incomplete data (n = 810), 1181 persons were available for analysis at follow up (Fig. 1). Comparison to UK Census data [30] showed the analytical sample to be similar in terms of gender (55.7 female cf. 51.9%) with fewer young adults (19.1% aged 18–34 cf. 29.4%) and more middle aged adults (61.4% aged 35–64 cf. 50.0%).
Flow diagram of participants
Participant characteristics
Participant mean age was 49.6 (Standard Deviation (SD) ±15.2) years and 658 (55.7%) were female (Table 1). At baseline, 880 (74.5%) reported pain and 411 (34.8%) reported one or more insomnia symptoms; 122 (10.3%) reported delayed sleep onset, 298 (25.2%) difficulty maintaining sleep, 188 (15.9%) early wakening, and 215 (18.2%) non-restorative sleep. The proportion of individuals with each respective sleep problem who reported additional sleep problems is shown in Table 2. 349 (29.6%) responders reported both pain and insomnia. This was 39.7% of those who reported pain, and 84.9% of those who reported insomnia. At 12 month follow-up, 200 (16.9%) reported RSA. Of this group, 109 (54.5%) reported pain and insomnia at baseline, 62 (31.0%) reported pain only, 17 (8.5%) reported one or more insomnia symptoms and 12 (6.0%) reported neither pain nor insomnia.
Table 1 Participant characteristics by baseline pain and insomnia status
Table 2 The number and proportion of individuals with each insomnia symptom and pain (by column) who reported each of the other insomnia symptoms (by row)
The association between baseline pain, insomnia symptoms and restricted social activity
Pain and all four insomnia symptoms were associated with RSA at 12 month follow-up; baseline pain [unadjusted odds ratio (OR:2.3;95%CI:1.5,3.5), delayed sleep onset (OR:6.1;95%CI:4.0,9.1), difficulty maintaining sleep (OR:3.2;95%CI:2.3,4.4), early wakening (OR:4.1;95%CI:2.9,5.9), and non-restorative sleep (OR:4.0;95%CI:2.8,5.8). All symptoms were statistically significant (p < .001).
When pain and insomnia symptoms were included in the multivariable model with adjustment for age, gender and occupational class (model 1), the associations attenuated; difficulty maintaining sleep (OR:1.3;95%CI:0.8,2.1;p = .173) and early wakening (OR:1.5;95%CI:0.8,2.6;p = .265) were not significantly associated with RSA at 12 month follow-up. When adjusted for comorbidity (model 2), the associations between RSA at 12 month follow-up and pain and non-restorative sleep attenuated to non-significance (p = .918). Delayed sleep onset (OR:2.6;95%CI:1.5,4.5;p = .001) remained significantly associated with RSA in the fully adjusted model (model 3). Results for multivariable analyses are given in Table 3.
Table 3 Association between baseline pain and insomnia symptoms and restricted social activity at follow-up
Interactions between pain and difficulty maintaining sleep, early wakening and non-restorative sleep were none significant predictors of RSA at 12 month follow-up (p > 0.05). Although significant, the coefficient for the interaction term between pain and delayed sleep onset in the final multivariable model was less than 1 (OR:0.3;95%CI:0.1,0.99;p = .049), indicating the combined effect to be less than that expected were the effect of the two factors to be totally independent of each other. When all interaction terms were included in the same model, the odds ratio for pain became insignificant (OR:1.6;95%CI:0.8,3.0;p = .180), and only delayed sleep onset remained significant of the insomnia symptoms (OR:2.6;95%CI:1.5,4.5;p = .001). In addition to delayed sleep onset, baseline depression (OR:1.5;95%CI:1.3,1.8;p < .001), low physical health related quality of life (OR:1.9;95%CI:1.2,3.2;p = 0.01), and baseline RSA (OR:4.6;95%CI:3.0,7.1;p < .001) were independently associated with RSA at follow-up in the final multivariable model.
The study reports the extent of co-occurrence of pain and insomnia in a primary care population, and the extent of its association with problems getting out and about, and engaging in social activities. The findings highlight the common occurrence of musculoskeletal pain and insomnia in adults in primary care patients; almost one third patients reported co-existing pain and insomnia. More than four in every five respondents with insomnia reported pain. Baseline pain and each sleep problem were associated with RSA at 12 month follow-up. The association between RSA at follow-up and pain, difficulty maintaining sleep, early wakening and non-restorative sleep attenuated with adjustment for depression, anxiety, physical health related quality of life and baseline RSA. However, delayed sleep onset was significantly associated with RSA at 12 month follow-up following adjustment for all confounders.
There was no multiplicative interaction between pain and insomnia defined by difficulty maintaining sleep, early wakening or non-restorative sleep. However there was evidence that the relationship between baseline pain and RSA at follow up was augmented by the presence of an insomnia symptom. For example, having pain but not insomnia was not significantly associated with RSA at follow-up (p = .180), whereas this increased to a greater than 7-fold increase in odds of RSA when delayed sleep onset was present (OR:7.4;95%CI:4.2,13.0).
The prevalence of insomnia symptoms in this study is comparable with the 10-40% reported in other population surveys [31, 32]. The prevalence of pain (72%) was high but is comparable to that reported in previous studies of community-dwelling adults [33–35]. The levels of co-occurring insomnia and pain were comparable with other studies [36, 37]. The association between musculoskeletal pain and RSA and insomnia and RSA have been reported in older adults but not in the general adult population. A systematic review of available literature (details available from the corresponding author) found no comparable population studies that have reported on the impact of estimates of co-occurring pain and insomnia and their impact on restricted social activity.
This study includes a number of strengths and limitations. The 1181 participants were recruited from general practice registers, which provide a sampling frame representative of the general population [17]. Furthermore, the response rates were comparable with other population based prospective studies that have used postal questionnaires. As in all longitudinal studies there was some attrition and missing data. Responders to the baseline survey were more likely to be younger and female. Those included in the analysis, compared to those who responded at baseline but not to the follow-up questionnaire, were less likely to have pain at baseline (p = 0.002) and more likely to be younger (p < 0.001), but they were no more likely to have insomnia at baseline (p = 0.67) or be female (p = 0.89). Non-participation bias may occur but it is unknown if the relationship between pain, insomnia and RSA in those who did not respond is different to those included in the analysis. The generalizability of the data may be limited by the characteristics of the study sample; the area covered by the study is more deprived in terms of health, education, and employment, but has fewer barriers to housing and services, than England as a whole.
The available data covered potential confounders of the relationship between pain and insomnia and RSA, however other potential confounders of the relationship have not been included (e.g. educational attainment). The questionnaires used to measure insomnia, anxiety, depression and RSA have been validated for use in general population samples and in postal surveys. RSA was operationalised as a binary measure, produced by dichotomising the six-level of responses to a single question. A sensitivity analysis, performed to check whether the choice of cut-off affected the relationship between sleep and RSA, found the association was not dependent on the cut-off used to define RSA. Pain was assessed using blank body manikins, a standard data-capture method used in postal surveys. This method has been shown to be a valid and reliable assessment of pain in mid-life adults, although the validity of manikin-derived pain in older people is less clear. High levels of inter-rater reliability for pain scoring (Kappa >0.60) has been demonstrated using this data-capture method [20].
In the pilot work for this study, there were some responders who reported pain interfering with work and but did not indicate pain on the manikin. This may have occurred because pain that interferes with work may not last for one day or longer and would not be reported on the manikin. The high prevalence of pain suggests that recall bias may be present, however the estimates are comparable with other studies that have measured the same phenotype (any pain that have lasted for a day or longer in the last month). It is also possible that pain captured includes that which is not musculoskeletal in origin which would inflate the prevalence estimates, however the majority of pain lasting one day or longer that is reported by adults in primary care is likely to be musculoskeletal in origin [35]. It is also possible that pain intensity may influence the association of musculoskeletal pain upon subsequent social activity restriction, as musculoskeletal pain intensity has been shown to predict greater negative health impact [38]. This study considers pain arising in any part of the body, future research could examine whether the specific location of pain, or pain phenotype (e.g. widespread, regional or none) influence the association with RSA. The co-occurrence of sleep problems was high, with early awakening and delayed sleep onset rarely occurring in isolation (3.7% and 12.3% of individuals reported isolated symptoms respectively). While early awakening was most likely to co-occur with waking several times (93.1% of those with early awakening), delayed sleep onset often co-occurred with each of the other insomnia symptoms (60.7%, 73.0% and 77.0% respectively) suggesting it may be a marker of more severe symptoms. This may explain why delayed sleep onset was found to be most strongly associated with subsequent restricted participation.
This study has implications for primary care clinicians. Firstly, results support the idea that all adults consulting with musculoskeletal pain should be asked about concurrent insomnia, and patients who present with sleep problems should be asked about pain. The study indicates the importance of offering interventions to people where pain or sleep problems are identified. Current management options are limited and tend to target pain and insomnia separately: General practitioners can prescribe analgesics which target pain or, drugs which influence sleep (although these should not be prescribed long-term, due to the risk of addiction) and there is evidence to support such approaches [39]. However, there are known adverse effects to some medications that may limit their usefulness [39]. Psychological therapies and exercise are also known to be beneficial but are not commonly available [40]. A multidisciplinary holistic approach to management is likely to be the way forward [41]; however access to pain clinics which offer such an approach may be limited.
Approaches that reduce pain and insomnia is necessary to offer acceptable treatments for the large number of adults in the general population who experience both symptoms. Primary care clinicians provide support to patients to manage their symptoms and act as gate-keepers to onward referral. They should systematically explore the range of symptoms when a patient presents a single problem, such as pain or sleep disturbance, including symptoms of anxiety and depression. In addition, the clinician should explore social circumstances of the patient, including range of social contacts. The clinician can then give specific advice about the constellation of symptoms and problems that the patient may have, and which are likely to be interacting with each other. Such advice should include education about the possible interaction between sleep disturbance and pain and facilitation of increasing social activity, and engagement with the third sector to promote patient and self-management. Patients receiving interventions that target mood and physical ability have potential to improve social participation which acts as a buffer against morbidities such as cardiovascular disease [42] and maintains healthy ageing [16, 43].
This study highlights co-occurring pain and insomnia as a prevalent problem in the general population, and suggests that those reporting both conditions experience greater impact upon social activity participation than those with only one condition. The study findings suggest co-occurring pain and insomnia may be an important target for clinical trials, rather than considering treatments for isolated symptoms. RSA risk factors which are potentially modifiable and treatable, such as anxiety and depression, present important targets for interventions and should be considered by those commissioning services. Further studies are warranted to determine how best to promote social activity participation in older people with comorbid pain and insomnia.
95%CI:
AUROC:
Area under the receiver operating characteristic curve
Odds ratio
Restricted social activity
SD:
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We thank the North Staffordshire GP Research Network for their assistance with the study. We also thank the network team and administrative staff of the Primary Care Sciences Research Centre and administrative staff of the Department of Medicines Management, Keele University, for their help and support with the study.
Baseline survey costs were funded by the Proprietary Association of Great Britain and the costs of the follow-up surveys were funded by the North Staffordshire Primary Care Research Consortium.
Data is not publically available in order to protect the participants' identity. Those interested in the data should in the first instance contact the corresponding author. A copy of the SF-12 health survey is available to view at: https://www.hss.edu/physician-files/huang/SF12-RCH.pdf.
SB performed the analyses and drafted the manuscript. RW participated in the design of the study and selection of statistical analysis. RW, JMB and CCG all helped to draft the manuscript. CCG advised on clinical implications of the research. All authors read and approved the final manuscript.
The views expressed in this article are our own and not an official position of the funders; we retain sole responsibility for this work and have no competing interests to declare.
Ethical approval was obtained from the North Staffordshire Local Research and Ethics Committee; Project No.1130. Respondents provided written consent to participation, further contact and access of medical records.
Research Institute for Primary Care & Health Sciences, Keele University, ST5 5BG, Keele, UK
Shula Baker
, John McBeth
, Carolyn A. Chew-Graham
& Ross Wilkie
Arthritis Research UK Centre for Epidemiology, University of Manchester, Manchester, M13 9PT, UK
John McBeth
Collaboration for Leadership in Applied Health Research and Care, West Midlands, Birmingham, UK
Carolyn A. Chew-Graham
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Correspondence to Shula Baker.
Epidemiology and research methodology in primary care
Impact of comorbidity and multimorbidity on primary care practice
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A RASSF1A-HIF1α loop drives Warburg effect in cancer and pulmonary hypertension
Swati Dabral1,
Christian Muecke1,
Chanil Valasarajan1,
Mario Schmoranzer1,
Astrid Wietelmann2,
Gregg L. Semenza3,
Michael Meister4,5,
Thomas Muley4,5,
Tamina Seeger-Nukpezah ORCID: orcid.org/0000-0002-4906-78346,
Christos Samakovlis ORCID: orcid.org/0000-0002-9153-60401,7,8,
Norbert Weissmann ORCID: orcid.org/0000-0003-2675-38718,
Friedrich Grimminger8,
Werner Seeger ORCID: orcid.org/0000-0003-1946-08941,8,
Rajkumar Savai ORCID: orcid.org/0000-0003-1538-20911,8 &
Soni S. Pullamsetti1,8
Nature Communications volume 10, Article number: 2130 (2019) Cite this article
Hypoxia signaling plays a major role in non-malignant and malignant hyperproliferative diseases. Pulmonary hypertension (PH), a hypoxia-driven vascular disease, is characterized by a glycolytic switch similar to the Warburg effect in cancer. Ras association domain family 1A (RASSF1A) is a scaffold protein that acts as a tumour suppressor. Here we show that hypoxia promotes stabilization of RASSF1A through NOX-1- and protein kinase C- dependent phosphorylation. In parallel, hypoxia inducible factor-1 α (HIF-1α) activates RASSF1A transcription via HIF-binding sites in the RASSF1A promoter region. Vice versa, RASSF1A binds to HIF-1α, blocks its prolyl-hydroxylation and proteasomal degradation, and thus enhances the activation of the glycolytic switch. We find that this mechanism operates in experimental hypoxia-induced PH, which is blocked in RASSF1A knockout mice, in human primary PH vascular cells, and in a subset of human lung cancer cells. We conclude that RASSF1A-HIF-1α forms a feedforward loop driving hypoxia signaling in PH and cancer.
Ras association domain family 1A (RASSF1A) is a scaffold protein modulating multiple apoptotic and cell cycle checkpoint pathways by facilitating assembly of multiple effector protein complexes1. Epigenetic silencing (promoter methylation) and genetic changes (somatic mutations) are observed in various cancers and in particular human cancer cells2,3,4, establishing RASSF1A as a bonafide tumor-suppressor5. However, a few studies reported an increase in RASSF1A expression in primary human cancer tissues of various origin6,7. Further, the molecular mechanisms underlying RASSF1A regulation and function in primary human non-malignant cells are largely elusive. In addition, how this protein is regulated via environmental cues such as hypoxia remains unknown.
Hypoxia, defined as a reduction in the amount of oxygen available to a cell, tissue, or organism, is a fundamental and life-threatening biological phenomenon, and organisms from protozoans to complex mammals have evolved intricate mechanisms to sense changes in oxygen levels that in turn allow physiologic adjustments8. Hypoxic signaling pathways are implicated in a plethora of physiological processes such as blood cell differentiation and organ morphogenesis9,10 Moreover, they are centrally involved in both malignant and non-malignant hyperproliferative disease processes. This is since long known as Warburg effect driving a fundamental metabolic (glycolytic) switch in the cancer cells11 and is also operative in the prototype non-malignant hypoxia-driven disease, pulmonary hypertension characterized by vascular remodeling due to hyperproliferation of pulmonary vascular smooth muscle cells and adventitial fibroblasts12. A central axis of hypoxic signaling is the activation of the transcription factor hypoxia inducible factor-1 (HIF-1)8. HIF-1 consists of an oxygen regulated HIF-1α subunit and a constitutively expressed HIF-1β subunit. In oxygenated cells, HIF-1α is hydroxylated on two proline residues (Pro402 and Pro564 in human HIF-1α) by prolyl hydroxylases (PHD), leading to its rapid proteasomal degradation. Under hypoxic conditions, prolyl hydroxylation of HIF-1α is inhibited, leading to its stabilization and nuclear translocation. In the nucleus, HIF-1α dimerizes with HIF-1β and binds to the consensus sequence 5′-RCGTG-3′ embedded within hypoxia response elements (HREs) of numerous target genes13. Downstream gene regulation promotes key adaptive mechanisms like glycolysis and angiogenesis, but also drives pro-survival signaling, cell proliferation and cell migration in cancer14 and pulmonary hypertension15. Hence, exploring regulators of HIF-1α activity will deepen our understanding of basic biological processes and offer future therapeutic strategies.
Here, we identify a molecular mechanism, where RASSF1A acts a crucial regulator of HIF-1α signaling. Upon hypoxia, RASSF1A protein is initially stabilized by reactive oxygen species (ROS)-driven and protein kinase C (PKC)-mediated phosphorylation, and is subsequently transcriptionally upregulated by HIF-1α. Vice-versa, RASSF1A directly interacts with HIF-1α, leading to increased HIF-1α stabilization, nuclear entry and transactivation of HIF-1 target genes (pyruvate dehydrogenase kinase 1 [PDK1], hexokinase 2 [HK2], and lactate dehydrogenase [LDHA]). This hitherto unknown feed-forward loop between RASSF1A and HIF-1α promotes the glycolytic shift in hypoxia-exposed human primary cells. Moreover, we provide genetic and clinical ex-vivo evidence for the function of this RASSF1A-HIF-1α loop in human lung cancer and pulmonary hypertension.
RASSF1A is upregulated in hypoxia exposed primary lung cells
To uncover the role of RASSF1A under physiological conditions such as hypoxia, we exposed various primary human cells to hypoxia (1% O2). We observed a strong basal expression of RASSF1A mRNA in different primary human cells, namely, human broncho-alveolar epithelial cells (HBECs), pulmonary arterial-smooth muscle cells (PASMCs), -adventitial fibroblasts (PAAFs) and –endothelial cells (PAECs) as compared to A549 cell line (where RASSF1A expression is strongly reduced due to promoter hyper-methylation) (Fig. 1a). Interestingly, in all the primary human cells, RASSF1A mRNA was further increased after 24 h hypoxia exposure (Fig. 1b). In order to delineate time-dependent regulation of RASSF1A under hypoxia, we exposed PASMCs and PAAFs to hypoxia and followed its levels (Fig. 1c). Acute hypoxia exposure (15 min –6 h) strongly induced RASSF1A expression at protein level with no effect on the mRNA expression (Fig. 1d–f). Interestingly at 12 h and 24 h hypoxia exposure, both RASSF1A mRNA and protein expression were significantly upregulated (Fig. 1g–i). No increase was observed in mRNA expression of RASSF1C, another RASSF1 isoform (Supplementary Fig. 1a). Similar to PASMCs, RASSF1A was increased in PAAFs exposed to different durations of hypoxia (Supplementary Fig. 1b–d). Collectively, these data outline RASSF1A as a hypoxia-regulated protein in various primary human cells.
RASSF1A is upregulated in hypoxia exposed primary lung cells. a Relative mRNA expression of RASSF1A in human primary cells: bronchial airway epithelial cells (HBECs), pulmonary arterial-smooth muscle cells (PASMCs), -adventitial fibroblasts (PAAFs), pulmonary microvascular endothelial cells (PMVECs) and A549 (lung carcinoma cell line). b BAECs, PASMCs, PAECs, and PAAFs were exposed to 21% O2 (normoxia: Nox) or 1% O2 (hypoxia: Hox) for 24 h, followed by screening for RASSF1A mRNA expression. c Scheme for screening for RASSF1A expression. d, e, g, h Human PASMCs were exposed to normoxia hypoxia for indicated intervals. Cell lysates from each time point were subjected to d, h real time PCRs and e left–g upper, western blotting for RASSF1A, followed by e right–g lower, densitometric quantification of relative RASSF1A expression. ACTB (β actin) was taken as the loading control. f, i Localization of RASSF1A was detected by immunostaining with RASSF1 monoclonal antibody in human PASMCs at indicated hypoxia intervals. Scale bar: 50 μm. *P < 0.05, **P < 0.01, ***P < 0.001 compared to normoxia, unpaired Student's t-test. n = 3 independent experiments from 3 biological replicates
Acute hypoxia enhances protein stability of RASSF1A
To identify upstream signaling events leading to the rapid hypoxia-mediated RASSF1A protein increase, we took a genetic (si-HIF-1α) and a pharmacological approach (N-acetylcysteine: NAC) to inhibit HIF signaling and ROS formation, respectively, both known to be enhanced in hypoxia16. Genetic ablation of HIF-1α (Supplementary Fig. 2a) in PASMCs exposed to 15 min hypoxia had no effect on the expression of RASSF1A, while, treatment of these cells with the non-specific ROS inhibitor NAC inhibited the RASSF1A protein accumulation induced by acute hypoxia (Fig. 2a). To further specify the ROS source associated with increased RASSF1A levels, we treated human PASMCs with different inhibitors of flavoproteins and of the individual respiratory chain complexes. Hypoxia-augmented RASSF1A expression was inhibited by DPI, an inhibitor of flavoproteins and by GTK137831, a specific NADPH oxidase (NOX) 1/4 inhibitor (Supplementary Fig. 2b, c). siRNAs targeting NOX1 (Fig. 2b, Supplementary Fig. 2d), but not NOX4 (Supplementary Fig. 2e), significantly inhibited acute hypoxia-induced RASSF1A protein increase. The inhibitors of mitochondrial respiratory chain complex I (rotenone), complex II (TTFA, 3-NPA), complex III (antimycin A) and complex IV (sodium azide, NaN3) did not show any effect on RASSF1A protein levels (Supplementary Fig. 2f–j). This analysis suggested that ROS production augments the protein levels of RASSF1A under acute hypoxic conditions, with a particular role of NOX1.
Hypoxia promotes RASSF1A protein stability and HIF1α regulates its transcription. a Human PASMCs were pre-treated with NAC (N-acetyl cysteine) at indicated concentrations for 1 h or b transfected with NOX1 siRNA for 48 h or c pre-treated with Gö6976 at the indicated concentrations for 1 h. a–c Treatments were followed by 15 min hypoxia exposure, a–c, upper western blotting and a–c lower quantification of RASSF1A expression. d, e HEK 293 cells were transfected with RASSF1A-FLAG or empty vector (EV), and exposed to hypoxia for 30 min, d without or e with pre-treatment of Gö6976 for 1 h, followed by phosphoserine IP and RASSF1A blotting. f Human PASMCs were transfected with PKCα siRNA (si-PRKCA) for 48 h, followed by 15 min hypoxia exposure, western blotting, and f, right densitometric quantification of RASSF1A. g, h HEK293 cells were transfected with plasmids as indicated, treated with 30 μg/ml cycloheximide (CHX) without g or with h MG132 pretreatment, followed by hypoxia exposure for 1 h and 3 h and western blotting. g, h, lower Densitometrical quantified data of % of RASSF1A remaining. i Human PASMCs were transfected with HIF1α siRNA (si-HIF1A) or HIF2α siRNA (si-HIF2A) or both, followed by 24 h hypoxia exposure, western blotting for indicated proteins i, upper and densitometric quantification i, lower of RASSF1A. j, left In silico analysis of HIF-1 binding sites (HBS) in human RASSF1A promoter. j, right Human PASMCs were exposed to hypoxia for 24 h, followed by ChIP with anti-HIF1α (HIF1A) and real time PCR with primers spanning the putative HBS sites in RASSF1A promoter. k HEK293 cells were transfected with indicated luciferase promoter plasmids, followed by 24 h hypoxia exposure and luciferase activity measurement. RLU relative luciferase units. *P < 0.05, **P < 0.01, ***P < 0.001 compared to b, f, i si-Control (Hypoxia), a, c, h Vehicle, g RASSF1A-FLAG at same time point, j IgG or k EV, one-way ANOVA followed by SNK multiple comparison test. g §§§P < 0.001 compared to RASSF1A-FLAG (S203A), two-way ANOVA. Data represent mean ± s.e.m. n = 3 independent experiments from 3 biological replicates for human PASMCs and n = 3 independent experiments for HEK cells
ROS have been reported to directly and indirectly activate PKC and ATM (Ataxia telangiectasia mutated) kinase17 and both kinases have been implicated in the phosphorylation of RASSF1A and regulation of its function18,19. To test the role of these kinases on RASSF1A phosphorylation upon hypoxia, we treated human PASMCs with ATM kinase inhibitor (Ku55933) or PKC inhibitor (Gö6976) and exposed them to 15 min hypoxia. The PKC inhibitor, not the ATM kinase inhibitor, attenuated RASSF1A expression (Fig. 2c and Supplementary Fig. 3a). To directly address the phosphorylation of RASSF1A under short hypoxia exposure, we immunoprecipitated phosphoserine modified proteins from HEK293 cells overexpressing RASSF1A under hypoxia in the presence/absence of Gö6976. Immunoblotting for RASSF1A showed a two-fold increase in its phosphorylation under hypoxia, which was completely abolished by treatment with Gö6976 (Fig. 2d, e). Furthermore, using specific siRNAs, targeting PKC-A and PKC-B isoforms, we found that the increase in RASSF1A expression in hypoxia requires PKC-A, while PKC-B inhibition had no effect (Fig. 2f and Supplementary Fig. 3b, c). To further investigate the role of phosphorylation on RASSF1A levels, we generated a phospho-mimic S203D-RASSF1A and a non-phosphorylable S203A-RASSF1A mutant. S203D RASSF mutant levels were markedly increased compared to wild type (WT) RASSF1A under normoxia, and showed a further increase upon hypoxia, while S203A-RASSF1A mutant showed reduced expression compared to WT in hypoxia (Supplementary Fig. 3d). To study the effect of RASSF1A phosphorylation on its stability over time, we treated HEK cells that overexpress RASSF1A WT, S203A or S203D mutant with CHX (30 μg/ml) for 1 and 3 h, followed by cell lysis and screening for RASSF1A expression. We observed that turnover of RASSF1A-S203A mutant was more rapid than that of RASSF1A WT while the S203D mutant showed much decreased turnover (Fig. 2g). Furthermore, to prove that the higher turnover of S203A mutant was dependent on proteasome-mediated degradation, HEK cells overexpressing RASSF1A-S203A mutant were pretreated with the proteasome inhibitor MG132, followed by CHX chase experiment. Treatment with MG132 successfully reversed the increased turnover of RASSF1A-S203A (Fig. 2h).
These data suggest that PKC-A phosphorylates and stabilizes RASSF1A upon hypoxia. PKC-A activation and RASSF1A phosphorylation and stabilization are induced by NOX1 activation and elevated ROS formation upon hypoxia.
HIF-1α regulates RASSF1A at transcriptional level
Interestingly, at longer time points of hypoxia (12–24 h), an increase in RASSF1A mRNA expression was observed. This was similarly noted when human PASMCs were treated with the PHD inhibitor dimethyloxalylglycine (DMOG), which stabilizes HIF (Supplementary Fig. 4a, b). These observations indicate that RASSF1A expression might additionally be transcriptionally regulated by HIF transcription factors (HIF-1α and HIF-2α). To examine this possibility, we studied the impact of siRNA-mediated knockdown of HIF-1α and HIF-2α on RASSF1A expression under conditions of 24 h hypoxia. si-HIF-1α significantly reduced and near normalized RASSF1A expression compared to si-Control (hypoxia) at mRNA (Supplementary Fig. 4c) as well as protein level (Fig. 2i), while si-HIF-2α did not exert any effect. To further examine whether HIF-1α directly binds to the RASSF1A promoter, we analyzed the human RASSF1 gene promoter sequence for HIF binding sites (HBS) and found two candidate sites at −187 bp and −2.1 kb (Fig. 2j left panel). To determine whether HIF-1α directly binds at these sites in the RASSF1A promoter, we performed ChIP assays in human PASMCs exposed to hypoxia for 24 h. These assays revealed a strong enrichment of HIF-1α binding in cells exposed to hypoxia (Fig. 2j right panel). Further, to test whether the HBS in the RASSF1 promoter function as HRE, we inserted 200-bp (containing HBS1) and 3000-bp (containing HBS1 and HBS2) fragments encompassing one or both binding sites upstream of firefly luciferase coding sequences in the pGL3 plasmid. HEK293 cells were transfected with the RASSF1A-HBS1 or -HBS1 plus HBS2 reporter and a control reporter (pGL3-Renilla) and exposed to hypoxia for 24 h. Both RASSF1A-HBS1 and -HBS1 plus HBS2 significantly increased luciferase activity in hypoxic HEK293 cells (Fig. 2k). Collectively, these data indicate that increased expression of RASSF1A under sustained hypoxia is mediated by HIF-1 binding to sites in the RASSF1 promoter.
RASSF1A promotes hypoxic proliferation and glycolytic shift
A large body of evidence indicates that hypoxic challenge of pulmonary vascular cells leads to an altered vascular phenotype (i.e., increased proliferation, survival and metabolic reprogramming to aerobic glycolysis), with subsequent pulmonary vascular remodeling20, leading to development of hypoxic PH. To test whether RASSF1A has a causative role in the induction of this phenotype, we carried out knockdown and overexpression of RASSF1A in both human PASMCs and PAAFs exposed to hypoxia, followed by assessment of proliferation, and expression of metabolic genes. The increase in proliferation of human PASMCs and PAAFs in response to hypoxia was significantly decreased by siRNA-mediated knockdown of RASSF1 (si-RASSF1; Fig. 3a, Supplementary Fig. 5a), while RASSF1A overexpression (RASSF1A-FLAG) further boosted the hypoxia-induced proliferation (Fig. 3b, Supplementary Fig. 5b). Importantly, si-RASSF1 was similarly potent as si-HIF-1α, to block the hypoxia-induced proliferative response, whereas the combination of si-RASSF1 and si-HIF-1α did not exert additional anti-proliferative effects (Fig. 3c).
RASSF1A promotes proliferation and glycolytic shift in hypoxic human PASMCs. Human PASMCs (a–c) were transfected with a RASSF1 siRNA (si-RASSF1) and control siRNA (si-Control) or c si-RASSF1 and HIF1α siRNA (si-HIF1A) in combination or b RASSF1A-FLAG and empty vector (EV). 24 h after transfection, cells were exposed to normoxia or hypoxia for 48 h and proliferation was measured by BrdU incorporation assay. Human PASMCs were transfected with d, e si-RASSF1 and si-Control or f, g RASSF1A-FLAG and EV. 24 h after transfection, cells were exposed to normoxia or hypoxia for 24 h. d, f Real time PCRs for indicated genes were performed. e, g Cell lysates were subjected to (left) western blotting, followed by (right) densitometric quantification of relative PDK1, LDHA and HK2 to ACTB expression. h HEK293 cells were transfected with RASSF1A-FLAG or EV and 24 h after transfection, exposed to normoxia or hypoxia for 24 h and intracellular lactate production was measured. *P < 0.05, **P < 0.01, ***P < 0.001 compared to a, c–e si-Control (hypoxia) or b, f–h EV (hypoxia), one-way ANOVA followed by SNK multiple comparison test. c §P < 0.01 compared to si-RASSF1, two-way ANOVA. n = 3 independent experiments from 3 biological replicates each; data represent mean ± s.e.m.
Similar to HIF-1α inactivation, si-RASSF1 significantly decreased mRNA expression of PDK1, LDHA, and HK2 in hypoxic human PASMCs and PAAFs (Fig. 3d and Supplementary Fig. 5c). Correspondingly, protein levels of PDK1, LDHA, and HK2 were also reduced by si-RASSF1 treatment (Fig. 3e). Conversely, RASSF1A-FLAG led to a further increase in mRNA (Fig. 3f and Supplementary Fig. 5d) and protein (Fig. 3g) levels of PDK1, LDHΑ, and HK2 in hypoxic human PASMCs. To further substantiate the functional effect of RASSF1A on glycolysis, lactate, the end product of glycolysis, was measured in cells transfected with empty vector or RASSF1A-FLAG and exposed to hypoxia for 24 h. Increased lactate production was observed in hypoxic cells and was further augmented by RASSF1A-FLAG (Fig. 3h). Collectively, these data indicate that RASSF1A induces a metabolic switch and drives the hyper-proliferative response in hypoxia-exposed human lung vascular cells.
RASSF1A regulates HIF-1α stability and transactivation
We hypothesized that the hitherto unrecognized role of RASSF1A in hypoxia sensing and signaling could be executed through modulation of HIF-1α activity. To evaluate this hypothesis, we inactivated RASSF1 in human PASMCs and PAAFs with siRNA. This resulted in a significant decrease in HIF-1α protein by 70% and 95% in hypoxic human PASMCs and PAAFs, respectively (Fig. 4a, Supplementary Fig. 6a). Further, RASSF1A-FLAG overexpression, in both human PASMCs and PAAFs led to a further increase in HIF-1α protein (Fig. 4b, Supplementary Fig. 6b). Interestingly, only RASSF1A overexpression but not RASSF1C, was able to rescue the effect of RASSF1 knockdown on HIF-1α protein expression and LDHA/PDK1 expression (Supplementary Fig. 6c, d). To determine whether RASSF1A influences HIF-1 mediated transcriptional activity, HeLa cells were co-transfected with the HIF-1-dependent reporter plasmid HRE-pGL3, containing 5 repeats of an HRE upstream of firefly luciferase, and control reporter pGL3-Renilla; in presence of si-RASSF1/si-control or RASSF1A-FLAG/empty vector. Transfected cells were exposed to hypoxia for 24 h. si-RASSF1 significantly reduced HIF-1 transcriptional activity as observed by a decrease in the firefly luciferase activity (Fig. 4c). Conversely, RASSF1A-FLAG increased the luciferase activity 1.8-fold (Fig. 4c), while, RASSF1C overexpression did not have an effect on HIF1A protein expression and its transcriptional activity (Supplementary Fig. 6e, f). Accordingly, RASSF1A-FLAG markedly increased HIF-1α occupancy at the PDK1, LDHA, and HK2 gene HREs as assessed by ChIP analysis (Fig. 4d).
RASSF1A regulates HIF1α protein stability and transcriptional activity. a, b Human PASMCs were transfected with a RASSF1 siRNA (si-RASSF1) and control siRNA (si-Control) or b RASSF1A-FLAG plasmid or EV. 24 h after transfection, cells were exposed to hypoxia or normoxia for further 24 h. Cell lysates were subjected to a, b, upper western blotting for indicated proteins, followed by a, b, lower densitometric quantification of relative RASSF1A expression. c A luciferase reporter under control of multiple HIF1α binding sites was transfected into HeLa cells with c, upper si-RASSF1 or c, lower RASSF1A-FLAG. 6 h after transfection, cells were exposed to hypoxia for 24 h. Cells were lysed and luciferase activity was measured and normalized to co-transfected Renilla luciferase internal control. RLU relative luciferase units. d From hypoxic HEK293 cells transfected with RASSF1A-FLAG or EV, chromatin was precipitated with anti-HIF1α (HIF1A) antibody or rabbit IgG (IgG) and was analyzed by real time PCR with primers spanning the hypoxia-response element (HRE) regions of mentioned genes (PDK1, LDHA, HK2). e Human PASMCs were transfected with EV, RASSF1A-FLAG, RASSF1A-FLAG (S203A) or RASSF1A-FLAG (S203D). 24 h later, cells were exposed to hypoxia or normoxia for further 24 h. Cell lysates were subjected to e, upper western blotting for indicated proteins, followed by e, lower densitometric quantification of relative HIF1A expression. f A luciferase reporter under control of multiple HIF1α binding sites (HRE) was transfected into HeLa cells with EV, RASSF1A-FLAG, RASSF1A-FLAG (S203A) or RASSF1A-FLAG (S203D). 6 h after transfection, cells were exposed to hypoxia for 24 h. Cells were lysed and luciferase activity was measured and normalized to co-transfected Renilla luciferase internal control. *P < 0.05, **P < 0.01, ***P < 0.001 compared to a, c si-Control (hypoxia) or b, c EV (normoxia) or e, f EV (hypoxia), §P < 0.05, §§P < 0.01, §§§P < 0.001 compared to b–d EV (Hypoxia) or e, f RASSF1A-FLAG (S203A), one-way ANOVA followed by SNK multiple comparison test. Data represent mean ± s.e.m. n = 3 independent experiments from 3 biological replicates
Further, to study the effect of RASSF1A phosphorylation on HIF-1α stability and function, we carried out overexpression of RASSF1A WT, S203A or S203D mutant in human PASMCs, followed by hypoxia exposure for 24 h. Overexpression of RASSF1A-S203D mutant increased expression of HIF-1α, similar to RASSF1A WT, while S203A mutant failed to show this effect (Fig. 4e). Consequently, S203A mutant did not lead to an increase in HIF-1α transcriptional activity as measured by HRE luciferase assay (Fig. 4f) in HeLa cells.
RASSF1A is a well-documented regulator of hippo signaling and Yap transcriptional activity (Supplementary Fig. 7a) and therefore, to study whether RASSF1A mediated effect on HIF-1α is hippo signaling driven, we overexpressed RASSF1A in presence of YAP wild type/mutant overexpression, followed by hypoxia exposure. Both YAP wild type/mutant overexpression further enhanced the hypoxia-driven stabilization of HIF-1α. However, it did not have any further effect on increased HIF-1α stabilization observed under RASSF1A overexpression (Supplementary Fig. 7b). This finding was further substantiated by HRE luciferase assay where again YAP overexpression (wild type or mutant) did not show any additional effect on RASSF1A mediated HIF-1α transcriptional activity (Supplementary Fig. 7c). Taken together, these data imply a role of RASSF1A in the regulation of HIF-1α expression and its transcriptional activity, independent of hippo signaling.
As RASSF1A overexpression leads to an increase in HIF-1α at the protein level but not at the mRNA level (Supplementary Fig. 7d), we hypothesized that RASSF1A mediates its effect by increasing HIF-1α stability. Thus, we investigated whether RASSF1A stabilizes HIF-1α by inhibiting its prolyl hydroxylation, its ubiquitination by von Hippel-Lindau protein (pVHL) and subsequent proteasomal degradation. We transfected human PASMCs with si-RASSF1, followed by treatment with different concentrations of the proteasome inhibitor MG132 under hypoxia. Notably, the decrease observed in HIF-1α protein levels after knockdown of RASSF1A was reduced in a dose-dependent manner by MG132 treatment (Fig. 5a). To further confirm this observation, HIF-1α was overexpressed in HEK cells in the presence of empty vector or RASSF1A-FLAG. 24 h after transfection, cells were exposed to hypoxia in the presence of 25 μM MG132 for 5 h. Cells lysates were immunoprecipitated with anti-HIF-1α antibody and immunoblotted with anti-ubiquitin (K48ubi) and anti-hydroxyproline (Pro-OH) antibodies. RASSF1A-FLAG expression led to decreased prolyl hydroxylation and concomitantly decreased ubiquitination of HIF-1α (Fig. 5b upper panel, c). In contrast, no prolyl hydroxylation was observed for the HIF-1α AA mutant (P402A/P564A) in presence or absence of RASSF1A-FLAG expression (Fig. 5b lower panel) indicating that the effect of RASSF1A on HIF-1α stabilization is indeed executed via inhibition of its prolyl hydroxylation. Moreover, co-immunoprecipitation (Co-IP) assays using anti-HIF-1α and anti-PHD2 antibodies demonstrated that RASSF1A-FLAG dose-dependently decreased the interaction of HIF-1α with PHD2 in hypoxic cells (Fig. 5d).
RASSF1A interacts with HIF1α. a Human PASMCs were transfected with si-RASSF1 and 48 h after transfection, pre-treated with indicated concentrations of MG132 for 30 min, followed by 6 h hypoxia exposure. Cell lysates were subjected to a, upper western blotting for indicated proteins, followed by a, lower densitometric quantification of relative HIF1A expression. *P < 0.05 compared to si-Control (hypoxia), one-way ANOVA followed by SNK multiple comparison test. Data represent mean ± s.e.m. n = 3 independent experiments from 3 biological replicates. b, c HEK293 cells were transfected with plasmids indicated on top of lanes. 24 h after transfection, cells were treated with 25 μM MG132, followed by 5 h hypoxia exposure. HIF1α (HIF1A) was immunoprecipitated (IP), followed by western blotting for b hydroxyl proline (Pro-OH) or c lys48 ubiquitin (K48ubi) antibody. d HEK293 cells were transfected with plasmids indicated on top of lanes and exposed to hypoxia for 6 h, followed by PHD2 IP and western blotting for indicated proteins. e HEK293 cells were transfected with plasmids indicated on top of lanes and exposed to hypoxia for 24 h. HIF1A IP and RASSF1A co-IP were detected by western blotting. f Human PASMCs were exposed to hypoxia for 24 h followed by f HIF1A IP and RASSF1A western blotting and g proximity ligation assay with HIF1A and RASSF1A antibodies. Each red spot represents for a single interaction between HIF1A and RASSF1A and DNA was stained with DAPI (blue). Scale bar: 50 μm. n = 2–3 independent experiments
RASSF1A serves as a scaffold for the assembly of multiple protein complexes, thereby regulating various cellular functions5. We thus hypothesized that a physical interaction of RASSF1A with HIF-1α may underlie its impact on hypoxic signaling. To test this hypothesis, we performed Co-IP assays in hypoxic cells expressing RASSF1A-FLAG and HIF-1α. RASSF1A-FLAG was immunoprecipitated by anti-HIF-1α antibody and vice versa (Fig. 5e, Supplementary Fig. 8a, b). Interestingly, as compared to RASSF1A WT and S203D mutant, S203A mutant displayed decreased interaction with HIF-1α in the pull down experiments. (Fig. 5e). Lack of RASSF1C-HIF1α interaction was also obvious upon overexpression of RASSF1C-FLAG (Supplementary Fig. 8c). Similarly, endogenous RASSF1A was immunoprecipitated specifically by anti-HIF-1α antibody, but not by IgG (Fig. 5f) in human PASMCs exposed to hypoxia. We were further able to substantiate these results by performing proximity ligation assay (PLA), where we observed that RASSF1A-HIF-1α interaction was majorly confined to the cytosolic compartment at different time points of hypoxia (Fig. 5g), in agreement with predominant cytosolic localization of RASSF1A (Supplementary Fig. 8d). Taken together, these findings strongly suggest that RASSF1A interacts with HIF-1α, preventing its prolyl hydroxylation, ubiquitination and degradation and hence, increasing its transcriptional activity.
RASSF1A is increased in pulmonary vessels of PH patients
An excellent model system for studying the role of hypoxia in disease pathogenesis is PH, where chronic exposure to alveolar hypoxia results in enhanced proliferation of smooth muscle cells and adventitial fibroblasts of small pulmonary arteries, leading to vessel wall thickening and luminal occlusion21. Indeed, chronic hypoxia plays a key pathogenic role in PH associated with chronic obstructive pulmonary disease (COPD), interstitial lung diseases, sleep-disordered breathing and chronic exposure to high altitude, and hypoxia-induced PH is regarded as a distinct diagnostic entity by the World Health Organization (WHO class III)22,23. In order to determine the expression pattern of RASSF1A in human healthy donor and PH patient (Idiopathic pulmonary arterial hypertension/IPAH, COPD-PH) lungs, we carried out laser-assisted micro-dissection of pulmonary vessels, followed by RNA isolation and real time PCRs with gene specific primers. Interestingly, we found significantly elevated RASSF1A mRNA in vessels from IPAH (Fig. 6a upper panel) and COPD-PH (Fig. 6a lower panel) samples as compared to healthy donor tissue. We additionally observed increased expression of HIF-1 regulated genes, LDHA and HK2, in both IPAH and COPD-PH vessels (Fig. 6a). In agreement with these findings, protein levels of RASSF1A, LDHA and PDK1 were increased in pulmonary arteries of IPAH patients in comparison to healthy donors (Supplementary Fig. 9a). Immunofluorescence staining of human lungs (IPAH, COPD-PH, and donors) demonstrated strong immunoreactivity of RASSF1A in the pulmonary arteries of IPAH and COPD-PH patients as compared to donors (Fig. 6b). Interestingly, co-immunostaining with HIF-1α antibody revealed co-localization of RASSF1A and HIF-1α in the pulmonary vessels (Fig. 6c). Thus, in addition to the post-transcriptional stabilization of RASSF1A upon acute hypoxic exposure of human cells, the analysis of PH patients shows that also RASSF1A mRNA levels are increased in pulmonary vessels. This mRNA induction is accompanied by the activation of HIF-1 downstream targets in these diseased vessels.
RASSF1A regulates proliferation and glycolytic metabolism in IPAH-PASMCs. a Pulmonary vessels from frozen lung sections of a, upper IPAH patients (n = 9), a, lower COPD-PH (n = 8) patients and donors (n = 8–9) were collected via laser-assisted microdissection. RNA was isolated and real time PCRs for indicated genes were performed. b, c Representative paraffin lung tissue sections from donors, IPAH patients, and COPD-PH patients were subjected to immunofluorescence staining of RASSF1, HIF1α (HIF1A), alpha smooth muscle actin (α-Actin), von-willebrand factor (vWF) and collagen 1 (Col1). Nuclei are counterstained with DAPI (blue). Scale bar: 20 μm. d, e Expression of RASSF1A in IPAH- vs donor-PASMCs as analyzed using d real time PCRs and e, upper western blotting, followed by e, lower densitometric quantification of relative RASSF1A expression. f Human PASMCs from IPAH patients were transfected with RASSF1 siRNA (si-RASSF1) and control siRNA (si-Control). 6 h after transfection, cells were placed in medium with growth factors for 48 h. Proliferation was measured by BrdU incorporation assay. g, h Cells were treated with siRNA as above-mentioned and cell lysates were subjected to g real time PCRs and h, left western blotting, followed by h, right densitometric quantification of relative PDK1, LDHA, and HK2 to ACTB expression. *P < 0.05, **P < 0.01, ***P < 0.001 compared to a–e donor or f–h si-Control, unpaired Student's t-test. n = 3 independent experiments from 3 biological replicates, Data represent mean ± s.e.m.
RASSF1A drives proliferation/glycolytic shift in IPAH PASMCs
Hyper-proliferative and apoptosis-resistant PASMCs in IPAH patients exhibit increased expression of HIF-1α and a shift to glycolytic metabolism20,24, similar to the response of control human PASMCs exposed to prolonged hypoxia. PASMCs from healthy donors and IPAH patients were isolated and analyzed for expression of RASSF1A. Increased expression of RASSF1A mRNA and protein was observed in IPAH-PASMCs as compared to donors (Fig. 6d, e). Similarly, increased expression was observed in IPAH-PAAFs in comparison to donors (Supplementary Fig. 9b, c). As our above studies put forward an explicit role of RASSF1A in regulating proliferation and metabolic gene expression in ex vivo hypoxia-exposed human PASMCs, we further investigated whether RASSF1A exerts a corresponding function in diseased PASMCs originating from IPAH patients. Indeed, si-RASSF1 significantly reduced the proliferation of IPAH PASMCs (Fig. 6f). Similar to the results obtained in hypoxia-exposed donor PASMCs (Fig. 3c), si-RASSF1 and si-HIF-1α decreased proliferation of IPAH PASMCs equally, whereas a combination of both did not display any additional effect (Supplementary Fig. 9d). Moreover, si-RASSF1 resulted in a strong decrease in the expression of the glycolytic enzymes PDK1, LDHA and HK2 at both the mRNA (Fig. 6g) and protein level (Fig. 6h). These results suggest that RASSF1A has a central function in both the metabolic switch and in the hyper-proliferative feature of pulmonary vascular adventitial fibroblasts and smooth muscle cells from IPAH patients.
RASSF1A knockout mice do not develop hypoxia-induced PH
Notably, Rassf1a expression was significantly increased in lungs of mice exposed to hypoxia compared to normoxic mice (Fig. 7a, Supplementary Fig. 10). To explore the role of RASSF1A in promoting hypoxia-induced PH in vivo, we exposed wild type littermates (WT), Rassf1a heterozygous (Rassf1a+/−) and homozygous (Rassf1a−/−) knockout (KO) mice to hypoxia (10% O2) or normoxia for 4 weeks. We analyzed the effects by magnetic resonance imaging (MRI) and cardiopulmonary hemodynamic measurements employing right heart catheterization. Under normoxic conditions, there were no differences in hemodynamic parameters such as right ventricular systolic pressure (RVSP) between WT and Rassf1a KO mice. In contrast to WT mice, which develop characteristic PH phenotypes after chronic hypoxia exposure, both homozygous (Rassf1a−/−) and heterozygotes (Rasssf1a+/−) KO mice exhibited significantly lower RVSP (Fig. 7b) and did not develop hypertrophy of the right ventricle (RV) (measured by RV/tibia length ratio; Fig. 7c). Additionally, pre-hypoxic and post-hypoxic MRI measurements revealed that Rassf1a inactivation protected mice against chronic hypoxia evoked right heart abnormalities such as enlargement of RV, end-diastolic volume (EDV) increase, end-systolic volume (ESV) increase and augmentation of RV mass (Fig. 7d, e). In line with the observed hemodynamic changes, Rassf1a KO mice did not show an increase in the medial wall thickness of resistance pulmonary arteries (<70 μm) as seen in the hypoxic WT mice (Fig. 7f, g). These protective effects on lung vascular remodeling were linked to decreased cell proliferation, as assessed by proliferating cell nuclear antigen (PCNA) stainings in small pulmonary arteries (Fig. 7h, i). Collectively, these data indicate that genetic ablation of Rassf1a is protective against hypoxia-induced lung vascular remodeling and RV hypertrophy and dilatation, and that ablation of one Rassf1a allele (Rasssf1a+/−) is sufficient to exert this effect.
Rassf1a knockout protects mice against Hypoxia induced PH. a Real time PCR measurement of Rassf1a mRNA in lungs from WT mice exposed to normoxia (n = 9) or hypoxia for 1 week (n = 5), 2 weeks (n = 5), 3 weeks (n = 9), and 5 weeks (n = 9). b–i Rassf1a KO mice (Rassf1a+/−, Rassf1a−/−) and wildtype littermates (WT) were exposed to Hypoxia (10% O2) for 28 days or maintained under normoxic conditions. b, c Physiological measurements were carried out on all groups of mice exposed to hypoxia and normoxia to determine b right ventricle systolic pressure (RVSP) and c RV hypertrophy (RV/tibia length). d All three groups of mice exposed to hypoxia were subjected to magnetic resonance imaging (MRI) pre- and post-hypoxia to determine right heart function presented as d, left end diastolic volume (EDV), d, middle, end systolic volume (ESV) and d, right end systolic (ES) mass. e Representative end diastolic and systolic images for each experimental group are shown. (n = 4–5 mice each group). f, g Lung sections were subjected to H&E staining, followed by morphometric analysis of pulmonary vessels (n = 4–5 each group). f Medial wall thickness of pulmonary arteries (20- to 70-μm in diameter) and representative photomicrographs (g) are shown. h, i Immunohistochemical analysis of PCNA in small (20- to 70-μm in diameter) pulmonary vessels from the groups described above was carried out (n = 3 each group). h Percentage of PCNA positive cells and i representative photomicrographs for PCNA staining (green) are shown. Nuclei are counterstained with DAPI (blue). Scale bar: 20 μm. *P < 0.05, **P < 0.01, ***P < 0.001 compared to a hypoxia 0 weeks or b–d, f, h hypoxic WT, one-way ANOVA followed by SNK multiple comparison test. Data represent mean ± s.e.m.
RASSF1A-HIF-1α axis in primary NSCLC cells
In contrast to several reports on decreased RASSF1A expression in a variety of tumors and tumor cell lines, a few reports have indicated a lack of such decrease or even an increase in RASSF1A expression in subsets of tumors of various origin6,7,25. We screened 56 non-small cell lung cancer (NSCLC) tissues with matched non-tumor tissues from the same lungs as controls for RASSF1A protein expression. Interestingly, in 39% of the tumor samples, we detected an increase in RASSF1A as compared to the non-tumor parts (Fig. 8a, Supplementary Fig. 11a). Further, the tumors positive for RASSF1A expression showed regions of co-immunolocalization between RASSF1A and HIF-1α as observed by immunohistochemistry (Fig. 8b) and higher fold increase in expression of hypoxic biomarkers, namely, LDHA and carbonic anhydrase 9 (CA9) (Fig. 8c). In order to establish a correlation if any between RASSF1A expression and clinical characteristics of cancer patients, we compared lung cancer pathological stage with RASSF1A expression. We observed a significant increase in expression of RASSF1A in stage III compared to stage I lung cancer patients (Fig. 8d). Next, we analyzed the RASSF1A expression in primary cancer cells isolated form the RASSF1A positive lung cancer tissue and found a strong basal expression of RASSF1A mRNA in these cancer cells as compared to A549 cell line (Supplementary Fig. 11b). To determine whether the RASSF1A-HIF-1α signaling axis is operative in these cells, we carried out HIF-1α and RASSF1A knockdown, followed by 24 h hypoxic stimulation in these primary lung cancer cells. Hypoxic exposure led to an increase in RASSF1A mRNA and protein expression in all cancer cells examined. Reduction of HIF-1α levels mediated by siRNA reversed the hypoxic increase of RASSF1A levels (Fig. 8e–i Supplementary Fig. 11c). Strikingly, knockdown of RASSF1A reduced HIF-1α levels, metabolic gene expression (LDHA, HK2: Fig. 8e–g, i–k), lactate production (Fig. 8h–l) as well as proliferation (Supplementary Fig. 11d). Together, these results suggest that RASSF1A expression is increased in a subset of non-small cell lung cancers and the primary cancer cells isolated from these tumors. Importantly, the interplay of RASSF1A-HIF-1α signaling regulates the glycolytic phenotype in these primary lung cancer cells, further supporting a broad role of RASSF1A as a hypoxia regulated protein and a crucial regulator of HIF-1α signaling.
RASSF1A-HIF-1α axis in primary lung tumor cells. a Representative western blots for RASSF1A protein expression as analyzed in proteins isolated from tumor (T) and non-tumor (N) areas of human non-small cell lung cancer lungs. b Paraffin lung tissue sections from lung tumor patients were subjected to immunohistochemical staining of RASSF1 and HIF1α (HIF1A). Scale bar: 20 μm. c RNA was isolated from tumor and matched non-tumor samples, followed by real time PCRs for indicated genes. The Ct values of tumor samples were divided by the Ct values of respective non-tumor samples to obtain the fold change of RASSF1A expression. n = 9 RASSF1Ahigh and n = 10 RASSF1Alow tumors. d Fold change in RASSF1A expression in various lung tumor tissues plotted vs the pathological stages (I, II, III) of the respective tumors. n = 15 stage I, n = 14 stage II, and n = 27 stage III human lung tumor tissues. *P < 0.05 compared to RASSF1Alow (c) or stage I (d), unpaired Student's t-test. e–l Primary cancer cells isolated from two patients with RASSF1A-positive lung tumor were transfected with RASSF1 siRNA (si-RASSF1), HIF1α siRNA (si-HIF1A), and control siRNA (si-Control). 24 h after transfection, cells were exposed to normoxia or hypoxia for 24 h. e, i Lysates obtained were subjected to western blotting for above-mentioned proteins. si-RASSF1 or si-control transfected lysates were further subjected to f, j real time PCRs for LDHA, HK2, g, k western blotting for LDHA, HK2 and h, l lactate assay. f, h, j, l *P < 0.05, **P < 0.01, ***P < 0.001 compared to si-control (hypoxia), one-way ANOVA followed by SNK multiple comparison test. Data represent mean ± s.e.m. For primary tumor cells, n = 2–3 independent experiments from 2 biological replicates (represented as separate)
The role of RASSF1A as a tumor suppressor gene, and its silencing due to methylation or mutations in different cancer cell lines has been previously established2,25,26. Although majorly studied in the field of malignancies, studies on its potential role in primary cells under different physiological cues such as hypoxia are unexplored. Here, we identify RASSF1A as a hypoxia regulated protein that directly promotes HIF-1α protein stabilization and transcriptional activity in various human primary cells (smooth muscle, fibroblast and cancer cells), thereby controlling the hypoxia-induced metabolic shift known as Warburg effect and cell proliferation.
Taking a step away from previous studies on RASSF1A, usually carried out in cell lines, we analyzed RASSF1A expression in different lung primary cells under hypoxia, where we noted basal expression of RASSF1A, not RASSF1C to be significantly boosted by hypoxic exposure. Further, this upregulation followed a biphasic pattern with increased protein stabilization of RASSF1A occurring as an immediate response to hypoxia, followed by prolonged transcriptional upregulation.
It is well documented that hypoxia, both acute and chronically sustained, induces a number of molecular changes with rapid and profound consequences on cell physiology27. Under acute hypoxic conditions (from seconds to minutes), rapid but transient changes in homeostatic mechanisms take place, primarily mediated by changes in cellular redox state and protein modifications and degradation. Particularly for the hypoxia-responsive pulmonary vascular cells, several groups have reported that low O2 levels can trigger increased ROS levels with complex III of the mitochondrial electron transport chain or NOX isoforms acting as the major ROS sources28. Increased ROS can trigger activation of a large number of protein kinases including PKC by promoting Ca2+ influx through voltage-dependent Ca2+ channels17. By employing pan- and specific ROS inhibitors and siRNA-mediated loss of function studies, we found that the increased RASSF1A protein stability, noted within a few minutes of hypoxia exposure, is largely mediated by NOX1 derived ROS. Further, ROS activated PKCα, but not PKCβ, led to phosphorylation of RASSF1A at Ser203 under hypoxic conditions, resulting in increased RASSF1A stabilization. The PKC-mediated Ser203 phosphorylation data are in line with previous in vitro kinase studies, which also showed that that Ser197 and Ser203 of RASSF1A can be phosphorylated in response to PKCα activation in various cell lines (murine fibroblast cell line (NIH3T3), monkey fibroblast cell line (Cos-7), human embryonic kidney cells (293T))18. Our findings, do not exclude the possibility of parallel PKC-independent pathways. Such pathways may include phosphorylation of RASSF1A by other kinases (ATM kinase, Aurora A, Aurora B, MST1), which might further impact the RASSF1A function29,30.
Increased mRNA expression of RASSF1A upon prolonged hypoxia and the established role of HIF-1α as the major hypoxic transcription factor31 led us to investigate the possible regulation of RASSF1A by HIF-1α. Interestingly, we found two HIF binding sites in the RASSF1A promoter and have shown a direct HIF binding on both of these sites, establishing RASSF1A as a HIF-1α target gene.
Overall, we identified a HIF-1-RASSF1A feed-forward mechanism, where apart from being a HIF-1α target gene, RASSF1A stabilizes HIF-1α and positively regulates its transcriptional activity in response to prolonged hypoxia. Our gain and loss of function studies of RASSF1A under hypoxic conditions indicated its role as a positive regulator of both HIF-1α protein stability and HIF-1 transcriptional activity. Further, RASSF1A overexpression augmented HIF-1α promoter occupancy and transactivation of PDK1, HK2 and LDHA in both smooth muscle cells and cancer cells. Further, Co-IP and PLA studies performed in smooth muscle cells showed a strong interaction between RASSF1A and HIF-1α. Several proteins have been previously described, which interact with and regulate the stability of HIF-1α protein via preventing its hydroxylation and proteasomal degradation. Histone deacetylase (HDAC) 7 interacts with HIF-1α and p300 to increase HIF-1 transcriptional activity32. STAT3 enhances HIF-1α protein stability through inhibition of pVHL binding to HIF-1α and preventing its ubiquitination33. It is conceivable that RASSF1A functions in a similar fashion to regulate HIF-1α stability. In line with this assumption, we found that (a) RASSF1A overexpression prevented prolyl hydroxylation of HIF-1α, (b) this was accompanied by a reduction of HIF-1α ubiquitination, and (c) binding of RASSF1A to HIF-1α negatively affected the interaction of HIF-1α with PHD2. Moreover, preliminary data suggest that RASSF1A also interacts with PHD2. All these lines of evidence indicate that RASSF1A serves as a scaffold to organize a multi-subunit complex that decreases the hydroxylation, ubiquitination and degradation of HIF-1α, thereby enhancing its transcriptional activity. Recently, Papaspyropoulos et. al. described the function of RASSF1A in stem cells differentiation which included RNA-seq data identifying hypoxia signaling downstream of RASSF1 knockdown34, hinting in direction of our findings.
Hypoxia has been associated with major alterations in cellular phenotypes including changes in proliferation, survival and metabolic shift towards glycolysis35,36,37. In fact, effective cellular oxygen delivery is a major factor in human physiology and alterations of hypoxia-related pathways have been implicated as key drivers of multiple pathological states including cancer, cardiovascular disease, stroke, and pulmonary hypertension38,39,40. Our study identifies a crucial role of a hitherto unknown HIF-1-RASSF1A feed-forward loop in driving the hypoxia-induced cellular phenotype. Importantly, the relevance of the RASSF1A-HIF-1α axis in the setting of human disease is demonstrated by the elevated expression of RASSF1A, HIF-1α and HIF-1-target genes in pulmonary vessels of IPAH and COPD-PH patients. We also showed that RASSF1A expression is a prerequisite for the development of hypoxia-induced PH in mice. Both Rassf1a−/− and Rasssf1a+/− knockout mice were resistant to the development of PH and were unable to generate vascular remodeling and RV hypertrophic responses to hypoxia, indicating that RASSF1A mediated proliferative and metabolic alterations are required for this disease phenotype.
Strikingly, we found a subset of non-small cell lung (NSCLC) tumors (39%, RASSF1Ahigh) showing an upregulation of RASSF1A expression, along with co-localization with HIF-1α and increased hypoxic signatures (LDHA, CA) expression. On comparing the lung cancer pathological stage with RASSF1A expression, we observed a significant increase in the expression of RASSF1A in stage III compared to stage I lung cancer patients. In nearly 50% of the stage III lung cancer patients a marked increase in RASSF1A expression was noted, which may suggest that RASSF1Ahigh lung cancers are particularly aggressive and/or have a worse prognosis via regulation of HIF-1α and metabolic switch. Further, basal expression of RASSF1A transcript was observed in primary cancer cells isolated from these tumors, which was strongly boosted by exposure to hypoxia. Gene silencing studies in these cells with siRASSF1 and siHIF-1α under hypoxic conditions resembled the findings in hypoxic vascular cells, verifying that the RASSF1A-HIF-1α axis regulates the metabolic shift and lactate production also under conditions of malignancy. Interestingly, our findings correspond to a previous report describing equal frequency of increase (16/38, 42%) and decrease of RASSF1A mRNA expression in lung epithelial cancer cells. The authors also showed that in renal cell carcinomas the frequency of RASSF1A mRNA expression increase was even higher (24/38, 63%)7. Another study also carried out in renal cell carcinoma demonstrated that tumor cells expressing RASSF1A showed increased tumor progression6. Hence, our study taken together with these reports suggests that non-small cell lung cancer presents as 2 phenotypes, RASSF1Alow where RASSF1A is epigenetically or genetically silenced26,41, and RASSF1Ahigh where RASSF1A expression is maintained and even increased in response to hypoxic microenvironment. Several previous studies suggested that RASSF1A has a tumor suppressor function during early tumor development, and that its silencing due to hypermethylation leads to activation of proliferative and migratory processes via inactivation of Hippo signaling42 and cyclins43 and RAS induced apoptosis44. In line with these observations, a prognostic value of RASSF1A downregulation in lung cancer was noted. However, though, strongly prevalent, hypermethylation is not observed in all tumors. Some tumors do not exhibit epigenetic or genetic silencing of RASSF1A, but it may even be increased (RASSF1Ahigh), and in this subset of tumors RASSF1A will promote the Warburg effect via HIF1α. We here show that this is linked with a hypoxic microenvironment, NOX1 expression and activity and HIF1α expression. Interestingly, both NOX1 and HIF1α expression have displayed positive correlation with clinical stages in NSCLC45,46.
Collectively, we report a hitherto unrecognized crucial role of RASSF1A in regulating HIF-1α to promote hypoxia-driven gene regulation, metabolic switch and hyperproliferation in pulmonary hypertension as a non-malignant hypoxia-induced prototype disease and lung cancer. The underlying molecular mechanisms unveiled here (Fig. 9) provide future targets for therapeutic intervention, to be exploited for improved therapy of these diseases.
Schematic depicture of RASFF1A mediated HIF regulation. Under normoxia, HIF1α is hydroxlyated at proline residues by PHDs, ubiquitinated, followed by proteasomal degradation. Under hypoxia, RASSF1A is phosphorylated by ROS activated PKCα, leading to increased stability. Increased RASSF1A binds to HIF1α, preventing its binding to PHD2 and prolyl hydroxylation, increased nuclear translocation and subsequent transcriptional activity. This in turn leads to increased expression of glycolytic genes (PDK1, HK2, LDHA) and RASSF1A itself, giving rise to a feed forward loop and increased proliferation and glycolysis, manifesting in pulmonary hypertension and lung cancer pathogenesis. RASSF1A: Ras association domain family 1A, pVHL: von Hippel-Lindau tumor suppressor protein, PHD2/3: prolyl hydroxylase 2/3, HIF1α: hypoxia-inducible factor 1 alpha, HIF1β: hypoxia-inducible factor 1 beta, HRE: hypoxia-response elements, Ub: ubiquitin, OH: hydroxylation, Pro: proline, NADPH: nicotinamide adenine dinucleotide phosphate hydrogen, ROS: reactive oxygen species, NOX1: NADPH oxidase 1, NADP: nicotinamide adenine dinucleotide phosphate, PKCα: protein kinase C alpha, P: phosphorylation, HK2: hexokinase 2, PDK1: pyruvate dehydrogenase kinase, isozyme 1, LDHA: lactate dehydrogenase A
Human lung samples
Human explanted lung tissues from subjects with IPAH or control donors were obtained during lung transplantation. Samples of donor lung tissue were taken from the lung that was not transplanted. The study protocol for tissue donation was approved by the ethics committee (Ethik Kommission am Fachbereich Humanmedizin der Justus Liebig Universität Giessen) of the University Hospital Giessen (Giessen, Germany) in accordance with national law and with Good Clinical Practice/International Conference on Harmonisation guidelines. Written informed consent was obtained from each individual patient or the patient's next of kin (AZ 58/15).
Biomaterials and data from NSCLC patients were provided by the Lung Biobank Heidelberg, a member of the accredited Tissue Bank of the National Center for Tumor Diseases (NCT) Heidelberg, the BioMaterial Bank Heidelberg and the Biobank platform of the German Center for Lung Research (DZL). All subjects gave their informed consent for inclusion before they participated in the study. The study was conducted in accordance with the Declaration of Helsinki. The use of biomaterial and data for this study was approved by the local ethics committee of the Medical Faculty Heidelberg (S-270/2001).
Human PASMCs was obtained from Lonza and grown in SmGM-2 Bulletkit medium (Lonza). Human PAAFs were obtained from ScienCell and grown on poly-lysine (Sciencell) coated dishes in fibroblast medium (ScienCell). Cells were maintained at 37 °C in a 5% CO2 incubator. Experiments were performed with cells from passages 6 to 7.
Explant-derived PASMCs were obtained from human pulmonary arteries (<2 mm in diameter) obtained from patients with IPAH. Segments of pulmonary artery were cut to expose the luminal surface. The endothelium was removed by gentle scraping with a scalpel blade, and the media was peeled away from the underlying adventitial layer. The medial explants were cut into ~1- to 2-mm2 sections, transferred to T75 flasks with Promocell smooth Muscle Cell Growth Medium 2 (Promocell) and allowed to adhere for 2 h at 37 °C and 5% CO2. Once the cells had adhered, the explants were incubated in DMEM supplemented with 20% FBS until cells had formed confluent monolayers. PASMCs were trypsinized, and subsequent passages were cultured in smooth muscle cell growth medium 2 and maintained at 37 °C in 5% CO2.
Primary tumor cells were obtained from University of Giessen and Marburg Lung Center (UGMLC) biobank and Lung Biobank Heidelberg, a member of the accredited Tissue Bank of the National Center for Tumor Diseases (NCT) Heidelberg, the BioMaterial Bank Heidelberg, and the Biobank platform of the German Center for Lung Research (DZL). Tumor cells were grown on collagen IV (Sigma) coated dishes in DMEM/Ham's F12 medium with different supplements (Sodium selenite, Ethanolamine, Phosphorylethanolamine, Sodium pyruvate, Adenine: all from Sigma, Airway epithelial growth medium supplement pack: Promocell, ROCK inhibitor: Selleckchem). Experiments were performed with cells from passages 5 to 8.
Various cell lines (HEK 293 and HeLA) were obtained from ATCC and cultured in DMEM medium containing 10% fetal calf serum and 1% antibiotics.
Hypoxia exposure of human PASMCs and PAAFs
Hypoxia experiments were performed in a chamber equilibrated with a water-saturated gas mixture of 1% O2, 5% CO2, and 94% N2 at 37 °C. Human PASMCs and human PAAFs were incubated in hypoxia or normoxia chambers for indicated time points in hypoxic medium (basal medium containing 1% FCS for human PASMCs and human PAAFs, serum free medium for tumor cells).
Transfection with siRNA
Human PASMCs and tumor cells were transfected with different siRNAs using Lipofectamine 3000 Transfection Reagent (Invitrogen) in optiMEM serum free medium. As a control, commercially available non-targeting siRNA (si-Control) was used. All siRNAs were obtained from Qiagen (Supplementary Table 2). Six hours after transfection, cells were cultured in serum-containing medium for a resting period of 24 h, followed by hypoxia exposure for different time points. Transfection of human PAAFs was carried out with siRNA targeting RASSF1 by electroporation using A-024 program of primary fibroblasts nucleofection kit (Amaxa, Lonza) according to manufacturer's instructions.
Transfection with plasmids
pCMV tag1-RASSF1A, pCMV tag1-RASSF1A S203D, pCMV tag1-RASSF1A S203A, pCMV tag1-RASSF1C and empty vector were provided by Prof. R. Dammann. pGL3-HRE plasmid was provided by Dr. Savai. p2xFLAG-hYAP1 (#17791), p2xFLAG-YAP1-S127A (#17790) and 8xGTIIC-luciferase (#34615) were obtained from Addgene. 180 bp and 2100 bp region from RASSF1A promoter were PCR amplified from human lung genomic DNA and cloned into pGL3 vector upstream of firefly luciferase gene. Human PASMCs and human PAAFs were transfected with plasmids using A-033 program of primary smooth muscle cells nucleofection kit and A-024 program of primary fibroblasts nucleofection kit respectively (Amaxa, Lonza). Six hours after transfection, medium was changed to serum-containing medium for a resting period of 24 h, followed by hypoxia exposure for different time points. HEK 293 cells were transfected with plasmids using turbofect (Thermo Scientific) directly in serum-containing medium. 24 h later, cells were exposed to hypoxia for different time points.
Treatment with compounds
Human PASMCs were incubated with hypoxia medium (1% FCS) in the absence or presence of N-acetyl cysteine (0.5 or 1 mM: Sigma-Aldrich), DPI (5 or 10 μM), rotenone (5 or 10 μM: Sigma-Aldrich), TTFA (5 or 10 μM: Sigma-Aldrich), antimycin A (5 or 10 μM: Sigma-Aldrich), sodium azide (0.5 or 1 mM), 3-Nitro propionic acid (3 or 5 mM: Sigma-Aldrich)Ku55933 (5 or 10 μM: Sigma-Aldrich), GKT137831 (5 or 10 μM) Gö6976 (0.5 or 1 μM: Roche) for 1 h followed by 15 min of hypoxia exposure. Relative change in RASSF1A protein expression was assessed by western blotting. The concentration of the compounds was chosen based on previous studies.
Human PASMCs grown on chamber slides were treated and fixed with acetone-methanol (1:1), washed 3 times for 5 min with PBS and blocked for 1 h with blocking buffer (5% BSA, 0.5% goat serum, 0.2% Triton-X in PBS), and incubated overnight with a RASSF1 primary antibody (1:100; abcam) overnight. This was followed by 1 h incubation with secondary antibody Alexa Fluor®-488 (1:1000, Life Technologies, A11008). After incubation, slides were counterstained with ToPro3 (for nuclear staining) and mounted with fluorescent mounting medium (Dako). Fluorescent images were taken with LSM 710 confocal microscope.
Human PASMCs were grown on chamber slides and exposed to hypoxia for different time points. After the exposure, cells were fixed with acetone: methanol (1:1), followed by Duolink® (Sigma Aldrich) proximity ligation assay according to manufacturer's protocol employing HIF1A and RASSF1A antibody. Fluorescent images were taken with LSM 710 confocal microscope.
Assessment of proliferation of primary cells
The influence of RASSF1A knockdown and overexpression on proliferation was assessed with BrdU incorporation assay (Roche Diagnostics) according to manufacturer's instructions. Absorbance was measured at 370 nm with reference at 492 nm in a plate reader (TECAN, Germany). Proliferation of cells was plotted as a percentage of absorbance compared to control cells absorbance.
Coimmunoprecipitation (Co-IP)
HEK293 cells were grown to 80% confluence in 100 mm dishes and then, transfected with various plasmids (RASSF1A-FLAG, RASSF1A-FLAG (S203A), RASSF1A-FLAG (S203D) or HIF1A) using Turbofect (Thermo Scientific). 6 h after transfection, cells were subjected to 24 h hypoxia or normoxia, followed by cell lysate preparation in Co-IP lysis buffer (Thermo Scientific). Addtionally, for imunoprecipitations carried out to check post-translational modifications (prolyl-hydrxylation, lys48 ubiquitination) of HIF1α, cells were pretreated with MG132 (Santa Cruz) for 30 min before hypoxia exposure, followed by 6 h hypoxia exposure and lysis in Co-IP lysis buffer. Lysates were centrifuged and supernatants were further used for CoIP. Equal amounts of proteins were incubated overnight on rotation with anti FLAG (Sigma), anti-HIF1A (abcam), anti-PHD2 (Novus biological) or IgG (Santa Cruz), followed by 3 h incubation with Protein G sepharose beads (GE healthcare). After incubation, beads were repeatedly washed with PBS + 0.1% tween20, followed by addition of SDS sample buffer and analysis by western blotting.
Chromatin-immunoprecipitation (ChIP)
Cells (human PASMCs or HEK293) were exposed to 20% or 1% O2 for 24 h, cross-linked with 1% formaldehyde for 10 min at room temperature, and quenched in 0.125 M glycine. DNA was immunoprecipitated from the sonicated cell lysates using anti-HIF1A antibody (Abcam) and immunoprecipitates were recovered by addition of Salmon Sperm DNA/Protein A Agarose-50% Slurry. After washing, elution, and reverse cross-linking, DNA was purified by PCR purification kit (Qiagen). Purified DNA was quantified by SYBR Green real-time PCR (Bio-Rad) using specific primers (Supplementary Table 1). Data is expressed as percentage of input, calculated from the formula: % of Input is equal to 2(−dCt), dCt is Ct ChIP – (Ct Input − log2 dilution factor). The average from IgG control was set to 1.
Lactate assay
HEK 293 cells were grown to 80% confluence and then transfected with RASSF1A or empty vector. 24 h after transfection, cells were exposed to 24 h hypoxia or normoxia, followed by measurement of lactate production using lactate assay kit (Abcam) according to manufacturer's protocol. Absorbance was measured at 450 nm in a plate reader (TECAN). Lactate concentrations were determined on basis of the lactate standards and normalized to total protein content of each sample. Tumor cells were transfected with siRNA against RASSF1 and Control siRNA as described before and 24 h after hypoxia exposure, lactate production was measured.
Reporter gene assays
HEK293/HeLa cells were grown to 80% confluence in 48 well plates and then co-transfected with HRE luciferase construct or an empty pGL3 vector (Promega), various expression vectors mentioned in the text or RASSF1 siRNA and the internal control pRL-CMV vector (Promega). 6 h after transfection, cells were exposed to hypoxia or normoxia for further 24 h before the preparation of cell lysates. Both firefly and Renilla luciferase activities were quantified using the dual-luciferase reporter assay system (Promega) according to the manufacturer's instructions and employing a spectrofluorometer (BioTek Instruments). The ratio of luciferase signal to Renilla signal for each well was calculated. The average from control samples was set to 1.
Promoter analysis
Sense and antisense strands of the human RASSF1 promoter were screened upstream and downstream of the coding sequence of the RASSF1 gene (NM_007182.4) for potential HIF-1 binding sites (HBS:G/ACGTG).
Animal experiments
The experiments were performed in accordance with the US National Institutes of Health Guidelines on the Use of Laboratory Animals. Both the University Animal Care Committee and the federal authorities for animal research of the Regierungspräsidium Giessen and Darmstadt (Hessen, Germany) approved the study protocol (B2/325). Mice (male, 12–14 weeks old) were used for experiment.
Mice carrying targeted alleles were genotyped by PCR. For genotyping mouse RASSF1A lines, primers used were: Primer1 5′-TTGTGCCGTGCCCCGCCCA-3′; Primer2 5′-TGACCAGCCCTCCACTGCCGC-3′ and Primer3 5′-GGGCCAGCTCATTCCTCCCAC-3′. DNA was extracted from mouse tails, and 4 μl was used in the subsequent PCR reaction. Cycling conditions were 5 min at 95 °C; 35 cycles of 30 s at 95 °C, 20 s at 64 °C and 60 s at 72 °C; followed by 7 min at 72 °C. The WT and knock out alleles resulted in 520-bp and 380-bp bands, respectively.
Hypoxia exposure of mice
Hypoxic pulmonary vascular remodeling was induced by exposure of mice to chronic hypoxia (10% O2) in a ventilated chamber, as previously described47. Briefly, animals were age-matched and randomly distributed to groups exposed to normoxia or chronic hypoxia (28 days).
MRI, hemodynamic, and RV hypertrophy measurements
Cardiac MRI measurements were performed on a 7.0T Bruker Pharmascan, equipped with a 380 mT/m gradient system, using a custom-built circularly polarized birdcage resonator and the IntraGateTM self-gating tool (Bruker, Ettlingen, Germany). The parameters for identification of the ECG were adapted for one heart slice and transferred afterwards to the navigator signals of the remaining slices. Thus the in-phase reconstruction of all pictures is guaranteed48. The 14 weeks old mice were measured pre and 4 weeks post hypoxia under volatile isoflurane (1.5–2.0%) anesthesia. The measurement is based on the gradient echo method (repetition time = 6.2 ms; echo time = 1.6 ms; field of view = 2.20 × 2.20 cm; slice thickness = 1.0 mm; matrix = 128 × 128; repetitions = 100). The imaging plane was localized using scout images showing the 2- and 4-chamber view of the heart, followed by acquisition in short axis view, orthogonal on the septum in both scouts. Multiple contiguous short-axis slices consisting of 7–10 slices were acquired for complete coverage of the left and right ventricle. MRI data were analyzed using Qmass digital imaging software (Medis, Leiden, Netherlands).
Hemodynamics in KO and WT mice were measured as described previously49. Briefly, anesthesia was given to mice as described above. After intubation, the mouse was placed in a supine position on a homeothermic plate (AD Instruments, Spechbach, Germany) and connected to a small-animal ventilator (MiniVent type 845, Hugo Sachs Elektronik, March-Hugstetten, Germany). Body temperature was controlled by a rectal probe connected to a control unit (AD Instruments) and was kept at 37 °C during catheterization. The right external jugular vein was catheterized with a high-fidelity 1.4F micromanometer/Mikro-Tip Pressure catheter (Millar Instruments, Houston, TX) and advanced into the RV to assess RVSP. Subsequently, the 1.4F micromanometer catheter was inserted into the aorta and the LV through the left carotid artery for measurement of SAP. Data were collected and analyzed using the PowerLab data acquisition system (MPVS-Ultra Single Segment Foundation System, AD Instruments) and LabChart 7 for Windows software.
After exsanguination, the left lung was fixed for histology in 10% neutral buffered formalin, and the right lung was snap frozen in liquid nitrogen. For right-heart hypertrophy, the RV was separated from the LV plus septum, and the RV/tibia length ratio was determined from the tissue.
Immunofluorescence staining and assessment of proliferation
Paraffin-embedded lung tissue sections (3-μm thick) were deparaffinized in xylene and rehydrated in a graded ethanol series to PBS (pH 7.2). Antigen retrieval was performed by pressure cooking in citrate buffer (pH 6.0) for 15 min. Double immunofluorescence staining was performed with primary antibodies to RASSF1 (1:200, ab52857, Abcam Ltd., Cambridge, UK), HIF1A (1:200), α-actin (1:400, A2547, Sigma, Saint Louis, MO), vWF (1:200, IS527, Dako) and collagen I (1:200, c2456, Sigma). After overnight incubation, slides were washed and incubated with the respective secondary antibodies, Alexa 488- and Alexa 555-conjugated goat anti-rabbit IgG (1:1000, Molecular Probes) for 1 h. All sections were counterstained with nuclear DAPI (1:1000) and mounted with fluorescent mounting medium (Dako).
Tissue sections were also stained for PCNA (1:100, sc-7907, Santa Cruz Biotechnology) to detect proliferation. PCNA positive pulmonary vascular cells were counted throughout the entire section and expressed as fold change in percentage of the control lung by calculating the number of PCNA-positive cells per pulmonary vessel.
Medial wall thickness measurement
For morphometric analysis, Hematoxylin and eosin staining was performed according to common histopathological procedures. Analysis was done in a blinded fashion. To assess the type of remodeling of muscular pulmonary arteries, microscopic images were analyzed using a computerized morphometric system (QWin; Leica). Media thickness was defined as the distance between the lamina elastica interna and the lamina elastica externa. Depending on the external diameter of the pulmonary arteries, they were categorized as follows. Category I included arteries with an external diameter of 25–70 µm and category II included arteries with an external diameter of 70–150 µm and category III included arteries with external diameter greater than 150 µm.
Laser-assisted microdissection of pulmonary vessels
Laser-assisted microdissection of eight donor lungs and eight lungs from patients with IPAH or COPH-PH was performed as described. 100–150 arteries per patient were collected; cryosections from lung tissues were mounted on glass slides. After brief staining with hemalaun, intrapulmonary vessels were microdissected from the sections with the use of the Laser Microbeam System (P.A.L.M., Bernried, Germany) as described50. Total cellular RNA from vessels that adhered to the dissecting needles was isolated with the micro RNeasy kit (Qiagen).
RNA isolation, cDNA synthesis, and qPCR
Total mRNA was extracted from frozen human pulmonary arteries and various cells with the RNeasy Mini kit (Qiagen) or Trizol (Life technologies) respectively. Equal amounts of isolated RNA were subsequently transcribed into cDNA using High-capacity cDNA reverse transcription kit (Applied Biosystems) according to the manufacturer's instructions. qPCR was then performed with the iQ SYBR Green Supermix (Bio-Rad) kit. Intron-spanning human-specific, mouse-specific and rat-specific primers for the mentioned genes, were designed using sequence information from the NCBI database and were purchased from Metabion (Martinsried, Germany). Expression was analyzed with the ∆Ct method. The Ct values of the target genes were normalized to that of the housekeeping gene (endogenous control) encoding beta-2-microglobulin (B2M) or hypoxanthine-guanine phosphoribosyltransferase (HPRT) using the equation ∆Ct = Ctreference − Cttarget and expressed as ∆Ct. The primers used in this study are shown in Supplementary Table 1. Relative mRNA expression is also shown, with the average from control samples set as 1.
Western blotting and quantification
Lung tissue samples, pulmonary artery samples and cells were homogenized in RIPA lysis buffer (Thermo scientific), quantified and lysates were separated on 10% polyacrylamide gels and transferred to nitrocellulose membranes. After blocking, the membranes were probed with one of the following antibodies: anti-HIF1A (1:1000, BD Biosciences), anti-HIF2A (1:1000, Novus Biologicals), anti-ACTB as a loading control (1:5000, NB600–502, Novus Biologicals) and anti-RASSF1A (1:500, ab23950), anti-HK2 (1:2000, ab9464), anti-PDK1 (1:500, ab9461) and anti-LDHA (1:1000) all from Abcam Ltd. This was followed by 1 h incubation with secondary antibodies conjugated with horseradish peroxidase (HRP). Bound antibodies were detected by chemiluminescence with the ECL detection system (Thermo Scientific,) using Image reader (GE Healthcare) and densitometric analysis of the blots was obtained using multi gauge software (Fujifilm, Tokyo, Japan). In some experiments, Image reader (Fujifilm) was used for visualizing and quantifying western blot bands. Expression was quantified using band intensity values (in arbitrary units), which were normalized to ACTB. Uncropped images of all western blots are provided in the Supplementary Figs. 12–27. Detailed information of antibodies is provided in Supplementary Table 3.
All data are expressed as mean ± standard error of the mean (s.e.m.). Statistical comparisons of samples were performed by Student's t test for comparing two groups or one-way ANOVA followed by the Student–Newman–Keuls (SNK) post-hoc test for multiple comparisons. Grouped comparisons were carried out by two-way ANOVA. Difference with P < 0.05 between the groups was considered significant. All statistical analyses were performed using Prism 5.0 and Prism 6.0 (GraphPad Software).
Reporting summary
Further information on research design is available in the Nature Research Reporting Summary linked to this article.
The data supporting the findings of this study are available from the corresponding author upon request.
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The authors would like to thank Prof. Reinhard Dammann, Institute for Genetics, Justus-Liebig University Giessen for excellent suggestions with regard to RASSF1A and providing all the RASSF1A and RASSF1C constructs; Prof. Joachim Fandrey, Institute of Physiology, University of Duisburg-Essen for support with cell lines for RASSF1screening. The authors thank Uta Eule, Vanessa Golchert, Ewa Bieniek, and Natascha Wilker for the valuable technical assistance. The Max Planck Society, the Scientific and Economic Excellence in Hesse (LOEWE) Program, DFG, SFB 1213 (Project A01, A05, A06, A07), and the Excellence Cluster 147 Cardio-Pulmonary System (ECCPS, EXC 147) supported this work.
Department of Lung Development and Remodeling, Member of the German Center for Lung Research (DZL), Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, 61231, Germany
Swati Dabral
, Christian Muecke
, Chanil Valasarajan
, Mario Schmoranzer
, Christos Samakovlis
, Werner Seeger
, Rajkumar Savai
& Soni S. Pullamsetti
MRI and µCT Service Group, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, 61231, Germany
Astrid Wietelmann
Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, Biological Chemistry, and Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD21205, MD, USA
Gregg L. Semenza
Translational Research Unit, Thoraxklinik at Heidelberg University Hospital, Heidelberg, 69126, Germany
& Thomas Muley
Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, 69120, Germany
Department I of Internal Medicine and Center for Integrated Oncology, University of Cologne, Cologne, 50937, Germany
Tamina Seeger-Nukpezah
Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, S-10691, Stockholm, Sweden
Christos Samakovlis
Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), ECCPS, Member of the DZL, Justus-Liebig University, Giessen, 35392, Germany
, Norbert Weissmann
, Friedrich Grimminger
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S.D., C.M., R.S., C.V., and M.S. acquired the data. S.D., R.S., C.S., C.V., A.W., and S.S.P. analyzed and interpreted the data. S.D., W.S., and S.S.P. conceived and designed research. G.L.S. and N.W. contributed HIF constructs and NOX siRNAs. M.M., T.M., and T.S.-N. have provided primary tumor cells and microdissected human tumor vs non-tumor samples. S.D., C.S., N.W., W.S., F.G., and S.S.P. drafted the manuscript. W.S. and S.S.P. handled the funding and supervision.
Correspondence to Soni S. Pullamsetti.
Journal peer review information: Nature Communications thanks the Brian Graham and other anonymous reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.
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Dabral, S., Muecke, C., Valasarajan, C. et al. A RASSF1A-HIF1α loop drives Warburg effect in cancer and pulmonary hypertension. Nat Commun 10, 2130 (2019) doi:10.1038/s41467-019-10044-z
DOI: https://doi.org/10.1038/s41467-019-10044-z
RASSF1A Tumour Suppressor: Target the Network for Effective Cancer Therapy
Lucía García-Gutiérrez
, Stephanie McKenna
, Walter Kolch
& David Matallanas
Cancers (2020)
Hypoxia: Overview on Hypoxia-Mediated Mechanisms with a Focus on the Role of HIF Genes
Alexandru Andrei Tirpe
, Diana Gulei
, Stefana Maria Ciortea
, Carmen Crivii
& Ioana Berindan-Neagoe
International Journal of Molecular Sciences (2019)
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Nobel Prize in Physiology or Medicine 2019
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Is this nutrient the answer to dozens of health problems? Or is it a scam?
Just about every week we hear about one single nutrient deficiency that's linked to yet another disease. Studies claim that at least part of the solution to these illnesses — and sometimes the sole answer — is to raise blood levels of this common nutrient.
Osteoporosis, diabetes, heart disease, MS, lupus, cancer, rheumatoid arthritis, skin cancer, and asthma are just a few of the dozens of health problems they say respond to vitamin D therapy. How can one vitamin/hormone be a key factor in so many chronic diseases? Does vitamin D really play such a significant role in our health? Or is this an exaggeration? Or worse, a scam?
The role of vitamin D on your health is very real. It's definitely not a scam. And it's not exaggerated. In fact, it could be understated.
Researchers at the University of Oxford recently made an interesting and very important discovery. They found out how and why vitamin D affects so many health conditions. It interacts with your DNA and directly influences more than 200 genes! That means that "genetic" illnesses like MS, Crohn's disease, or type-1 diabetes may have a different cause. It may mean that low vitamin D is a key factor.
Vitamin D interacts with our DNA through vitamin D receptors — proteins this vitamin activates. The receptors attach themselves to your DNA and influence which proteins your genetic code makes.
Now, here comes the explanation for vitamin D's widespread influence on our health. So far, researchers have found 2,776 binding sites for vitamin D receptors! And that's not all. They found these sites concentrated near genes associated with susceptibility to autoimmune diseases.
This means that everyone with a known or suspected autoimmune disease should evaluate their vitamin D levels. It's quite possible they're deficient. This includes anyone with gluten sensitivity who could have Celiac disease — an autoimmune condition.
Since vitamin D deficiency is so rampant, ask your doctor to order a simple blood test called 25-hydroxy vitamin D. While most doctors say that anything above 30 ng/mL is sufficient, I disagree. And so do many doctors of integrative medicine. You want yours to be between 60 and 80 ng/mL.
It's impossible to get enough Vitamin D from sunlight unless you live near the Equator. So add a supplement to your daily regime. Most people need at least 5,000 IU per day. This is why most dietary and supplement sources won't give you vitamin D sufficiency. Many of the vitamin D supplements at the average pharmacy contain only 400 IU.
However, you can find capsules containing 5,000 IU in most health food stores or from Advanced Bionutritionals. Make sure you take vitamin D3, the most active — and easily absorbed — kind.
Ramagopalan SV, Heger A, Berlanga AJ, Maugeri NJ, Lincoln MR, Burrell A, Handunnetthi L, Handel AE, Disanto G, Orton S, Watson CT, Morahan JM, Giovannoni G, Ponting CP, Ebers GC, Knight JC. A ChIP-seq-defined genome-wide map of vitamin D receptor binding: Associations with disease and evolution. Genome Research, 2010; DOI: 10.1101/gr.107920.110.
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Eight-year follow-up after palliative embolization of a neonatal intracranial dural arteriovenous fistula with high-output heart failure: Management strategies for symptomatic fistula growth and bilateral femoral occlusions in pediatric patients: Case report
Adam S. Reig, Scott Simon, Wallace W. Neblett, Robert A. Mericle
Department of Neurosurgery
The authors report the 8-year follow-up of a patient previously described in the literature who originally presented in high-output cardiac failure secondary to a complex neonatal intracranial dural arteriovenous fistula (DAVF). The earlier case report described palliative treatment with a combination of extracorporeal membrane oxygenation (ECMO) and endovascular embolization for life-threatening high-output cardiac failure secondary to a DAVF. Access was obtained using the ECMO cannula, and embolization was performed while the patient was connected to the ECMO machine. The patient made an excellent recovery following partial embolization of the fistula, but then presented again 7 years later with worsening headaches secondary to significant growth of the known residual portion of the fistula identified on CT angiography. The child also developed bilateral femoral artery (FA) occlusions secondary to multiple previous FA punctures. To achieve complete obliteration of the remaining fistula, the patient required a retroperitoneal approach to the iliac artery and percutaneous puncture of the internal jugular vein. Embolization was performed with a combination of platinum coils and ethylene vinyl alcohol copolymer liquid embolic agent. There were no complications, and the child remains neurologically normal, with no signs of permanent cardiovascular sequelae. In this case report, the authors discuss the long-term management of AVFs treated by endovascular strategies early in life. After neonatal access, sometimes the FAs occlude, requiring more invasive access strategies. The authors also discuss the follow-up method, intervals, and threshold for further treatment for these lesions, and present a review of the literature.
https://doi.org/10.3171/2010.9.PEDS10185
Dive into the research topics of 'Eight-year follow-up after palliative embolization of a neonatal intracranial dural arteriovenous fistula with high-output heart failure: Management strategies for symptomatic fistula growth and bilateral femoral occlusions in pediatric patients: Case report'. Together they form a unique fingerprint.
Central Nervous System Vascular Malformations Medicine & Life Sciences 100%
Fistula Medicine & Life Sciences 65%
Extracorporeal Membrane Oxygenation Medicine & Life Sciences 64%
Thigh Medicine & Life Sciences 58%
Heart Failure Medicine & Life Sciences 53%
Pediatrics Medicine & Life Sciences 46%
Femoral Artery Medicine & Life Sciences 38%
Reig, A. S., Simon, S., Neblett, W. W., & Mericle, R. A. (2010). Eight-year follow-up after palliative embolization of a neonatal intracranial dural arteriovenous fistula with high-output heart failure: Management strategies for symptomatic fistula growth and bilateral femoral occlusions in pediatric patients: Case report. Journal of Neurosurgery: Pediatrics, 6(6), 553-558. https://doi.org/10.3171/2010.9.PEDS10185
Reig, Adam S. ; Simon, Scott ; Neblett, Wallace W. et al. / Eight-year follow-up after palliative embolization of a neonatal intracranial dural arteriovenous fistula with high-output heart failure : Management strategies for symptomatic fistula growth and bilateral femoral occlusions in pediatric patients: Case report. In: Journal of Neurosurgery: Pediatrics. 2010 ; Vol. 6, No. 6. pp. 553-558.
@article{8a934979ac844cfb87c5afe64b9ec197,
title = "Eight-year follow-up after palliative embolization of a neonatal intracranial dural arteriovenous fistula with high-output heart failure: Management strategies for symptomatic fistula growth and bilateral femoral occlusions in pediatric patients: Case report",
abstract = "The authors report the 8-year follow-up of a patient previously described in the literature who originally presented in high-output cardiac failure secondary to a complex neonatal intracranial dural arteriovenous fistula (DAVF). The earlier case report described palliative treatment with a combination of extracorporeal membrane oxygenation (ECMO) and endovascular embolization for life-threatening high-output cardiac failure secondary to a DAVF. Access was obtained using the ECMO cannula, and embolization was performed while the patient was connected to the ECMO machine. The patient made an excellent recovery following partial embolization of the fistula, but then presented again 7 years later with worsening headaches secondary to significant growth of the known residual portion of the fistula identified on CT angiography. The child also developed bilateral femoral artery (FA) occlusions secondary to multiple previous FA punctures. To achieve complete obliteration of the remaining fistula, the patient required a retroperitoneal approach to the iliac artery and percutaneous puncture of the internal jugular vein. Embolization was performed with a combination of platinum coils and ethylene vinyl alcohol copolymer liquid embolic agent. There were no complications, and the child remains neurologically normal, with no signs of permanent cardiovascular sequelae. In this case report, the authors discuss the long-term management of AVFs treated by endovascular strategies early in life. After neonatal access, sometimes the FAs occlude, requiring more invasive access strategies. The authors also discuss the follow-up method, intervals, and threshold for further treatment for these lesions, and present a review of the literature.",
author = "Reig, {Adam S.} and Scott Simon and Neblett, {Wallace W.} and Mericle, {Robert A.}",
doi = "10.3171/2010.9.PEDS10185",
journal = "Journal of Neurosurgery: Pediatrics",
publisher = "American Association of Neurological Surgeons",
Reig, AS, Simon, S, Neblett, WW & Mericle, RA 2010, 'Eight-year follow-up after palliative embolization of a neonatal intracranial dural arteriovenous fistula with high-output heart failure: Management strategies for symptomatic fistula growth and bilateral femoral occlusions in pediatric patients: Case report', Journal of Neurosurgery: Pediatrics, vol. 6, no. 6, pp. 553-558. https://doi.org/10.3171/2010.9.PEDS10185
Eight-year follow-up after palliative embolization of a neonatal intracranial dural arteriovenous fistula with high-output heart failure : Management strategies for symptomatic fistula growth and bilateral femoral occlusions in pediatric patients: Case report. / Reig, Adam S.; Simon, Scott; Neblett, Wallace W. et al.
In: Journal of Neurosurgery: Pediatrics, Vol. 6, No. 6, 01.12.2010, p. 553-558.
T1 - Eight-year follow-up after palliative embolization of a neonatal intracranial dural arteriovenous fistula with high-output heart failure
T2 - Management strategies for symptomatic fistula growth and bilateral femoral occlusions in pediatric patients: Case report
AU - Reig, Adam S.
AU - Simon, Scott
AU - Neblett, Wallace W.
AU - Mericle, Robert A.
N2 - The authors report the 8-year follow-up of a patient previously described in the literature who originally presented in high-output cardiac failure secondary to a complex neonatal intracranial dural arteriovenous fistula (DAVF). The earlier case report described palliative treatment with a combination of extracorporeal membrane oxygenation (ECMO) and endovascular embolization for life-threatening high-output cardiac failure secondary to a DAVF. Access was obtained using the ECMO cannula, and embolization was performed while the patient was connected to the ECMO machine. The patient made an excellent recovery following partial embolization of the fistula, but then presented again 7 years later with worsening headaches secondary to significant growth of the known residual portion of the fistula identified on CT angiography. The child also developed bilateral femoral artery (FA) occlusions secondary to multiple previous FA punctures. To achieve complete obliteration of the remaining fistula, the patient required a retroperitoneal approach to the iliac artery and percutaneous puncture of the internal jugular vein. Embolization was performed with a combination of platinum coils and ethylene vinyl alcohol copolymer liquid embolic agent. There were no complications, and the child remains neurologically normal, with no signs of permanent cardiovascular sequelae. In this case report, the authors discuss the long-term management of AVFs treated by endovascular strategies early in life. After neonatal access, sometimes the FAs occlude, requiring more invasive access strategies. The authors also discuss the follow-up method, intervals, and threshold for further treatment for these lesions, and present a review of the literature.
AB - The authors report the 8-year follow-up of a patient previously described in the literature who originally presented in high-output cardiac failure secondary to a complex neonatal intracranial dural arteriovenous fistula (DAVF). The earlier case report described palliative treatment with a combination of extracorporeal membrane oxygenation (ECMO) and endovascular embolization for life-threatening high-output cardiac failure secondary to a DAVF. Access was obtained using the ECMO cannula, and embolization was performed while the patient was connected to the ECMO machine. The patient made an excellent recovery following partial embolization of the fistula, but then presented again 7 years later with worsening headaches secondary to significant growth of the known residual portion of the fistula identified on CT angiography. The child also developed bilateral femoral artery (FA) occlusions secondary to multiple previous FA punctures. To achieve complete obliteration of the remaining fistula, the patient required a retroperitoneal approach to the iliac artery and percutaneous puncture of the internal jugular vein. Embolization was performed with a combination of platinum coils and ethylene vinyl alcohol copolymer liquid embolic agent. There were no complications, and the child remains neurologically normal, with no signs of permanent cardiovascular sequelae. In this case report, the authors discuss the long-term management of AVFs treated by endovascular strategies early in life. After neonatal access, sometimes the FAs occlude, requiring more invasive access strategies. The authors also discuss the follow-up method, intervals, and threshold for further treatment for these lesions, and present a review of the literature.
U2 - 10.3171/2010.9.PEDS10185
DO - 10.3171/2010.9.PEDS10185
JO - Journal of Neurosurgery: Pediatrics
JF - Journal of Neurosurgery: Pediatrics
Reig AS, Simon S, Neblett WW, Mericle RA. Eight-year follow-up after palliative embolization of a neonatal intracranial dural arteriovenous fistula with high-output heart failure: Management strategies for symptomatic fistula growth and bilateral femoral occlusions in pediatric patients: Case report. Journal of Neurosurgery: Pediatrics. 2010 Dec 1;6(6):553-558. doi: 10.3171/2010.9.PEDS10185
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Enzymes play the most significant and crucial role in the digestive process since they are the main factors responsible for degradation of complex bio-molecules into their simpler forms. And any imbalance in this regard may result in serious health complications. But Creon is the ultimate medication for various clinical conditions such as cystic fibrosis, chronic inflammation of pancreas and blockage of pancreatic ducts that lacks digestive enzymes. Creon contains three important enzymes lipase, protease and amylase (also known as pancrelipase) in conjugation to carry out its action.
Enhancing your digestive mechanism so that you can lead a happy and complications free life is the main aim of Creon. Hydrolyzing the fats into glycerol and fatty acids, converting starches into dextrin and sugars and breaking down proteins into proteoses is the mechanism of action of Creon.
Creon is a boon for all those individuals who suffer from complications of improper digestion. Your medical condition, degree of fat content and steatorrhea in your diet plays an important role in deciding your dosage of Creon and hence, your medical professional may recommend accordingly. It should be taken with regards to meals for obtaining good results from its treatment.
Creon is found to be most accurate and unique medication for treating various digestive related disorders and is also recommended in patients who underwent surgical removal of pancreas. The effectiveness, potency and safety profile of Creon are added advantages to its already existing features.
Creon has the capability to flip your undigested and unhealthy life to a better and healthy life. But following some really important precautionary measures are mandatory to achieve its full benefit. Creon should not be taken in case you have any unusual or allergic reaction to any of its active or inactive components, allergic to pork, pregnant (or planning to become pregnant), breastfeeding or suffer from serious medical complications.
Common side effects of Creon usually do not pose any threat to normal health (since they disappear after some time) include bloating or gas, diarrhea, constipation, nausea, vomiting, rectal irritation, stomach pain or upset and greasy stools.
Whereas serious side effects of Creon that are reported in extreme cases include difficulty in breathing and severe allergic reactions such as itching or hives and swelling of your face, lips, tongue or throat. These symptoms may require urgent medical assistance if any of these persist for longer duration.
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The most common symptoms of a wound are pain, swelling, and bleeding. The amount of pain, swelling, and bleeding of a wound depends upon the location of the injury and the mechanism of injury.
Some large lacerations may not hurt very much if they are located in an area that has few nerve endings, while abrasions of fingertips (which have a greater number of nerves) can be very painful.
Some lacerations may bleed more if the area involved has a greater number of blood vessels, for example, the scalp and face.
Pediatrician doctor bandaging child's leg. Mother holding baby in her hands. Close-up.
Most wounds can be treated at home with routine first aid including thorough washing and dressing to prevent infection.
If the wound is caused by an animal bite. There is also a need to consider rabies immunizations, if appropriate.
Article provided by eMedicine Health. For more information click here.
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Your health care team can help you and your child access and coordinate specialty care, other health care and educational services, in and out of home care, family support, and other public/private community services that are important to the overall well-being of you and your child.
Well-Visit Planner: This guide helps you identify important topics you may want to discuss with your physician.
The Wisconsin Medical Home Initiative is dedicated to promoting the concepts of medical home for primary care clinicians, families and service providers throughout Wisconsin.
Care Notebook is a tool to help you organize information about your child's medical needs to share with practitioners, schools and childcare staff.
Please ask your child's doctor or contact the regional center at 800-234-KIDS (5437) if you have any questions about the medical home concept or are unsure which doctor or health system is your child's medical home.
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MRI Beats CT for Acute Stroke Diagnosis
BETHESDA, Md. -- MRI is better than CT for detecting acute strokes of any kind, and should be the diagnostic imager of choice in the ER, according to NIH researchers.
BETHESDA, Md., Jan. 25 -- MRI is better than CT for detecting acute strokes of any kind, and should be the diagnostic imager of choice in the ER, according to NIH researchers.
Comparing the two modalities in patients with suspected acute stroke, the investigators found that the sensitivity of MRI for diagnosing acute strokes was 83%, compared with just 26% for CT performed on the same patients.
MRI was also superior to CT at diagnosing acute hemorrhagic stroke and chronic stroke, and was comparable at detecting intracranial hemorrhage, reported Steven Warach, M.D., Ph.D., of the National Institute for Neurological Disorders and Stroke, and colleagues, in the Jan. 27 issue of The Lancet.
Among patients presenting within three hours of the onset of symptoms, representing the window for thrombolytic therapy of ischemic stroke, MRI successfully detected 46% of the cases, whereas CT's batting average was only 7%, they found.
"Our sample was representative of the range of patients who are likely to present with a clinical suspicion of acute stroke, including patients who ultimately proved to have a different diagnosis. Therefore, our results are directly applicable to clinical practice," they wrote.
In view of their results, they said, it is no longer justifiable for CT scans to be the standard criterion for diagnosis of acute stroke on the sole basis of accuracy.
In an accompanying editorial, Geoffrey A. Donnan, M.D., of the National Stroke Research Institute at the University of Melbourne in Australia, and colleagues, applauded the study, saying that it's about time someone answered the critical question of the preferred stroke imaging method.
"Why is MRI such an attractive imaging option for patients presenting with acute stroke?" they wrote. "The answer lies in its extraordinary ability to allow an immediate diagnosis of stroke and to generate non-invasively such a range of information about the status of blood vessels and the brain. The anatomical location of the area of ischemia and its viability (on diffusion-weighted imaging), together with arterial imaging (on magnetic resonance angiography), are important pieces of information, which allow the clinician to establish the mechanism of stroke."
Dr. Warach and colleagues conducted a single-center, prospective, blind comparison of non-contrast CT and MRI with diffusion-weighted and susceptibility weighted images in a consecutive series of patients who were referred to the Suburban Hospital in Bethesda for emergency assessment of suspected acute stroke.
A total of 356 consecutive patients were entered into the study, without regard to time of symptom onset, severity of symptoms, or the ultimate clinical diagnosis.
The patients were assigned to undergo both MRI and CT scanning, with the order of scans determined by clinical expediency, because randomization to one or the other first might have resulted in unjustifiable delays in clinical care, the authors noted. In most cases, patients underwent both scans within two hours of one another.
The images were analyzed independently by two expert neuroradiologists and two expert stroke neurologists who were not involved in the care of the patients and who were unaware of all clinical information. The image readers were asked to record whether they saw evidence of acute ischemic stroke, acute or chronic hemorrhage, no acute stroke, or a combination.
In all, 217 of the 356 patients (61%) had a final clinical diagnosis of acute stroke. The authors found that MRI more frequently correctly diagnosed acute stroke (either ischemic or hemorrhage), acute ischemic stroke, and chronic hemorrhage significantly more frequently than CT (P
"MRI can be used as the sole modality for the emergency imaging of patients with suspected acute stroke, whether ischemic or hemorrhagic," the investigators wrote.
"The high diagnostic accuracy of MRI was the same for scans within the first three hours as it was for the entire sample, and thus is relevant to patients who might be eligible for standard thrombolytic treatment of stroke," they continued. "Many stroke centers use MRI as the basis of thrombolytic treatment decisions, and where MRI is immediately available for emergency stroke diagnosis, initiation of thrombolytic treatment will not be substantially delayed."
In discussing the significance of the results, the authors wrote, "Although CT scanning has been the criterion that is standard for diagnosis of acute stroke, our study shows that use of CT is no longer justifiable on the basis of diagnostic accuracy alone."
They did acknowledge that non-contrast CT is generally more readily available and cheaper to perform than diffusion-weighted or susceptibility-weighted MRI. They therefore called for a study comparing whether immediate MRI or immediate CT in the emergency setting could improve patient outcomes and reduce costs associated with hospitalization, rehabilitation, and disability from acute strokes.
In their editorial, Dr. Donnan and colleagues noted that the only drawback to the study findings was that 11% of patients could not undergo MRI, either because of claustrophobia, the presence of cardiac pacemakers, or neurological or medical instability.
"Medical instability can be a problem when time in the scanner might be up to 30 minutes with standard imaging sequences, but these can be shortened to three to five minutes without losing crucial information," they wrote.
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» The American Heart Hospital Journal - Volume 7 No.2
» ST Segment Elevation During Adenosine Pharmacological Stress Testing in a Patient with Coronary Artery Disease
ST Segment Elevation During Adenosine Pharmacological Stress Testing in a Patient with Coronary Artery Disease
Jaffar Ali Raza
Nazim Uddin Azam Khan
Jamal S Mustafa
Assad Movahed
American Heart Hospital Journal 2009;7(2):122–4
https://doi.org/10.15420/ahhj.2009.7.2.122
Case history: a 76-year-old African-American female presented to a community hospital with complaints of chest pain. Her medical history was significant for hypertension, gastroesophageal reflux disease (GERD), hyperlipidemia, and bipolar disorder. On arrival at the emergency department, electrocardiogram showed acute inferior wall myocardial infarction (MI). The patient received thrombolytic therapy with tenecteplase (TNKase™) with successful reperfusion. On arrival at our hospital, the patient denied any chest pain and her electrocardiogram showed sinus bradycardia with small Q-waves in the inferior leads II, III, and AVF (see Figure 1). She was treated with aspirin, heparin, lisinopril, simvastatin, and clopidogrel. Beta-blocker was not started as the patient was having bradycardia. The patient was scheduled to undergo myocardial perfusion scan 48 hours following her uncomplicated inferior wall MI.
At rest, the patient received 12.0mCi of technetium 99m-sestamibi. Seventy-five minutes later, rest myocardial perfusion images were obtained by non-gated single photon emission computed tomography (SPECT). Then she received adenosine infusion at 140μg/kg/minute for six minutes. Blood pressure and 12-lead electrocardiogram were obtained every minute and the patient's symptoms were recorded. Resting heart rate was 67. Heart rate three minutes into the adenosine infusion was 73, and heart rate six minutes into the adenosine infusion was 85. Resting blood pressure was 152/69. Blood pressure three minutes into the adenosine infusion was 128/54, and blood pressure six minutes into the adenosine infusion was 70/47. Resting electrocardiogram showed normal sinus rhythm, small inferior Q-waves, and ST–T changes. There was an additional 1–2mm ST segment depression in the electrocardiographic leads I, AVL, and V2, plus 1–3mm additional ST segment elevation was noted in II, III, and AVF during and up to three minutes-post adenosine infusion (see Figure 2). There were occasional premature ventricular complexes and premature atrial complexes before, during, and post-adenosine infusion. The patient did not report chest pain during or after adenosine infusion.
Three minutes into the adenosine infusion, 44mCi of technetium 99m sestamibi was injected intravenously. One hour and 50 minutes later, the stress (adenosine) myocardial perfusion images were obtained by gated SPECT.
SPECT images were acquired with a dual-head gamma camera using the step-and-shoot detector rotation, obtaining 32 projections over 180º arcs (45º right anterior oblique to 45º left posterior oblique). The camera was equipped with a low-energy, high-resolution collimator. Rest and stress images were acquired with a 20% window centered over the 140KeV photo peak. Gated acquisitions were obtained using eight frames per cardiac cycle with a 40% acceptance window. Acquisition times were 40 seconds per projection. The summed projection data sets were filtered with a butterworth filter (order 5 cut-off 0.33). Short-, vertical-, long-, and horizontal-axis images were evaluated for transient, partially reversible, and fixed perfusion defects.
The rest and stress (adenosine) myocardial perfusion images revealed normal-sized left ventricle and mild to moderate transient myocardial perfusion defect (mild to moderate ischemia) superimposed on mild fixed myocardial perfusion defect (superimposed on mild scar) involving the inferior, inferoapex, and inferolateral wall of the left ventricle (see Figure 3). There were hypokinetic inferior, inferoapex, and inferolateral walls of the left ventricle, with resting global left ventricular ejection fraction (LVEF) of 40%. The right ventricle was normal in size and function.
Following the adenosine myocardial perfusion scanning, the patient underwent cardiac catheterization. Cardiac catheterization showed normal left main, left anterior descending, and circumflex arteries. The right coronary artery showed a 75% stenosis in the mid segment (see Figure 4). The patient had a 3.5x16mm stent deployed without any complications. Her post-procedure course in the hospital was uneventful and she was discharged the following day in a stable condition.
Adenosine acts via its four subtypes (A1, A2A, A2B, and A3) of receptors in the coronary artery.1 A2A adenosine receptor is the predominant subtype on the endothelium and smooth muscle of the coronary blood vessels that causes coronary vasodilatation.1,2 However, A2B subtype has also been reported in the coronary vessels and may play a role in coronary vasodilatation but to a lesser extent in normal than in pathophysiological situations.1,3 On the other hand, both A1 and A3 adenosine receptors have been shown to play an inhibitory role in the regulation of coronary blood flow.4,5
In this case history, transient myocardial perfusion defect with corresponding ST segment elevation has been noted with adenosine infusion induced ischemia.6,7 This has been postulated to be secondary to myocardial ischemia that occurs during adenosine infusion, which causes a fall in regional coronary flow below resting levels caused by a steal phenomenon.8 When these patients were treated with anti-anginal medications and re-studied by echocardiography, wall motion abnormality and ST depression were less frequent.9 Rare cases of MI after adenosine stress testing have been reported.10 However, adenosine myocardial perfusion scanning has been safely performed within 24 hours after an uncomplicated MI.11 We reported a case of adenosine-induced coronary vasospasm with significant ST elevation in a patient with normal coronary arteries.12 Although there could be similarities between this case and the one reported earlier without significant coronary artery disease where A1 receptor activation by adenosine in the vascular smooth muscles may provide an explanation, other possible explanations should be considered. These include the overexpression of A1 receptors compared with A2A/B receptors in the damaged endothelium and/or underlying smooth muscle and/or the increase in sympathetic tone due to adenosine infusion causing vasospasm. Finally, unless we fully understand the pharmacology of adenosine receptors in diseased coronary artery, these are mere speculations based on recent work that shows more heterogeneity of the adenosine receptor population in animal models than previously appreciated.1
Abebe W, Hussain T, Olanrewaju H, Mustafa SJ, Role of nitric oxide in adenosine receptor-mediated relaxation of procine coronary artery, Am J Physiol Heart Circ Physiol, 1995;269:H1672–8.
Tabrizchi R, Bedi S, Pharmacology of adenosine receptors in the vasculature, Pharmacol Ther, 2001;91:133–47.
Morrison RA, Talukder MAH, Ledent C, Mustafa SJ, The cardiac effects of adenosine in A2A receptor knockout hearts: uncovering A2B receptors, Am J Physiol Heart Circ Physiol, 2002;282:H437–44.
Tawfik HE, Schnermann J, Oldenburg PJ, Mustafa SJ, Role of A1 adenosine receptors in regulation of vascular tone, Am J Physiol Heart Circ Physiol, 2005;288(3):H1411–16.
Talukder MAH, Morrison RR, Jacobson MA, et al., Targeted deletion of adenosine A3 receptors augments adenosine-induced coronary flow in isolated mouse heart, Am J Physiol Heart Circ Physiol, 2002;282:H2183–9.
Picano E, Simonetti I, Masini M, et al., Transient myocardial dysfunction during pharmacologic vasodilation as an index of reduced coronary reserve: a coronary hemodynamic and echocardiographic study, J Am Coll Cardiol, 1986;8:84–90.
Iskandrian AS, Heo J, Nguyen T, et al., Assessment of coronary artery disease using single-photon emission computed tomography with thallium-201 during adenosine-induced coronary hyperemia, Am J Cardiol, 1991;67:1190–94.
Patterson RE, Kirk ES, Coronary steal mechanisms in dogs with one-vessel occlusion and other arteries normal, Circulation, 1983;67:1009–15.
Lattanzi F, Picano E, Bolognese L, et al., Inhibition of dipyridamole-induced ischemia by antianginal therapy in humans: correlation with exercise electrocardiography, Circulation, 1991;83:1256–62.
Polad JE, Wilson LM, Myocardial infarction during adenosine stress test, Heart, 2002;87(2):E2.
Kulhanek J, Sorrell VL, Ershadi RE, et al., Adenosine myocardial perfusion single photon emission computed tomographic stress testing 24–72 h after uncomplicated myocardial infarction, Intl J Cardiovasc Imag, 2002;18:269–72.
Golzar J, Mustafa SJ, Movahed A, Chest pain and ST segment elevation three minutes after completion of adenosine pharmacological stress testing, J Nucl Cardiol, 2004;11:744–6.
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Who is interested in the quality of everyday psychiatric care?
Results of treatment of schizophrenia: is the glass half full or half empty?
Is Interpersonal Fairness in the Doctor-Patient Relationship Associated with Long-Term Compliance in Patients with Schizophrenia?
by Leucht, Stefan, Heres, Stephan, Kissling, Werner, Davis, John M.
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Researchers suggest that frequent mouthwash use could increase the risk of diabetes.
Researchers suggest that using mouthwash at least twice every day destroys "friendly" oral bacteria, which can, in turn, alter blood sugar metabolism and promote diabetes, particularly for people who are already at high risk for the condition.
Study co-author Rakesh P. Patel — from the Department of Pathology and Center for Free Radical Biology in the University of Alabama at Birmingham — and colleagues have published their findings in the journal Nitric Oxide.
It is estimated that around 30.3 million people in the United States have diabetes, which is a condition characterized by high blood glucose levels.
A further 84.1 million adults in the U.S. have prediabetes, wherein blood glucose levels are higher than normal but are not high enough to warrant a diabetes diagnosis.
Being overweight is one of the biggest risk factors for diabetes. According to the new study, the simple practice of using mouthwash could exacerbate this risk.
The scientists came to their intriguing findings by analyzing the data of 1,206 overweight or obese adults aged 40–65. All adults were part of the San Juan Overweight Adults Longitudinal Study, and they were free of diabetes and major cardiovascular diseases at study baseline.
As part of the study, participants were asked how often they used mouthwash. A total of 43 percent of the subjects said that they used mouthwash at least once daily, while 22 percent said that they used it at least twice daily.
Over an average of 3 years of follow-up, the team monitored the development of prediabetes or diabetes among the participants. A total of 945 subjects were included in the final analysis.
Drinking as few as two sugary beverages each week could lead to type 2 diabetes, say researchers.
Compared with participants who did not use mouthwash, those who reported using mouthwash at least twice daily were 55 percent more likely to develop prediabetes or diabetes over 3 years.
There was no association between using mouthwash less than twice per day and the risk of prediabetes or diabetes, the researchers report.
These findings persisted after accounting for a number of possible confounding factors, including diet, oral hygiene, sleep disorders, medication use, fasting glucose levels, income, and education levels.
"Frequent regular use of over-the-counter mouthwash was associated with increased risk of developing prediabetes/diabetes in this population."
Many mouthwashes contains antibacterial compounds — such as chlorhexidine — that kill bacteria in order to help prevent gingivitis, tooth decay, and other oral health conditions.
Patel and colleagues suspect that these compounds also destroy "good" bacteria in the mouth that are important for the formation of nitric oxide, which is a chemical compound that helps to regulate insulin — the hormone that controls blood sugar levels.
Therefore, the destruction of this beneficial bacteria could encourage the development of diabetes.
Given that more than 200 million people in the U.S. use mouthwash, these latest findings could be a cause for concern. However, it is important to note that the study is purely observational.
Patel and colleagues say that further research is needed to determine whether a seemingly innocent oral hygiene product is really a risk factor for diabetes.
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Incledon says that the main point of this study to him is that we are learning about new doorways to treating cancer. And, maybe it can have a positive effect just like other environmental triggers. "To me, there's no downside because smelling something can't hurt you," says Incledon. "It is not invasive, so looking into this as a complementary strategy makes sense. At Causenta, they consider lighting and sound in treatment rooms as a way to reduce fear and anxiety. The idea is that patients will respond better to therapy if they feel happy and calm.
Considering alternative therapies is especially important with bladder cancer because of the high rate of recurrence. Bladder cancer cells are very invasive meaning they spread deep into tissues and get into the blood. They can also become resistant to any kind of treatment, including radiation and chemotherapy as well as natural options like Vitamin C. There is no one-size-fits-all treatment for bladder cancer and Incledon urges patients to consider all treatment options.
As part of the support system, it is also necessary that people support any behavioral or mindset changes the patient undergoes as part of treatment. Sometimes patients will eat healthy foods while at the center, which is helping to decrease inflammation and body fat positively impacting their results. Once they return home, they go back to eating, which can be a setback to treatment progress.
To learn more about bladder cancer and personalized, holistic treatment options at Causenta, schedule a complimentary 30-minute consultation today.
What is the difference between resectable and unresectable gallbladder canc... My child was just diagnosed with ALL. What sort of prognosis are we facing?
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The organic ingredients, including argan oil, work on the skin cells in the scalp, providing oxygen and nutrients required for healthy,luxuriant hair growth.
Working against the swelling caused by stagnation of the blood flow, as well as various other skin complaints, our medical head spa comes from a clinic which aims to preserve health and beauty.
In our salon you'll live the Shirodhara experience with flowerfall.
A 100% organic oil head spa made from wild herbal ingredients.
Improvement of hair and scalp conditions by making them "super moisturized". Providing "double care" head spa and salon treatment of the highest quality.
After cleansing the scalp, the treatment provides nutrients and improves blood circulation. This beauty treatment works against hair complaints, improving the condition of your hair.
Hairs affected by aging and split ends are given new life as our deep care treatment promotes healthy hair growth.
This is a highly effective treatment by Italy of the venerable brand, already used in over 60 countries worldwide.
The cream bath makes use of a specially formulated cream containing natural herbs from plant sources. In addition to creating a sense of deep relaxation, the cream clears the pores of any impurities, creating healthy, silky hair.
Head massage and scalp shampoo designed to relieve tirednessof the head, eyes and hands and promote healthy scalp and hair growth.
We decline treatment for pregnant customers due to the risk of our aroma oils and massages treatments inducing unforeseen changes to their physical condition. We appreciate your understanding.
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Yes, though it is very rarely suggested.
Women are more likely to develop Coccydynia due to its association with childbirth. However, it is a rare type of pain, which usually goes away with time. Coccyx plays an important role in supporting our weight when we sit. In medical literature, there are various suggestions regarding the importance of non-surgical treatment that should be tried before recommending surgery.
If the pain is persistent and is not alleviated with the treatments and/or activity changes, surgical removal of the coccyx, called Coccygectomy, is considered as an option. Yet, it is still rarely recommended and performed. You may either remove the complete coccyx or just a part of it.
Reviews of the successful operations suggest that there were no disadvantages to the patient caused by the absence of coccyx. However, the most common complication is the infection that spreads post-operation. While the surgery is relatively a simple procedure, the recovery can pose great difficulty for the patient as it is a long and uncomfortable process.
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Home Health Ketomac cream: the new innovation of Antiseptic creams.
Ketomac cream: the new innovation of Antiseptic creams.
Ketomac cream is a small miracle of cosmetic science that does wonders to skin. Skin serves as a defensive barrier for our bodies and we must take care of it, even when it is just a scratch or it is a wound. But, it is important to note that if the wounds are different, they are to be treated differently and they take their own course of time to heal.
It is important to take care of infections as they are extremely dangerous and severe. When the skin breaks, it is prone to attacks by microorganisms who penetrate through the skin and cause irritation and inflammation of the skin.
The medicated ketomac cream should be used according to the prescription and one is strictly not supposed to stop the medication midway, even if the problem seemed to have faded away because it might cause opposite reactions. This might also increase your risk of further infection that is resistant to antifungal medication.
Ketoconazole cream in India is being widely used these days and prescribed by efficient dermatologists. The topical cream with a concentration of 2% is also used to treat s skin condition known as pityriasis (tinea versicolor), a fungal infection that causes a lightening or darkening of the skin of the neck, chest, arms, hands or legs. This is an anti-fungal medication that belongs to the same family of drugs as fluconazole (Diflucan), itraconazole (Sporanox), and miconazole (Micatin, Monistat).
The preferred room temperature to store the ketomac cream is 20 C to 25 C (68 F to 77 F). Ketoconazole works by harming the yeast and fighting the infection. It has to be applied topically once or twice a day, as prescribed. The area over which the cream has to be applied should be completely dry and clean. It is advised to apply sufficient amount of cream in the affected area and rub that area smoothly. It should not be covered or wrapped with any cloth or bandage and should be kept away from direct sunlight. The skin area should not interact with water for atleast three hours.
redness of the treated skin, etc.
There are many skin infections that are essentially treated by ketoconazole creams. The fungus in the infection produces egosterol that further develops fungus cell membranes. Here comes in the role of ketomac that gives targeted results and also prevent suct infections in future.
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(Redirected from Autologous conditioned plasma)
Concentrate of platelet-rich plasma protein derived from whole blood
Platelet-rich plasma injection into the hand
[edit on Wikidata]
Platelet-rich plasma (PRP), also known as autologous conditioned plasma, is a concentrate of platelet-rich plasma protein derived from whole blood, centrifuged to remove red blood cells. Though promoted to treat an array of medical problems, evidence for benefit is mixed as of 2020, with some evidence for use in certain conditions and against use in other conditions.[1][2][3] The cost per injection is generally US$500 to $2,000 as of 2019.[4]
1 Medical use
2 Adverse effects
3 Composition
5 Society and culture
5.1 Doping
Medical use[edit]
Evidence for benefit of PRP is mixed, with some evidence for use in certain conditions and against use in other conditions.[5][6][3] It has been investigated for chronic tendinitis,[7] osteoarthritis,[8] in oral surgery,[9] and in plastic surgery.[10]
A 2019 review found it not to be useful in rotator cuff disease.[3] While an older review found that it may be useful.[11] Tentative evidence supports its use in osteoarthritis (OA) of the knee.[12][13] A 2019 meta-analysis found that PRP might be more effective in reducing pain and improving function than hyaluronic acid in knee OA.[14]
A 2009 review found few randomized controlled trials that adequately evaluated the safety and efficacy of PRP treatments and concluded that PRP was "a promising, but not proven, treatment option for joint, tendon, ligament, and muscle injuries".[15] As compared to other conservative treatments for non-surgical orthopedic illnesses (e.g. steroid injection for plantar fasciitis), evidence does no support the use of PRP as a conservative treatment.[16] A 2018 review found that evidence was lacking for Achilles tendinopathy.[17] A 2019 meta-analysis found that, for most outcomes in Achilles tendinopathy, PRP treatment did not differ from placebo treatment.[18]
A 2010 Cochrane review of use in sinus lifts during dental implant placement found no evidence of benefit.[9] A 2013 review stated more evidence was needed to determine effectiveness for hair regrowth.[19]
A 2014 Cochrane review of PRP in musculoskeletal injuries found very weak evidence for a decrease in pain in the short term, and no difference in function in the short, medium or long term. There was weak evidence that suggested that harm occurred at comparable, low rates in treated and untreated people.[20] Similarly, another 2017 review for treating pain on skin graft donor sites found the evidence for benefit was poor.[21]
It has not been shown to be useful for bone healing.[22] A 2016 review of PRP use to augment bone graft found only one study reporting a difference in bone augmentation, while four studies found no difference.[23]
Adverse effects[edit]
Adverse effects have been poorly studied. The single systematic review of the literature did not report of the types and number of adverse events.[24] In 2019, Health Canada stated that most autologous cell therapies have little evidence showing they work and can pose risks, such as cross-contamination between people if equipment is not sterilized properly or potentially dangerous immune reactions.[25] Health Canada stopped Canadian clinics from offering these types of services with a donor-patient model.[26] Health Canada later clarified that PRP treatments harvested from, and given back to, the same person (in a single procedure) was not covered by its initial guidance as the procedure falls under health care provider regulatory bodies (rather than Health Canada).[27]
Composition[edit]
Whole blood placed in Centrifuge prior to two stage centrifugation
There are four general categories of preparation of PRP based on its leukocyte and fibrin content: leukocyte-rich PRP (L-PRP), leukocyte reduced PRP (P-PRP; leukocyte reduced or pure PRP), leukocyte platelet-rich fibrin and pure platelet-rich fibrin.[28][29]
The efficacy of certain growth factors in healing various injuries and the concentrations of these growth factors found within PRP are the theoretical basis for the use of PRP in tissue repair.[30] The platelets collected in PRP are activated by the addition of thrombin and calcium chloride, which induces the release of the mentioned factors from alpha granules. The growth factors and other cytokines present in PRP include:[30][31]
platelet-derived growth factor
transforming growth factor beta
fibroblast growth factor
Interleukin 8
keratinocyte growth factor
connective tissue growth factor
Manufacturing[edit]
PRP is prepared by taking blood from the person, and then putting it through two stages of centrifugation designed to separate PRP from platelet-poor plasma and red blood cells. This is usually done by the clinic offering the treatment, using commercially available kits and equipment.[32] The resulting substance varies from person to person and from facility to facility, making it difficult to understand how safe and effective any specific use is.[32][33]
Blood drawn from patient
Removal of PRP after double centrifugation
PRP is Injected into area of injury via ultrasound guidance
Society and culture[edit]
The cost of a PRP treatment in the U.S. has been quoted as $1000 out-of-pocket expenses, as it is usually not covered by health insurance.[34] PRP has received attention in the popular media as a result of its use by athletes.[35][36][37][34] Use in an office setting is not approved by the FDA.[38]
In the 2010s, contentious cosmetic procedures marketed under the name of "vampire facials" grew in popularity, fueled by celebrity endorsement. These "vampire facials" generally center on PRP treatment, and usually (but not always) involve microneedling.[39][40]
PRP has also been injected into the vagina, in a procedure called "O-shot" or "orgasm shot" with claims that this will improve orgasms.[41] There is no evidence, however, to support these claims.[41][42]
Doping[edit]
Some concern exists as to whether PRP treatments violate anti-doping rules.[30] As of 2010 it was not clear if local injections of PRP could have a systemic impact on circulating cytokine levels, affecting doping tests and whether PRP treatments have systemic anabolic effects or affect performance.[30] In January 2011, the World Anti-Doping Agency removed intramuscular injections of PRP from its prohibitions after determining that there is a "lack of any current evidence concerning the use of these methods for purposes of performance enhancement".[43]
Autologous blood injection
Autologous conditioned serum
Hypoxia preconditioned plasma
Platelet-rich fibrin matrix
Platelet swirling
^ Xu, Q; Chen, J; Cheng, L (July 2019). "Comparison of platelet rich plasma and corticosteroids in the management of lateral epicondylitis: A meta-analysis of randomized controlled trials". International Journal of Surgery (London, England). 67: 37–46. doi:10.1016/j.ijsu.2019.05.003. PMID 31128316.
^ Belk, JW; Kraeutler, MJ; Houck, DA; Goodrich, JA; Dragoo, JL; McCarty, EC (17 April 2020). "Platelet-Rich Plasma Versus Hyaluronic Acid for Knee Osteoarthritis: A Systematic Review and Meta-analysis of Randomized Controlled Trials". The American Journal of Sports Medicine: 363546520909397. doi:10.1177/0363546520909397. PMID 32302218.
^ a b c Hurley, ET; Hannon, CP; Pauzenberger, L; Fat, DL; Moran, CJ; Mullett, H (May 2019). "Nonoperative Treatment of Rotator Cuff Disease With Platelet-Rich Plasma: A Systematic Review of Randomized Controlled Trials". Arthroscopy: The Journal of Arthroscopic & Related Surgery. 35 (5): 1584–1591. doi:10.1016/j.arthro.2018.10.115. PMID 31000394.
^ "Platelet-Rich Plasma is Profitable, But How Well Does It Work?". American Council on Science and Health. 12 February 2019. Retrieved 30 September 2019.
^ Mohammed, W; Farah, S; Nassiri, M; McKenna, J (2020). "Therapeutic efficacy of platelet-rich plasma injection compared to corticosteroid injection in plantar fasciitis: A systematic review and meta-analysis". Journal of Orthopaedics. 22: 124–134. doi:10.1016/j.jor.2020.03.053. PMC 7177161. PMID 32336895.
^ Lin, MT; Wei, KC; Wu, CH (28 March 2020). "Effectiveness of Platelet-Rich Plasma Injection in Rotator Cuff Tendinopathy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials". Diagnostics. 10 (4): 189. doi:10.3390/diagnostics10040189. PMC 7235747. PMID 32231127.
^ Mishra A, Woodall J, Vieira A (January 2009). "Treatment of tendon and muscle using platelet-rich plasma". Clinics in Sports Medicine. 28 (1): 113–25. doi:10.1016/j.csm.2008.08.007. PMID 19064169.
^ Andia I, Sánchez M, Maffulli N (January 2012). "Joint pathology and platelet-rich plasma therapies". Expert Opinion on Biological Therapy. 12 (1): 7–22. doi:10.1517/14712598.2012.632765. PMID 22171664. S2CID 39322743.
^ a b Esposito M, Grusovin MG, Rees J, Karasoulos D, Felice P, Alissa R, Worthington H, Coulthard P (Spring 2010). "Effectiveness of sinus lift procedures for dental implant rehabilitation: a Cochrane systematic review". European Journal of Oral Implantology. 3 (1): 7–26. PMID 20467595.
^ Por YC, Shi L, Samuel M, Song C, Yeow VK (May 2009). "Use of tissue sealants in face-lifts: a metaanalysis". Aesthetic Plastic Surgery. 33 (3): 336–9. doi:10.1007/s00266-008-9280-1. PMID 19089492. S2CID 26761928.
^ Chen, Xiao; Jones, Ian A.; Park, Caron; Vangsness, C. Thomas (July 2018). "The Efficacy of Platelet-Rich Plasma on Tendon and Ligament Healing: A Systematic Review and Meta-analysis With Bias Assessment". The American Journal of Sports Medicine. 46 (8): 2020–2032. doi:10.1177/0363546517743746. ISSN 1552-3365. PMC 6339617. PMID 29268037.
^ Dai WL, Zhou AG, Zhang H, Zhang J (March 2017). "Efficacy of Platelet-Rich Plasma in the Treatment of Knee Osteoarthritis: A Meta-analysis of Randomized Controlled Trials". Arthroscopy. 33 (3): 659–670.e1. doi:10.1016/j.arthro.2016.09.024. PMID 28012636.
^ Shen L, Yuan T, Chen S, Xie X, Zhang C (January 2017). "The temporal effect of platelet-rich plasma on pain and physical function in the treatment of knee osteoarthritis: systematic review and meta-analysis of randomized controlled trials". Journal of Orthopaedic Surgery and Research. 12 (1): 16. doi:10.1186/s13018-017-0521-3. PMC 5260061. PMID 28115016.
^ Han, Yanhong; Huang, Hetao; Pan, Jianke; Lin, Jiongtong; Zeng, Lingfeng; Liang, Guihong; Yang, Weiyi; Liu, Jun (July 1, 2019). "Meta-analysis Comparing Platelet-Rich Plasma vs Hyaluronic Acid Injection in Patients with Knee Osteoarthritis". Pain Medicine (Malden, Mass.). 20 (7): 1418–1429. doi:10.1093/pm/pnz011. ISSN 1526-4637. PMC 6611633. PMID 30849177.
^ Foster TE, Puskas BL, Mandelbaum BR, Gerhardt MB, Rodeo SA (November 2009). "Platelet-rich plasma: from basic science to clinical applications". The American Journal of Sports Medicine. 37 (11): 2259–72. doi:10.1177/0363546509349921. PMID 19875361. S2CID 5914979.
^ Franchini M, Cruciani M, Mengoli C, Marano G, Pupella S, Veropalumbo E, Masiello F, Pati I, Vaglio S, Liumbruno GM (November 2018). "Efficacy of platelet-rich plasma as conservative treatment in orthopaedics: a systematic review and meta-analysis". Blood Transfusion = Trasfusione del Sangue. 16 (6): 502–513. doi:10.2450/2018.0111-18. PMC 6214820. PMID 30201082.
^ Zhang, YJ; Xu, SZ; Gu, PC; Du, JY; Cai, YZ; Zhang, C; Lin, XJ (August 2018). "Is Platelet-rich Plasma Injection Effective for Chronic Achilles Tendinopathy? A Meta-analysis". Clinical Orthopaedics and Related Research. 476 (8): 1633–1641. doi:10.1007/s11999.0000000000000258. PMC 6259774. PMID 29601383.
^ Liu, Chun-jie; Yu, Kun-lun; Bai, Jiang-bo; Tian, De-hu; Liu, Guo-li (April 2019). "Platelet-rich plasma injection for the treatment of chronic Achilles tendinopathy: A meta-analysis". Medicine. 98 (16): e15278. doi:10.1097/MD.0000000000015278. ISSN 0025-7974. PMC 6494278. PMID 31008973.
^ Valente Duarte de Sousa IC, Tosti A (May 2013). "New investigational drugs for androgenetic alopecia". Expert Opinion on Investigational Drugs. 22 (5): 573–89. doi:10.1517/13543784.2013.784743. PMID 23550739. S2CID 21653303.
^ Moraes VY, Lenza M, Tamaoki MJ, Faloppa F, Belloti JC (April 2014). "Platelet-rich therapies for musculoskeletal soft tissue injuries". The Cochrane Database of Systematic Reviews. 29 (4): CD010071. doi:10.1002/14651858.CD010071.pub3. PMC 6464921. PMID 24782334.
^ Sinha S, Schreiner AJ, Biernaskie J, Nickerson D, Gabriel VA (November 2017). "Treating pain on skin graft donor sites: Review and clinical recommendations". The Journal of Trauma and Acute Care Surgery. 83 (5): 954–964. doi:10.1097/TA.0000000000001615. PMID 28598907. S2CID 44520644.
^ Griffin XL, Smith CM, Costa ML (February 2009). "The clinical use of platelet-rich plasma in the promotion of bone healing: a systematic review". Injury. 40 (2): 158–62. doi:10.1016/j.injury.2008.06.025. PMID 19084836.
^ Pocaterra A, Caruso S, Bernardi S, Scagnoli L, Continenza MA, Gatto R (August 2016). "Effectiveness of platelet-rich plasma as an adjunctive material to bone graft: a systematic review and meta-analysis of randomized controlled clinical trials". International Journal of Oral and Maxillofacial Surgery. 45 (8): 1027–34. doi:10.1016/j.ijom.2016.02.012. PMID 26987695.
^ Frautschi RS, Hashem AM, Halasa B, Cakmakoglu C, Zins JE (March 2017). "Current Evidence for Clinical Efficacy of Platelet Rich Plasma in Aesthetic Surgery: A Systematic Review". Aesthetic Surgery Journal. 37 (3): 353–362. doi:10.1093/asj/sjw178. PMID 28207031.
^ Canada, Health (2019-05-15). "Health Canada Policy Position Paper – Autologous Cell Therapy Products". aem. Retrieved 2019-07-09.
^ "Health Canada orders halt to unproven stem cell-based injection treatments". Retrieved 2019-07-09.
^ "Health Canada clarifies position on Platelet Rich Plasma treatments". Health Canada. Health Canada. 26 July 2019. Retrieved 7 January 2020.
^ Pavlovic V, Ciric M, Jovanovic V, Stojanovic P (2016). "Platelet Rich Plasma: a short overview of certain bioactive components". Open Medicine. 11 (1): 242–247. doi:10.1515/med-2016-0048. PMC 5329835. PMID 28352802.
^ Bielecki T, Dohan Ehrenfest DM, Everts PA, Wiczkowski A (June 2012). "The role of leukocytes from L-PRP/L-PRF in wound healing and immune defense: new perspectives". Current Pharmaceutical Biotechnology. 13 (7): 1153–62. doi:10.2174/138920112800624373. PMID 21740376.
^ a b c d Borrione P, Gianfrancesco AD, Pereira MT, Pigozzi F (October 2010). "Platelet-rich plasma in muscle healing". American Journal of Physical Medicine & Rehabilitation. 89 (10): 854–61. doi:10.1097/PHM.0b013e3181f1c1c7. PMID 20855985.
^ Yu W, Wang J, Yin J (April 2011). "Platelet-rich plasma: a promising product for treatment of peripheral nerve regeneration after nerve injury". The International Journal of Neuroscience. 121 (4): 176–80. doi:10.3109/00207454.2010.544432. PMID 21244302. S2CID 26837842.
^ a b Dhurat R, Sukesh M (2014). "Principles and Methods of Preparation of Platelet-Rich Plasma: A Review and Author's Perspective". Journal of Cutaneous and Aesthetic Surgery. 7 (4): 189–97. doi:10.4103/0974-2077.150734. PMC 4338460. PMID 25722595.
^ Kanchanatawan W, Arirachakaran A, Chaijenkij K, Prasathaporn N, Boonard M, Piyapittayanun P, Kongtharvonskul J (May 2016). "Short-term outcomes of platelet-rich plasma injection for treatment of osteoarthritis of the knee". Knee Surgery, Sports Traumatology, Arthroscopy. 24 (5): 1665–77. doi:10.1007/s00167-015-3784-4. PMID 26387122. S2CID 35221300.
^ a b Kolata G (2010-01-12). "Popular Blood Therapy May Not Work". New York Times.
^ Schwarz A (2009-02-16). "A Promising Treatment for Athletes, in Blood". New York Times. New York.
^ Reynolds G (2011-01-26). "Phys Ed: Does Platelet-Rich Plasma Therapy Really Work?". New York Times.
^ Storrs C (2009-12-18). "Is Platelet-Rich Plasma an Effective Healing Therapy?". Scientific American.
^ Beitzel K, Allen D, Apostolakos J, Russell RP, McCarthy MB, Gallo GJ, Cote MP, Mazzocca AD (February 2015). "US definitions, current use, and FDA stance on use of platelet-rich plasma in sports medicine". The Journal of Knee Surgery. 28 (1): 29–34. doi:10.1055/s-0034-1390030. PMID 25268794.
^ Georgiou, Aristos (14 September 2018). "What is a vampire facial?". Newsweek. Retrieved 29 March 2019.
^ "What it's really like to get the infamous vampire facial". The Independent. 28 February 2018. Retrieved 29 March 2019.
^ a b Osborne, Hannah (8 July 2016). "Injecting blood plasma into your clitoris for $2,500 won't give you with better orgasms". International Business Times UK. Retrieved 1 October 2018.
^ Goodman, Michael P. (2016). Female Genital Plastic and Cosmetic Surgery. John Wiley & Sons. p. PT391. ISBN 9781118848487. There is presently no information in peer reviewed literature.
^ "World Anti-Doping Agency announces changes to Prohibited List". Irish Medical Times. 2011-01-10.
Retrieved from "https://en.wikipedia.org/w/index.php?title=Platelet-rich_plasma&oldid=1000569578"
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Trends and outcomes of infective endocarditis in patients on dialysis
Nirmanmoh Bhatia, Vanderbilt University Medical Center
Sahil Agrawal, St. Luke's University Health Network
Aakash Garg, St. Peter's University Hospital
Divyanshu Mohananey, Cleveland Clinic Foundation
Abhishek Sharma, SUNY Downstate Health Sciences University
Manyoo Agarwal, University of Tennessee Health Science Center
Lohit Garg, Lehigh Valley Hospital and Health Network
Nikhil Agrawal, Beth Israel Deaconess Medical Center
Amitoj Singh, St. Luke's University Health Network
Sudip Nanda, St. Luke's University Health Network
Jamshid Shirani, St. Luke's University Health Network
Dialysis patients are at high risk for infective endocarditis (IE); however, no large contemporary data exist on this issue. We examined outcomes of 44 816 patients with IE on dialysis and 202 547 patients with IE not on dialysis from the Nationwide Inpatient Sample database from 2006 thorough 2011. Dialysis patients were younger (59 ± 15 years vs 62 ± 18 years) and more likely to be female (47% vs 40%) and African-American (47% vs 40%; all P < 0.001). Hospitalizations for IE in the dialysis group increased from 175 to 222 per 10 000 patients (P trend = 0.04). Staphylococcus aureus was the most common microorganism isolated in both dialysis (61%) and nondialysis (45%) groups. IE due to S aureus (adjusted odds ratio [aOR]: 1.79, 95% confidence interval [CI]: 1.73-1.84), non-aureus staphylococcus (aOR: 1.72, 95% CI: 1.64-1.80), and fungi (aOR: 1.4, 95% CI: 1.12-1.78) were more likely in the dialysis group, whereas infection due to gram-negative bacteria (aOR: 0.85, 95% CI: 0.81-0.89), streptococci (aOR: 0.38, 95% CI: 0.36-0.39), and enterococci (aOR: 0.78, 95% CI: 0.74-0.82) were less likely (all P < 0.001). Dialysis patients had higher in-hospital mortality (aOR: 2.13, 95% CI: 2.04-2.21), lower likelihood of valve-replacement surgery (aOR: 0.82, 95% CI: 0.76-0.86), and higher incidence of stroke (aOR: 1.08, 95% CI: 1.03-1.12; all P < 0.001). We demonstrate rising incidence of IE-related hospitalizations in dialysis patients, highlight significant differences in baseline comorbidities and microbiology of IE compared with the general population, and validate the association of long-term dialysis with worse in-hospital outcomes.
10.1002/clc.22688
Bhatia, Nirmanmoh; Agrawal, Sahil; Garg, Aakash; Mohananey, Divyanshu; Sharma, Abhishek; Agarwal, Manyoo; Garg, Lohit; Agrawal, Nikhil; Singh, Amitoj; Nanda, Sudip; and Shirani, Jamshid, "Trends and outcomes of infective endocarditis in patients on dialysis" (2017). Department of Cardiovascular Medicine Articles & Publications. 14.
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SIGNIFICANCE Visual performance with wavefront-guided (WFG) contact lenses has only been reported immediately after manufacture without time for habituation, and comparison has only been made with clinically unrefined predicate conventional lenses. We present comparisons of habitual corrections, best conventional scleral lenses, and WFG scleral lenses after habituation to all corrections.
PURPOSE The purpose of this study was to compare, in a crossover design, optical and visual performance of eyes with corneal ectasias wearing dispensed best conventional scleral lens corrections and dispensed individualized WFG scleral lens corrections.
METHODS Ten subjects (20 eyes) participated in a randomized crossover study where best conventional scleral lenses and WFG scleral lenses (customized through the fifth radial order) were worn for 8 weeks each. These corrections, as well as each subject's habitual correction and normative data for normal eyes, were compared using (1) residual higher-order aberrations (HORMS), (2) visual acuity (VA), (3) letter contrast sensitivity (CS), and (4) visual image quality (logarithm of the visual Strehl ratio, or logVSX). Correlations were performed between Pentacam biometric measures and gains provided by WFG lenses.
RESULTS Mean HORMS was reduced by 48% from habitual to conventional and 43% from conventional to WFG. Mean logMAR VA improved from habitual (+0.12) to conventional (−0.03) and further with WFG (−0.09); six eyes gained greater than one line with WFG over conventional. Area under the CS curve improved by 26% from habitual to conventional and 14% from conventional to WFG. The percentage of the eyes achieving normal levels were as follows: HORMS, 40% for conventional and 85% for WFG; VA, 50% for conventional and 85% for WFG; and CS, 60% for conventional and 90% for WFG. logVSX improved by 16% from habitual to conventional and 25% further with WFG. Reduction in aberrations with WFG lenses best correlated with posterior cornea radius of curvature.
CONCLUSIONS Visual performance was superior to that reported with nonhabituated WFG lens wear. With WFG lenses, HORMS and logVSX significantly improved, allowing more eyes to reach normal levels of optical and visual performance compared with conventional lenses.
Funding/Support: National Eye Institute (R01EY019105; to RAA); National Eye Institute (R01EY008520; to JDM); National Eye Institute (P30EY07551); U.S. Navy (N00259-10-P-1354; to RAA); and University of Houston (Borish Endowment; to RAA).
Conflict of Interest Disclosure: The University of Houston owns patents on which authors JDM and RAA are listed as coinventors. The university played no role in the study design, conduct, analysis and interpretation, or the writing of this report. Institutional review board approval was obtained from the university.
Author Contributions and Acknowledgments: Conceptualization: RAA, LCN, JDM; Data Curation: GDH, LCN, MJK, RTH, JDM; Formal Analysis: GDH, RAA, LCN, MJK, JDM; Funding Acquisition: RAA, JDM; Investigation: GDH, RAA, LCN, MJK, RTH, JDM; Methodology: GDH, RAA, LCN, MJK, RTH, JDM; Project Administration: RAA, LCN, MJK, JDM; Resources: RAA, LCN, MJK, JDM; Software: GDH, JDM; Supervision: RAA, JDM; Validation: GDH, RAA, LCN, MJK, RTH, JDM; Visualization: GDH, RAA, LCN, MJK, RTH, JDM; Writing – Original Draft: GDH; Writing – Review & Editing: GDH, RAA, LCN, MJK, RTH, JDM.
The authors thank Drs. Katrina Parker, Maria Walker, Anita Ticak, Amber Gaume Giannoni, Eric Ritchey, Anna-Kaye Logan, Tiffany Chen, Sheila Morrison, Jan Bergmanson, Judith Perrigin, and Norman Leach of the University Eye Institute at the University of Houston College of Optometry; Drs Ayeswarya Ravikumar and Yue Shi; Dr Larry Thibos and Hope Queener for contributions to the visual image quality metric, contact lens design, and statistics software; and Kimberly Thompson for assistance with figures.
Portions of these findings were presented at the International Society for Contact Lens Research 2017 meeting in Stevenson, OR; the Association for Research in Vision and Ophthalmology 2018 meeting in Honolulu, HI; and the International Society of Contact Lens Specialists 2018 meeting in Washington, DC.
Who Will Benefit Most from Wavefront-guided Lenses?
Decreased visual performance in corneal ectasias such as keratoconus is predominantly optical in origin, typically resulting from bilaterally asymmetric elevated higher-order aberrations caused by the rotationally asymmetric irregular profiles of anterior and posterior corneal surfaces.1–3 Onset of most ectatic conditions is during adolescence, and these individuals usually experience normal visual stimulation throughout critical periods of development and undergo typical neural development. Hence, if the aberrated optics of these eyes can be appropriately corrected, normal levels of visual performance are expected to recover after habituation to the improved retinal image.
Current standards of care for corneal ectasias are rigid corneal or scleral lenses, which partially mask anterior cornea irregularities through approximate refractive index matching of the post-lens tear film and cornea and by providing a new optically well-formed first surface for the eye. Those refractive indices are, however, not perfectly matched, and residual anterior corneal surface aberrations remain, as do aberrations from the irregular posterior corneal surface,1–3 which cannot be masked by rigid contact lenses.
Although customized wavefront-guided contact lenses have been manufactured and demonstrated with varying levels of efficacy in laboratory settings7–16 and studied using simulations and theoretical modeling,17–25 those studies that measured visual performance with these lenses7–16 did so immediately after manufacturing and fitting the lenses without allowing time for the visual systems of the wearers to habituate to the new percept.
Previous studies compared wavefront-guided lenses with habitual or conventional lenses that served as predicate stepping stones (for wavefront-guided lenses) and were not necessarily clinically optimized in terms of their fit and optics.10–12,14,16 In some studies, spherocylindrical components of the wavefront-guided lenses have been corrected using spectacle trial lenses before evaluating visual performance,11,14,15 and consequently, lenses were not dispensed.
Given that the visual system is adapted to its habitual aberration structure26,28 and given the considerable reduction in aberration magnitude imparted by wavefront-guided lenses (in this study and others14,16) along with the reversal2,3 in key aberrations (such as coma) associated with directional blur, patients should habituate to the corrections before visual performance is evaluated. Although visual performance reported with wavefront-guided lenses has been improved, we postulate that it has hitherto remained worse than normal (despite reduced levels of aberration12–14,16,29) because of insufficient habituation time and/or the interaction of residual aberrations being detrimental to visual image quality.
As wavefront-guided technology becomes more accessible, it is important to present controlled comparisons of state-of-the-art wavefront-guided scleral lenses with the best conventional scleral lenses prescribed in practice. In fact, first achieving clinically typical performance with best conventional scleral lenses is an essential prerequisite in appreciating any real gains in performance provided by wavefront-guided lenses and in identifying which eyes would benefit most from wavefront-guided lenses over conventional lenses.
Therefore, this article presents comparison of three corrections: (1) the subject's habitual correction, (2) a best conventional scleral lens, (3) and a best individualized wavefront-guided scleral lens, after lenses were dispensed and worn as part of daily life by eyes with corneal ectasias, which allowed approximately 8 weeks of habituation to each new correction in a crossover manner. This comparison is presented in terms of (1) residual higher-order root mean square wavefront error, (2) high-contrast visual acuity, (3) letter contrast sensitivity, and (4) the visual image quality metric logVSX (the logarithm of the visual Strehl ratio). Correlations between ocular biometric measures and the reduction in higher-order aberrations provided by the wavefront-guided lenses over conventional lenses are examined.
This research adhered to the tenets of the Declaration of Helsinki. Before data collection, the nature and potential consequences of the study were explained to each subject, and a University of Houston institutional review board–approved informed consent form was signed.
Ten subjects (nine male, one female) with corneal ectasia were recruited; nine were diagnosed as having bilateral keratoconus and one was diagnosed as having bilateral pellucid marginal degeneration. These conditions characteristically present with bilaterally asymmetric disease severities,4,30 and the ectasias of some fellow eyes were quite mild (these eyes stood to benefit less from wavefront-guided lenses than more severe ectasias). Nonetheless, both eyes of each subject (20 eyes) were included because each eye presented unique optical and fitting challenges. Appropriate statistical methods31,32 (see Results) were used to account for any dependency between the right and left eyes of each individual.
Table 1 classifies the severity of the subjects in terms of the ABCD keratoconus grading system,34 which incorporates anterior ("A") and posterior ("B") corneal radii of curvature and thinnest pachymetry ("C"), all determined by Topometric/KC Staging software on the Pentacam HR (Oculus Inc., Arlington, WA), as well as best-corrected distance visual acuity ("D"). Grading ranges from 0 (normal) to 4 (most severe).
Five subjects used spectacles for the habitual correction measurements; three used contact lenses on both eyes (two wore scleral lenses, one wore hybrid lenses); one used a toric soft lens on one eye and was unaided in the other; and one subject performed the habitual correction measurements unaided. Mean ± standard deviation age of the subjects was 34.4 ± 11.1 years (range, 24 to 55 years). Inclusion criteria were as follows: no corneal scarring over the central 7 mm of the pupil and unremarkable systemic and other ocular health.
Performance measures were recorded monocularly.
Three wavefront error measurements recorded using a COAS HD wavefront sensor (Johnson & Johnson Vision, Santa Ana, CA) and described by a 10th radial order normalized Zernike polynomial fit were averaged over a common dilated pupil size.
High-contrast visual acuity was measured in a darkened room and calculated with per-letter scoring, terminating after five missed letters, as the mean of three unique Early Treatment Diabetic Retinopathy Study logMAR charts displayed with −100% Weber contrast (Display++ monitor; Cambridge Research Systems, Kent, United Kingdom) and a background luminance of 116 cd/m2 (Minolta LS-110; Konica Minolta, Ramsey, NJ).
Using the same monitor and darkened room, letter contrast sensitivity was measured using letter sizes having fundamental-spatial frequencies of 4, 8, and 16 cycles per degree (20/150, 20/75, and 20/37.5, respectively), and the area under the log contrast sensitivity function curve35 was calculated. For each letter size, contrast threshold was estimated to the nearest 0.2 log unit, after which three measures of contrast threshold were determined using rows of unique Sloan letters that began at a contrast level of 0.4 log unit greater than the initial estimate and reduced in steps of 0.1 log unit per line until five letters were missed.
VSX ranges from 0 (worst) to 1 (best). The (base 10) logarithm of 1 is 0; thus, the closer the value of logVSX to 0 (the less negative the value), the better the visual image quality. logVSX was calculated from mean wavefront error (of the corrected eyes) over 5-mm pupil diameters.
The study protocol began with measurement of the four outcomes using the habitual correction. Thereafter, fitting (but not necessarily dispensing) of conventional scleral lenses commenced, which involved adjusting the designs of the lenses to provide healthy, comfortable fits that were rotationally and translationally stable and to refine the sphere, cylinder, and axis.
After allowing for settling on the eye for 30 minutes, lens engravings were monitored to quantify lens rotation, and the orientation of the peripheral toric annulus was adjusted in subsequent lens designs to compensate for the observed rotation.16,42 When a stable and correctly oriented lens with a clinically acceptable fit was achieved, the location of the pupil center relative to the geometric center of the lens was measured such that the wavefront-guided prescription could be offset in opposite xy directions relative to the lens center to compensate. Most scleral lenses rested inferior and temporal relative to the center of the pupil,14 and consequently, most wavefront-guided prescriptions were offset superior and nasal relative to the lens center (Fig. 1). Thresholds for tolerable lens movements are inversely proportional to the magnitudes of wavefront-guided prescriptions17,18,22,24,25 and therefore varied across the range of ectasia severities included here.
Wavefront-guided lenses were designed using the macro parameters of the stable conventional lens. Residual wavefront error was measured through the stable lens after dilation (one drop of 1% tropicamide, one drop of 2.5% phenylephrine), and an offset wavefront-guided prescription targeting residual aberrations up to the fifth Zernike radial order33 was imparted into the anterior lens surface.
Median diameter of the wavefront-guided prescription was 8 mm (mean, 7.84 mm); this was limited on the low end by the maximal dilated pupil size, and the wavefront error measurements for the eyes with larger pupils were scaled43 down to 8 mm.
At this point, a crossover study design was initiated where each subject wore a best conventional scleral lens daily for approximately 8 weeks and a wavefront-guided scleral lens daily for an additional 8 weeks. This provided an opportunity for the visual system of each subject to habituate to the retinal image formed by each lens in his or her everyday environment, and follow-up visits provided opportunities (if needed) for refinement of the optics and the fit of each lens (which necessitated manufacture of new lenses). Subjects generally conformed to the 8-week period; some subjects wore a lens type for slightly longer, for example, because of travel or work obligations, illness, or natural disaster (hurricane Harvey). The order of lens wear was randomized; three subjects wore conventional lenses first, and seven wore wavefront-guided lenses first. Some subjects who wore the wavefront-guided lenses first expressed such substantial unhappiness during the conventional lens (second) part of the crossover that we will reevaluate this randomization during future studies. One subject did not complete the conventional lens part of the crossover but still wore the wavefront-guided lens for 8 weeks.
At the final visit with each lens, visual acuity and contrast sensitivity were measured with the lenses through natural pupils, and residual wavefront error was measured over dilated pupils.
Both statistical and clinical significance are considered. All standard deviations were calculated using analysis of variance and components of variance analyses to account for any dependence of the right and left eyes.31,32 Similarly, P values were calculated using split-plot analyses of variance.31,32 Plots for individual eyes use lines to track each eye across the three (categorical) corrections, and any given eye is consistently represented by the same color, symbol, and line across all four outcomes. The best conventional lens for 18 eyes was spherical, and that for two eyes was spherocylindrical.
Higher-order root mean square results were scaled43 to a 5-mm pupil diameter to better agree with habitual physiological pupil sizes and pupil sizes during visual acuity and contrast sensitivity measures, and they are presented up to the sixth radial order.
Mean ± standard deviation higher-order root mean square wavefront error decreased from the habitual correction (0.886 ± 0.589 μm, mean across modalities) to conventional lenses (0.458 ± 0.238 μm) and further decreased to within normal limits with wavefront-guided lenses (0.260 ± 0.077 μm; Fig. 2). These represent statistically significant reductions of 48% (P = .02) from habitual to conventional, 43% (P = .004) from conventional to wavefront guided, and 71% (P = .001) from habitual to wavefront guided. Note the reduction in variability with wavefront-guided lenses.
The unique reduction in higher-order root mean square wavefront error for each eye may be better appreciated as the percentage of the eyes within age-matched normal (normal eye)44 limits: 15% of the eyes were within normal limits wearing the habitual correction, 40% with best conventional scleral lenses, and 85% with wavefront-guided lenses. A representative example of higher-order wavefront error maps (across unaided and the three corrections) for one subject with moderate keratoconus is shown in Fig. 3.
Reduction in higher-order aberrations by wavefront-guided lenses over conventional lenses was best correlated (Fig. 4) with posterior corneal radius of curvature (dimension B34; R 2 = 0.75) followed by the mean severity grading (averaging across dimensions ABC and D for the conventional lens [R 2 = 0.62]).
Mean ± standard deviation logMAR visual acuity improved from the habitual correction (+0.09 ± 0.18, mean across modalities) to conventional lenses (−0.03 ± 0.09) and improved further with wavefront-guided lenses (−0.09 ± 0.10; Fig. 5). Disease severity dimension D (best-corrected distance visual acuity) thus varies depending on which correction (habitual, conventional, wavefront guided) is used; for example, subjects in each severity grade of D (0:1:2:3:4) were 8:10:2:0:0 with habitual, 12:8:0:0:0 with conventional, and 17:3:0:0:0 with wavefront-guided corrections.
Mean improvements from habitual to conventional and from habitual to wavefront guided were statistically significant (P = .05 and P = .007, respectively). Mean improvement from conventional to wavefront guided was not (P = .07); however, from an individual perspective, six eyes showed clinically significant improvements of greater than one line of logMAR visual acuity, and substantially more eyes reached normal45 levels: habitual correction, 25%; conventional lenses, 50%; and wavefront-guided lenses, 85%.
At each fundamental spatial frequency, most eyes improved in letter contrast sensitivity from the habitual correction to conventional scleral lenses and improved further with wavefront-guided lenses.
Mean ± standard deviation area under the log contrast sensitivity function35 (Fig. 6) improved from the habitual correction (11.07 ± 3.48, mean across modalities) to conventional lenses (13.91 ± 2.20) and improved further with wavefront-guided lenses (15.82 ± 2.34). These correspond to significant gains of 26% (P = .009) from habitual to conventional and 43% (P < .001) from habitual to wavefront guided. The 14% gain from conventional to wavefront guided was not significant (P = .09). The proportions of the eyes that were within normal limits were as follows: 30%, habitual correction; 60%, conventional lenses; and 90%, wavefront-guided lenses.
This study sought to determine the benefit of transferring individuals with corneal ectasia from their habitual correction to best conventional scleral lenses and to personalized wavefront-guided lenses by dispensing each type of lens and allowing for approximately 8 weeks of habituation to the retinal image formed by each.
Achieving equivalent or better than clinically representative performance with best conventional scleral lenses is an essential prerequisite in appreciating any gains in performance provided by wavefront-guided lenses.
Comparisons are made with (1) attempts to correct measured aberrations of real eyes and (2) benchmark modalities of clinical practice.
Visual acuity is a variable subjective quantity50 that can be relatively insensitive to visual blur,51 which could have contributed to lack of significance in gain between best conventional and wavefront-guided lenses. Nonetheless, mean logMAR visual acuity with wavefront-guided lenses in this study (−0.09) is clinically equivalent or better than other reports of scleral wavefront-guided lenses,14,16 better than wavefront-guided soft lenses,7,13,15 better than conventional scleral lenses in this study and elsewhere,46 and better than reports of highly aberrated eyes wearing corneal rigid gas-permeable lenses.48 These differences may be due to habituation.
Sabesan et al.14 presented change in contrast sensitivity with wavefront-guided lenses as a multiple of contrast sensitivity with conventional lenses. This can bias the performance of the wavefront-guided lenses because the conventional lenses were unrefined predicate lenses, as has been common practice.10–12,16 Overall, we found an opposite pattern of contrast sensitivity results in that performance with wavefront-guided lenses in this study gained more at higher spatial frequencies than at lower spatial frequencies. Comparing with their Fig. 5, mean log contrast sensitivity reported here was equivalent for 4 cycles per degree (1.64 ± 0.14) and significantly better for 8 cycles per degree (1.41 ± 0.19), and mean log contrast sensitivity reported here for 16 cycles per degree (1.01 ± 0.25) was significantly better than that at the highest spatial frequency (12 cycles per degree) they reported. These differences may be due to habituation.
This indicates that further improvement in visual quality is possible as wavefront-guided corrections continue to be improved and might involve, for example, targeting particular aberrations such that the residual distributions of higher-order aberrations better resemble those of normal eyes.
Health care is evolving toward personalized treatments tailored to the individual needs of each specific patient. Wavefront-guided contact lenses are serving as an ophthalmic application of such individualized medicine for corneal ectasias. However, the investments of time, technology, and cost involved in fitting wavefront-guided products are greater than conventional corrections, making them more comparable with prosthetic devices. Although the choice of corrections is influenced by the visual quality expectations of an individual in addition to the investments of time and money, it is desirable—perhaps even ethically necessary—to estimate the benefits that an individual could gain from wavefront-guided lenses over conventional scleral lenses. This is pertinent given that we are in the infancy of the clinical translation of wavefront-guided lenses, which will become more widely accessible, further improved, and an option for certain individuals with normal eyes wishing to reduce higher-order aberrations.
Residual higher-order root mean square wavefront error through best conventional scleral lenses best predicted (R 2 = 0.94) the additional reduction in higher-order aberrations achieved by wavefront-guided lenses over conventional lenses. This is not surprising because wavefront-guided lenses were designed to specifically target residual higher-order root mean square wavefront error. Estimating a patient's potential gains using residual higher-order root mean square wavefront error through a conventional lens is reasonable because a best conventional lens is a prerequisite for a wavefront-guided lens. However, as visual processing is better understood and visual image quality metrics are better developed, it is likely that the field should strive to optimize these metrics as opposed to simplistically targeting a reduction in aberration terms.
Of the biometric measures, posterior corneal radius of curvature best correlated (R 2 = 0.75) with the reduction in higher-order aberrations provided by wavefront-guided lenses, followed by mean disease severity (averaging grading dimensions A, B, C, and D for the conventional lens; R 2 = 0.62), both of which can be evaluated with Pentacam software (Oculus Inc.).
Based on posterior corneal radius of curvature, the present sample of the eyes could be divided into (1) those of severity grades 0 and 1 (>5.7 mm) and (2) those of severity grades 2, 3, and 4 (<5.7 mm). Seventy-five percent of the eyes in the first group were within normal levels of higher-order root mean square wavefront error with a best conventional lens compared with 31% of the eyes in the second group. The eyes in the first group experienced a mean reduction of 0.057 μm in higher-order root mean square wavefront error (5-mm pupil) with the wavefront-guided lens over the conventional, whereas a mean reduction of 0.233 μm was experienced by the second group. A greater sample of eyes is needed before this threshold criterion could be confidently advocated.
If these insights were followed, some eyes fit with wavefront-guided lenses in this study would not be fit in practice; these eyes experienced smaller gains with the wavefront-guided lenses. Both eyes of each subject were fit here by experimental design to gain insights into who would benefit most. Given the bilateral asymmetry that characterizes corneal ectasias and the current state of wavefront-guided lenses, these individuals might currently be well served wearing a wavefront-guided lens on their more severe eye and a conventional lens on the less severe eye.
Predicting the individual benefit in this way only considers the unique optical challenges presented by each eye but neglects the many traditional challenges of scleral lens fitting; both sets of challenges need to be resolved for the successful fitting of wavefront-guided lenses. In this study, as is true of clinical practice, the challenges of fitting a stable scleral lens were sometimes significant. In contrast, the incorporation of the wavefront-guided correction was relatively easy (requiring additional two to three visits) once a stable well-fitting conventional scleral lens was achieved. Identifying individuals who stand to benefit from wavefront-guided lenses is important because the eyes in this study that experienced substantial gains, reported the investment of time to fit wavefront-guided lenses as worthwhile, and described the gains in visual performance and quality as life changing.
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Optometry and Vision Science96(4):238-247, April 2019.
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Coronavirus Disease 2019. Information as at March 12, 2020
WFC Public Health Committee
On March 11, 2020 COVID-19 was declared by the World Health Organization (WHO) as a
pandemic. Chiropractors are primary contact health care professionals and therefore
need to keep updated with the latest information. The WFC recognizes WHO as the
authoritative global source for information regarding COVID-19. The following
information is from WHO sources.
COVID-19 is the infectious disease caused by the recently discovered novel (new) coronavirus. Several coronaviruses are known to cause respiratory infections in humans. This new virus and disease were unknown before the outbreak began in Wuhan, China, in December 2019. On January 30, 2020 the International Health Regulations Committee of the World Health Organization (WHO) declared the outbreak a "public health emergency of international concern" and on March 11, 2020 it was officially declared a pandemic.
What is a pandemic?
Declaring a pandemic has nothing to do with the characteristics of the disease but is instead associated with concerns over its geographic spread. According to WHO, a pandemic is declared when a new disease for which people do not have immunity spreads around the world beyond expectations. Once a pandemic is declared it becomes more likely that community spread will eventually happen, and governments and health
systems need to ensure they are prepared for that.
How does COVID-19 spread?
People can catch COVID-19 from others who have the virus. The disease can spread from person to person through small droplets from the nose or mouth which are spread when a person with COVID-19 coughs or exhales if one breathes in these droplets. Another way is when these droplets land on objects and surfaces and one touches these surfaces, then touch their eyes, nose or mouth, they can catch COVID-19. WHO is assessing ongoing research on the ways COVID-19 is spreading and will continue to share updates.
How long is the incubation period for COVID-19?
The ?incubation period?means the time between catching the virus and beginning to have symptoms of the disease. Most estimates of the incubation period for COVID-19 range from 1-14 days, most commonly around 5 days. These estimates will be updated by WHO as more data become available.
Spread of COVID-19
As at March 12, 2020, WHO is reporting 124,847 confirmed cases of COVID-19 in 118 countries. There have been 4613 deaths. China (80,981), Italy (12,462), Iran (9000) and the Republic of Korea (7869) account for 88% of all reported cases.
WHO is publishing current figures via its COVID-19 Situation Dashboard.
What are the symptoms of COVID-19?
The most common symptoms are fever, tiredness, and dry cough. Some patients may have aches and pains, nasal congestion, runny nose, sore throat or diarrhea. These symptoms are usually mild and begin gradually. Some people become infected but don?t develop any symptoms and don't feel unwell. Most people (about 80%) recover from the disease without needing special treatment. Around 1 out of every 6 people who gets COVID-19 becomes seriously ill and develops difficulty breathing. Older people, and those with underlying medical problems (particularly high blood pressure, heart disease, diabetes, chronic respiratory disease and cancer) are more likely to develop serious illness. About 2% of people with the disease have died. People with fever, cough and difficulty breathing should seek medical attention.
Should I wear a mask to protect myself?
People with no respiratory symptoms, such as cough, do not need to wear a medical mask. WHO recommends the use of masks for people who have symptoms of COVID-19 and those caring for individuals who have symptoms, such as cough and fever. The use of masks is crucial for health workers and people who are taking care of someone (at home or in a health care facility).
WHO advises rational use of medical masks to avoid unnecessary wastage of precious resources and misuse of masks. Use a mask only if you have respiratory symptoms (coughing or sneezing), have suspected COVID-19 infection with mild symptoms, or are caring for someone with suspected COVID-19 infection. A suspected COVID-19 infection is linked to travel in areas where cases have been reported, or close contact with someone who has traveled in these areas and has become ill.
- Regularly and thoroughly wash your hands with soap and water or alcohol-based hand cleaner.
- Maintain at least 1 meter (3 feet) distance from anyone who is coughing or sneezing.
- Avoid touching your eyes, nose and mouth.
- Follow good respiratory hygiene. Cover your mouth and nose with your bent elbow or tissue when you cough or sneeze. Dispose of the used tissue immediately.
- Clean surfaces with disinfectant.
- Avoid unprotected contact with farm or wild animals.
- Within health care facilities, enhance standard infection prevention and control practices in hospitals, especially in emergency departments.
- If you feel unwell, stay at home.
- If you develop fever, cough and difficulty breathing, seek medical advice promptly as this may be due to a respiratory infection or other serious condition. Call in advance and tell your provider of any recent travel or contact with travelers.
- Stay informed on the latest developments about COVID-19. Follow advice given by your healthcare provider, your national and local public health authority or your employer on how to protect yourself and others from COVID-19.
According to WHO, the following measures are NOT effective against COVID-2019 and can be harmful
- Smoking
- Taking traditional herbal remedies
- Wearing multiple masks
- Taking self-medication such as antibiotics. Antibiotics do not work against viruses, such as COVID-19.
There are no specific antiviral treatments or vaccines currently available for COVID-19. People with COVID-19 should receive supportive care to help relieve symptoms. For severe symptoms, treatment should involve care to support vital organ functions. People who think they have been exposed to COVID-19 should contact their health provider immediately.
WHO information
WHO information about COVID-19 can be found at
https://www.who.int/emergencies/diseases/novel-coronavirus-2019
Further information and resources
WHO advice for Healthcare Providers Center for Disease Control (United States)
Recommendations for the workplace Health Care Professional information
Health Care Worker information COVID-19 overview
WHO situation reports
WHO advice for the Public
Advice for the public
MythBusters information for the public
Three videos about COVID-19 here, here and here
Coronavirus Disease 2019. Information as at March 3, 2020
Information about COVID-19 is evolving rapidly. Chiropractors are primary contact health care professionals and therefore need to keep updated with the latest information. The WFC recognizes the World Health Organization (WHO) as the authoritative global source for information regarding COVID-19. The following information is from WHO sources.
COVID-19 is the infectious disease caused by the recently discovered novel (new) coronavirus. Several coronaviruses are known to cause respiratory infections in humans. This new virus and disease were unknown before the outbreak began in Wuhan, China, in December 2019. On January 30, 2020 the International Health Regulations Committee of the World Health Organization (WHO) declared the outbreak a "public health emergency of international concern."
The "incubation period" means the time between catching the virus and beginning to have symptoms of thedisease. Most estimates of the incubation period for COVID-19 range from 1-14 days, most commonly around 5 days. These estimates will be updated by WHO as more data become available.
The most common symptoms are fever, tiredness, and dry cough. Some patients may have aches and pains, nasal congestion, runny nose, sore throat or diarrhea. These symptoms are usually mild and begin gradually. Some people become infected but don?t develop any symptoms and don't feel unwell. Most people (about 80%) recover from the disease without needing special treatment. Around 1 out of every 6 people who gets COVID-19 becomes seriously ill and develops difficulty breathing. Older people, and those with underlying medical problems (e.g., high blood pressure, heart problems or diabetes) are more likely to develop serious illness. About 2% of people with the disease have died. People with fever, cough and difficulty breathing should seek medical attention.
Recommendations for figure
Chiropractic Spinal Manipulation of Children Under 12. November 1, 2019
Report of an independent review by Safer Care Victoria
Summary of outcomes and recommendations
As a consequence of concerns expressed by members of the public following the publication of a video showing the treatment by a chiropractor of a newborn infant in August 2018, the Minister of Health for the State of Victoria in Australia commissioned an independent review of the practice of spinal manipulation in children under the age of 12 years.
In March 2019 a panel was established to conduct this review. Panellists included medical experts in pediatrics, chiropractors, and regulators. It was chaired by the head of Safer Care Victoria, Professor Euan Wallace. The panel included Adjunct Professor Matthew Fisher, Chief Executive Officer of the Australian Chiropractors Association and Dr Wayne Minter, Chair of the Chiropractic Board of Australia.
The review included a public consultation, consultation with practitioners and regulators and a systematic review of the evidence by Cochrane Australia. For the purposes of the review, spinal manipulation was defined in terms of the application of a high velocity, low amplitude thrust beyond the physiological range of movement of a joint but within the limits of anatomical integrity. In Australia, the practice of spinal manipulation is limited to chiropractors, osteopaths, medical practitioners and physiotherapists.
Review of the evidence of harm
A search of the available literature was conducted by Cochrane Australia along with an analysis of patient complaints, practitioner notifications and an evaluation of insurance claims data from chiropractic insurers.
The review found very little evidence of patient harm for spinal manipulation in the treatment of children under 12 years. No patient complaints were identified and there were no practitioner notifications.
Three reports of serious harm were reported relative to spinal manipulation in children under 12 years. None of these events involved chiropractors, nor did they feature techniques used by chiropractors in Australia.
It was considered that there were 2 main reasons why evidence of harm was low:
- Spinal manipulation is rarely applied by chiropractors in the treatment of children under 2 years.
- Chiropractors utilise modified force techniques such that there is little likelihood of children receiving high velocity, low amplitude thrust spinal manipulation.
Despite these findings, the review states that spinal manipulation in children under the age of 12 years cannot be considered wholly without risk and that any risk of harm should be weighed against the evidence of benefit, especially in children under the age of 2 years.
Review of the evidence of effectiveness
Safer Care Victoria commissioned Cochrane Australia to undertake a systematic review of the effectiveness and safety of spinal manipulation in children under the age of 12 years.
The resulting systematic review concluded that the evidence base was very poor. It concluded that no strong evidence of effectiveness exists for the following conditions:
- Infantile colic
- Enuresis (bed wetting)
- Back and neck pain
- Headache
- Asthma
- Otitis media
- Cerebral palsy
- Hyperactivity
- Torticollis
Weak evidence was found for modestly reduced crying time in infantile colic and reduced wet nights in children with enuresis.
The review concluded that spinal manipulation cannot be recommended for headache, asthma, otitis media, cerebral palsy, hyperactivity or torticollis. It further concluded that the unlikely evidence of benefit versus the potential risks of harm should be considered in the use of spinal manipulation in the treatment of infantile colic and enuresis.
A public consultation resulted in 21,824 responses from people who had accessed chiropractic spinal care for children under the age of 12 years.
99.7% of respondents reported a positive experience of chiropractic care of children.
98% reported an improvement in symptoms following chiropractic care.
The panel noted a strong thread in the responses stressing the importance of the right of parents to choose the best care for their children.
The most common conditions for which chiropractic spinal care was sought for children under 12 years were as follows:
- Posture
- Colic
- Neck pain
- Breastfeeding issues
0.3% of respondents reported a negative experience. Principal reasons cited included cost of care relative to perceived benefit, excessive use of x-rays, pressure to avoid medication or advice to avoid previously-consulted health professionals).
Health practitioner consultation
2735 responses were received from health care practitioners. Of the 85% of those confirming they provided spinal care for children, 99.5% were chiropractors.
Of the respondents, 80% stated they treated children aged 0-3 months, while 88% confirmed they treated children aged 0-24 months.
The most commonly reported benefits of care described by respondents were decreased pain, improved sleep patterns, more relaxed, improved breastfeeding and latching, and improved range of movement.
1. Spinal manipulation should not be provided to children under 12 for general wellness or for the management of the following conditions:
- Developmental or behavioural disorders
- Hyperactivity disorders
- Autism spectrum disorders
- Bedwetting
- Ear infections
- Digestive problems
2. National boards of those professions permitted to perform spinal manipulation should consider recommendation (1) when reviewing their policies in relation to the care of children.
3. Prior to treatment with spinal manipulation of children under 12, practitioner should provide written information setting out the proposed benefits and possible risks of care.
4. National boards should review notification data regularly to identify trends requiring modifications of policies, in line with the principle of risk-based regulation.
Improving quality
5. Practitioner groups permitted to perform spinal manipulation in Australia should urgently undertake research to develop an evidence base for spinal manipulation on children. The practice of spinal manipulation on children under 12 years should be ceased when there is the evidence shows no benefit. Ministers should consider whether funding should be allocated for the purpose of research.
6. Practitioner groups permitted to perform spinal manipulation in Australia must lead on developing evidence-based guidance on spinal manipulation of children for both practitioners and consumers, using National Health and Medical Research Council endorsed methods. This guidance material should form the basis of written information for parents in line with recommendation (3).
7. Consideration should be given by the Chiropractic Board of Australia to various models of advanced chiropractic training in pediatric care, particularly in spinal manipulation. Post-registration training on offer to chiropractors with a special interest in paediatrics should be assessed against the evidence-based guidelines.
Eliminating false advertising
8. Chiropractors should continue to be audited by regulatory authorities for their compliance with guidance relating to advertising.
9. National boards should consider whether prohibitive advertising statements are issued regarding spinal manipulation in children where there is evidence of no benefit.
10. Ministers should consider increasing penalties for advertising offences where a registered practitioner claim benefits of spinal manipulation in children that have no evidence base.
The full report is available at http://bit.ly/SCVpaediatric. It includes an Executive Summary, recommendations, a detailed description of the public consultation, and the systematic review undertaken by Cochrane Australia.
WFC releases new guiding principles document
Statements reflect strong commitment to global advancement
Toronto, September 24, 2019. The World Federation of Chiropractic (WFC) has today published a suite of guiding principles that will support its strategy for supporting, empowering, promoting and advancing chiropractic globally.
The WFC's new Principles document consists of 20 statements that set out clearly what the organization stands for and how it views chiropractic as a contemporary global health profession. The statements, which align with the WFC's mission to advance awareness, utilization and integration of chiropractic internationally, were approved unanimously by the Board of Directors.
Launching the Principles, WFC Interim President Dr Vivian Kil said, "These Principles say who we are. It is important that our member national associations, corporate partners, supporters and the public clearly understand the role that the WFC plays internationally in representing chiropractors in over 90 countries worldwide. As our #BeEPIC campaign gathers momentum, these Principles underscore our values and our vision for the future."
In drafting the statements the WFC has been mindful of the social determinants of health that influence access to care and the variety of environments in which chiropractic is practiced. Secretary-General Dr Richard Brown commented: "The WFC is an inclusive, global organization and we want these statements to resonate with chiropractors around the world. They reflect our commitment to support and develop the profession for the benefit of patients and the public and we're excited to be launching the Principles document at this time."
The WFC's Principles are available for download and distribution in English, French and Spanish.
The WFC Principles
For over 30 years the World Federation of Chiropractic has been at the forefront of the global development of chiropractic. Representing the interests of the profession in over 90 countries worldwide, the WFC has advocated, defended and promoted the profession across its 7 world regions. These WFC Principles set out who we are, what we stand for, and how chiropractic as a global health profession can impact on nations so that populations can thrive and reach their full potential.
Our 20 principles
1. We envision a world where people of all ages, in all countries, can access the benefits of chiropractic.
2. We are driven by our mission to advance awareness, utilization and integration of chiropractic internationally.
3. We believe that science and research should inform care and policy decisions and support calls for wider access to chiropractic.
4. We maintain that chiropractic extends beyond the care of patients to the promotion of better health and the wellbeing of our communities.
5. We champion the rights of chiropractors to practice according to their training and expertise.
6. We promote evidence-based practice: integrating individual clinical expertise, the best available evidence from clinical research, and the values and preferences of patients.
7. We are committed to supporting our member national associations through advocacy and sharing best practices for the benefit of patients and society.
8. We acknowledge the role of chiropractic care, including the chiropractic adjustment, to enhance function, improve mobility, relieve pain and optimize wellbeing.
9. We support research that investigates the methods, mechanisms, and outcomes of chiropractic care for the benefit of patients, and the translation of research outcomes into clinical practice.
10. We believe that chiropractors are important members of a patient's healthcare team and that interprofessional approaches best facilitate optimum outcomes.
11. We believe that chiropractors should be responsible public health advocates to improve the wellbeing of the communities they serve.
12. We celebrate individual and professional diversity and equality of opportunity and represent these values throughout our Board and committees.
13. We believe that patients have a fundamental right to ethical, professional care and the protection of enforceable regulation in upholding good conduct and practice.
14. We serve the global profession by promoting collaboration between and amongst organizations and individuals who support the vision, mission, values and objectives of the WFC.
15. We support high standards of chiropractic education that empower graduates to serve their patients and communities as high value, trusted health professionals.
16. We believe in nurturing, supporting, mentoring and empowering students and early career chiropractors.
17. We are committed to the delivery of congresses and events that inspire, challenge, educate, inform and grow the profession through respectful discourse and positive professional development.
18. We believe in continuously improving our understanding of the biomechanical, neurophysiological, psychosocial and general health effects of chiropractic care.
19. We advocate for public statements and claims of effectiveness for chiropractic care that are honest, legal, decent and truthful.
20. We commit to an EPIC future for chiropractic: evidence-based, people-centered, interprofessional and collaborative.
WFC Survey of Chiropractic Global Workforce Reveals Huge Imbalance in Service Provision. July 26, 2019
Toronto, July 24, 2019. The results of a global survey of the chiropractic profession have revealed a significant lack of provision in low- and middle-income countries, according to a new paper published today in Chiropractic and Manual Therapies.
The survey, undertaken by the World Federation of Chiropractic, gathered data from its constituent national associations, government websites, internet searches and personal correspondence. Information was sourced from all 193 United Nations member nations, including 90 countries where at least one chiropractor was practising.
The results showed that overwhelmingly chiropractors were mostly located in North America (United States and Canada).
The survey also revealed that of the 48 educational institutions offering chiropractic programs, the majority were in high-income countries with almost 60% located in North America or Europe.
The World Health Organization's (WHO) Global Strategy on Human Resources for Health: Workforce 2030 has targeted universal availability, accessibility, acceptability, coverage and quality of health systems within strengthened health systems. The WFC's mission statement (to advance awareness, utilization and integration of chiropractic internationally) aligns with this strategy.
WFC Secretary-General Richard Brown comments: "With low back pain being the biggest single cause of years lived with disability and an increasing ageing population, it is clear that there is a shortfall in the numbers of health workers globally who are trained to effectively manage spinal pain and disability. Chiropractors, as non-surgical experts in spine care, are well placed to make a positive impact, yet numbers need to rise. Expansion of educational provision in low- and middle- income countries and increased awareness by health policy makers are instrumental factors in meeting the needs of underserved populations."
As with many global surveys, responses were mixed and the authors highlighted the need for further information gathering, monitoring and reporting of data. Despite this, the message is clear: health inequities seen throughout the world are reflected in the provision of chiropractic and more needs to be done to ensure adequate numbers of chiropractors in countries where the impact of spinal pain and disability is profound.
The full paper can be downloaded from Chiropractic and Manual Therapies at http://bit.ly/ChiroWorkforce
Australian Chiropractors Association Publishes Submission to Safer Care Victoria Independent Review into Chiropractic Spine Care For Children. June 28, 2019
Following the publication in Australia earlier this year of a video showing a chiropractor treating a baby, the Health Minster for the state of Victoria called for the prohibition of chiropractic spinal manipulation for children under the age of 12 years. As a result, an independent panel has been appointed by Safer Care Victoria to examine the evidence and provide recommendations for the chiropractic care of children.
The role of the panel is to (a) examine and assess the available evidence, including information from consumers, providers, and other stakeholders, for the use of spinal manipulation by chiropractors on children less than 12 years of age and (b) provide recommendations regarding this practice to the Victorian Minister for Health.
Members of the public and key stakeholders, including the WFC's member for Australia, the Australia Chiropractors Association (AusCA), were invited to submit observations. The AusCA's submission can be read here.
The AusCA has drawn heavily in its response on the principles of evidence-based, people-centered, interprofessional and collaborative (EPIC) care.
Points to note are as follows:
1. The AusCA has taken a strongly evidence-based approach to its response, emphasising the safety and protection of the public, while setting out its position on the role of chiropractors in the Australian health care system.
2. The document draws attention to the need for chiropractors to practice ethically, competently and professionally and in line with the code of conduct as drafted by the Chiropractic Board of Australia.
3. The need for chiropractors to possess an approved qualification from an approved educational institution is emphasised.
4. The AusCA has clearly defined spine care as the major or defining clinical purpose, with chiropractors being defined as community-based primary care health providers.
5. The international, interdisciplinary evidence base for chiropractic is emphasised. The challenges of effective knowledge translation are described (noting that in general medicine, knowledge translation can sometimes take 15 years or more).
6. Integration into the health care system is described, with chiropractic being described as a popular, highly utilised profession.
7. In respect of infants, children and adolescents, evidence-based prevention and treatment strategies for musculoskeletal conditions are emphasised.
8. The report describes 30,000 treatments per week (8-10% of all treatment provided) being provided to the paediatric population in Australia.
9. The report emphasises the safety of chiropractic treatment by reference to 2 systematic reviews and insurance data from Scandinavia.
10. The duty binding on chiropractors to obtain informed consent to care is supported.
11. The report sets out the levels of effectiveness for manual therapies for paediatric conditions, noting its variable quality (in line with other professions) but stating that it is mostly 'moderate-positive' or 'inconclusive-favourable'.
12. The document states that there is no evidence that would support restriction of parental or patient choice when seeking chiropractic care for children under 12 years as there is no evidence of harm. There is, however, expressed outcome of benefit.
13. The submission calls for a considered response by the Victoria government, noting that similar restrictions on the provision of care to those proposed have never been implemented. Instead, guidelines that minimise harm and define good practice have helped to ensure that consumers make informed choices about the care they receive have been introduced.
14. The AusCA calls for:
a. A trial of monitoring care, including outcomes, for children under 12 years;
b. Refinement of industry-led standards and clinical guidelines informed by best practice, including CPD/CE and consensus approaches to care including interprofessional understanding;
c. A commitment to knowledge translation;
d. A call for greater support of research in investigating the role of chiropractors in the treatment of children.
Australian Chiropractors Association
The Australian Chiropractors Association is the peak body for the chiropractic profession in Australia. Representing over 3000 members, it provides a strong, unified voice for chiropractors in Australia. Its work involves advocacy, membership services, research, public engagement and governance. Its current president is Dr Anthony Coxon.
The Australian Chiropractors Association is the WFC member for Australia and is located in the WFC's Pacific Region.
UK to offer new university-based chiropractic program at University of Central Lancashire. June 24, 2019
WHO Focus on Low Back Pain Demonstrates Unprecedented Opportunities For Chiropractors. June 5, 2019
Rehabilitation Competency Framework published. May 30, 2019
WFC Announces Interim President. May 15, 2019
Global Diversity As WFC Announces Council 2019-2022. January 28, 2019
Greg Kawchuk re-appointed as WFC Research Chair. January 15, 2019
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Choosing Glasses
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Dry Eye Clinic
A LENS FOR THE FUTURE
University of Liverpool engineers have developed a contact lens that has been found to reliably track Intra ocular pressure changes which is an indicator for glaucoma changes in a small clinical study
A contact lens developed by University of Liverpool engineers may help improve the treatment of glaucoma.
The soft silicone hydrogel device was found to accurately measure changes in intraocular pressure (IOP) with little discomfort to the patient in a small clinical trial involving 12 volunteers.
The volunteers wore the device for over an hour under clinical supervision at Royal Liverpool University Hospital and Moorfields Eye Hospital.
The contact lens contains a pressure sensor that detects IOP changes and then transmits them wirelessly to a portable external controller the size of a mobile phone.
University of Liverpool biomedical engineers developed the device in collaboration with engineers from specialist contact lens manufacture, Ultravision CLPL.
Professor of Biomaterial Mechanics, Ahmed Elsheikh, highlighted that the device has the potential to provide glaucoma patients with information to ensure that they are treated correctly.
"The results of this study are very positive and show that the device is comfortable for people to wear and gives good measurements of IOP," he added.
Funding for the project was provided by the National Institute for Health Research.
With thanks to Selina Powell from Optometry Today
S W & C Jacksons Opticians
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Effect of Solvents on Phytochemicals Content and Antioxidant Activity of Ganoderma lucidum
Moyen Uddin Pk1, 2, 3, Rabiul I. Talukder3, Mohammad K. I. Sarkar4, *, Tasnia Rahman4, Rumana Pervin5, Matiar Rahman5, Elina A. Zenat6, Lima Akther7
1 Institute of Biological Science, University of Rajshahi, Rajshahi, Bangladesh
2 Department of Biochemistry & Molecular Biology, University of Rajshahi, Rajshahi, Bangladesh
3 Department of Biochemistry, Primeasia University, Dhaka, Bangladesh
4 School of Environmental Science and Management, Independent University Bangladesh (IUB), Dhaka, Bangladesh
5 Department of Biochemistry & Molecular Biology, University of Rajshahi, Bangladesh
6 Bangladesh Council of Scientific and Industrial Research (BCSIR), Dhaka, Bangladesh
7 Department of Chemistry, Comilla University, Bangladesh
The aim of this study was to assess the induction of solvents on the total phenol and flavonoid content and also the antioxidant activity of Ganoderma lucidum extracts.
Materials & Methods:
In this study, two concentrations (100% and 75%) of diethyl ether, ethanol, butanol, chloroform, and acetone were used as extractants of Ganoderma lucidum. Total phenol and flavonoid contents were measured by spectrophotometric methods and 1, 1-diphenyl-2-picrylhydrazyl (DPPH). Free radical scavenging assay was used for the investigation of antioxidant activity.
Results & Discussion:
Extractants significantly affected the % yield of extract, the quantity of phenol and flavonoids and antioxidant activity of Ganoderma lucidum mushroom. The highest extraction yield, around 38%, was achieved by 75% acetone, followed by 100% acetone (about 36%) and 75% chloroform (approximate 21%). Hydro-acetone extract exhibited the most significant antioxidative properties (EC50 value; 645.55 µg/mL) comprised of a higher total of phenol content. In conclusion, the total phenol content encouraged the antioxidative potential of Ganoderma lucidum mushroom.
These findings indicate that the selective extraction of Ganoderma lucidum shows significant biological activities.
Keywords: : Edible mushroom, Free radical scavenging, Chronic diseases, Functional foods, Antioxidative potential, Ganoderma lucidum mushroom.
© 2019 Uddin Pk et al.
* Address correspondence to this author at the School of Environmental Science and Management, Independent University Bangladesh (IUB), Dhaka, Bangladesh Tel: +8801711230892; E-mail: [email protected]
There are several chronic diseases namely cancer, diabetes, hypertension, and aging which are affected by producing free radicals during metabolism [1Choudhary Raghuveer TR. Consumption of functional food and our health concerns. Pak J Physiol 2009; 5(1): 8.]. Anti-oxidants from natural sources will reduce the formation of free radicals in vivo while most of the synthetic antioxidants will show side effects [2Praveen K, Awang Bono R. Antioxidant activity, total phenolic and flavonoid content of Morinda citrifolia fruit extracts from various extraction processes. J Eng Sci Tech 2007; 2(1): 1-11.].
It has been reported that synthetic antioxidants such as Butylated Hydroxytoluene (BHT), Butylated Hyd-roxyanisole (BHA) and amass in vivo cause liver diseases and cancer [3Jiangning G, Xinchu W, Hou W, Qinghua L, Kaishun B. Antioxidants from a Chinese medicinal herb – Psoralea corylifolia L. Food Chem 2005; 91(2): 287-92.[http://dx.doi.org/10.1016/j.foodchem.2004.04.029] ]. Edible mushrooms, Pleurotus ostreatus, Ganoderma lucidum, and Lentinula edodes are available in Bangladesh and comprise different phytochemicals such as polyphenols, flavonoids, tannins, steroids [4Islam MR, Omar M, Pk MMU, Mia R. Phytochemicals and antibacterial activity screening of three edible mushrooms Pleurotus ostreatus, Ganoderma lucidum and Lentinula edodes accessible in Bangladesh. Am j biol life sci 2015; 3(2): 31-5.; ]. It was reported that some edible mushrooms exhibited the antioxidant activity, which was correlated with the total phenol content [5Boonsong S, Klaypradit W, Wilaipun P. Antioxidant activities of extracts from five edible mushrooms using different extractants. Agric Nat Resour (Bangk) 2016; 50(2): 89-97.[http://dx.doi.org/10.1016/j.anres.2015.07.002] ]. Suphaphit Boonsong et al. have shown that different extractants induced antioxidant potential of edible mushrooms [6Yang J-H, Lin H-C, Mau J-L. Antioxidant properties of several commercial mushrooms. Food Chem 2002; 77(2): 229-35.[http://dx.doi.org/10.1016/S0308-8146(01)00342-9] ]. In 2002, Yang et al. from China have demonstrated that tree oyster mushrooms were signal properties of free radical scavenging abilities and comprised the highest content of total phenol [7Barros L, Ferreira M-J, Queirós B, Ferreira ICFR, Baptista P. Total phenols, ascorbic acid, β-carotene and lycopene in Portuguese wild edible mushrooms and their antioxidant activities. Food Chem 2007; 103(2): 413-9.[http://dx.doi.org/10.1016/j.foodchem.2006.07.038] ]. The free radical scavenging activity of Ganoderma lucidum was encouraged by the presence of total phenol content [8Mau J-L, Lin H-C, Chen C-C. Antioxidant properties of several medicinal mushrooms. J Agric Food Chem 2002; 50(21): 6072-7.[http://dx.doi.org/10.1021/jf0201273] [PMID: 12358482] ]. Polysaccharides, triterpenoids and other several components of Ganoderma lucidum illustrated antioxidant activity [8Mau J-L, Lin H-C, Chen C-C. Antioxidant properties of several medicinal mushrooms. J Agric Food Chem 2002; 50(21): 6072-7.[http://dx.doi.org/10.1021/jf0201273] [PMID: 12358482] ]. Ganoderma lucidum is presently popular and used in the production of functional foods. From several previous studies, it is known that Ganoderma lucidum comprises potential phytoconstituents which are concomitant with the advancement of good health as well as used for alternative medicine [9Lee J-M, Kwon H, Jeong H, et al. Inhibition of lipid peroxidation and oxidative DNA damage by Ganoderma lucidum. Phytother Res 2001; 15(3): 245-9.[http://dx.doi.org/10.1002/ptr.830] [PMID: 11351361] ].
In this study, the induction of solvents on antioxidant activities of alcoholic and hydro-alcoholic (75%) extracts of Ganoderma lucidum were investigated and examined; the correlation of total phenol and flavonoid contents with DPPH scavenging potentials of 10 different extractants. Here, we also observed how extractants induced the production of percent yield of extracts of Ganoderma lucidum mushroom.
2. METHODS AND MATERIALS
2.1. Mushroom Collection and Authentications
The fruiting bodies of Ganoderma lucidum were collected from Mushroom Development Institute, which belongs to the Department of Agriculture Extension, Ministry of Agriculture, Bangladesh, Savar, Dhaka-1340. The mushroom was acknowledged and authenticated by a research officer from Mushroom Development Institute, Bangladesh.
2.2. Preparation of Mushroom Extracts
Dried fruiting bodies of Ganoderma lucidum were blended to form fine powder and extracted using different extractants-diethyl ether (DE), 75% of DE, Ethanol (E), 75% of E, Butanol (B), 75% of B, Chloroform (C), 75% of C, Acetone (A), and 75% of acetone. Approximately 100g of mushroom powder was submerged in selected solvents and stirred gently with a 2-hour interval. After seven days, all individual fractions were collected and concentrated. Dried fractions were used to prepare the required concentrations for this study.
2.3. Determination of Total Phenolic Content
According to Turkoglu et al, the total phenol content of extracts of Ganoderma lucidum obtained from 10 different extractants were determined [10Paterson RRM. Ganoderma - A therapeutic fungal biofactory. Phytochemistry 2006; 67(18): 1985-2001.[http://dx.doi.org/10.1016/j.phytochem.2006.07.004] [PMID: 169051 65] ]. In this experiment, gallic acid was used as a standard compound and the total phenol contents were calculated from a calibration curve constructed by plotting the absorbance against concentrations of the gallic acid standard. Results were expressed as the % w/w of each test. All samples were analyzed in triplicate (n=3).
2.4. Determination of Total Flavonoid Content
Total flavonoid contents were determined according to a procedure provided by Dewanto et al. [11Turkoglu A, Duru ME, Mercan N, Kivrak I, Gezer K. Antioxidant and antimicrobial activities of Laetiporus sulphureus (Bull.) Murrill. Food Chem 2007; 101(1): 267-73.[http://dx.doi.org/10.1016/j.foodchem.2006.01.025] ]. According to this method, aliquot of diluted sample and catechin (used as a standard) were added to 5% of sodium nitrate solution (75 mL) and gently mixed for 5 minutes after which 10% of aluminum chloride solution (0.15 mL) was added. After 10 minutes of incubation, 0.5 mL of 1M sodium hydroxide was added and final reaction volume was adjusted to 2.5 mL with double distilled water and mixed comprehensively. The absorbance of each dose of sample and standard was recorded at 510 nm and total flavonoid content was determined from a standard curve constructed from catechin absorbance from 0 to 500 mg/mL. Samples were examined in three replicates [11Turkoglu A, Duru ME, Mercan N, Kivrak I, Gezer K. Antioxidant and antimicrobial activities of Laetiporus sulphureus (Bull.) Murrill. Food Chem 2007; 101(1): 267-73.[http://dx.doi.org/10.1016/j.foodchem.2006.01.025] ].
2.5. 1-Diphenyl-2-Picrylhydrazyl Scavenging Activity Assay
According to Devi et al. the total antioxidant activity of mushroom extracts was determined. Here, triplicate reaction mixture comprised 50 µL of each mushroom sample and 5.0 mL of DPPH solution (0.04% w/v in ethanol) followed by 80% ethanol as a blank preparation. All test tubes were covered with Aluminum foil and after 30 minutes of incubation, discoloration of the reaction was measured at 517 nm [12Dewanto V, Wu X, Adom KK, Liu RH. Thermal processing enhances the nutritional value of tomatoes by increasing total antioxidant activity. J Agric Food Chem 2002; 50(10): 3010-4.[http://dx.doi.org/10.1021/jf0115589] [PMID: 11982434] ]. DPPH scavenging effect was determined using the following equation;
Where Ao was the absorbance of control, As was the absorbance of the selected sample.
BHT was used as a positive control and for comparison with each sample's activity against free radical scavenging. The effective concentration for 50% of free radical scavenging activity of positive control and mushroom samples were determined using standard curve (r2=0.9994).
2.6. Statistical Analysis
GraphPad Prism 6 (Pad Software, Inc., USA) was used to analyze data, and results were expressed as mean±SD. Error bars were expressed as 95% CI. One way Analysis of Variance (ANOVA) and post-hoc Tukey's Range tests were utilized to decide the distinctions among the methods. An estimation of P < 0.05 was thought to be statistically significant.
Fig. (1 ) illustrates the percentage of extract yield of Ganoderma lucidum directed by different solvents effect. Here we found that the maximum percentage of extract yield was produced in 75% acetone extraction method. 38.11% and 36.17% extracts of mushroom were produced for 75% acetone and acetone extraction methods accordingly.
On the other hand, second maximum yield production was found in chloroform extraction method and nearly equal amounts of the yield of extract from Ganoderma lucidum were found by the extraction methods of butanol solvents (5.44% for 75% butanol and 5.12% for butanol).
The ethanol extraction produces 6.75% yield of extract whereas 8.34% yield of the extract is found in 75% ethanol extraction. About 5% yield of extract was found in 75% diethyl ether extraction and the lowest percentage of yield of extract was produced by diethyl ether extraction method.
In conclusion, the percentage of yielding extract was induced by sample extraction methods as well.
Table 1 shows the total phenol and flavonoid contents of Ganoderma lucidum mushroom measured in selected extraction methods. Overall, the maximum total phenolic content was found in acetone extraction and ethanol extract showed the highest content of total flavonoid.
Determination of total phenol and flavonoid contents (% w/w).
About 2% (w/w) total phenol was determined from acetone extract and around 1.5% TPC was also calculated from butanol and chloroform extracts. On the other hand, ethanol and diethyl ether extract exhibited around 1% TPC content of Ganoderma lucidum.
Ethanol extract shows the highest content of total flavonoid, which is 1.3% and chloroform extract exhibits around an equal amount of TFC. On the other hand, nearly the same amount of flavonoid content was calculated in the extracts of acetone and diethyl ether and the lowest (0.6%) TFC was found in butanol extract of Ganoderma lucidum. From Table 1, it is clear that solvent extraction methods boost the release of total phenol and flavonoid contents from the extracts of Ganoderma lucidum mushroom.
Fig. (2 ) explicates the percent inhibition of free radical scavenging activity of Ganoderma lucidum extracts, which are produced by different extraction methods and also compares their activity. The signal DPPH radical scavenging activity was found in acetone extract and the results were almost similar to BHT (p>0.05). The diethyl ether and 75% diethyl ether shared nearly equal percent inhibition. In Fig. (2A ), the significant difference in the antioxidant activity was observed at a lower dose of DE extract, compared to BHT and approximately similar activities were found with higher concentrations of that extract. The same patterns of free radicals scavenging activities of mushroom were monitored in different solvents' extract (Figs. 2B , 2C , 2D , and 2E ).
Percentage of the yield of the extract by different extraction methods from Ganoderma lucidum. BHT-Butylated Hydroxytoluene; DE-Diethyl ether; Ethn-Ethanol; Butn-Butanol; Chln-Chloroform; Acetn-Acetone.
In vitro free radical scavenging activities of different extracts of Ganoderma lucidum. GL- Ganoderma lucidum; DEGL-diethyl ether extract of GL, BEGL-Butanol extract of GL; EEGL-ethanol extract of GL; CEGL-chloroform extract of GL, and AEGL-acetone extract of GL; BHT-Butylated Hydroxytoluene; DE-Diethyl ether; Ethn-Ethanol; Butn-Butanol; Chln-Chloroform; Acetn-Acetone. The given graphs also illustrate the mean percentage of DPPH radical formation during reaction time. Acetone and ethanol extract exhibit almost equal free radical scavenging potentials as well.
IC50 values (µg/mL) of free radicals scavenging by different solvents extract of Ganoderma lucidum.
The results obtained revealed the indicative difference of free radical scavenging potentials of solvents induced mushroom extracts. Here, it is cleared that, at the highest concentration of mushroom extract, the almost equal tendency to prevent DPPH radical's production during reaction time was demonstrated. The effective concentrations (IC50) of mushroom extracts were calculated to assess their potency for reducing free radicals. The most effective crude mushroom extract was 75% acetone extract (IC50 value; 645.445 µg/ml) and followed by 75% ethanol, ethanol, butanol, 75% diethyl ether, and diethyl ether extracts. On the other hand, extract of 75% butanol shows the lowest potency against the scavenging of free radicals (IC50 value; 2029.4366 µg/ml). Results are shown in Table 2 as a whole.
In this study, we have determined total phenol and flavonoid content and antioxidant activity of Ganoderma lucidum mushroom extracts obtained using ten different extraction methods. The total phenol and flavonoid contents of mushroom depended on the extractants. Acetone (75%) extract showed the highest % yield of extract comprised the highest content of total phenol content while 75% ethanol extract exhibited the highest content of total flavonoids. It has been demonstrated that the phenol content of plant extract depended on the solvent used and its polarity and also shown that the acetone extract gave the highest polyphenol content [13Devi KP, Suganthy N, Kesika P, Pandian SK. Bioprotective properties of seaweeds: In vitro evaluation of antioxidant activity and antimicrobial activity against food borne bacteria in relation to polyphenolic content. BMC Complement Altern Med 2008; 8(1): 38.[http://dx.doi.org/10.1186/1472-6882-8-38] [PMID: 18613983] ]. Solvent polarity directly induced the phenolic solubility [14Medini F, Fellah H, Ksouri R, Abdelly C. Total phenolic, flavonoid and tannin contents and antioxidant and antimicrobial activities of organic extracts of shoots of the plant Limonium delicatulum. Journal of Taibah University for Science 2014; 8(3): 216-24.[http://dx.doi.org/10.1016/j.jtusci.2014.01.003] ], the polyphenol extraction from plant materials was induced by extractants [15Naczk M, Shahidi F. Phenolics in cereals, fruits and vegetable: Occurrence, extraction and analysis. J Pharm Biomed Anal 2006; 41(5): 1523-42.[http://dx.doi.org/10.1016/j.jpba.2006.04.002] [PMID: 16753277] ]. Ganoderma lucidum contains various antioxidants such as, triterpene, that was tested for its antioxidant activity [16Gálvez M, Martín-Cordero C, Houghton PJ, Ayuso MJ. Antioxidant activity of methanol extracts obtained from Plantago species. J Agric Food Chem 2005; 53(6): 1927-33.[http://dx.doi.org/10.1021/jf048076s] [PMID: 15769115] ], There are various methods developed to assess antioxidant activity of plant materials through scavenging free radicals, inhibition of lipid peroxidation and so on [17Zhu M, Chang Q, Wong LK, Chong FS, Li RC. Triterpene antioxidants from ganoderma lucidum. Phytother Res 1999; 13(6): 529-31.[http://dx.doi.org/10.1002/(SICI)1099-1573(199909)13:6<529::AID-PTR481>3.0.CO;2-X] [PMID: 10479768] , 18Mahdi-Pour B, Jothy SL, Latha LY, Chen Y, Sasidharan S. Antioxidant activity of methanol extracts of different parts of Lantana camara. Asian Pac J Trop Biomed 2012; 2(12): 960-5.[http://dx.doi.org/10.1016/S2221-1691(13)60007-6] [PMID: 23593 576] ]. Here we measured the antioxidant activity of different extracts through scavenging DPPH radicals and hydro-acetone extract which showed that the signal antioxidant activity comprised high phenol content.
Extracts of Ganoderma lucidum obtained from hydro-acetone (EC50 value; 645.44 µg/mL) and hydro-ethanol (EC50 value; 823.62 µg/mL) exhibited strong antioxidative properties comprised higher phenolic content than that of diethyl ether (EC50 value; 1100.80 µg/mL), 75% diethyl ether (EC50 value; 867.81 µg/mL), ethanol (EC50 value; 833.79 µg/mL), butanol (EC50 value; 862.91 µg/mL), 75% butanol (EC50 value; 2029.43 µg/mL), chloroform (EC50 value; 1879.04 µg/mL), 75% chloroform (EC50 value; 1759.85 µg/mL), and acetone (EC50 value; 1266.05 µg/mL). Hydro-acetone extraction method produced the maximum percentage (%) yield of extract (p<0.05).
From this study, it is clear that the total phenol content induced the antioxidative potential of Ganoderma lucidum mushroom. These findings designate that the selective extraction of phytochemicals from mushroom shows signal biological activities which can be used as a rationale for the development of alternative medicines.
The authors approve that all data essential for the findings are completely available without constraint. All pertinent data are within the paper and its backup information files.
The authors received no specific funding for this work. Funder provided support in the form of salaries for authors, but did not have any additional role in the study design, data collection & analysis, decision to publish, and preparation of the manuscript.
[1] Choudhary Raghuveer TR. Consumption of functional food and our health concerns. Pak J Physiol 2009; 5(1): 8.
[2] Praveen K, Awang Bono R. Antioxidant activity, total phenolic and flavonoid content of Morinda citrifolia fruit extracts from various extraction processes. J Eng Sci Tech 2007; 2(1): 1-11.
[3] Jiangning G, Xinchu W, Hou W, Qinghua L, Kaishun B. Antioxidants from a Chinese medicinal herb – Psoralea corylifolia L. Food Chem 2005; 91(2): 287-92.[http://dx.doi.org/10.1016/j.foodchem.2004.04.029]
[4] Islam MR, Omar M, Pk MMU, Mia R. Phytochemicals and antibacterial activity screening of three edible mushrooms Pleurotus ostreatus, Ganoderma lucidum and Lentinula edodes accessible in Bangladesh. Am j biol life sci 2015; 3(2): 31-5.;
[5] Boonsong S, Klaypradit W, Wilaipun P. Antioxidant activities of extracts from five edible mushrooms using different extractants. Agric Nat Resour (Bangk) 2016; 50(2): 89-97.[http://dx.doi.org/10.1016/j.anres.2015.07.002]
[6] Yang J-H, Lin H-C, Mau J-L. Antioxidant properties of several commercial mushrooms. Food Chem 2002; 77(2): 229-35.[http://dx.doi.org/10.1016/S0308-8146(01)00342-9]
[7] Barros L, Ferreira M-J, Queirós B, Ferreira ICFR, Baptista P. Total phenols, ascorbic acid, β-carotene and lycopene in Portuguese wild edible mushrooms and their antioxidant activities. Food Chem 2007; 103(2): 413-9.[http://dx.doi.org/10.1016/j.foodchem.2006.07.038]
[8] Mau J-L, Lin H-C, Chen C-C. Antioxidant properties of several medicinal mushrooms. J Agric Food Chem 2002; 50(21): 6072-7.[http://dx.doi.org/10.1021/jf0201273] [PMID: 12358482]
[9] Lee J-M, Kwon H, Jeong H, et al. Inhibition of lipid peroxidation and oxidative DNA damage by Ganoderma lucidum. Phytother Res 2001; 15(3): 245-9.[http://dx.doi.org/10.1002/ptr.830] [PMID: 11351361]
[10] Paterson RRM. Ganoderma - A therapeutic fungal biofactory. Phytochemistry 2006; 67(18): 1985-2001.[http://dx.doi.org/10.1016/j.phytochem.2006.07.004] [PMID: 169051 65]
[11] Turkoglu A, Duru ME, Mercan N, Kivrak I, Gezer K. Antioxidant and antimicrobial activities of Laetiporus sulphureus (Bull.) Murrill. Food Chem 2007; 101(1): 267-73.[http://dx.doi.org/10.1016/j.foodchem.2006.01.025]
[12] Dewanto V, Wu X, Adom KK, Liu RH. Thermal processing enhances the nutritional value of tomatoes by increasing total antioxidant activity. J Agric Food Chem 2002; 50(10): 3010-4.[http://dx.doi.org/10.1021/jf0115589] [PMID: 11982434]
[13] Devi KP, Suganthy N, Kesika P, Pandian SK. Bioprotective properties of seaweeds: In vitro evaluation of antioxidant activity and antimicrobial activity against food borne bacteria in relation to polyphenolic content. BMC Complement Altern Med 2008; 8(1): 38.[http://dx.doi.org/10.1186/1472-6882-8-38] [PMID: 18613983]
[14] Medini F, Fellah H, Ksouri R, Abdelly C. Total phenolic, flavonoid and tannin contents and antioxidant and antimicrobial activities of organic extracts of shoots of the plant Limonium delicatulum. Journal of Taibah University for Science 2014; 8(3): 216-24.[http://dx.doi.org/10.1016/j.jtusci.2014.01.003]
[15] Naczk M, Shahidi F. Phenolics in cereals, fruits and vegetable: Occurrence, extraction and analysis. J Pharm Biomed Anal 2006; 41(5): 1523-42.[http://dx.doi.org/10.1016/j.jpba.2006.04.002] [PMID: 16753277]
[16] Gálvez M, Martín-Cordero C, Houghton PJ, Ayuso MJ. Antioxidant activity of methanol extracts obtained from Plantago species. J Agric Food Chem 2005; 53(6): 1927-33.[http://dx.doi.org/10.1021/jf048076s] [PMID: 15769115]
[17] Zhu M, Chang Q, Wong LK, Chong FS, Li RC. Triterpene antioxidants from ganoderma lucidum. Phytother Res 1999; 13(6): 529-31.[http://dx.doi.org/10.1002/(SICI)1099-1573(199909)13:6<529::AID-PTR481>3.0.CO;2-X] [PMID: 10479768]
[18] Mahdi-Pour B, Jothy SL, Latha LY, Chen Y, Sasidharan S. Antioxidant activity of methanol extracts of different parts of Lantana camara. Asian Pac J Trop Biomed 2012; 2(12): 960-5.[http://dx.doi.org/10.1016/S2221-1691(13)60007-6] [PMID: 23593 576]
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The current study involved an evaluation of the Attention Network Test (ANT) as a neurocognitive tool for assessing fitness to drive in the senior population. The ANT measures three distinct functions of attention: alerting, orienting and executive control. This test has been successfully utilized in a variety of clinical and research settings. Few studies have applied the ANT to driving research and none have examined the psychometric properties of the ANT over multiple time points. The participants in this study were senior drivers from the Candrive study. Overall, the ANT was found to have strong psychometric properties. Specifically, the ANT has good test-retest reliability demonstrated high convergent and divergent validity with other commonly used measures (i.e., MoCA, MMSE, Trails A and B, MVPT-3 and SIMARD-MD). In our sample, only Trails A, the SIMARD-MD and alerting scores showed significant change over time. Although the ANT was not more sensitive to cognitive decline as predicted, the cognitive changes were not redundant with other neurocognitive assessment tools. This high functioning sample of seniors coupled with only three annual measurement points may have limited our ability to detect drastic cognitive decline. Nonetheless, the current study provided valuable insight into the utility of a test of attentional processes, the Attention Network Test.
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Health care associated infections are an unwelcome reality in modern health care settings across the globe, and as such we strive to prevent and control these infections in our hospital sites.
St. Joseph's is not included in the annual Hospital Standardized Mortality Ratio (HSMR) report released by the Canadian Institute for Health Information (CIHI). Results are not released for ineligible hospitals (those with less than 2,500 HSMR cases in each of the four years being reported) because the low numbers make the results less stable and, therefore, less reliable.
St. Joseph's infection prevention and control practices, including environmental cleaning practices, are aligned with the Provincial Infectious Diseases Advisory Committee (PIDAC) best practices documents, as well as the Ministry's of Health and Long-Term Care's "Just Clean Your Hands" program. Independent of these initiatives, along with our partner London Health Sciences Centre, we have also formed a Hand Hygiene Improvement Project Steering Committee, to provide direction on development, implementation and evaluation of an effective, sustainable hand hygiene program in our hospitals, which will further support our efforts to continually improve the care we deliver.
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\section{Introduction}
While examining the mineralogical collection of the \'{E}cole Nationale des Mines in Paris, Charles Friedel found an artifact claimed to be ``Graphite from Catherinebourgh, Sibiria'' --- which instead he reported in the year 1873 to be composed from equimolar quantities of Cu$^+_2$O with the combination of Fe$^{3+}_2$O$_3$, about 3.5\% Al$_2$O$_3$ \cite{Friedel1873}. This chemical composition can be written as Cu(Fe,Al)O$_2$. The new mineral was given the name delafossite. In the years since Friedel's discovery a large number of other A$^+$B$^{3+}$O$_2$ compounds have become known that show basically the same structural features: BO$_6$ octahedra form layers that are stacked parallel to $(001)$, and these edge-sharing octahedral sheets are connected along the [001] direction by linear O\,---A$^+$---\,O bonds. Depending on details of the stacking sequence, the structures are usually either hexagonal or trigonal \cite{wolff_nora}. As an exception, Cu$^+$Mn$^{3+}$O$_2$ is monoclinic with space group $C2/m$ \cite{Topfer95}. Shannon et al. \cite{Shannon71} revealed that not only copper and silver can acts as the A$^+$ element, but also other quite noble metals like palladium or even pla\-tinum. This is surprising because oxides of the platinum group metals are not only scarce and often unstable, but also the known platinum group binary oxides show oxidation states of 2+ or higher, e.g. PdO, PdO$_2$, PtO, PtO$_2$, PtO$_3$, and not Pt$^{1+}$ as occours in Pt-containing delafossites.
Oxide materials based on the ABO$_2$ delafossite structure are of particular interest due to the novel properties that accompany their cation variation at A and B sites. These properties are of interest to fundamental science \cite{Hicks12, Takatsu07, Kushwaha15, Daou17, Sunko17} as well as applications \cite{Kawazoe00}. Usually, the semiconductor delafossites consist of Ag or Cu at the A-site and several trivalent cations like Al, Fe or Ga at the B-site. Important among the semiconducting delafossites is CuAlO$_2$ with its relatively high mobility for a p-type transparent conducting oxide \cite{Kawazoe97}. Pd- and Pt-based compounds (for A$^+$) are metallic delafossite oxides where B-site cations are transition metals like Co, Cr or Rh \cite{Shannon71, Prewitt71, Rogers71}. Among these, the growth of single crystalline PdCoO$_2$ has become of interest due to its ultra-high conductivity at room temperature. Recently an in-plane resistivity $\rho_{ab}=2.6\,\mu\Omega\cdot$cm at 295\,K was measured for sub-mm-sized PdCoO$_2$ crystals, which makes this material the most conductive oxide known, comparable to the best metallic conductors Ag, Cu, Au and Al \cite{Hicks12}. Even though it is a platinum group oxide, this material has a fairly high thermal stability up to $900^{\,\circ}$C \cite{Shannon71}.
The excellent properties exhibited by delafossites, including a mean-free path of about 20$\mu$m at low temperature in PdCoO$_2$, \cite{Hicks12} invites the growth of delafossite heterostructures. In such heterostructures bandgap engineering \cite{Capasso87}, strain engineering \cite{Schlom14}, symmetry breaking and other thin-film approaches could be applied to modify the properties of delafossites as has become commonplace for other oxides \cite{Ramesh19}. Unfortunately, there are no commercially available delafossite substrates.
So far, epitaxial layers have mainly been grown on sapphire substrates \cite{Brahlek19, Harada18, Yordanov19} -- unfortunately with significantly degraded quality resulting from the not well matched crystallographic lattice of sapphire ($R\bar{3}c$, $a=4.7602$\,\AA, $c=12.9933$\,\AA\ \cite{Lewis82}) and PdCoO$_2$ ($R\bar{3}m$ $a=2.830$\,\AA, $c=17.743$\,\AA\ \cite{Takatsu07}). The resulting delafossite films contain in-plane rotation twins and other defects that result in the best of today's PdCoO$_2$ films \cite{Brahlek19} having resistivities at room temperature 1.8 times higher than PdCoO$_2$ single crystals \cite{Mackenzie17} and 145 times higher resistivities at 4 K. For the growth of high quality epitaxial layers, isostructural single crystalline substrates with similar lattice constants are required.
The aim of this work is to grow relatively large delafossite crystals that in subsequent studies can be used as substrates for the growth of high quality delafossite films. According to the structural parameters, CuAlO$_2$ ($R\bar{3}m$, $a=2.8571$\,\AA, $c=16.940$\,\AA\ \cite{Shannon71}) would be the most suitable substrate material for PdCoO$_2$. Unfortunately, the melt growth of bulk CuAlO$_2$ crystals with sufficient size is impossible, because the substance melts peritectically under the formation of solid Al$_2$O$_3$ and the growth window (= CuAlO$_2$ liquidus) between the peritectic and eutectic points is too small \cite{Wolff18,Wolff19}. The melting points of iron oxides (Fe$_2$O$_3$ decomposes to Fe$_3$O$_4$, which melts at $1597^{\,\circ}$C) are significantly lower than for Al$_2$O$_3$ ($T_\mathrm{f}=2054^{\,\circ}$C \cite{FactSage7_4}), and consequently a larger growth window for CuFeO$_2$ ($R\bar{3}m$, $a=3.0351$\,\AA, $c=17.166$\,\AA) can be expected. (Some CuO--Fe$_2$O$_3$ phase diagrams \cite{Zhao95b,Song16} in the literature neglect the decomposition of Fe$_2$O$_3$ and show the congruent melting point of Fe$_3$O$_4$ instead.) CuFeO$_2$ is the only delafossite compound, that has already be grown with reasonable quality in diameters up to 5--8\,mm by the optical floating zone (OFZ) technique \cite{Zhao95b,Zhao95,Zhao96}.
So far CuFeO$_2$ single crystals have been grown from stoichiometric sintered rods by the OFZ technique. Our prior thermodynamic investigations have shown that growth methods involving crucibles are unsuitable as the aggressive copper melt attacks all crucible materials \cite{Wolff18}. In addition to pure CuFeO$_2$, CuFe$_{1-x}$Ga$_x$O$_2$ with $x\leq\ $12\% have been grown by Song et al. by the OFZ method \cite{Song16}. For CuCr$_{1-x}$Al$_x$O$_2$ it was shown that solid solution formation with mixed occupancy on the B-site seems to stabilize the delafossite phase thermodynamically \cite{Kato17}, but CuFeO$_2$ with high ($\approx30$\%) Al$^{3+}$ content only grew in polycrystalline form, presumably as a result of severe segregation in the CuFeO$_2$--CuAlO$_2$ solid solution system. The present work focuses on the growth of pure CuFeO$_2$ with sufficient size and perfection to be useful for delafossite substrates. We show that the oxygen fugacity $p_{\mathrm{O}_2}$ in the gas phase acts on the equilibria between the relevant oxidation states of copper ($+2,+1,0$) and iron ($+3,+2$) --- which then influences the crystallization behavior of delafossites.
\section{Experimental}
Growth experiments were carried out in an OFZ furnace from Crystal System Corporation (type FZ-T-10000-H-VII-VPO-PC). The equipment has a four-mirror setup with 1000\,W or 1500\,W halogen lamps and a fused silica protection tube. An argon flow of 0.3\,l\,min$^{-1}$ with 5N purity and total pressure of 1 atm was used as the growth atmosphere, to stabilize the CuFeO$_2$ phase \cite{Wolff19}. The seed and feed rods were rotated at 15\,rpm in opposite directions, and pulling rates between 0.4 and 1.1\,mm\,h$^{-1}$ were employed. Due to the incongruent melting, the lamp power was decreased slowly during the first 5-10\,h of the experiments.
To prepare the rods, vacuum-dried powders of Cu$_2$O (Fox Chemicals, 4N purity) and Fe$_2$O$_3$ (Alfa Aesar, 4N8 purity) in 1:1 molar ratio were mixed and sintered for 25\,h at $900^{\,\circ}$C in 1 atm of argon. XRD powder analysis confirmed that a pure delafossite phase resulted from this annealing process. Following grinding of the sintered CuFeO$_2$, the powder was compacted in a plastic bag and pressed for 3\,min at 2\,kbar at room temperature in a cold isostatic press from Engineered Pressure International NV, Belgium. To increase the density, the pressed block was again sintered for 8\,h at $900^{\,\circ}$C in argon. Rods with diameters of 6, 8 and 12\,mm and 120\,mm length were drilled out of the sintered blocks with a core drill. The density of the rods was 70-80\% of the theoretical value. The grown crystals were characterized by X-ray diffraction (XRD), energy-dispersive Laue mappings (EDLM) and X-ray fluorescence (XRF) spectroscopy. The latter were performed using a $\mu$-XRF spectrometer M4 Tornado (Bruker). Laue method was used to orient the crystals and prepare planar substrates oriented perpendicular to the $c$-axis.
\section{Results}
Five growth experiments were performed that are summarized in Table~\ref{tab:OZF}. In order to optimize the quality and size of the crystals, the diameter of the polycrystalline source rods was increased and the growth rate was reduced in the later growth experiments. Due to the incongruent melting of the compound, slow growth rates $<0.4$\,mm\,h$^{-1}$ are preferable and gave the best results. In addition, lower growth rates facilitate the transport of oxygen gas from the environment to the growth interface to oxidize the iron (Fe$^{2+}\rightarrow$~Fe$^{3+}$), as is discussed in the next section. Higher growth rates lead to polycrystalline growth, and the crystal orientation during the growth experiment often changes. At low growth rate the $c$ axis is the prevailing growth direction. Occasional changes in growth orientation are clearly visible on the crystal surface of the grown rod because the $(001)$ planes of the delafossite are shiny and the others appear dull. This means that a crystal that is grown along $\left[001\right]$ should not have a shiny lateral surface. In contrast to recent observations during the growth of CuLaO$_2$ delafossite in pure argon \cite{Mohan14}, no outer ring containing Cu$^{2+}$ was observed in our experiments with CuFeO$_2$.
Fig.~\ref{fig:Xtal-1} shows a rod that was grown with a high growth rate of 1.1\,mm\,h$^{-1}$. In order to visualize the single crystalline regions and composition, the rod was sawn along its axis and investigated by EDLM. Elemental maps of the cross sections revealed a composition close to the stoichiometric of the grown material. Spatial mapping of a Bragg peak (EDLM), showed that only the tail end of the grown rod is a single crystal \cite{Guguschev15a}.
\begin{table}[ht]
\centering
\caption{OFZ growths experiments with CuFeO$_2$. $d$ -- rod diameter, $v$ -- growth rate, $P$ -- lamp power.}
\begin{tabular}{lcccl}
\hline
Grown Rod \# & $d$ (mm) & $v$ (mm\,h$^{-1}$) & $P$ (W) & remarks \\ \hline
1 & 6 & 1.1 & 1000 & Fig.~\ref{fig:Xtal-1} \\
2 & 8 & 0.55 & 1000 & Fig.~\ref{fig:Xtal-3}a) \\
3 & 8 & 0.4 & 1000 & Fig.~\ref{fig:Xtal-3}b) \\
4 \& 5 & 12 & 0.4 & 1500 & Fig.~\ref{fig:Xtal-4}, best results \\ \hline
\end{tabular}
\label{tab:OZF}
\end{table}
\begin{figure}[htb]
\includegraphics[width=0.70\textwidth]{Xtal-1}
\caption{a) CuFeO$_2$ grown rod \#1 (cf. Table~\ref{tab:OZF}). b) EDLM results of the same rod sectioned parallel to the growth direction.}
\label{fig:Xtal-1}
\end{figure}
The reduction of the growth rate to 0.55\,mm\,h$^{-1}$ and then to 0.4\,mm\,h$^{-1}$ resulted in significantly better crystal quality (Fig.~\ref{fig:Xtal-3}a) and b), respectively). With a growth rate of 0.4\,mm\,h$^{-1}$, the change in crystal orientation during the growth process could be avoided. Even though the $c$-axis is slightly tilted with respect to the growth direction (part of the lateral surface is shiny), the longest delafossite single crystal known to date was grown.
\begin{figure}[htb]
\includegraphics[width=0.70\textwidth]{Xtal-3}
\caption{a) CuFeO$_2$ rod \#2. b) CuFeO$_2$ rod \#3 (cf. Table~\ref{tab:OZF}).}
\label{fig:Xtal-3}
\end{figure}
\begin{figure}[htb]
\includegraphics[width=0.70\textwidth]{Xtal-4}
\caption{a) Unstable growth of CuFeO$_2$ in the initial growth state of rod \#5 (cf. Table~\ref{tab:OZF}). b) Single crystal part of the same rod.}
\label{fig:Xtal-4}
\end{figure}
The handling of larger diameters $\geq10$\,mm is more difficult because the surface tension of the larger melt zone is less stable, resulting in overflow (Fig.~\ref{fig:Xtal-4}a)). Stable growth became possible if the diameter of the growing rod did not exceed 10\,mm. Fig.~\ref{fig:Xtal-4}b) shows the separated single crystalline part of the grown rod, which is homogeneous without any shiny $(001)$ planes on the surface. This part has a size of 10\,mm in diameter and 23\,mm in length. Laue measurements at both cutting ends confirmed the segment of the rod to be a single crystal grown along the $c$-axis without any tilting. The crystal that was grown at a rate of 0.4\,mm\,h$^{-1}$ will be used as substrate material for the growth of PdCoO$_2$ films by molecular-beam epitaxy.
\section{Discussion}
Like other delafossites, CuFeO$_2$ is known to melt incongruently. This means the solid (with Cu:Fe = 1:1) is not in equilibrium with a liquid of the same composition. Typically the melting behavior is described to be peritectic, which means that upon heating in addition to melt with different composition some higher melting solid phase is formed. For CuAlO$_2$, $\alpha$-Al$_2$O$_3$ is the higher melting phase, and in some recent publications Fe$_2$O$_3$ is claimed to play this role for CuFeO$_2$ \cite{Zhao95b,Song16}. This assumption is, however, incorrect because Fe$_2$O$_3$ decomposes to Fe$_3$O$_4$ and cannot be treated as a stable component of the system. Instead Cu, Fe and O$_2$ should be chosen as system components, see e.g. Fig.~1 in Ref. \cite{Wolff19}.
More detailed FactSage \cite{FactSage7_4} calculations of the melting behavior of the Cu--Fe--O system are shown in Fig.~\ref{fig:PDs}. In the left phase diagram a fixed copper concentration of 52\,mol-\% is assumed, which is only a small Cu excess over Fe. On the right rim a ``melt'' phase field exists were the whole system forms a single copper-iron-oxide melt around $\log_{10}[p(\mathrm{O}_2)/\mathrm{bar}]\approx-2.5$. Upon cooling from this melt either Fe$_2$O$_3$ or Fe$_3$O$_4$ crystallizes first, depending on the oxygen fugacity. (For high $p_{\mathrm{O}_2}$ or high Cu excess the spinel Cu$^+$Fe$^{3+}_2$O$_4$ can also crystallize first.) The primary crystallization of iron oxide from Cu:Fe=1:1 mixtures was also observed experimentally (Fig.~\ref{fig:Xtal-1}) and depletes the melt of iron.
A thermodynamic assessment of the complete Cu--Fe--O system is beyond the scope of this paper. Such assessments have been provided by Khvan et al. \cite{Khvan11} and more recently by Shishin et al. \cite{Shishin13}. Irrespective of differences in the models that are used by these authors, they agree on several key points that are relevant for the current crystal growth experiments. First, at temperatures between 1100--1400 K the delafossite CuFeO$_2$ is stable only for medium oxygen fugacities $\approx10^{-7}-10^{-1}$\,bar, which overlaps well with the experimental conditions of this study. Second, the melt consists basically of Cu$^+$, Cu$^{2+}$, Fe$^{2+}$, Fe$^{3+}$ and O$^{2-}$. Minor amounts of Cu$^0$ and Fe$^0$ are present for metal-rich melts. Cu$^{3+}$, which was reported under very high oxygen pressure \cite{Schramm05}, can be neglected under the growth conditions we use in this study.
The authors of reference \cite{Shishin13} include several of the authors of the FactSage \cite{FactSage7_4} thermodynamic system, and consequently the FactSage calculations that are used in the present paper are in good agreement with both prior assessments \cite{Khvan11,Shishin13} --- except the circumstance that FactSage so far contains no data for Cu$^{2+}$ (CuO) in the melt. Nevertheless, under the growth conditions for CuFeO$_2$ the CuO content was found to be low, $<10$\% \cite{wolff_nora}, which agrees well with the literature (see Fig.~16 in Ref. \cite{Shishin13}). Consequently, these current FactSage calculations give a realistic description of the growth experiments.
The ``CuFeO$_2$+melt'' phase field has no connection to ``melt'' because the delafossite melts peritectically. Depletion of the melt by iron, however, shifts the Cu:Fe ratio towards larger values. In Fig.~\ref{fig:PDs}b) the Cu concentration is increased to 60\,mol-\% and this higher copper concentration leads to significantly lower liquidus temperatures. Between $1220^{\,\circ}$C and $1192^{\,\circ}$C both phase fields are directly connected and along this curve CuFeO$_2$ crystallizes first. In typical binary concentration vs. temperature ($x-T$) phase diagrams peritectics are horizontal (isotherm) lines in the diagram; this is not so here where $p(\mathrm{O}_2)$ influences the temperature where the solid crystallizes.
\begin{figure}[htb]
\includegraphics[width=0.49\textwidth]{PD_052}
\includegraphics[width=0.49\textwidth]{PD_060}
\caption{Predominance phase diagram of the system Cu--Fe--O$_2$ for a molar Cu concentration of a) 52\%; b) 60\%. The red (dashed) arrow at $\log_{10}[p(\mathrm{O}_2)/\mathrm{bar}]=-3$ is explained in Fig.~\ref{fig:cooling_06}.}
\label{fig:PDs}
\end{figure}
Fig.~\ref{fig:cooling_06} (which should be read from the right to the left) analyzes the crystallization path that is marked by a red dashed arrow in Fig.~\ref{fig:PDs}b). For the sake of simplicity, only the relative amounts (in moles) of Fe(II) oxide and Fe(III) oxide in the melt, the corresponding molar fraction of Fe$_2$O$_3$(melt), and the amounts (in moles) of solid CuFeO$_2$ and Cu$_2$O are shown. It is evident that above the $1202^{\,\circ}$C liquidus the amount of Fe$_2$O$_3$(melt) rises slightly at the expense of FeO(melt) because a lower temperature shifts the equilibrium to higher valency. The first solid to crystallize is thus CuFeO$_2$, which contains only Fe$^{3+}$. With cooling below $1202^{\,\circ}$C, not only does the fraction of Fe$_2$O$_3$(melt) decrease, but so does FeO(melt). Obviously additional free oxygen must be absorbed from the gas phase to oxidize FeO to Fe$_2$O$_3$, from which the delafossite finally forms. After passing the left boundary of the ``CuFeO$_2$+melt'' phase field at $1081^{\,\circ}$C, the melt disappears completely and solid Cu$_2$O + additional CuFeO$_2$ crystallize together. This corresponds to the eutectic point in a standard $x-T$ phase diagram.
Note that the oxygen fugacity $\log_{10}[p(\mathrm{O}_2)/\mathrm{bar}]=-3$ used for the calculation of Fig.~\ref{fig:cooling_06} is expected to be close to the true conditions used in the crystal growth experiments. In the ideal case, one can assume that 5N (99.999\%) Ar contains oxygen background impurities around $2\times10^{-6}$\,bar, which sets a lower boundary on the oxygen partial pressure used during growth \cite{Klimm05b}. The leaks in the growth chamber and out-gassing of chemicals and constructed parts will further increase the oxygen level. But even if the estimated oxygen fugacity is incorrect by one or two orders of magnitude, or if the database and our own thermodynamic values \cite{wolff_nora,FactSage7_4} that were used for the calculation of Figs.~\ref{fig:PDs} and \ref{fig:cooling_06} would be somewhat erroneous, the general topology is not significantly changed. Hence, these figures are expected to give a realistic model.
\begin{figure}[htb]
\includegraphics[width=0.70\textwidth]{cooling_06}
\caption{Crystallization of the Cu-Fe-oxide melt that is shown in Fig.~\ref{fig:PDs}b) under a constant oxygen fugacity of 1\,mbar: Even if only CuFe$^{3+}$O$_2$ starts to crystallize around $1200^{\,\circ}$C, the amount of Fe$^{2+}$O in the melt drops.}
\label{fig:cooling_06}
\end{figure}
Copper can exist in the melt with oxidation states $+2,+1$ and $0$, as shown in Fig.~6 of \cite{Wolff18}, but with recent thermodynamic data for copper oxide melts \cite{wolff_nora} one finds that, under the conditions of CuFeO$_2$ growth, $>90$\% of the copper atoms are Cu$^+$, which is the same valency as in the solid.
The importance of the gas phase to the crystal growth process is not restricted to the delafossite CuFeO$_2$; during the growth of the delafossite CuAlO$_2$, the gas phase is also significantly involved. Fig.~4 in our recent paper \cite{Wolff18} shows DTA/TG heating curves for several Cu$_2$O--Al$_2$O$_3$ mixtures, and the peritectic melting of CuAlO$_2$ can clearly be seen as an endothermic peak near $1230-1250^{\,\circ}$C for the samples with 6\% and 10\% Al$_2$O$_3$. The melting peak is always accompanied by a small mass gain. If Cu$^+$Al$^{3+}$O$_2$ melts, Al$^{3+}$ maintains its oxidation state. Cu$^+$ is partially oxidized to Cu$^{2+}$ because a deep eutectic (ca. 150\,K below the congruent melting point of pure Cu$_2$O) appears between Cu$_2$O and CuO where the melt is entropically stabilized \cite{Schramm05}. This means that upon cooling to achieve crystal growth, CuO must be partially reduced to Cu$_2$O, releasing free oxygen. Beyond the unfavorable position of the peritectic and eutectic points in this system, the permanent production of free oxygen at the phase boundary is detrimental to crystal growth. This is in contrast to the Cu--Fe--O system described here, because the necessary oxidation of Fe$^{2+}$ to Fe$^{3+}$ can be performed without the formation of gas. For the growth of CuFeO$_2$ the oxygen production that would result from Cu$^{2+}\rightarrow$\,Cu$^+$ reduction is likely compensated by the Fe$^{2+}\rightarrow$\,Fe$^{3+}$ oxidation. Indeed, during DTA/TG experiments, no mass change is observed during melting or crystallization, because the O$_2$ exchange with the atmosphere is insignificant. Another potential explanation for the lack of mass change could be the partial incorporation of Cu$^{2+}$ into the delafossite structure, which was observed e.g., for LaCuO$_{2.5+x}$ and YCuO$_{2.5+x}$ delafossites \cite{Cava93}. A significantly different oxidation behavior of Cu$^+$B$^{3+}$O$_2$ delafossites for different B$^{3+}$ ions was reported elsewhere \cite{Amrute13}.
\section{Conclusions}
Using the OFZ technique single crystals of CuFeO$_2$ with diameters up to 10\,mm are grown. These are the largest synthetic delafossite single crystals ever grown and have sufficient size and quality for the preparation of wafers for the epitaxial deposition of thin films of other functional delafossites. The growth is performed from stoichiometric rods prepared from 1:1 (molar) mixtures of Cu$_2$O and Fe$_2$O$_3$ in an argon atmosphere. The melting behavior of CuFeO$_2$ is almost peritectic, by which we mean that the material CuFeO$_2$ crystallizes from a melt that is enriched in Cu$_2$O/CuO. A low but significant oxygen fugacity ($\approx1$\,mbar) must be available in the growth atmosphere to oxidize Fe$^{2+}$, which is partially present in the melt, to Fe$^{3+}$ which is incorporated into the growing CuFeO$_2$ crystal. Hence, the melting behavior of CuFeO$_2$ is not simply peritectic (which would mean that two solid phases are in equilibrium with the melt). Rather the gas phase is also involved in the crystallization process, which makes crystal growth more complex and requires comparably low growth rates (cf. Table~\ref{tab:OZF}).
\section*{Acknowledgments}
A. Kwasniewski is acknowleged for performing X-ray powder analysis and Laue measurements. We are indebted to C. Guguschev who performed energy-dispersive Laue mappings and X-ray fluorescence spectroscopy and to S. Ganschow for continuous support of this work. The authors acknowledge funding by the German Research Foundation (DFG) under project SI 463/9-1. D.G.S. acknowledges funding provided by the Alexander von Humboldt Foundation for his sabbatical stay at the Leibniz-Institut für Kristallzüchtung and support from the U.S. Department of Energy, Office of Basic Sciences, Division of Material Sciences and Engineering, under Award No. DE-SC0002334.
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This division operates and maintains the Wastewater Treatment Plant. The plant staff is responsible for receiving, treating and disposing of the treated wastewater. The plant is continuously monitored to ensure it is in compliance of all Federal and State discharge requirements.
Provides preliminary, primary, and secondary treatment to domestic, commercial and industrial wastewater for the City of Gainesville.
Provides physical, biological, chemical treatment for wastewater to remove pollutants, disinfect, and produce and effluent, which is suitable and safe for reintroduction back into the natural stream environment.
The preliminary treatment is provided by the climber type bar screen to remove large items from the waste stream and a grit removal system.
Primary treatment facilities include sludge sedimentation in two primary clarifiers and sludge stabilization in two high rates, complete mix anaerobic digesters. The anaerobic digesters meet or exceed the Process to Significantly Reduce Pathogens (PSRP) in wastewater sludge. The sludge is dried on sand filter beds and spread on a Beneficial Land Use site permitted by the Texas Natural Resource Conservation Commission for that purpose.
Secondary treatment is achieved through the use of three high rate trickling filters and an activated sludge process. Final clarification is followed by disinfection with chlorine and de-chlorination with sulphur dioxide. The final effluent is used for the irrigation of the soccer fields in Kenetso Park and is discharged into the Elm Fork of the Trinity River. The Elm Fork is classified as a high aquatic habitat and contact recreation stream, which requires the treated effluent to be free of contaminants and have high levels of dissolved oxygen when discharged.
The Wastewater Treatment Plant is manned 24 hours a day 7 days a week by plant personnel.
For more information about the plant or to schedule a tour for your group please call (940) 668-4543.
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Review sparks global kidney study
Kidney failure shortens the life of affected people, reduces quality of life and is expensive to treat. Prevention is key, as relatively few treatments have been shown to be effective.
IgA Nephropathy, where abnormal activity of the immune system causes kidney damage, is one of the most common causes of kidney failure but no specific proven treatment is currently available. Affecting mostly young adults, IgA nephropathy is the most common primary glomerular disease worldwide, and many patients develop chronic, slowly progressive kidney injury.
A new systematic review led by Dr Jicheng Lv from The George Institute, China and the Peking University First Hospital included nine trials that involved over 500 patients with IgA nephropathy. Researchers investigated the role of steroids in preventing kidney failure. The review found that steroid therapy appeared to prevent kidney failure, but at a cost of a 55% higher risk of adverse events.
According to researchers the quality of existing trials assessed in the review was suboptimal, raising concerns about the robustness of the findings. The new results, which were published in the Journal of the American Society of Nephrology call for more high quality and reliable trials to be completed among IgA nephropathy patients.
For this reason, the authors from China, Australia, India, the UK, the United States of America and Canada are planning a global study of high-risk kidney patients, called the 'Therapeutic Evaluation of STeroids in IgA Nephropathy Global Study' (TESTING Study). The study will include 1300 people from around the world and follow them for five years, and assess whether steroids safely prevent kidney failure.
The TESTING study will provide data that will guide the treatment of IgA nephropathy patients globally. The study will engage with patients via hospitals in China initially, and study leaders are currently working to enrol additional centres from Australia, India and other countries around the world.
The first patients were enrolled in the study from the Peking University First Hospital in May 2012. Over coming years, a large number of additional patients will participate in the TESTING study, and will provide reliable and precise evidence about the effects of this promising intervention.
LV Jicheng
Professor Vlado Perkovic
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Cardiovascular disease—including coronary atherosclerosis and cerebrovascular disease, remains the number one cause of mortality in the United States. One out of three people in this country will die of cardiovascular causes. Although I can't say that the other top causes of mortality are particularly attractive--cancer, chronic lung disease, accidents and dementia—premature cardiovascular death can certainly be very devastating and it makes sense to do our best to prevent it.
In November 2013 updated guidelines for the treatment of high cholesterol were released by the American College of Cardiology-American Heart Association. These guidelines were the subject of significant controversy. In contrast to the previous guidelines from 2002, the current guidelines do not suggest treatment based primarily on numerical cholesterol targets. Rather, the guidelines stratify people according to determined cardiovascular risk and recommend either high intensity statin treatment, moderate intensity statin treatment, or no statin treatment. The guidelines do not support using other types of cholesterol-lowering drugs because at this point there is not good data to suggest that using other types of treatments is beneficial in terms of preventing actual cardiovascular outcomes (heart attack, stroke or cardiovascular death). This is despite the fact that there are treatments out there that do lower one's cholesterol numbers.
How is cardiovascular risk determined? With the new guidelines, a new risk calculator was proposed. In my clinical practice in the past I've used the Framingham Risk Calculator and the Reynolds Risk Calculator . The new risk calculator released with the 2013 guidelines is a bit different. Some experts have suggested that it overestimates risk. With the new risk calculator, if one's ten year risk of a cardiovascular event exceeds 7.5% then treatment with a statin is recommended.
Click here to calculate your risk. What qualifies as high intensity statin treatment? LDL lowering of 50% or greater. What is moderate intensity statin treatment? LDL lowering of 30-50%.
The guidelines suggest that particular statins may be better than others at achieving these goals and good outcomes: atorvastatin, simvastatin, and rosuvastatin. Other statins are typically used when patients experience unwanted side effects, like muscle pain.
How are things different with the new guidelines?
Let's take an example. A 71 year old white female, non-smoker, non-diabetic, with a history of hypertension, asked me whether or not she should be treated for high cholesterol. She is concerned about her risk of heart disease, as her mother had a stroke in her 60s and then sudden death, presumed cardiovascular, at age 83. My patient's most recent total cholesterol level was 204 mg/dL with an LDL level of 121 mg/dL and an HDL level of 64 mg/dL. A couple of years ago I calculated her Framingham Risk score, which is 6% with these risk factors. This represents low to intermediate risk. To get further information I also ordered a coronary calcium score, which was found to be zero. Last year, based on these numbers and the older guidelines, I recommended against treatment with a statin. However, now, based on the new risk assessment tool, the same patient has a ten year risk of 16%. With the new guidelines she would unequivocally qualify for moderate dose statin. At this point, I am not exactly sure what to do with the coronary calcium score, which probably projects that her risk is lower than the 16% that the new equation came up with. Nonetheless, I am not sure that coronary calcium scoring entirely predicts all cardiovascular risk—for example risk related to small vessel disease and stroke, so perhaps she should receive treatment. Low dose, statin treatment might be a good compromise here.
Interestingly, based on this new risk calculator virtually every 71 year old, even with optimal risk factors, would qualify for treatment with a statin. Herein lies the controversy with this tool.
Nonetheless, my own view of the new guidelines is mostly favorable. To me it simplifies things based on what we know from numerous well designed studies. Treatment, with an emphasis on statins, is based on risk projection and less attention is paid to absolute numbers. I hope that the next decade will continue to bring more a nuanced understanding of risk.
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Biochemistry, Genetics and Molecular Biology
Gene Structure Expression and Regulation
Advances in Molecular and Cell Biology
Biochemical Technology, Part A
Biochemical Technology, Part A, Volume 15
Authors: L. Bulow
Editors: B. Danielsson
Published Date: 6th May 1997
View all volumes in this series: Advances in Molecular and Cell Biology
Contents (Volume 15A). List of Contributors. Preface (K. Mosbach). Introduction. I Enzyme Technology. Enzymology- An Introduction (M. Mansson). Tailoring the Microenvironment of Enzymes in Water-Poor Media (B. Mattiasson, P. Adlercreutz, E. Wehtje, and M. Otamiri). Modification of Enzymes and Proteins with Bioimprinting Procedures (M. Mansson). A new kind of Abzymes Anti-Idiotypic Antibodies Exhibiting Catalytic Activities (A. Friboulet, C. Bedel-Cloutour, and D. Thomas). Modulation of the Catalytic Pathway of Carboxypeptidase a by Conjugation with Polyvinylalcohols (B. Solomon and L. Goldstein). Neural Networks in Enzymology (Y. Zhu, S. Linko, and P. Linko). Modern Enzymology of Plant Peroxidases (I.G. Gazaryan and A.M. Egorov). Capacity of the Yeast Trigonopsis Variabilis (DSM 70714) for the Enantioselective Reduction of Organosilicon Compounds (L. Fischer). Two-Step Sulfate-Enhanced Refolding: Recombinant Pneumocystis carinii Dihydrofolate Reductase (M. Goldberg, L.A. Greenstein, A. Levanon, and M.M. Werber). Marine Biotechnology based on Marine Microorgaisms (K. Sode, J.G. Burgess, and T. Matsunaga). Enzyme Engineering- Then and Now (P.W. Sundaram). Reflections on the History and Scientific Character of Biochemical Engineering (K. Buchholz). Part II Immobilized Catalysts. Immobilized Biocatalysts: an Introduction (S. Bimbaum). Biotransformations using Immobilized Biocatalysts-Past, Present, and Future (M.D. Lilly). Industrial Applications of Immobilized Biocatalysts and Biomaterials (I. Chibata). Preparation of Immobilized Proteins Covalently Coupled throught Silane Coupling Agents to Inorganic Supports (H.H. Weetall). Long-Term Stability of Continuously Perfused Animal Cells Immobilized on Novel Macroporous Microcarriers (H. Katinger, A. Assadian, G. Bluml, N. Borth, A. Buchacher, O. Doblhoff, T. Gaida, M. Reiter, C. Schmatz, K. Strutzenberger, W. Steinfellner, F. Unterluggauer, and N. Zach). Effects of Immobilization on the Catalytic Properties and Stabilities of Enzymes a Survey (B. Szajani, L. Boross, M. Abraham, and L.M. Simon). Characteristics of Laccase Immobilized on Different Supports for Wine-Making Technology (A. Lante, A. Crapisi, G. Pasini, A. Zamorani, and P. Spettoli). Lignin Peroxidase Production with an Immobilized Fungus Bioreactor (S. Linko and R. Haapala). Chelate Mediated Immobilization of Proteins (D. Kirstein). III Enzymatic Aspects of Cellular Metabolism. Enzymatic Aspects of Cellular Metabolism: an Introduction (L. Bulow). Are Substrates Channeled in the Krebs Citric Acid Cycle? (P.A. Srere, R.D. Brodeur, C.R. Malloy, A.D. Sherry, and B. Sumegi). Interaction between Chloroplast Phosphoglycerate Kinase and Glyceraldehyde-3-Phosphate Dehydrogenase (L.E. Anderson, X. Tang, G. Johansson, X. Wang, I.A. Marques, and J. Macioszek). Metabolic Control Analysis In Situ: Problems and Paradigms (G.R. Welch). Metabolic Engineering (J.E. Bailey). 'Togetherness'Between Proteins Generated by Gene Fusion (L. Bulow, H. Carlsson, P. Ljungcrantz, M. Persson, and C. Lindbladh). The Escherichia Coli Chaperone DnaK: Properties and Potentials (S. Enfors, K. Gustavsson, S. Yang, and A. Veide). Elicitation of Cultivated Plant Cells as a Tool in Biotechnology and Basic Biochemistry (P.E. Brodelius). Inhibition of Plant Growth by the Tetrapeptide Des-Arg Enterostatin VPDP (C. Erlanson-Albertsson and P. Albertsson).
In December 1992, the Department of Pure and Applied Biochemistry at the Chemical Center in Lund, Sweden, organized an international meeting, the Mosbach Symposium on Biochemical Technology, to celebrate the 60th birthday of professor Klaus Mosbach, one of the founders of modern biotechnology. The history of Pure and Applied Biochemistry had its start in 1970, a couple of years after the foundation of the Chemical Center. Klaus Mosbach has been its professor and head of Pure and Applied Biochemistry since its start. During the 1980's he also maintained a professorship at the ETH in Zürich, Switzerland.
Professor Mosbach is internationally well-known and he has world-leading position within the field of immobilization of bioactive substances and cells as well as affinity chromatography. In 1990, Professor Mosbach was awarded the gold medal by the Royal Swedish Academy of Engineering Sciences for his contributions to biotechnology, especially on the immobilization of bioactive substances.
The research activities of the Department of Pure and Applied Biochemistry cover a broad area, such as affinity and separation techniques, bioprocess control, biosensors, development of new carriers and new immobilization procedures for small molecules as well as proteins and cells, including animal and plant cells, gene technology, processes based on immobilized biocatalysts, and construction of organic polymers with enzyme-like properties. The hallmark of the department is its diversified research that generates considerable synergistic effects that are manifested by many new techniques and concepts emanating from the laboratory during the last 20 years. Several of these are marketed by various biotechnology companies. At this meeting we therefore arranged for some of the world's leading experts in biochemistry and biotechnology to give lectures. The topics covered comprise enzyme technology, immobilization of enzymes and cells, abzymes, metabolic engineering, biosensors, and molecular recognition.
The official gift from the symposium committee and the participants is this "Festschrift" which covers several important fields of research within the area of biochemical technology. We have made a very unusual approach and have let the "hero of the occasion" present the history of his research.
L. Bulow Author
Department of Pure and Applied Biochemistry, Chemical Center, Lund University, Lund, Sweden
B. Danielsson Editor
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Home / Homepage Feature / 2021 / December / 14 / Update: In-person exams, residence and testing
Update: In-person exams, residence and testing
In recent days we've seen news of other universities in Canada needing to shift their final exams from in-person to online, and reports of COVID-19 cases at one of our residence facilities at UBC Vancouver.
I understand that those developments and the uncertainty around the spread of the Omicron variant are deeply concerning for some of our community members. Particularly as we all observe other communities that are struggling with outbreaks of the newest variant, it is understandable that some members of our university community might have questions about the situation here at UBC.
I wish to reassure all members of the UBC community that the university is not currently seeing a spike in cases that present a risk to the health of our students, faculty and staff. Our situation is different from the universities that have needed to shift their exams to online. We have been assured by public health experts at Vancouver Coastal Health and Interior Health that it is safe for UBC to hold in-person exams on both campuses, given the control measures that are in place. Dr. Bonnie Henry, the Provincial Health Officer, and her team, are monitoring the post-secondary education sector closely. That being said, the university continues to work closely with Vancouver Coastal Health, Interior Health, and the Provincial Health Office to monitor the situation and we will adjust our approach when required. If we receive direction from public health experts to change our approach or introduce new control measures, we will of course advise our community immediately
As you may be aware, last week, out of an abundance of caution and in accordance with guidance and direction from Vancouver Coastal Health, Student Housing shared an exposure notice with all Totem Park residents. We have been assured by Vancouver Coastal Health that the number of cases at Totem is extremely low – so low in fact that the university cannot, for privacy reasons, disclose it, as doing so might identify the students affected. We've also been assured that the risk of transmission in Totem Park is low, as is the risk in classroom and examination settings.
As you know, UBC has provided rapid testing through the Rapid Testing Program for asymptomatic individuals who are unvaccinated, partially vaccinated or decline to disclose their vaccination status. I'm very pleased to note that the university is enhancing rapid testing on our campuses to include voluntary rapid testing for asymptomatic fully vaccinated students living in residence (excluding family housing). Testing for these fully vaccinated students will be by walk-in on both campuses and will run, at the UBC Vancouver campus, from December 15-22 and January 4-7, and at the UBC Okanagan campus, from December 15-17 and January 4-7. Starting in January we will be offering PCR testing on the UBC Vancouver campus for symptomatic students, faculty and staff. These measures will add a layer of protection and reassurance to our existing Rapid Testing Program and against potential transmission of SARS-CoV-2, the virus that causes COVID-19.
Finally, I know that exam periods are stressful for our students at the best of times. It's understandable that there is heightened anxiety as we head into exams and into the holidays. Please continue to take good care of yourselves and others and follow COVID-19 public health guidance so we can all stay safe and healthy. We are reminded that we must take extra care during the holiday season. Indoor social settings, where there are few or no public health controls in place, can lead to transmission of COVID-19, even among vaccinated people. Download your BC COVID-19 support app and complete your daily self-check with the BC COVID-19 self-assessment tool and best of luck with your exams.
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Home Top Global News Healthcare CDC identifies new COVID-19 syndrome in adults similar to MIS-C in kids,...
CDC identifies new COVID-19 syndrome in adults similar to MIS-C in kids, Report
Coronavirus Canada Updates: New Brunswick hits 75 per cent vaccination goal, reopening to begin Wednesday
Months after the discovery of a "multisystem inflammatory syndrome" tied to COVID-19 in children, health officials are warning that a similar condition can strike adults as well.
On Friday (October 2), the Centers for Disease Control and Prevention (CDC) released a report describing a "multisystem inflammatory syndrome in adults" or (MIS-A).
Like the syndrome in children, MIS-A is a severe illness that targets multiple organs and causes increased inflammation in the body, the report said.
And with both syndromes, many patients either test positive for SARS-CoV-2, the virus that causes COVID-19, or have antibodies against it, indicating a recent infection.
Currently, MIS-A appears rare, like its counterpart in children. The new CDC report identifies around two dozen cases of MIS-A.
Still, the new report, published in the CDC journal Morbidity and Mortality Weekly Report, urges doctors to consider a diagnosis of MIS-A in adults with compatible signs and symptoms.
"Ultimately, the recognition of MIS-A reinforces the need for prevention efforts to limit spread of SARS-CoV-2," the authors concluded.
Adult syndrome
Reports of a mysterious inflammatory syndrome in children first appeared in the spring, and doctors dubbed the condition MIS-C, or "multisystem inflammatory syndrome in children."
Children with this rare syndrome, which affects multiple organs and often requires hospitalization, can experience fever, abdominal pain, vomiting, diarrhea, neck pain, rash, bloodshot eyes, and fatigue, according to the CDC.
So far, the CDC has received reports of 935 cases of MIS-C in the United States, including 19 deaths. The official definition of MIS-C includes an age limit of 20 years old, and cases have been seen in children, teens and young adults.
Over the summer, there were reports of a similar syndrome popping up in adults. The new CDC report describes 27 cases of MIS-A from the United States and the United Kingdom.
Sixteen of these cases are described in detail, nine of which were officially reported to the CDC, and seven of which were described in published case reports.
Among the 16 cases, patients ranged in age from 21 to 50 years old. Just one case was reported in the UK, with the rest reported in the US, including cases in Maine, Florida, Louisiana, Georgia, New York, Massachusetts, and Texas.
Some adult symptoms were similar to those seen in children, including fever, gastrointestinal symptoms, and rash. Some patients reported chest pain or heart palpitations, and all had elevated levels of markers of inflammation.
All of the patients had either a positive COVID-19 test or positive antibody test. Ten patients required treatment in the intensive care unit, and two patients died, the report said.
The findings "indicate that adult patients of all ages with current or previous SARS-CoV-2 infection can develop a hyperinflammatory syndrome resembling MIS-C," the authors wrote.
The authors note that hospitalized patients with COVID-19 in general can experience inflammation and effects on organs beyond the lungs.
However, in most cases, those effects are accompanied by serious respiratory problems. However, with MIS-A, patients haven't shown serious respiratory symptoms. Of the 16 patients, half did not have any respiratory symptoms, and half had only mild ones.
Concerningly, of 22 patients in the study with information on race/ethnicity available, all but one patient belonged to a minority group.
"Long-standing health and social inequities have resulted in increased risk for infection and severe outcomes from COVID-19 in communities of color," the authors said.
A similar trend has been seen in children with MIS-C — more than 70 percent of reported U.S. cases have occurred in children who are Hispanic or Black, according to the CDC.
The underlying causes of MIS-C and MIS-A are not known. But 30 percent of adults in the current report and 45 percent of a sample of 440 children with MIS-C tested negative for SARS-CoV-2, but positive for antibodies against the virus, "suggesting MIS-A and MIS-C might represent postinfectious processes," the authors wrote.
Further research is needed to understand the exact causes of this condition and its long-term effects, they concluded.
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Probiotics have been found to be beneficial to host health. Their primary use in medicine has been for the management of intestinal tract problems. In recent years, probiotics have been used as a treatment to promote oral health. The aim of the present study was to review published studies regarding probiotics and their effects on the oral cavity. Studies reporting the anticariogenic effects of probiotics, their use in the treatment of periodontal disease, a reduced crevicular fluid volume and cytokine content, as well as their use in the treatment of halitosis and Candida albicans were identified. Studies assessing residence time of probiotics in the oral cavity were also selected for retrieval. Most authors concluded that the use of oral probiotics was associated with an improvement in oral health, including a significantly reduced level of cariogenic and periodontal pathogens and a lower crevicular fluid volume and cytokine concentration.
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Expression of teneurins is associated with tumor differentiation and patient survival in ovarian cancer
Rebecca Graumann,
Affiliation Center for Genetics and Genomics, Faculty of Medicine, Clínica Alemana-Universidad del Desarrollo, Santiago, Chile
Gabriella A. Di Capua,
Juan E. Oyarzún,
Current address: Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
Marcos A. Vásquez,
Current address: Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
Christine Liao,
Jorge A. Brañes,
Affiliation Division of Obstetrics and Gynecology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
Iván Roa,
Current address: Creative Bioscience, Santiago, Chile
Affiliation Division of Pathology, Clínica Alemana de Santiago, Santiago, Chile
Paola Casanello,
Affiliation Perinatology Research Laboratory, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
Alejandro H. Corvalán,
Affiliation Advanced Center for Chronic Diseases (ACCDiS), and UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile
Gareth I. Owen,
Affiliations Advanced Center for Chronic Diseases (ACCDiS), and UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile, Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile
Iris Delgado,
Affiliation Center for Epidemiology and Health Policies, Faculty of Medicine, Clínica Alemana-Universidad del Desarrollo, Santiago, Chile
Uwe Zangemeister-Wittke,
Affiliation Institute of Pharmacology, University of Bern, Bern, Switzerland
Annemarie Ziegler
* E-mail: [email protected]
Gareth I. Owen
Rebecca Graumann Gabriella A. Di Capua ... Annemarie Ziegler
Teneurins are a family of highly conserved pair-rule proteins involved in morphogenesis and development of the central nervous system. Their function in adult tissues and in disease is largely unknown. Recent evidence suggests a role for dysregulated expression of Teneurins in human tumors, but systematic investigations are missing. Here, we investigated Teneurin-2 and Teneurin-4 expression in various cancer cell lines and in ovarian tumor tissues. Teneurin-2 and Teneurin-4 were expressed in most of the breast cancer cell lines tested. Teneurin-4 was also detected in ovarian cancer cell lines, and throughout ovarian tumors and normal ovary tissue. Ovarian tumors with low Teneurin-4 expression showed less differentiated phenotypes and these patients had shorter mean overall survival. Similarly, Teneurin-2 expression correlated with overall survival as well, especially in patients with serous tumors. In the various cell lines, 5-Aza-cytidine-induced changes in DNA methylation did not alter expression of Teneurin-2 and Teneurin-4, despite the existence of predicted CpG islands in both genes. Interestingly, however, we found evidence for the control of Teneurin-2 expression by the oncogenic growth factor FGF8. Furthermore, we identified multiple transcript splicing variants for Teneurin-2 and Teneurin-4, indicating complex gene expression patterns in malignant cells. Finally, downregulation of Teneurin-4 expression using siRNA caused a cell-type dependent increase in proliferation and resistance to cisplatin. Altogether, our data suggest that low Teneurin-4 expression provides a growth advantage to cancer cells and marks an undifferentiated state characterized by increased drug resistance and clinical aggressiveness. We conclude that Teneurin-2 and Teneurin-4 expression levels could be of prognostic value in ovarian cancer.
Citation: Graumann R, Di Capua GA, Oyarzún JE, Vásquez MA, Liao C, Brañes JA, et al. (2017) Expression of teneurins is associated with tumor differentiation and patient survival in ovarian cancer. PLoS ONE 12(5): e0177244. https://doi.org/10.1371/journal.pone.0177244
Editor: Kwong-Kwok Wong, The University of Texas MD Anderson Cancer Center, UNITED STATES
Received: January 27, 2017; Accepted: April 24, 2017; Published: May 4, 2017
Copyright: © 2017 Graumann et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: This work was supported by grant N° 1100605 from the "Fondo Nacional de Desarrollo Científico y Tecnológico" (Fondecyt) (A.Z.), http://www.conicyt.cl/fondecyt/. The activities performed by A.H.C. were financed by a "Fondo de Financiamiento de Centros de Investigación en Areas Prioritarias" (FONDAP) grant N° 15130011, http://www.conicyt.cl/fondap/. Both funding sources depend from the "Comisión Nacional de Investigación Científica y Tecnológica" (CONICYT), from the Government of Chile (http://www.conicyt.cl/).
Teneurins (Ten-M/ODZ) are highly conserved pair-rule proteins with fundamental roles in embryonic development [1–4], in particular as regulators of neuronal pathfinding within the central nervous system [4–7]. Vertebrates possess four distinct teneurin genes (TENM 1–4), which encode related and highly conserved type II transmembrane glycoproteins of ∼300 kDa [4]. Expression of teneurin genes is tightly regulated in space and time to yield non-redundant patterns within the evolving nervous system and in regulatory sites of morphogenesis, such as the limb buds and developing eyes [8–10]. At the molecular level, Teneurins can undergo dimerization mediated by covalent bridging between adjacent cysteine residues in their extracellular domains [11]. This interaction is essential for homophilic binding during targeted recognition and selective cell-cell adhesion between neighboring neurons [12,13], a process that can guide neuronal connectivity and might drive neuronal regeneration. On the other hand, the intracellular domain (ICD) of some Teneurins can be cleaved upon homophilic interactions and translocate to the nucleus [14], where it could function in transcriptional control [15]. Further evidence has suggested a tight interplay between Teneurins and cytoskeletal components. Teneurin-1 (herein termed Ten-1) can interact with CAP/Ponsin [15], an adaptor protein involved in the regulation of actin polymerization [16]. As a result, Ten-1 ICD translocates to the nucleus and colocalizes with the methylation-dependent repressor MBD1, which is consistent with the postulated role of Teneurins in controlling gene expression. Additional data showed that disruption of the actin cytoskeleton can impair homophilic Teneurin binding [13] and, conversely, interference with Teneurin-mediated intercellular contact can impair microtubule and spectrin architecture during synaptogenesis [17]. Teneurins have also been implicated in the maintenance of basal membrane integrity [18]. Current data thus point to a functional interdependence of Teneurins and cytoskeletal components.
Impaired expression of Teneurins derived from germline alterations has been associated with phenotypes consistent with their essential role during embryogenesis. Hence, mice lacking Ten-3 showed localized visual impairments that limit binocular vision [19,20], and a similar phenotype was recently described for a Ten-2 knockout [21]. Concordantly, a homozygous null mutation in human Ten-3 was identified in a family with microphthalmia and visual defects [22]. Partial deletions affecting the TENM1 gene were further detected in a family with an X-linked lymphoproliferative disorder [23], although a definite genotype-phenotype relation could not be unambiguously established. Current findings are thus consistent with deleterious effects of Teneurin deficiency on specific morphogenetic processes. In contrast, it is currently not known which functions Teneurins may fulfill in adult tissues and if their expression remains essential at such stage. Likewise, a role for somatic changes has not been explored.
Using in silico analysis of transcriptomics data, we recently found evidence for altered expression of Ten-2 and Ten-4 in various tumor types [24], and expression of Ten-2 at the protein level has been detected in malignant pleural mesothelioma using a chemo-proteomic strategy [25]. Moreover, recurrent structural changes in the TENM3 gene have been identified in neuroblastoma, and low Ten-3 mRNA levels in these tumors were associated with shorter patient survival [26]. The authors proposed that alterations in Teneurins and other genes affecting neurite outgrowth could be associated with high-risk neuroblastoma. In spite of this data, studies systematically investigating the function of Teneurins in tumor formation and malignant progression are scarce and were all derived from incidental findings. Based on the above evidence, here we examined the expression of Ten-2 and Ten-4 in tumor cell lines of various histotypes and in ovarian tumor tissues and normal ovary tissue as control to delineate for the first time potential mechanisms of Teneurin regulation in human tumors. Furthermore, we investigated the effect of targeted Teneurin downregulation using siRNA on tumor cell proliferation and resistance to cisplatin.
Patients and tumor samples
The use of human tissue samples was approved by the Ethics Committees of all participating institutions involved in providing and/or analyzing the samples (Comité de Ética de la Investigación, Faculty of Medicine, Clínica Alemana—Universidad del Desarrollo, http://medicina.udd.cl/centro-bioetica/sobre-el-centro/comite-de-etica/; and Comité Ético-Científico, Faculty of Medicine, Pontificia Universidad Católica de Chile http://facultadmedicina.uc.cl/comite/comite.html). A total of 77 frozen samples (62 ovarian tumors, 10 benign lesions, and 5 normal ovaries) were included in the study, and for immunohistochemical detection of Ten-2, one frozen biopsy of a mammary tumor was used. All samples were obtained with written informed consent from patients with exception of 12 archived biopsies corresponding to previously deceased patients. To protect patient confidentiality, all samples were ciphered and handled anonymously. Clinical diagnosis was based on standard histological examination of biopsies by pathologists of the different participating centers.
Cell lines derived from breast (BT474, MCF7, MDA-MB231, T47D and ZR75), ovarian (Ovca420, Ovcar3 and Skov3), cervical (HeLa) and gastric (MKN45 and SNU1) cancer, and the neuroblastoma cell line SHSY5Y, were maintained in DMEM with 10% fetal bovine serum (HyClone, Thermo Scientific, South Logan, UT), 2 mM L-glutamine, and 40 μg/ml gentamicin, in a humidified incubator at 37°C with 5% CO2.
Analysis of gene expression
RNA purification and reverse transcription.
Cell line RNA was purified with the PureLinkTM RNA Mini Kit (Ambion, Carlsbad, CA) and concentrations were measured in a NanoDrop 2000 (Thermo Scientific, Wilmington, DE) spectrophotometer. RNA (500 ng) was reverse-transcribed in 20 μl using high performance MMLV reverse transcriptase (Epicentre, Madison, WI) according to instructions. For frozen tumors, 80–100 mg tissue in 1 ml chilled Trizol (Ambion) were homogenized on a Precellys-24 tissue lyser (Bertin Technologies, Montigny, France) 3 times 30 sec at 6500 rpm using 2.8 mm zirconium oxide beads. RNA integrity was evaluated by electrophoresis on 2% agarose gels. Reverse transcription of 400 ng RNA was performed in 20 μl using the High-Capacity cDNA Reverse Transcription kit (Applied Biosystems, Foster City, CA) as instructed. We previously optimized this system to warrant non-saturated, linear cDNA synthesis and amplification by real-time PCR [25].
PCR and real-time PCR.
Standard PCR reactions in 30 μl contained 1x Reaction Buffer (Bioline, Taunton, MA), 1.5–2.5 mM MgCl2, 200 μM of each dATP, dCTP, dGTP and dTTP, 0.2 μM of each forward and reverse primers, 0.75 U MangoTaqTM (Bioline), and 1 μl cDNA. Amplifications were performed in an Applied Biosystems 2720 thermal cycler. Quality of cDNA was checked by amplification of β2-microglobulin. Primer sequences are summarized in S1 Table. Selected PCR fragments were subcloned into the pGEM-T Easy vector (Promega, Madison, WI), and sequenced for identity confirmation (Macrogen, Seoul, Korea). For real-time PCR, predesigned TaqMan assays (Applied Biosystems) were used as instructed. Amplifications were performed in an Mx3005P thermocycler (Agilent Technologies, Santa Clara, CA) in 12 μl containing 1 μl cDNA. Real-time PCR data was analyzed with the MxPro software (Agilent) as described [27]. PCR reactions were performed in duplicates (cell lines) or triplicates (tumor tissues), and included two normalizing assays (GAPDH and B2M). TaqMan assays used were Hs99999907_m1 (B2M), Hs99999905_m1 (GAPDH), Hs00393060_m1 (TENM2), Hs01008081_m1 (TENM4), Hs00608023_m1 (BCL2), Hs004194392_s1 (BIRC5), Hs00234387_m1 (CASP3), Hs01018151_m1 (CASP8), and Hs00900055_m1 (VEGFA).
Methylation analysis.
Two applications were used for identification of CPG clusters in Teneurin genes. The first consisted on sequence analysis with the EMBOSS-CPGPlot program (http://www.ebi.ac.uk/Tools/seqstats/emboss_cpgplot/) using standard settings, the second used the more stringent Takai-Jones parameters [28]. For DNA demethylation, cultured cells were incubated for 72 h with 1μM 5-Azacytidine and gene expression was measured by RT-PCR as indicated above.
Gene silencing by siRNA transfection.
Cells were reverse-transfected in 24-well plates using siPORT NeoFX (Applied Biosystems) transfection reagent as instructed. In brief, 1 μl siPORT NeoFX and 2.5 μl Silencer Select siRNA (Ambion) were each diluted to 25 μl in Opti-MEM I medium (Gibco, Grand Island, NY) and mixed to 50 μl final volume after 10 min. The mixture was added to 40000 freshly trypsinized cells in 450 μl culture medium containing 2% FCS. Cells were incubated for 24–72 h without replacing the medium. Biological duplicates were performed for each treatment.
Cells grown on uncoated glass coverslips were fixed for 15 min in 3% paraformaldehyde. Endogenous peroxidase activity was quenched for 20 min in 0.1% H2O2, and cells were permeabilized for 5 min in 0.05% saponin (Calbiochem, La Jolla, CA). Immunohistochemical staining was performed using the Elite Universal Vectastain kit (Vector, Burlingame, CA) as instructed. Incubation with primary antibodies was done overnight at 4°C. Staining was visualized by 1–3 min incubation with 3,3'-diaminobenzidine (Vector). Cells were counterstained with hematoxylin and coverslips were mounted with Vectamount AQ (Vector). For one frozen biopsy, sections were fixed with acetone and stained following the same procedure, but using Vector Red (Vector) as chromogen. Staining was analyzed on an Olympus CX31 microscope and images were recorded on a ProgRes C3 (Jenoptik, Jena, Germany) digital camera. Primary antibodies were DOC4-T15 and DOC4-M17 (Santa Cruz Biotechnology, Dallas, TX) for Ten-4, and HPA038420 (Sigma-Aldrich, St. Louis, MO) for Ten-2.
Cell viability and cytotoxicity determinations
Cells in 96-well plates were seeded at 3000 cells/well and allowed to attach for 24 h at 37°C. For cytotoxicity measurements, cisplatin (Sigma-Aldrich) was added and incubation was continued for 48–96 h. Cell viability was determined using the MTS-based CellTiter 96® AQueous One Solution Cell Cytotoxicity Assay (Promega, Madison, WI) as instructed. Absorbance at 570 nm was read on a Phomo Autobio Microplate Reader (Autobio Labtec Instruments, Zhengzou City, P.R. China). All measurements were performed in triplicates. For concomitant treatment with siRNAs and cisplatin, siRNAs were added when plating cells as outlined above.
Statistics analysis
For real-time PCR and MTS, differences between mean values were analyzed by parametric comparison of independent means using the EPIDAT 3.1 software, with CI95% and considering equal variances. Overall survival was analyzed by Kaplan-Meier estimates and log rank tests using the SPSS version 21.0 (IBM SPSS Inc., Chicago, Illinois) software. Owing to the small case size, the threshold to rank teneurin expression as "high" or "low" was assigned to generate groups with comparable case numbers, which set the cut-off close to median teneurin values. The differences between teneurin mean values according to tumor differentiation, and mean survival in different patient subgroups, was analyzed by Student's t-test with P<0.05 regarded as significant.
Complex expression patterns of Ten-2 and Ten-4 in cancer cells
So far, expression of Teneurins in human tumors has been scarcely investigated. Using RT-PCR to screen a series of cell lines derived from breast, ovarian and cervix cancer, and from neuroblastoma, we could detect widespread expression of Ten-4 throughout most of these tumor cells (Fig 1A). In contrast, Ten-2 mRNA was primarily expressed in breast and cervix cancer and in neuroblastoma cells, and migrated as two discrete amplification bands (Fig 1A). Gastric cancer cell lines appeared to express these Teneurins at low to undetectable levels, which agrees with our previous observation based on search of the Human Protein Atlas repository [24]. The identity of all PCR products was validated by subcloning and sequencing, and confirmed that amplified sequences entirely matched those of predicted Ten-2 and Ten-4 transcripts (Genbank accessions NM_001122679.1 and NM_001098816.2, respectively).
Fig 1. Expression of Teneurins in tumor cells.
A, Expression of Ten-4 (TENM4), Ten-2 (TENM2) and EMX2 mRNA was analyzed in breast (BT474, MCF7, MDA-MB-231, T47D, ZR75), ovarian (Ovca420, Ovcar3, Skov3), cervix (HeLa), neuroblastoma (SHSY5Y), and gastric (MKN45, SNU1) tumor cell lines by RT-PCR. Amplification of Beta-2-microglobulin (B2-MG) was used as internal control. B, Immunohistochemical detection of Teneurins. Ten-2 staining was visualized with Vector Red chromogen in breast cancer tissue (a, b) and Ten-4 with 3,3'-diaminobenzidine (light brown staining) in Ovcar3 cells (c, d), at 40X (a, c, d) and 100X (b) magnification, respectively. Nuclei were counterstained with hematoxylin. Staining was absent in the negative control (c) when primary antibody was omitted. Arrow-heads mark punctuated peri-nuclear and cytoplasmic staining areas. The arrow points to Ten-4 enrichment at intercellular contact sites. C, Western blot analysis of Ten-4 in cell line extracts. The expected size of full-length Ten-4 is indicated by the arrowhead. A secondary band migrates at ∼120 kDa. Migration of the molecular weight standards is indicated at the left.
Consistent with transcript data, Ten-2 and Ten-4 protein expression could be visualized by immunohistochemistry in a breast tumor sample and in Ovcar3 ovarian cancer cells, respectively (Fig 1B). Immunoreactivity was mainly localized to perinuclear and cytoplasmic areas, and for Ten-4, sites of intercellular contact were also stained. This is concordant with validation results reported for the Ten-2 antibody used (The Human Protein Atlas, http://www.proteinatlas.org/ENSG00000145934), while surface staining was expected from the predicted subcellular localization of Teneurins and from previous immunostaining studies [29]. Cytoplasmic localization has also been reported for Ten-1 in papillary thyroid carcinoma [30]. Immunohistochemical anaylsis of additional cell lines is shown in S2 Fig and exhibited consistent staining patterns.
By Western blotting, full-sized Ten-4 (∼300 kDa) could be detected in SHSY5Y neuroblastoma cells, which had the highest Ten-4 transcript level among the cell lines tested (Fig 1C and S1A Fig). A secondary band was detected at ∼120 kDa in most cell lines, which is compatible with the band pattern specified by the manufacturer of this antibody and might correspond to a cleaved or alternatively spliced subspecies. This is in line with the multiple splice variants encountered during sequence-based verification of Teneurin amplification products. For Ten-2, we could identify a conserved splicing variant inserting 27 bp between exons 12 and 13 (Fig 2) [31], additional splicing variants involving the third and fourth exons, and an alternative translation initiation site within the second intron of the predicted TENM2 gene (S3 Fig). We termed it exon 1' since it was the first exon whose expression could clearly be confirmed in several cell lines that lacked detectable expression from predicted exons 1 and 2 (as defined in Genbank accession NM_001122679.1) (S1B Fig). Transcript variants were also identified for TENM4 (summarized in S2 Table). Taken together, these data confirm that Ten-2 and Ten-4 are expressed in human tumor cells. Expression patterns appear complex, with frequent coexistence of alternatively spliced transcript forms and concomitant presence of both Teneurins in some of the cell lines analyzed.
Fig 2. Identification of Ten-2 splice variant.
A, Position of PCR primers (arrowheads), expected amplification product (solid line), and 27 bp insert within the Ten-2 mRNA. Vertical lines denote predicted splice sites and rhombs mark the position of extracellular EGF-repeats. B, Ten-2 RT-PCR amplification products obtained in breast and ovarian cancer cells using primers outlined in A. The position of bands (400 and 427 bp) is marked at the right. C, Scheme showing site of alternative splicing, and sequence of 27 bp insert with predicted amino-acids based on predicted, in-frame ORF.
Since EMX2 is a transcription factor implicated in the control of Teneurin gene expression [32,33], we searched for evidence of a potential association of EMX2 and the Teneurins in tumor cells. As shown in Fig 1A, concomitant expression of Ten-4 and EMX2 was indeed observed in SHSY5Y neuroblastoma and in ovarian cancer cells, whereas Ten-2 and EMX2 showed an inverse expression pattern in HeLa and in breast cancer cells. These data indicate tissue-dependent expression patterns for EMX2 and the Teneurins in tumors. Although EMX2 and Ten-4 were coexpressed in some cell lines, additional tissue-specific regulation mechanisms must exist in tumors lacking EMX2 expression.
Prevalent expression of Ten-4 in benign and malignant ovarian tissues
The screening of cell lines revealed that Ten-4 was frequently expressed in breast and ovarian cancer cells (Fig 1A). Based on these findings, we analyzed Ten-4 expression in frozen biopsies of tumors, benign lesions and normal tissue derived from ovaries. The corresponding patient data are summarized in S3 Table. As in ovarian cancer cell lines, we could detect Ten-4 and concomitant expression of EMX2 mRNA in all tissue samples examined, independent of their histology and malignant condition (Fig 3). However, differences existed in transcript levels, as revealed by comparative assessment using real-time PCR (Fig 4A). For instance, mucinous tumors showed lower and borderline lesions higher Ten-4 mRNA (means -1.76 vs. 1.90, respectively; P < .001, t-test), a trend also detected for Ten-2 (means 1.20 vs. 3.79, respectively; P = .012; S4A Fig). For the entire group of measurements, mean cτ values were significantly higher for Ten-2 than for Ten-4 (means 29.04 vs. 23.49; P < .001). Although absolute quantification was not performed, this large difference suggests that Ten-2 transcript levels were comparatively lower than those of Ten-4, a finding compatible with the PCR measurements in cell lines (Fig 1A).
Fig 3. Expression of Ten-4 and EMX2 mRNA in ovarian tissues.
Ten-4 (TENM4) and EMX2 mRNA levels were analyzed by RT-PCR in ovarian tumors, benign lesions, and normal ovaries. Patient sample codes are indicated on top of the figure and the corresponding tissue types underneath. Beta-2-microglobulin (B2-MG) was used as internal amplification control. BLK, no-template negative control.
Fig 4. Detection of Ten-4 mRNA in ovarian tissues by real-time RT-PCR.
A, Ten-4 mRNA levels were analyzed in 77 ovarian samples corresponding to serous carcinoma (SC, shaded bars), mucinous tumors (MC, dark), endometroid tumors (E, lined), borderline tumors (Bo, white), benign lesions (Be, dashed), normal ovaries (N, grey), and stromal tumors (St, dotted bars). B, Based on grading, tumors were assigned into the well differentiated (GI, shaded bars, plus GII, white bars) or poorly differentiated (GIII, dashed bars, plus undifferentiated, dark bars) group, and plotted according to Ten-4 expression levels. Values were normalized to Beta-2-microglobulin content. Ten-4 ratios are expressed as log2 of fold-change and error bars indicate standard deviations for triplicate measurements. Fold-change was calculated using a benign lesion as calibrator.
To assess if expression of Teneurins was associated with clinicopathological parameters, we analyzed the larger subgroup of serous tumors. We found that Ten-4 mRNA levels were significantly higher in the group of well differentiated (Grades I + II) than in the group of less differentiated (Grade III + undifferentiated) tumors (means 1.63 vs. -0.83, respectively; P < .001, t-test) (Fig 4B). The same trend was observed for Ten-2. Although in this case the association was not significant (means 2.76 vs. 1.32, respectively; P = .078) (S4B Fig), removal of a single outlier value sufficed to achieve significance (P = .035), suggesting that association with tumor differentiation might also hold true for Ten-2.
Since loss of differentiation is a hallmark of increased malignancy and aggressiveness of cancer [34], we analyzed patient survival with regard to tumor differentiation and Teneurin expression. As expected, the mean survival was longer for patients with better differentiated (GI + GII) than with less differentiated (GIII + undifferentiated) serous tumors (51.6 vs. 24.2 months, respectively, P = .006, t-test), but the difference in overall survival was not significant (P = 0.203, log rank test). In contrast, decreased expression of Ten-2 was significantly associated with shortened overall survival in patients with any malignant ovarian tumor (Fig 5A), (P = .025), and highly significantly in the subgroup with serous carcinomas (Fig 5B), (P = .005). Mean survival was 50.0 vs. 23.8 months (low vs. high Ten-2, respectively, P = .008, t-test) for patients with serous carcinomas, and 48.5 vs. 30.2 months (P = .026) for patients with any malignant tumor. For Ten-4, decreased expression was associated with shorter mean survival in patients with serous carcinomas (49.7 vs. 21.4 months, low vs. high Ten-4, respectively; P = .004, t-test) or with any malignant tumor (47.5 vs. 29.5 months, P = .029). However, overall survival did not significantly differ between both groups (P = .105 for serous tumors, and P = .126 for any malignant tumor, log rank test), (S5 Fig). To obtain additional support for the observed trends, we used the Kaplan-Meier Plotter tool (http://kmplot.com/analysis/) to analyze overall survival of patients with serous ovarian carcinoma based on publicly accessible microarray expression data for Ten-4 and Ten-2. As in our study, cut-offs were set at median Teneurin values to generate comparable groups with high and low expression. Data from 1207 patients could be queried based on Ten-4 expression but only 523 patients had available data for Ten-2. As shown in S6 Fig, lower Ten-4 expression was significantly associated with shortened overall survival (P = 0.027) in patients with serous ovarian carcinoma. Although the same trend was observed for Ten-2, it did not attain statistical significance (P = 0.39). The latter was based on pooled results from several smaller patient cohorts, which suggests that additional data might be required for reliable analysis. Taken together, our data and the results obtained in silico show concordant trends and agree with recent findings recently reported for other cancers (see Discussion). In synthesis, we have shown a predominant expression of Ten-4 in human ovary and identify Ten-2 and Ten-4 as potential prognostic factors in ovarian cancer. In ovarian tumors, Teneurin transcript levels tend to decrease as differentiation is lost.
Fig 5. Kaplan-Meier survival curves according to Ten-2 expression levels.
Survival was analyzed for patients with any malignant ovarian tumor (A, n = 62) and for the subgroup with serous carcinomas (B, n = 40) by Kaplan-Meier estimates and log rank tests. Curves correspond to patients with low (solid lines) and high (dotted lines) Ten-2 expression levels. Owing to the small number of patients, the threshold to rank Ten-2 expression as high or low was assigned as to generate two groups of comparable size.
Control of Teneurin gene expression in tumor cells
Effect of DNA demethylating treatment.
Epigenetic changes are common in cancer and can contribute to dysregulated expression of oncogenic and tumor suppressor genes [35]. We thus sought for evidence of a methylation-mediated regulation of Teneurin gene expression. In effect, increased methylation of TENM3 upstream sequences had previously been reported in breast ductal carcinomas in situ [36], and sequence-based prediction of CpG clusters (see Materials and Methods) identified CpG-rich islands surrounding the predicted ATG transcription initiation site in the Ten-4 gene (S7 Fig). CpG clusters were also present in introns of both Ten-2 and Ten-4 genomic regions. In spite of this, demethylating treatment of breast, ovarian and gastric cancer cells with 5-Azacytidine (5AzaCy) failed to induce expression of Ten-2 or Ten-4 in cells lacking basal expression of either gene (Fig 6). This was consistent with results obtained by in silico analysis of transcriptomic data derived from Decitabine-treated breast and ovarian cancer cell lines (S4 Table). Methylation-mediated control of Teneurin expression might thus be constrained to the TENM3 gene or show tumor-dependent differences.
Fig 6. Demethylating Treatment of Cell Lines.
Breast and ovarian cancer cell lines were treated with 1μM 5-Azacytidine for 72 h. Expression of Ten-2 (TENM2) Ten-4 (TENM4), EMX2 and transketolase-like protein-1(TKTL1) mRNA was measured by RT-PCR (A) and real-time RT-PCR (B), expression of Beta-2-microglobulin (B2-MG) was used as internal amplification control and as normalizing assay, respectively. Real-time PCR ratios are expressed as relative change calibrated against the highest value in each group. TKTL1 was used as demethylation-responsive control gene. BLK, no-template negative control.
Control of Ten-2 gene expression by FGF8.
In cancer, FGF family members are involved in induction of autocrine cell growth [37,38] and some could be of prognostic value [39–41]. Previous experiments with chicken embryos demonstrated that Ten-2 gene expression can be induced by FGF8 [31]. We therefore tested the effect of exogenous FGF8 in Skov3 and Ovcar3 cells, which showed low endogenous expression of both FGF8 and Ten-2 (S8 Fig). As shown in Fig 7A, FGF8 induced a dose-dependent increase in Ten-2 mRNA in Skov3 cells, but showed an opposite effect in Ovcar3 cells, the latter achieving significance (P = .0131 and P = .0132, for 5 and 50 ng/ml FGF8, respectively, parametric comparison of independent means). FGF8 further induced a modest increase in proliferation in Skov3 cells (8% at 100 ng/ml FGF8, P = .0125), but a stronger opposite effect in Ovcar3 (Fig 7B) (P = .0017 and P = .0137, at 10 and 20 ng/ml FGF8 respectively). At 10 ng/ml FGF8, the difference in proliferation between both cell lines was highly significant (P = .0007). These cell lines do not harbor FGFR2 mutations that could impair receptor activation [42], but only Skov3 cells express the FGFR2-IIIc splicing variant involved in FGF8-mediated responsiveness [43,44] (S8 Fig). These data strongly suggest that expression of Ten-2 is responsive to FGF8 in ovarian cancer cells, but that effects are tumor-specific and might depend on particular FGFR isoforms and/or on other downstream signaling molecules.
Fig 7. Effect of FGF8 treatment on Ten-2 expression and on Proliferation.
A, Relative Ten-2 mRNA levels were measured by real-time RT-PCR in Skov3 and Ovcar3 ovarian tumor cells treated for 8 h with 0, 5 and 50 ng/ml FGF8b. Values were normalized to B2-MG content and ratios are expressed as relative change calibrated against the untreated control. GAPDH is included as housekeeping control gene. B, Skov3 and Ovcar3 cells were treated for 24 h with different doses of FGF8b, and cell viability was measured by MTS assay.
Effect of Teneurin down-regulation on cancer-relevant cell responses
The function of Teneurins in tumor cells is still completely unknown. We thus used RNA interference to reduce the expression of Ten-2 and Ten-4 in various cancer cell lines, and analyzed the effects on cell proliferation and on the expression of representative genes involved in apoptosis and angiogenesis. In different cell lines, siRNAs reduced Ten-2 and Ten-4 mRNA levels by 80–85% and by 70–90%, respectively, which however did not cause consistent effects on the expression of BCL2, BIRC5, CASP3, and CASP8 (S9 Fig). Similarly, VEGF mRNA levels were not significantly altered, although a potential role of Ten-4 in angiogenesis was previously suggested based on its immunolocalization in coronary and tumor blood vessels [45,46]. In contrast, we consistently measured a ∼20% increase in proliferation at 72 h in MCF7 and BT474 cells treated with Ten-4-specific siRNA, with the latter achieving significance (P = .0024, parametric comparison of independent means) (Fig 8A). These results suggest a potential of Ten-4 to affect tumor cell proliferation in a cell type-specific manner. Owing to the small magnitude of the effect, more stringent molecular tools for Teneurin depletion will be required to better assess the role of Teneurins on proliferation.
Fig 8. Effect of Teneurin down-regulation on Cell proliferation and cisplatin sensitivity.
A, Cells cultured in 96-well plates were treated for 72 h with 10 μM siRNAs or transfection vehicle, and cell growth was determined by MTS assay. Values were normalized to vehicle-treated cells and are expressed as relative absorbance. All measurements were performed in triplicates. Bars represent the mean of two biological replicates. Basal expression of Ten-4 was detected in all cells, and basal Ten-2 was detected in BT474 and Skov3, only. SiRNAs were targeted against Ten-2 (TENM2), Ten-4 (TENM4), or scrambled sequences (CN1). B, Skov3 cells in 96-well plates were treated for 48 h with 10 μM siRNAs and varying concentrations of cisplatin (CisPt), and the fraction of live cells was determined by MTS assay. All measurements were performed in triplicates. SiRNAs were directed against TENM2 (siTNM2), TENM4 (siTNM4), or a scrambled control sequence (siCN1); Vehicle, medium with transfection solution; Medium, untreated control. C, IC50 values were calculated using the GraphPad Prism® 6 (version 6.05) software, and mean values were plotted with the according standard deviations. Significance was analyzed by parametric comparison of independent means using EpiDat.
Previously, massive overexpression of Ten-2 was reported in a vincristine-resistant Skov3 breast cancer subline, although a causal relationship between Ten-2 levels and drug resistance was not assessed [47]. Here, we found that downregulation of Ten-4 in Skov3 cells for 48 h decreased the sensitivity to cisplatin (Fig 8B), with mean IC50 values of 8.83 μM and 12.01 μM for untreated and siRNA-treated cells, respectively (P = .0012, parametric comparison of independent means) (Fig 8C). The difference to vehicle- and scrambled-treated controls was also significant (P = .0036 and P = .0191, respectively). Similarly, downregulation of Ten-2 also decreased the sensitivity to cisplatin (IC50 = 11.12) compared to untreated (P = .0027) and vehicle-treated (P = .00135) cells, but not to scrambled siRNA treated cells (P = .175). Our data demonstrate, at least for Ten-4, that its downregulation has potential to increase resistance to anti-cancer drugs. Additional studies are warranted to explore the opposite condition of Teneurin overexpression and how it impacts on drug sensitivity.
The role of Teneurins in neuronal development has been vastly documented [48–50], but their appearance in the field of oncology is recent and their phenotypic contribution to tumorigenesis and malignant progression is unclear. We previously identified Ten-2 as a potential biomarker for malignant mesothelioma [25], and found evidence for dysregulated expression of Ten-2 and Ten-4 in other cancers through search of in the literature and by mining transcriptomics datasets [24]. Here we report for the first time that Ten-2 and Ten-4 are expressed throughout different tumor cell lines, and show that expression can be redundant and involve the simultaneous presence of complex splicing forms. For Ten-2, some cell lines showed no evidence for expression of predicted exons 1–2. Instead, transcriptional initiation occurred from an alternative ORF upstream of exon 3. This would alter the N-terminal, intracellular domain (ICD), potentially impairing phosphorylation-triggered signaling and conformational changes, or the reported transcriptional activity of the cleaved ICD [14]. In contrast, all Ten-2 transcript variants retained a histidine- and proline-rich SH3 domain in exon 4, which should preserve interaction with SH3-containing proteins such as the cytoskeletal adapter CAP/Ponsin [15]. This is relevant since interaction with cytoskeletal components seems crucial for proper Teneurin function [48], and has been reported in various model systems [12,15,51]. Similarly, we identified an intron-coded insert in Ten-4 predicted to add a proline-rich sequence to the ICD. This motif mediates recognition by proteins harboring SH3 or WW domains, many of which have been implicated in cancer [52,53]. It should be emphasized that an identical insertion was reported in murine Ten-4 isoforms (UniProt accessions Q3UHK6-2 and Q3UHK6-3, respectively). Such interspecies conservation was also confirmed by a Ten-2 splicing variant inserting 27 bp at the end of exon 12, which is highly homologous to a reported avian isoform of unknown functional significance [31]. Altogether, these data suggest a functional relevance of highly conserved Teneurin variants, which deserve further detailed characterization in tumors and other tissues to better understand the biology of these proteins and their impact in tumorigenesis.
As with their structural variability, the mechanisms controlling expression of Teneurins have not been studied in detail, except for the transcriptional activation by FGF8-mediated signaling and through the homeobox transcription factor EMX2 [31–33]. Here we found a striking and tissue-specific coexpression of EMX2 and Ten-4 in all ovary-derived tissues (n = 77) and cell lines (n = 3) analyzed. This agrees with the essential role of EMX2 in gonadal development [54], but among the Teneurins, only Ten-1 has been associated with organogenesis of the reproductive tract [18,55]. In fact, a concomitant increase of EMX2 and Ten-1 was recently reported in the endometrium of infertile patients with Müllerian duct anomalies, and the authors suggested a role for EMX2-mediated upregulation of Ten1 in this pathology [56]. This is highly reminiscent of the striking coexpression of Ten-4 and EMX2 observed in the ovary. Further, since EMX2 knock-out mice showed Ten-4 downregulation in the brain [32], a functional interaction between EMX2 and Ten-4 should be clarified in additional adult tissues, including those of the reproductive tract. In tumor cells derived from other tissues, Teneurins and EMX2 were not necessarily coexpressed. Our data thus support the existence of tissue-specific expression patterns and probably of distinct regulatory mechanisms. The same holds true for FGF8, which showed cell line-specific effects on proliferation and on Ten-2 expression, probably due to the presence of different FGFR2 isoforms or downstream signaling components. Such findings are not unusual and have been reported for other FGF8-mediated regulatory processes [57]. Since FGF family members display oncogenic actions [58] that can drive autocrine proliferation in cancers of the breast and ovary [37,59], the functional effects of FGF8 on Ten-2 expression in these tumors could be relevant for tumorigenesis and tumor growth, and therefore warrants further investigation. Finally, our data and in silico analyses do not support a methylation-mediated control of Ten-2 and Ten-4 gene expression in tumor cells, despite the presence of potential CpG-rich regions in both TENM2 and TENM4 genomic sequences. Methylation of TENM3 was reported in premalignant, non-invasive breast lesions, but functional consequences were not addressed in that study [36]. With regard to regulatory mechanisms, we thus conclude that EMX2 and FGF8 deserve an in-depth analysis in benign and malignant ovarian tissues, which will require additional approaches beyond the aims of this work. Further mechanisms controlling the expression of Teneurins under normal and malignant conditions remain to be identified.
Due to their structural complexity and tissue-specific expression, functional analysis of Teneurins in tumor cells will likely be less straightforward. In fact, our broad screen for effects of Teneurin depletion on the expression of representative read-out genes implicated in angiogenesis, cell survival or apoptosis, did not reveal significant changes in several cell lines tested. However, we could identify a consistent increase in proliferation rates upon reduction of Ten-4 in at least two cell lines (BT474 and Skov3). Moreover, the resistance of Skov3 cells to cisplatin increased upon Ten-4 downregulation. This is the second report that associates changes in Teneurin expression with an altered drug response in this cell line. Interestingly, Ten-2 transcript levels were increased >240-fold in vincristine-resistant Skov-3 cells. [47]. However, it was not assessed whether Ten-2 overexpression was causative of vincristine resistance or secondary to other alterations in these cells. Vincristine is a microtubule-destabilizing agent acting through a different mechanism than the DNA damaging drug cisplatin [60,61]. Teneurins might thus intervene differently in a drug-dependent manner. Also, opposing effects might compare to those of the adhesion molecule E-cadherin, whose expression decreases with transition to increased malignancy [62]. However, E-cadherin overexpression can occur as well and involves shedding of proteolytically cleaved domains with oncogenic properties, a process highly reminiscent of the C-terminal peptide (TCAP) spliced from Teneurins [63]. These issues will require intense additional investigation. It should also be noted that reductions in EMX2 have been associated with resistance to cisplatin in lung tumors [64] and have been proposed as a predictive marker of drug resistance [65]. Although we did not measure absolute EMX2 levels, it should be examined if reductions in EMX2 parallel those of Ten-4 in ovarian tumors and underlie potential resistance mechanisms to this drug.
In line with the above findings, we show that decreased expression of Ten-4 was significantly associated with loss of differentiation in serous ovarian carcinomas. This entirely agrees with reported roles of Ten-4 in the regulation of differentiation, both as a positive [66] and a negative modulator [67]. Our data implies that reduced expression of Ten-4 might relate to tumor dedifferentiation and increased proliferation, processes known to contribute to tumor growth, malignant progression and disease aggressiveness [34].
With regard to a prognostic relevance, we found that ovarian cancer patients with reduced tumor levels of Ten-2 had significantly shortened overall survival, and the trend was close to significant for those with low Ten-4. This entirely matches findings reported for neuroblastoma patients, where reduced Ten-3 expression in tumors was also associated with poor survival [26]. Further, two recent articles reported a prognostic impact of Ten-1 overexpression in papillary thyroid carcinoma and prolactin pituitary tumors, respectively [30,68]. In the former, Ten-1 overexpression was significantly associated with clinical indicators including an advanced stage and extrathyroidal invasion, and was thus proposed as a potential marker of disease progression. Accordingly, in pituitary tumors Ten-1 was upregulated in aggressive-invasive samples. Together, current evidence thus strongly supports the prognostic impact of Teneurin expression on patient survival, but it is evident that tissue-specific differences exist and that both under- and upregulated Teneurin expression can be of significance.
Considering the emerging association of Teneurins with malignancy, the question arises of potential somatic changes targeting the TENM genes. Up or downregulated Teneurin expression could be an indirect consequence of changes in other cancer-related genes, such as altered expression of EMX2 in some tumor types [64,69]. However, structural aberrations in the TENM3, TENM4 and TENM2 genes were identified in neuroblastoma [26,70], and in the case of Ten-4, expression of gene chimeras was demonstrated by RNA-Seq, strongly supporting a functional involvement of these aberrations in tumor development [70]. Such translocations were also reported in other tumors and tumor cell lines, although functional analyses were not performed [70–73]. Further, nonsynonimous Ten-4 mutations have recently been identified by WES in almost 50% of primary lymphomas of the central nervous system [74]. The fact that single nucleotide variants can impact on Teneurin function is supported by the association of germline changes with inheritable conditions. These include a null mutation of TENM3 in microphtalmia [22] and missense mutations of TENM4 in essential tremor [75]. Importantly, the latter study demonstrated that mutant Ten-4 species altered their localization pattern in the cell membrane upon transfection, and affected axonal guiding in a zebra fish model. This is a definite proof that pathogenic variants in Teneurin genes can be encountered in clinical conditions, and that somatic variants in tumors are likely to be identified in the near future. Further studies are mandatory to address all these upcoming issues.
In conclusion, our work is the first to purposely address Teneurin expression, regulation and biological functions in human cancer. We identified tissue-specific expression of Ten-2 and Ten-4 in tumor cell lines, and show complex and redundant expression of different Teneurin splicing variants. The widespread expression of Ten-4 in normal and malignant ovarian tissues deserves further investigation. The same holds true for the pending identification of mechanisms regulating Teneurin expression in tumors and other adult tissues. Importantly, evidence is accumulating of dysregulated Teneurin expression in several tumor types. Together with their reported prognostic impact, a functional contribution to tumorigenesis and malignant progression can be expected and should be studied further. Here we show that Teneurins are associated with patient survival in ovarian cancer, possibly due to a regulatory effect on tumor differentiation, cell proliferation and drug resistance.
S1 Fig. Additional RT-PCR data of Ten-1 and Ten-2 Transcripts.
A, Expression of Ten-2 (TENM2) and Ten-4 (TENM4) mRNA was measured by RT-PCR in cell lines indicated at the bottom. Data are normalized to Beta-2-microglobulin and ratios are expressed as relative change using Skov3 as calibrator. B, PCR analysis of expression of Ten-2 (TENM2) predicted exons 1 and 2, and alternative exon 1' in Skov3 and ZR75 cells. PCR was performed with internal primers for each exon. A human genomic DNA sample was used as positive amplification control (+CTRL) and amplification of Beta-2-microglobulin (B2-MG) was used to control for template quality.
S2 Fig. Immunohistochemical analysis of additional cell lines.
MCF-7 (A, B), SKOV3 (C, D), MDA-MB231 (E, F) and T47D (G, H) cells were subjected to immunohistochemical analysis for Ten-2 (F, H) and Ten-4 (B, D), respectively. Staining was visualized with 3,3'-diaminobenzidine and nuclei were counterstained with hematoxylin. All images were taken at 40X magnification. Staining was absent in the negative controls (A, C, E, G) when primary antibodies were omitted.
S3 Fig. Ten-2 mRNA splice variants detected in Skov3 ovarian cancer cells.
A, multiple Ten-2 amplification products obtained by RT-PCR between alternative exon 1' (GeneBank accession AK056053.1) and exon 4. The expected product size was 560 bp based on predicted splicing sites (GeneBank accession NM_001122679) and assuming expression of all encompassed exons, or 350 bp for a transcript lacking exon 3. B, Transcript variants identified by direct sequencing of PCR products depicted in Fig 1A. The corresponding transcripts and PCR products are labelled A-D in both figures. Primer sequences are summarized in S1 Table, transcript GeneBank accession numbers in S2 Table. Blk, no template control.
S4 Fig. Detection of Ten-2 mRNA in ovarian tissues by real-time RT-PCR.
S5 Fig. Kaplan-Meier survival curves based on Ten-4 mRNA levels in tumors.
Overall survival (OS) was analyzed for patients with serous ovarian carcinoma (A, n = 40) or with any malignant ovarian tumor (B, n = 62) by Kaplan-Meier estimates and log rank tests. Curves correspond to patients with low (solid lines) and high (dotted lines) Ten-4 expression levels.
S6 Fig. Kaplan-Meier survival curves based on analysis of expression arrays.
Overall survival for patients with serous ovarian carcinoma was analyzed using publicly accessible data for Ten-4 (A) and Ten-2 (B) expression with the Kaplan-Meier Plotter tool (http://kmplot.com/analysis/). Affymetrix expression data were based on available single probes 213273_at and 231867_at for Ten-4 and Ten-2, respectively. Cut-offs were set at median values to generate comparable groups with high and low Teneurin expression. For Ten-4, the complete patient set (n = 1207) could be queried. In contrast, TCGA data could not be evaluated for Ten-2 since the corresponding probe was not included in these data sets. Accordingly, data from 523 patients was used for Ten-2-based analysis. Numbers at the bottom of each figure represent patients alive at the corresponding measurement time.
S7 Fig. Distribution of CpG island clusters in human Ten-2 and Ten-4 genomic DNA and predicted transcripts.
Figures represent human Ten-2 genomic DNA (A) and predicted mRNA (B), and Ten-4 genomic DNA (C) and predicted mRNA (D), respectively. Prediction was done using the EMBOSS-CPGPlot application (http://www.ebi.ac.uk/Tools/seqstats/emboss_cpgplot/) with default parameters (length >200 bp; o/e ratio >0.6; C+G >50%; corresponding CpG clusters are indicated by black arrowheads and shaded boxes), and also applying the more stringent criteria of Takai-Jones (length >500 bp; o/e ratio >0.65; C+G >55%; clusters indicated by white arrows and dashed boxes). Blue bars represent predicted exons. The location of alternative exon 1' is marked by an asterisk. Blue arrowheads indicate transcriptional start (ATG) and end (TAA, TGA) sites, respectively.
S8 Fig. RT-PCR analysis of FGF8-mediated signaling components.
Shown are specific amplification products for Ten-2 (TENM2), FGF8 and FGF receptors (FGF-R) 1 to 4 in breast (BT474, MCF7, MDA-MB231, T47D, ZR75) and ovarian (Ovcar3, Skov3) cancer cell lines. Beta-2-microglobulin (B2-MG) was used as internal amplification control. PCR fragment size is indicated at the right. For FGF-R2, two isofoms were detected, showing the presence of a known splicing variant (amplified at 406 bp) in Ovcar3, MCF7 and T47D cells. Endogenous expression of FGF8 was prevalent in breast cancer cell lines. BLK, no-template negative control.
S9 Fig. Effect of Teneurin targeted siRNA treatment on the expression of selected genes.
Shown are representative results obtained with T47D breast cancer cells. Cultured cells in 24-well plates were treated for 72 h with transfection vehicle (V), or with 10 μM siRNAs directed at Ten-2 (TN2), Ten-4 (TN4), or scrambled sequences (CN1, CN2). Gene expression was measured by real-time RT-PCR. Values were normalized to expression of beta-2-microglobulin and are expressed as fold-change using vehicle-treated cells as calibrator. Ratios are expressed as relative change calibrated against the vehicle-treated control. All measurements were performed in duplicates. Bars represent the mean of two biological replicates. The genes measured are indicated on top of each graph. The higher variability of Bcl2 mRNA measurements is the result of very low basal expression in these cells. Comparable results were obtained with other cell lines (not shown).
S1 Table. Summary of PCR primers used in this study.
Primer sequences are listed in 5'-3' direction. Locations refer to exon numbers. The expected size of all amplification products was confirmed experimentally and by predictive in silico PCR (UCSC In-Silico PCR, http://genome.ucsc.edu/cgi-bin/hgPcr?org=Human). (*) Exon 1' corresponds to an alternative first exon identified in human Ten-2 transcripts in our work (see S1 Fig). A corresponding isolated cDNA clone had previously been reported (GeneBank accession AK056053.1) which has not been integrated into the predicted Ten-2 mRNA sequence (GeneBank accession NM_001122679).
(DOC)
S2 Table. GenBank accession numbers for Ten-4 and Ten-2 transcript variants identified in the Skov3 cancer cell line.
S3 Table. Summary of patient data.
S4 Table. In silico analysis of Ten-2 and Ten-4 gene expression in breast and ovarian cell lines treated with the demethylating agent 5-aza-2'-deoxycytidine (Decitabine).
Analysis of two large-scale profiling data sets (N. Matsumara et al. Genome Res. 2011, 21:74–82; and D.S. Shames et al. PLOS Medicine 2006, 3: e486). No significant changes (≥1.5-fold) were observed in transcript levels for Ten-2 (ODZ2) and Ten-4 (ODZ4) upon treatment of breast and ovarian cancer cell lines with 5-aza-2'-deoxycytidine (5-Aza-Cy). Gene probes are named according to previous gene designation, before introduction of TENM consensus nomenclature.
We are grateful to Soledad Lantadilla and Tamara Sánchez for technical assistance with isolation of tumor RNAs and immunohistochemistry, and to Gabriela Repetto for support with the supervision of participating students. Some of the cell lines used were kindly provided by Rolf Stahel (Switzerland), and by Paulette Conget and Marco T. Núñez (Chile).
Conceptualization: AZ JAB IR.
Data curation: GADC CL.
Formal analysis: ID UZ-W AHC.
Funding acquisition: AZ AHC.
Investigation: RG GADC JEO CL MAV AZ PC.
Methodology: RG GADC JEO CL MAV AZ.
Project administration: AZ.
Resources: AZ IR JAB GO.
Supervision: AZ.
Validation: AZ RG GADC JEO CL MAV.
Visualization: AZ.
Writing – original draft: AZ.
Writing – review & editing: AZ AHC GO UZ-W RG.
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Psychosocial Hazardous Neighborhoods Linked to Impaired Cognitive Function
Residing in a psychosocially hazardous neighborhood is associated with worse cognitive function in older age for persons with the apolipoprotein E ε4 allele (an alternative form of the gene), according to a report in the March issue of Archives of General Psychiatry, one of the JAMA/Archives journals.
"A prominent genetic factor of relevance to cognitive decline is the ε4 variant of the apolipoprotein E (APOE) gene, a strong predictor of increased risk and earlier onset of Alzheimer disease," the authors write as background information in the article. Apolipoprotein E is critical for basic neurological processes relevant to non-demented neurological health. "In the present article, we tested the hypothesis that living in psychosocially hazardous neighborhood environments may interact with APOE genotype to influence cognitive function."
Brian K. Lee, Ph.D., of Drexel University's School of Public Health, and colleagues analyzed data from the Baltimore Memory Study on 1,124 urban residents between 50 and 70 years of age to assess the association between living in a psychosocially hazardous neighborhood and cognitive function in aging. Patients were mostly white (53.8 percent) or African American (41.5 percent), and resided in any of the 63 Baltimore neighborhoods included in the study. Psychosocially hazardous neighborhoods are defined as areas that "give rise to a heightened state of vigilance, alarm, or fear in residents that may lead to a biological stress response."
Overall, 30.4 percent of participants possessed at least one ε4 allele, however the presence of the APOE ε4 differed by race/ethnicity, with 37.3 percent of African Americans ε4 positive compared with 24.7 percent of non-African Americans.
Before adjustment for outside factors (such as race, sex, wealth, etc.), participants living in the most psychosocially hazardous neighborhoods performed substantially worse in all seven cognitive domains tested (language, processing speed, eye-hand coordination, executive functioning, verbal memory and learning, visual memory, and visuoconstruction). In adjusted analysis with both neighborhood and APOE terms, persons living in the most psychosocially hazardous neighborhoods scored lower only on eye-hand coordination than other participants. APOE ε4 was associated with worse performance in executive function and visuoconstruction (ability to organize and manually manipulate spatial information, usually in the reproduction of geometric figures).
Compared with persons negative for APOE ε4 allele in less psychosocially hazardous neighborhoods, those who are negative for the allele and were living in the most psychosocially hazardous neighborhoods did not perform worse in any of the tested domains, nor did persons positive for APOE ε4 who were living in less psychosocially hazardous neighborhoods. However, persons positive for APOE ε4 living in the most psychosocially hazardous neighborhoods performed significantly worse than all three groups in processing speed, eye-hand coordination, executive functioning and visuoconstruction.
"Our findings provide evidence that among persons with the APOE ε4 allele, cognitive performance in processing speed and executive function was significantly worse for persons residing in neighborhoods with higher levels of psychosocial hazards, with additional suggestive evidence for eye-hand coordination," the authors conclude. Additionally, "for genetically vulnerable persons, a psychosocially hazardous neighborhood environment may be detrimental for cognitive function in aging."
(Arch Gen Psychiatry. 2011;68[3]:314-321. Available pre-embargo to the media at www.jamamedia.org.)
Editor's Note: This study was supported by grants from the National Institutes of Health and the Johns Hopkins Bayview Medical Center General Clinical Research Center. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.
JAMA/Archives Media Relations, 312/464-JAMA (5262) or [email protected]
Rich Ochab, Drexel University School of Public Health, 215-762-4732 or [email protected]
Niki Gianakaris, Drexel UniversityOffice of University Communications, 215-895-6741 or [email protected]
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Aquaculture is an activity producing fish or shellfish mainly for human consumption. It is carried out in ponds, enclosures or in open water bodies and thus involves continuous interaction with the environment. Aquaculture can be a sustainable activity, if it is carried out in socially and environmentally responsible manner, by adopting good aquaculture practices. Sustainable aquaculture means an aquaculture production system that operates in harmony with the environment and living systems, utilizing renewable resources as far as possible, providing living conditions to the animals as close to that of their natural habitats as well as in tune with the human and social environment of the locality. Sustainability can be achieved by adopting Better Management Practices (BMPs). BMPs involve legal compliance, social responsibility, good site selection and farm construction, good practices in farm management right from pond preparations to harvest and post harvest management activities. Adoption of BMPs would result in better production, productivity and returns on the one hand and environmental and social responsibilities on the other.
Pond preparation practices : To provide the shrimp with a clean pond bottom and good, stable water quality. a. Increase the water holding capacity of the ponds.
to reduce disease risks & to reduce the excessive reliance on water exchange, pond water holding capacity has to be increased maintaining water depth at minimum water level of 1.2 meter at the middle of the pond.
Complete draining of water helps in removing the disease carrying fish and crustaceans from previous crops in the pond. If it is not possible to drain the water follow wet preparation method.
Organic matter releases toxic gases like ammonia and hydrogen sulfide in the pond leading to stress or death of shrimps. Organic waste is in the form of layer on the soil with black color found in feeding area, corners, trenches and in the centre in ponds with aerators and should be checked for the presence of black layer when it is in wet condition. Make sure that the displaced organic waste does not enter the pond again through rain water. If it is difficult to completely remove the black soil, plough when it is wet and let it dry.
When the ponds cannot be dried farmers can follow wet pond preparation as given below.
After the ploughing drain out the water from the pond.
This will help in improving mineral content of the pond bottom especially in ponds with low soil fertility and ponds which are in culture for more than 10 years.
Spread the vermin compost/compost manure all along the pond bottom.
1. Use a soil pH meter to test the soil pH. Soil should be wet while using the equipment. The levels of lime application during pond preparation depends on the pH of the soil. Follow dosages given in the table below.
Spread the lime all along the pond bottom and along the slopes of the pond bund. A large proportion of the lime needs to be applied along the feeding areas and on the wet portions of the pond. When applying lime farmers/workers should wear face mask.If the soil pH is more than 7, there is no need of Lime application.
Water screening is very important in keeping the disease carriers away. If good water screening is followed, no need for further disinfectants. Use double layer of fine mesh filter net (60#) at water inlet point. Tie filter nets to the delivery pipe and it should be supported properly. Provide additional two layers of 80 mesh hapa below the inlet. Use of reservoir is recommended in the 3:1 ratio (pond area: reservoir area). Pond should be filled with water within 4 days. Foot valve should be placed in bamboo basket or metal cage and it should be covered with 20# mesh to prevent large animals getting in to inlet mesh.Do not use pesticides to disinfect or kill fish, shrimp and crabs in the pond. If necessary use Tea seed cake @ 10 PPM (50 kg/ha at 0.5 m water depth) to kill unwanted fish in the pond.
Plankton bloom is essential to successful shrimp culture. It shades the pond bottom and prevents the growth of benthic algae, provide the darker environment which the shrimp find less stressful. One week after the water is filled, normally bloom develops in vermicompost /compost manure applied ponds. 3. If the color of the pond water is clear,carry out chain dragging once a week which also helps in stabilizing the plankton bloom. Add 200kg of Dolomite per ha during sunny period. Apply 2 days fermented mixture of rice bran, jaggery and quality brewers yeast @ of 25kg+10kg+0.25 kg/ ha in doses for three days during the morning period. Spread the fermented mixture across the pond using floating device When the color of the water is green the pond is ready for stocking. If there are benthic or floating algae in the pond, remove them. The best approach is manual removal.
Do not heavily fertilize the water to get dark green water. It will reduce the oxygen in water during night time thus suffocating the shrimps. It is one of the reasons for lower survival rate of shrimp seeds. During the first month of culture whenever the water color intensity reduces (Secchi disc reading of more than 50 cm), add fermented mixture of rice bran, jaggery and yeast @ of 25kg+10kg+0.25 kg/ha. Do not carry out chain dragging from day of seed stocking until 45 DOC. After 45 DOC follow chain dragging of entire pond phased over 3 to 4 days at least once a week. Wherever possible run the aerators two hours every day.
Biosecurity in shrimp farming involves stocking disease free seed, pond preparation, water screening, prevention of entry of disease carriers, personal hygiene and sanitation. General biosecurity precautions that need to be established for each pond to help disease prevention and disease control are given below.
Ensure all farmers in the society implement these biosecurity measures while pond preparation so that it reduces the risk of disease. The objective is to create a fortress like condition at the pond to prevent entry of animals, predators and carriers whichm could pose disease risk.
Area surrounding the farm should be kept clean, should have a toilet in good sanitary condition, located 20 to 30 m away from farm area. must avoid contamination of domestic sewage , avoid use of animal manure. Provide the disinfect solutions like bleached water or KMnO4 in one container and plain water in another container at the entrance of each pond. Each pond should have a separate water sampling container. Farmers/workers should avoid getting in to ponds unless it is very necessary.
Selection and stocking of good quality and appropriate quantity of shrimp seed (PL) in to the pond is necessary.
Avoid wild seed and seed from poorly managed commercial nurseries. All the farmers in the area should stock the shrimp seed at the same time as per the crop calendar (within a period of one to two weeks) under contract hatchery system. from sources selling certified specific pathogen-free (SPF) stock or High health disease free seed from registered hatcheries.
PCR tested healthy seeds from healthy disease free tested brood stock should be procured from approved hatcheries complying norms. Shrimp seed should pass a salinity stress tests for salinity and formalin. Seeds of the same batch form a hatchery are to be packed with enough oxygen for optimum quantity based on the distance and time required and temperature maintenance.
Seed should be released in to pond after proper acclimatization during cool hours of the day, i.e., after 8 PM or before 8 AM. Make sure the plankton bloom is good and stable (green color water). Avoid stocking if pond has transparent water or dark green water.
Feed management is one of the most important aspects of successful shrimp production as the feed accounts for 50 to 60% of the operating cost. Feed should be fresh and of good quality and not more than 90 days old form date of manufacture. Ascertain Size and quantity of feed to be applied following the chart of the manufacturer. Reduce feeding during periods of low DO, plankton crash, rain fall, molting, extremes of temperature and during disease outbreaks. Install feed trays after 10 days of stocking and monitor the feeding from 20 days. Do regular sampling of shrimps once a week after 45 days to determine growth rate and to calculate FCR. Slightly under feeding is better than over feeding. Never mix any antibiotics with the feed. It is preferable to switch off the aerators just before feeding until 2 hrs after feeding, based on stocking density.
Store feed in clean, cool and ventilated area, well protected from sunlight keeping bags stacked neatly on pallets (no more than 10 bags per stack) 30 cm away from walls to prevent feed from being in direct contact with damp floor. Keep the store and outside premises clean and use traps to prevent rodents. Do not keep any fuel or liquid items in the feed store. It is important to protect feed bags from sunlight and rain, by storing them off the ground in simple, pond side storage sheds. During the rain proper care should be taken to prevent feed bags getting moist. Store the empty feed bags properly and recycle them by selling to traders.
To reduce risk of disease through contamination with the water from outside the farm follow the minimal water exchange system*. If water quality and the pond bottom are good, shrimps are healthy and growing well there is no need to exchange water. Plankton bloom is essential to successful shrimp culture. Avoid use of ground water.
Do not exchange or in-take water frequently. Starting third month, if necessary, water exchange can be done but try to minimize as low as possible. Do not release or in-take more than 10-20 cm (8 to 15%) of water per day. 4. It is recommended to use water for exchange from a reservoir wherever possible. If there is no reservoir, take the water in only when there is no disease contamination in water source. Do not exchange water when there is drainage from nearby disease affected pond. Wait for couple of days. Always follow good water screening as mentioned earlier. In early stages of culture (4 to 6 weeks) if the color of the pond water is clear, add fermented mixture of jaggery, rice bran and yeast @ of 25 kg+10kg+025 kg/ha to get bloom. If the water color is too dark, do not use any chemicals to kill the algae, instead change 10cm of top water, if you can during afternoon and intake during the night preferably at high tide. If you cannot, reduce/stop feeding during this period. To control water pH within the optimum range of 7.5-8.3, and limit diurnal pH fluctuation to less than 0.5, o If the pH is lower than 7.5 apply shell lime to increase the pH. High pH results from over liming and excess plankton bloom. If the pH is higher than 8.3, apply 50 litres of molasses or fermented juice of rice powder, jaggery and yeast to reduce the pH. 10. After every water intake / exchange and after rains, use agricultural lime. Agrilime (100 Kg/Ha) should be mixed with water and applied through out the pond. It acts as a buffering agent for water.
For optimum growth of shrimp maintain water quality parameters in the below given range.
Use aerators where stocking density exceeds 30,000/ha. The use of aerators in pond has a strong influence on the maximum yield that can be achieved from the pond.If concentrations fall below 4 ppm during night and early morning, use aerators. If oxygen levels deplete in the pond, shrimp will start swimming near the water surface especially during early morning period. Use one HP aerator for every increase in 400 kg of shrimp biomass in the pond. For biomass less than 500 kg in extensive ponds there is no need for aerators. Fix aerators at least 3 m away from the dyke. Maintain the aerators RPM 80 to 100. Aerator should be positioned correctly and operated efficiently to minimize pond dike erosion and suspension of pond bottom sediments The position and orientation (clockwise direction) of the aerators should encourage the maximum water flow within the pond adequate to concentrate waste in the centre of the pond and provide a clean feeding area. Aeration can be used while application of lime and fermented juice into the water. Stop aeration during feeding and chain dragging If for any reason of mismanagement or equipment failure the pond gets into 3 ppm dissolved oxygen levels, first increase mechanical aeration, and as the last choice perform (bottom) water exchange.
Presence of benthic, filamentous algae and hydrilla results in increased water pH, reduced minerals in water. If not removed, they will decay in the pond bottom and release toxic gases and become stressful shrimp. Do not use fertilizer in the ponds where benthic, floating algae or hydrilla present. Remove them manually without disturbing whole pond. Follow chain dragging during morning and remove benthic algae in the evening when it comes to the corners. If the water is transparent carry out chain dragging followed by application of fermented juice of rice powder, jaggery and yeast. After completion of removal apply dolomite to compensate for the loss of minerals. Maintain water level of 1.2 m throughout the crop period.
Pond contains lot of major and minor minerls naturally. In general they will be available in water source and also through various inputs. In shrimp farming especially in vananmei farming calcium and magnesium plays major role. Minerals in water can be verified through test kits or chemically at laboratories. What ever the farming system, an ratio of 1:3 of Ca:Mg to be maintained for vannamei farming.
Condition of the pond bottom has major effect on the shrimp where shrimp spend most of the time. Maintaining a healthy pond bottom is essential in all types of culture system. Check the bottom soil weekly for the presence of black soil or bad smell. If the soil is black or smells it means pond bottom has deteriorated. Avoid feeding in areas where the soil is black. Check the feeding rate, reduce the feeding rate for couple of days. Change 5-10 cm of bottom water while exercising precautions. Do regular Chain dragging at feeding areas to get organic matter oxidized. Chain dragging can also help to dislodge the benthic algae but this practice should not be applied to more than ¼ of the pond bottom in any one day. Fermented mixture should be applied immediately after the chain dragging. Take out accumulated benthic algae/black soil at the pond corners regularly. During routine application of Agri. lime to the pond, spread more lime in areas where the pond bottom is bad. Clean feeding area can be maintained with adequate number of properly positioned of aerators.
Check the health of shrimp in feed check trays on daily basis. If there is poor feed consumption for consecutive three to four days it indicates health problem of shrimp. Check the general health and growth of shrimp collected by cast net on weekly basis. Carry out sampling during early morning or late evening at different places. The shrimp should be clean with normal color, have a full gut and without any infection of legs or antennae. Gut content of >80% of the shrimp sampled from a healthy, recently fed pond should be full of food. If not it could be an indication of onset of disease. If there is antennae cut with out black tip, check under feeding. If the antennae tip is black it could be bacterial infection due to poor pond bottom. If the gills of shrimp are black it means that the pond bottom is not clean. Improve the pond bottom by adopting better pond bottom management practices. Check shrimp for external fouling-which is growth of organisms and accumulation of debris on the surface of the shrimp. This indicates poor pond condition. Improve water quality to encourage shrimp to moult regularly. Check if the shrimp have black spot- The causes include -Localized bacterial infections- eg. Vibrio sp. -Fungal infections, eg. Fusarium sp. -High nitrite levels -acidic water Solution- keep the feeding area clean. Vibriosis- Infection caused by bacteria of the genus Vibrio. -Shrimp at the side or surface of the pond –lethargy -lack of appetite -discoloration either red or blue Solution-Improve pond water quality. If sick/dark shrimp are found on the surface water then check if they have dirty or black gills. If so, reduce feeding and exchange cm of water exercising precaution. Check the pond daily during early morning hours for sick or dead shrimp or other signs (oxygen problems or any other unusual observations) and follow the disease management practices and inform all the society farmers.
Make sure total biosecurity including good water screening is maintained through out the crop period. Any problem during the crop like shrimp coming to the side, mortality should be immediately reported to all society farmers, farmers should be called to address the issue immediately. If there is antenna cut, fouling or gill problem–corrective measures to improve general pond condition should be carried out. If shrimp have white spots do not let water out and inform immediately all the farmers of society. Do not panic in emergency situation, co-ordinate with other farmers. All society farmers should implement agreed emergency action plan in case of white spot disease outbreak. If any serious infectious disease is detected which has the potential to spread widely the pond should be isolated, a. If the size of the shrimp is small, do not abandon/ drain the pond disinfect the affected pond with 20 ppm chlorine. Keep the water for one week with out discharge. If the size of the shrimp is harvestable, harvest all the shrimp with out draining the water. Disinfect the affected pond with 20 ppm chlorine. Keep the water for one week with out discharge. When the disinfected water is discharged after a week inform all society farmers and ensure water is not pumped in at least for two days. Put up bird net to prevent birds picking up dead shrimp and carrying it to other ponds. Care should be taken to collect all the shrimp in the pond to prevent contamination. Dead and affected shrimp would be buried under soil away from the pond area. Necessary precautions should be taken to avoid transfer of shrimp or equipments or anything used in the disease-affected pond to other ponds. Cooperation and communication with neighboring shrimp farmers and farm workers with regular meetings regarding disease problem should be practiced to minimize the spread of disease. Do not stop feeding the normal ponds during disease outbreak. With out feeding shrimp gets weak and susceptible for disease During disease situation, stay at farm and ensure there is no contamination from other workers and animals. Do not move any equipments from affected pond to other ponds. Wherever possible let farmers put up KMnO4 solution for washing hands, dipping legs, washing equipments etc.
To improve the freshness and quality of shrimp for the export markets following BMPs are suggested for harvesting and post-harvest handling of shrimps. Coordinate the harvest with the contract processor. Exchange 20% of the water one week before the planned harvest date. Immediately after water exchange apply agricultural lime (100-200 kg/ha) to the pond and pond bottom where it is more black especially in corners. Avoid harvest during the molting period (full moon or new moon). 2 days before harvest check if there are any newly molted shrimp, if newly molted shrimp are>10%, delay the harvest by a day or two. Do not exchange water or reduce water level 2 to 3 days before harvest. Do not feed the shrimp 6 hours prior to harvesting to keep the gut empty and improve the shelf life. Complete the harvesting process (draining and harvesting) within 6-8 hrs. between 6 PM to 6 AM. Avoid harvesting and packing shrimp during hot time of the day. Use the Drag net to harvest. Avoid using cast nets. If normal draining of the pond water is difficult, use artificial gates (made up of bamboo sticks or fish nets) in a corner at deeper side of pond for fixing the bag net. Use more pumps if necessary to complete the harvesting in time and to catch most of the shrimp with the bag net. Thoroughly wash the handpicked shrimps in clean water and pack them separately from bag net harvested shrimp. Do not use any chemicals while washing the shrimp or chill killing with out processors knowledge Make sure good quality ice is used (preferably from the processor) during harvesting and packing. Workers with wounds, open sores or skin infections should not handle harvested shrimps. Do not smoke or spit in packing area. Pack the shrimps in transport tubs (insulated boxes) with crushed ice:shrimp @2:1 ratio for better preservation. Load the packed crates quickly to the truck and send to the processing plant immediately without any delay. Ensure the insulated truck temperature is <50C.
Record keeping is a key component of managing shrimp farm efficiently. Records are necessary for identifying water quality problems, monitoring day-to-day activities, identifying and learning from past mistakes and for minimizing production costs. Society farmers should make use of NaCSA supplied pond record books to keep full records of following general management, key activities/events and parameters.
All the records must be kept safely for three years.
Involvement of farmer: In shrimp farming complete involvement of farmer in day today operations is very important as the shrimp farming needs more attention compared to other husbandry practices. Farmers must spend time in the farms at night and early morning hours.
Adequate Investment: Farmers must invest sufficiently in implementing BMPs and other crop activities to get successful crop. Part of the profit must be invested back in improving farming facilities.
Farm workers management: Employ local workers. Workers must be paid fair wages as per the national labor laws and essential facilities like proper accommodation, toilets, safe drinking water must be provided. Farm workers must be adequately trained in all practical aspects of BMP implementation. No child labor should be employed.
Personnel safety Workers must be trained in safe operation of pumps, motors, aerators and other electrical equipments. Care must be taken during water exchange. Farmers and farm workers should be aware of nearest hospital with anti venom in case of any snake bite. First aid facilities must be provided on site.
Harmony with neighbors: Good relationship with neighbors should be maintained. Traditional access route to public resources has to be maintained.
Farm Security: Adequate security must be provided to prevent theft during night hours.
Equipments Maintenance: All the farm equipments must be serviced and maintained regularly for smooth operation. In the off season all equipments must be serviced, painted wherever necessary and must be kept safely. Farmers should have backup generator in case of electricity failure.
Resource management: Rain water can be judiciously harvested and used in the farm. Solar lights can be made use of in the farm.
Waste Management: Farm premises must be kept clean, waste generated must be segregated and reused as much as possible and unused items must be disposed off properly. Fuels and lubricants should not be stored near feed, in employee housing or kitchen areas, or near harvest equipments.
Precautions during natural calamities: Adequate precautions must be taken prior to any natural calamity when there is advanced information available. Have emergency plan in place to face any natural calamity successfully.
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Blood filtration in patients with peripheral vascular disease
Authors: Winkenwerder, William | Adams, Kirkwood | Lineberger, Thomas | Johnson Jr., George
Affiliations: Departments of Surgery and Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, 27514
Note: [] Accepted by: Editor G.V.F. Seaman
Abstract: Erythrocytes must undergo considerable deformation to pass through the capillaries of the microcirculation. A decrease in the deformability of these cells could be especially detrimental to the patient with peripheral vascular disease (PVD). Experiments were designed to separate the filtration abnormalities of plasma versus the red cell in PVD patients. Polycarbonate filters 25 mm in diameter with 3 or 5 micron pores and a high porosity (4 × 105) were used. To study the effects of red cells without plasma, they were suspended in a sodium chloride tris buffer at a hematocrit of 0.5%. The filtrate was passed using only gravity and the results reported as the time in seconds for one milliliter to pass through the filter (FT). Forty-three PVD patients and 34 controls were studied. Suspensions of red cells in their native plasma at an hematocrit of 3.2% were studied to assess the influence of plasma factors. Matched blood types of patients and controls were also used in mixing studies on plasma and red cells. There was a small but significant increase in the FT of the PVD patient's RBC. However, acellular plasma of these patients showed marked prolongation of filtration time which could account for all of the changes found in whole blood. In the mixing studies the PVD plasma had a prolonged FT and the plasma from the control patients had a normal FT regardless of which red cells were being studied. Although the PVD patient's RBC may have a slightly prolonged FT, studies of acellular plasma and mixed samples demonstrate that the plasma is the main cause of the prolonged whole blood FT in the patient with PVD.
Keywords: Erythrocyte, deformability, peripheral vascular disease
DOI: 10.3233/CH-1982-2304
Journal: Clinical Hemorheology and Microcirculation, vol. 2, no. 3, pp. 201-207, 1982
Received 28 July 1981
Revision received 2 March 1982
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Beta-Derm is mainly used to reduce and treat conditions such as redness, itching, swelling and other skin conditions. Beta-Derm is a topical corticosteroid. Beta-Derm works by depressing the formation, release, and activities of various cells and chemicals that cause swelling, redness and itching of the skin.
However, Beta-Derm may also be used for other conditions as determined by the doctor. Consult your doctor before using this medication to be monitored. Do not use this medicine in case you are allergic to it or any ingredient in it. Consult the doctor if any of these conditions applies to you.
Beta-Derm dosage is administered in the form of topical: cream, ointment, lotion, gel and foam. The dosage should be administered as an intravenous infusion only. However, the dosage is dependent on the user and should be determined by the doctor only. The amount of dosage to be administered depends on the strength of the medicine and the condition of the patient. Note, overdose can lead to serious side effects.
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Facial cosmetics and attractiveness: comparing the effect sizes of professionally-applied cosmetics and identity
Jones, A.L. and Kramer, R.S.S. (2016) Facial cosmetics and attractiveness: comparing the effect sizes of professionally-applied cosmetics and identity. PLoS ONE, 11 (10). 0164218. ISSN 1932-6203
Full content URL: https://doi.org/10.1371/journal.pone.0164218
Jones & Kramer 2016.pdf
Jones & Kramer 2016.pdf - Whole Document
Forms of body decoration exist in all human cultures. However, in Western societies, women are more likely to engage in appearance modification, especially through the use of facial cosmetics. How effective are cosmetics at altering attractiveness? Previous research has hinted that the effect is not large, especially when compared to the variation in attractiveness observed between individuals due to differences in identity. In order to build a fuller understanding of how cosmetics and identity affect attractiveness, here we examine how professionally-applied cosmetics alter attractiveness and compare this effect with the variation in attractiveness observed between individuals. In Study 1, 33 YouTube models were rated for attractiveness before and after the application of professionally-applied cosmetics. Cosmetics explained a larger proportion of the variation in attractiveness compared with previous studies, but this effect remained smaller than variation caused by differences in attractiveness between individuals. Study 2 replicated the results of the first study with a sample of 45 supermodels, with the aim of examining the effect of cosmetics in a sample of faces with low variation in attractiveness between individuals. While the effect size of cosmetics was generally large, between-person variability due to identity remained larger. Both studies also found interactions between cosmetics and identity-more attractive models received smaller increases when cosmetics were worn. Overall, we show that professionally- applied cosmetics produce a larger effect than self-applied cosmetics, an important theoretical consideration for the field. However, the effect of individual differences in facial appearance is ultimately more important in perceptions of attractiveness.
Cosmetics, Judgment, Social Perception, Face perception, Attractiveness
C Biological Sciences > C830 Experimental Psychology
C Biological Sciences > C880 Social Psychology
https://www.scopus.com/inward/record.uri...
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Rocks, N.; Bekaert, S.; Coia, I.; Paulissen, G.; Gueders, M.; Evrard, B.; Van Heugen, J. C.; Chiap, P.; Foidart, J. M.; Noel, A.; Cataldo, D.
Curcumin-cyclodextrin complexes potentiate gemcitabine effects in an orthotopic mouse model of lung cancer
Br J Cancer
Bioware cell linesIVIS Imaging Systems
LL/2-luc-M38, LL/2-luc, Lewis Lung Carcinoma, IVIS
BACKGROUND: Overall clinical outcome for advanced lung cancer remains very disappointing despite recent advances in treatment. Curcumin has been reported as potentially active against cancer. METHODS: Owing to poor curcumin solubility, we have used cyclodextrins (CD) as an excipient allowing a considerable increase of aqueous solubility and bioavailability of curcumin. The effects of solubilised curcumin have been evaluated in cell cultures as well as in an in vivo orthotopic lung tumour mouse model. RESULTS: Cell proliferation was reduced while apoptosis rates were increased when lung epithelial tumour cells were cultured in the presence of curcumin-CD complexes. For in vivo experiments, cells were grafted into lungs of C57Bl/6 mice treated by an oral administration of a non-soluble form of curcumin, CDs alone or curcumin-CD complexes, combined or not with gemcitabine. The size of orthotopically implanted lung tumours was reduced upon curcumin complex administration as compared with treatments with placebo or non-solubilised curcumin. Moreover, curcumin potentiated the gemcitabine-mediated antitumour effects. CONCLUSION: Our data demonstrate that curcumin, when given orally in a CD-solubilised form, reduces lung tumour size in vivo. In vitro experiments show impaired tumour cell proliferation and increased cell apoptosis. Moreover, our data underline a potential additive effect of curcumin with gemcitabine thus providing an efficient therapeutic option for antilung cancer therapy.
PKI @ kd.modi @ 3
Gule, N. P.; Bshena, O.; de Kwaadsteniet, M.; Cloete, T. E.; Klumperman, B.
Immobilized furanone derivatives as inhibitors for adhesion of bacteria on modified poly(styrene-co-maleic anhydride)
Biomacromolecules
Bioware bacteria
Xen5, Xen 5, Pseudomonas aeruginosa
The ability of brominated furanones and other furanone compounds with 2(3H) and 2(5H) cores to inhibit bacterial adhesion of surfaces as well deactivate (destroy) them has been previously reported. The furanone derivatives 4-(2-(2-aminoethoxy)-2,5-dimethyl-3(2H)-furanone and 5-(2-(2-aminoethoxy)-ethoxy)methyl)-2(5H)-furanone were synthesized in our laboratory. These furanone derivatives were then covalently immobilized onto poly(styrene-co-maleic anhydride) (SMA) and electrospun to fabricate nonwoven nanofibrous mats with antimicrobial and cell-adhesion inhibition properties. The electrospun nanofibrous mats were tested for their ability to inhibit cell attachment by strains of bacteria commonly found in water ( Klebsiella pneumoniae Xen 39, Staphylococcus aureus Xen 36, Escherichia coli Xen 14, Pseudomonas aeruginosa Xen 5, and Salmonella tymphimurium Xen 26). Proton nuclear magnetic resonance spectroscopy ((1)H NMR), electrospray mass spectroscopy (ES-MS), and attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) were used to confirm the structures of the synthesized furanones as well as their successful immobilization on SMA. To ascertain that the immobilized furanone compounds do not leach into filtered water, samples of water, filtered through the nanofibrous mats were analyzed using gas chromatography coupled with mass spectroscopy (GC-MS). The morphology of the electrospun nanofibers was characterized using scanning electron microscopy (SEM).
Zhuang, H.; Jiang, W.; Zhang, X.; Qiu, F.; Gan, Z.; Cheng, W.; Zhang, J.; Guan, S.; Tang, B.; Huang, Q.; Wu, X.; Huang, X.; Hu, Q.; Lu, M.; Hua, Z. C.
Suppression of HSP70 expression sensitizes NSCLC cell lines to TRAIL-induced apoptosis by upregulating DR4 and DR5 and downregulating c-FLIP-L expressions
J Mol Med (Berl)
A549-luc-C8, A549-luc, IVIS, Bioware
Many cancer cell types are resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Here, we examined whether HSP70 suppression by small interfering RNA (siRNA) sensitized non-small cell lung cancer (NSCLC) cells to TRAIL-induced apoptosis and the underlying mechanisms. We demonstrated that HSP70 suppression by siRNA sensitized NSCLC cells to TRAIL-induced apoptosis by upregulating the expressions of death receptor 4 (DR4) and death receptor 5 (DR5) through activating NF-kappaB, JNK, and, subsequently, p53, consequently significantly amplifying TRAIL-mediated caspase-8 processing and activity, cytosolic translocation of cytochrome c, and cell death. Consistently, the pro-apoptotic proteins Bad and Bax were upregulated, while the anti-apoptotic protein Bcl-2 was downregulated. The luciferase activity of the DR4 promoter was blocked by a NF-kappaB pathway inhibitor BAY11-7082, suggesting that NF-kappaB activation plays an important role in the transcriptional upregulation of DR4. Additionally, HSP70 suppression inhibited the phosphorylation of ERK, AKT, and PKC, thereby downregulating c-FLIP-L. A549 xenografts in mice receiving HSP70 siRNA showed TRAIL-induced cell death and increased DR4/DR5 levels and reduced tumor growth. The combination of psiHSP70 gene therapy with TRAIL also significantly increased the survival benefits induced by TRAIL therapy alone. Interestingly, HSP27 siRNA and TRAIL together could not suppress tumor growth or prolong the survival of tumor-bearing mice significantly, although the combination could efficiently induce the apoptosis of A549 cells in vitro. Our findings suggest that HSP70 suppression or downregulation might be promising to overcome TRAIL resistance in cancer.
Oashi, K.; Furukawa, H.; Nishihara, H.; Ozaki, M.; Oyama, A.; Funayama, E.; Hayashi, T.; Kuge, Y.; Yamamoto, Y.
Pathophysiological Characteristics of Melanoma In-Transit Metastasis in a Lymphedema Mouse Model
B16-F10-luc2, Melanoma, B16F10-luc2, IVIS
In-transit metastasis (ITM) is a unique manifestation of intralymphatic tumor dissemination, characterized by the presence of melanoma cells between the primary lesion and the draining regional lymph node basin that is clinically associated with poor prognosis. In this study, we aimed to establish an experimental animal model of melanoma ITM, as research progress in this field has been hampered by a lack of suitable experimental models. We reproduced melanoma ITM in a mouse hind limb by transplanting melanoma cells into the footpad of a mouse with lymphedema (LE). The tumor cells at the ITM site were highly proliferative, and mice with ITMs were more likely than control mice to develop distant lymph node and lung metastases. Peritumoral lymphatic vessels and tumor-associated blood vessels were increased in the primary tumor site of the LE mice. Our established ITM melanoma mouse model enabled us to clarify the molecular determinants and pathophysiology of ITM. This ITM model is also comparable to the unfavorable clinical behavior of melanoma ITM in humans and, moreover, underlined the importance of lymphangiogenic factors in the tumor dissemination through the lymphatic system.Journal of Investigative Dermatology advance online publication, 6 September 2012; doi:10.1038/jid.2012.274.
PKI @ kd.modi @ 10
Domanska, U. M.; Timmer-Bosscha, H.; Nagengast, W. B.; Oude Munnink, T. H.; Kruizinga, R. C.; Ananias, H. J.; Kliphuis, N. M.; Huls, G.; De Vries, E. G.; de Jong, I. J.; Walenkamp, A. M.
CXCR4 inhibition with AMD3100 sensitizes prostate cancer to docetaxel chemotherapy
PC-3-luc2, Prostate Cancer, Bioware, IVIS
Several in vitro and in vivo models have revealed the key role of CXCR4/CXCL12 axis in tumor-stroma interactions. Stromal cells present in the tumor microenvironment express high levels of CXCL12 protein, directly stimulating proliferation and migration of CXCR4-expressing cancer cells. This specific prosurvival influence of stromal cells on tumor cells is thought to protect them from cytotoxic chemotherapy and is postulated as a possible explanation for the minimal residual disease in hematological and solid cancers. Therefore, CXCR4/CXCL12 signaling is an attractive therapeutic target in cancer, as proven in preclinical leukemia mouse models, where CXCR4 inhibition sensitized cancer cells to conventional chemotherapy. This study investigates whether inhibition of CXCR4 with the specific inhibitor AMD3100 sensitizes human prostate cancer cells to docetaxel. We showed that both mouse and human stromal cell lines have a protective effect on PC3-luc cells by promoting their survival after chemotherapy. Furthermore, we demonstrated that AMD3100 sensitizes PC3-luc cells to docetaxel. In a subcutaneous xenograft mouse model of human prostate carcinoma, we showed that a combination of docetaxel and AMD3100 exerts increased antitumor effect compared with docetaxel alone. We concluded that CXCR4 inhibition chemosensitizes prostate cancer cells, both in vitro and in vivo. To explore the relevance of these findings, we analyzed CXCR4 expression levels in human prostate cancer samples. We found that cancer cells present in bone metastatic lesions express higher CXCR4 levels relative to the cells present in primary tumors and lymph node metastatic lesions. These findings underscore the potential of CXCR4 inhibitors as chemosensitizing agents.
Lee, S.; Vinegoni, C.; Feruglio, P. F.; Fexon, L.; Gorbatov, R.; Pivoravov, M.; Sbarbati, A.; Nahrendorf, M.; Weissleder, R.
Real-time in vivo imaging of the beating mouse heart at microscopic resolution
Nat Commun
AngioSense
Real-time imaging of moving organs and tissues at microscopic resolutions represents a major challenge in studying the complex biology of live animals. Here we present a technique based on a novel stabilizer setup combined with a gating acquisition algorithm for the imaging of a beating murine heart at the single-cell level. The method allows serial in vivo fluorescence imaging of the beating heart in live mice in both confocal and nonlinear modes over the course of several hours. We demonstrate the utility of this technique for in vivo optical sectioning and dual-channel time-lapse fluorescence imaging of cardiac ischaemia. The generic method could be adapted to other moving organs and thus broadly facilitate in vivo microscopic investigations.
Carlisle, R.; Seymour, L. W.; Coussios, C. C.
Targeting of Liposomes via PSGL1 for Enhanced Tumor Accumulation
Pharm Res
IVIS, B16-F10-luc-G5, B16F10-luc-G5, B16-F10-luc, B16F10-luc
PURPOSE: To improve the delivery of liposomes to tumors using P-selectin glycoprotein ligand 1 (PSGL1) mediated binding to selectin molecules, which are upregulated on tumorassociated endothelium. METHODS: PSGL1 was orientated and presented on the surface of liposomes to achieve optimal selectin binding using a novel streptavidin-protein G linker molecule. Loading of PSGL1 liposomes with luciferin allowed their binding to e-selectin and activated HUVEC to be quantified in vitro and their stability, pharmacokinetics and tumor accumulation to be tested in vivo using murine models. RESULTS: PSGL1 liposomes showed 5-fold (p < 0.05) greater selectin binding than identically formulated control liposomes modified with ligand that did not contain the selectin binding domain. When added to HUVEC, PSGL1 liposomes showed >7-fold (p < 0.001) greater attachment than control liposomes. In in vivo studies PSGL1 liposomes showed similar stability and circulation to control liposomes but demonstrated a >3-fold enhancement in the level of delivery to tumors (p < 0.05). CONCLUSIONS: The technologies and strategies described here may contribute to clinical improvements in the selectivity and efficacy of liposomal drug delivery agents.
Chauhan, A.; Lebeaux, D.; Ghigo, J. M.; Beloin, C.
Full and broad-spectrum in vivo eradication of catheter-associated biofilms using gentamicin-EDTA antibiotic lock therapy
Xen31, Xen 31, MRSA, S. aureus, IVIS, Bioluminescence
Biofilms that develop on indwelling devices are a major concern in clinical settings. While removal of colonized devices remains the most frequent strategy for avoiding device-related complications, antibiotic lock therapy constitutes an adjunct therapy for catheter-related infection. However, currently used antibiotic lock solutions are not fully effective against biofilms, thus warranting a search for new antibiotic locks. Metal-binding chelators have emerged as potential adjuvants due to their dual anticoagulant/antibiofilm activities, but studies investigating their efficiency were mainly in vitro or else focused on their effects in prevention of infection. To assess the ability of such chelators to eradicate mature biofilms, we used an in vivo model of a totally implantable venous access port inserted in rats and colonized by either Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, or Pseudomonas aeruginosa. We demonstrate that use of tetrasodium EDTA (30 mg/ml) as a supplement to the gentamicin (5 mg/ml) antibiotic lock solution associated with systemic antibiotics completely eradicated Gram-positive and Gram-negative bacterial biofilms developed in totally implantable venous access ports. Gentamicin-EDTA lock was able to eliminate biofilms with a single instillation, thus reducing length of treatment. Moreover, we show that this combination was effective for immunosuppressed rats. Lastly, we demonstrate that a gentamicin-EDTA lock is able to eradicate the biofilm formed by a gentamicin-resistant strain of methicillin-resistant S. aureus. This in vivo study demonstrates the potential of EDTA as an efficient antibiotic adjuvant to eradicate catheter-associated biofilms of major bacterial pathogens and thus provides a promising new lock solution.
Pello, O. M.; Chevre, R.; Laoui, D.; De Juan, A.; Lolo, F.; Andres-Manzano, M. J.; Serrano, M.; Van Ginderachter, J. A.; Andres, V.
In Vivo Inhibition of c-MYC in Myeloid Cells Impairs Tumor-Associated Macrophage Maturation and Pro-Tumoral Activities
IntegriSense
Although tumor-associated macrophages (TAMs) are involved in tumor growth and metastasis, the mechanisms controlling their pro-tumoral activities remain largely unknown. The transcription factor c-MYC has been recently shown to regulate in vitro human macrophage polarization and be expressed in macrophages infiltrating human tumors. In this study, we exploited the predominant expression of LysM in myeloid cells to generate c-Myc(fl/fl) LysM(cre/+) mice, which lack c-Myc in macrophages, to investigate the role of macrophage c-MYC expression in cancer. Under steady-state conditions, immune system parameters in c-Myc(fl/fl) LysM(cre/+) mice appeared normal, including the abundance of different subsets of bone marrow hematopoietic stem cells, precursors and circulating cells, macrophage density, and immune organ structure. In a model of melanoma, however, TAMs lacking c-Myc displayed a delay in maturation and showed an attenuation of pro-tumoral functions (e.g., reduced expression of VEGF, MMP9, and HIF1alpha) that was associated with impaired tissue remodeling and angiogenesis and limited tumor growth in c-Myc(fl/fl) LysM(cre/+) mice. Macrophage c-Myc deletion also diminished fibrosarcoma growth. These data identify c-Myc as a positive regulator of the pro-tumoral program of TAMs and suggest c-Myc inactivation as an attractive target for anti-cancer therapy.
Sehrawat, A.; Arlotti, J. A.; Murakami, A.; Singh, S. V.
Zerumbone causes Bax- and Bak-mediated apoptosis in human breast cancer cells and inhibits orthotopic xenograft growth in vivo
Breast Cancer Res Treat
MDA-MB-231-D3H1, MDA-MB-231-luc-D3H1, IVIS, Bioware, Breast Cancer
The present study was undertaken to determine the anticancer efficacy of zerumbone (ZER), a sesquiterpene from subtropical ginger, against human breast cancer cells in vitro and in vivo. ZER treatment caused a dose-dependent decrease in viability of MCF-7 and MDA-MB-231 human breast cancer cells in association with G(2)/M phase cell cycle arrest and apoptosis induction. ZER-mediated cell cycle arrest was associated with downregulation of cyclin B1, cyclin-dependent kinase 1, Cdc25C, and Cdc25B. Even though ZER treatment caused stabilization of p53 and induction of PUMA, these proteins were dispensable for ZER-induced cell cycle arrest and/or apoptosis. Exposure of MDA-MB-231 and MCF-7 cells to ZER resulted in downregulation of Bcl-2 but its ectopic expression failed to confer protection against ZER-induced apoptosis. On the other hand, the SV40 immortalized mouse embryonic fibroblasts derived from Bax and Bak double knockout mice were significantly more resistant to ZER-induced apoptosis. ZER-treated MDA-MB-231 and MCF-7 cells exhibited a robust activation of both Bax and Bak. In vivo growth of orthotopic MDA-MB-231 xenografts was significantly retarded by ZER administration in association with apoptosis induction and suppression of cell proliferation (Ki-67 expression). These results indicate that ZER causes G(2)/M phase cell cycle arrest and Bax/Bak-mediated apoptosis in human breast cancer cells, and retards growth of MDA-MB-231 xenografts in vivo.
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Psychological and educational interventions may prevent anxiety.
Frequent cannabis use was shown to be associated with an increased risk of major depressive disorder and suicidal ideation.
Mixed state does not increase the risk for suicidal behavior beyond the risk associated with the depressive component.
Psychosis in patients with bipolar disorder was not associated with worse clinical or functional outcomes.
Binge-eating disorder relapse risk with lisdexamfetamine was markedly lower than with placebo.
Major depressive disorder and alcohol dependence share common genetic factors.
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The average pay for a Compliance Coordinator is €40,788 a year and €20 an hour in Finland. The average salary range for a Compliance Coordinator is between €29,947 and €49,704. On average, a Bachelor's Degree is the highest level of education for a Compliance Coordinator. This compensation analysis is based on salary survey data collected directly from employers and anonymous employees in Finland.
Coordinates all internal and external changes associated with products or services, typically in a health plan or within a medical facility or institution, to assure legal compliance with regulatory guidelines.
Organizes compliance communications and audits.
Supports management in monitoring compliance procedures covering the privacy of access to patient health information.
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Governments require high-quality scientific evidence to prioritize resource allocation and the cost-of-illness (COI) methodology is one technique used to estimate the economic burden of a disease. However, variable cost inventories make it difficult to interpret and compare costs across multiple studies.
A scoping review was conducted to identify the component costs and the respective data sources used for estimating the cost of foodborne illnesses in a population. This review was accomplished by: (1) identifying the research question and relevant literature, (2) selecting the literature, (3) charting, collating, and summarizing the results. All pertinent data were extracted at the level of detail reported in a study, and the component cost and source data were subsequently grouped into themes.
Eighty-four studies were identified that described the cost of foodborne illness in humans. Most studies (80%) were published in the last two decades (1992–2012) in North America and Europe. The 10 most frequently estimated costs were due to illnesses caused by bacterial foodborne pathogens, with non-typhoidal Salmonella spp. being the most commonly studied. Forty studies described both individual (direct and indirect) and societal level costs. The direct individual level component costs most often included were hospital services, physician personnel, and drug costs. The most commonly reported indirect individual level component cost was productivity losses due to sick leave from work. Prior estimates published in the literature were the most commonly used source of component cost data. Data sources were not provided or specifically linked to component costs in several studies.
The results illustrated a highly variable depth and breadth of individual and societal level component costs, and a wide range of data sources being used. This scoping review can be used as evidence that there is a lack of standardization in cost inventories in the cost of foodborne illness literature, and to promote greater transparency and detail of data source reporting. By conforming to a more standardized cost inventory, and by reporting data sources in more detail, there will be an increase in cost of foodborne illness research that can be interpreted and compared in a meaningful way.
Foodborne illnesses are an important public health problem worldwide . The World Health Organization (WHO) has created an initiative to estimate the global burden of foodborne illnesses, and they have stated that the achievement of certain Millennium Development Goals are being directly compromised due to foodborne illness [2, 3]. However, governments have finite resources with which to address the health of their populations, and thus require high-quality scientific evidence to prioritize resource allocation. Accurate burden of illness estimates are useful for decision makers seeking to allocate resources to address the issues caused by foodborne pathogens [4, 5]. The cost-of-illness (COI) methodology is one technique used to estimate the economic burden of a disease . However, there is concern in the scientific literature that COI estimates are limited in usefulness, due to variability in their execution (e.g., varying cost inventories and study methodologies), and a lack of transparency and detail when describing such methodologies. Of particular concern are the differing cost inventories being used when estimating the cost of foodborne illnesses [7–10].
The COI approach traces the flow of resources associated with adverse health outcomes through the quantification of measurable individual and societal level costs [7, 11, 12]. Costs at the individual level are divided into direct and indirect costs. Direct costs represent the value of goods, services, and other resources consumed in providing care due to an illness . These include medical care expenditures associated with the diagnosis, treatment, and management of a disease in an individual. Indirect costs represent productivity losses due to illness or death and intangible costs such as pain and suffering. Costs associated with overhead activities that are shared amongst individuals and expenditures incurred in the process of seeking care are also indirect costs. Operational expenditures for healthcare facilities and personal transportation costs are examples of indirect costs . Costs incurred at the population level are deemed societal costs [8, 9, 12], which are costs that cannot be completely attributed to an individual's illness but can be incurred when a person or a group of people become ill . Societal costs primarily include expenditures incurred by industry and government . Component costs are the specific costs that make up the above categories, and all of the costs included in a COI estimate comprise the cost inventory for that particular study .
Many studies employing a COI methodology have demonstrated that foodborne illnesses generate a considerable disease burden and economic loss . According to the United States Department of Agriculture (USDA), foodborne illness costs the United States economy between $10-83 billion United States dollars (USD) per year . In Australia and New Zealand, the cost of foodborne illness has been estimated at $1.289 billion and $86 million USD respectively per year [14, 19]. In Europe, the annual cost of foodborne illness was estimated to be $171 million USD in Sweden and $2 million USD in Croatia . Many estimates for specific foodborne pathogens, or groups of pathogens, have been published [4, 21, 22]. Although economic estimates for foodborne illness have not been completed in Canada in the past 20 years , it has been recently estimated that 4 million episodes of domestically acquired foodborne illness occur annually in Canada .
Research has indicated that COI studies employ varied methodological approaches, and that there is little consistency in the cost inventories used in the COI literature [7–10]. This is an issue when interpreting and designing new COI studies, and also when comparing existing estimates for the same illnesses. When designing a study, it is difficult to determine which types of costs to include (e.g., direct, indirect, societal), which component costs in those categories to include (e.g., treatment costs, productivity losses, industry costs), and the level of detail by which costs should be estimated (e.g., which types of treatment or industry costs to include). It is also challenging to interpret or compare estimates without fully understanding which component costs were included in a study. Another concern is the lack of transparency when describing how specific component costs were estimated and the data sources being used for such estimates [8, 25, 26].
To investigate the reporting of component costs in the cost of foodborne illness literature, along with their relevant data sources, a review of the evidence is needed. The scoping study, or scoping review, is one approach used to survey the literature and aims to map the key concepts underpinning a research area . The framework for conducting a scoping review emphasizes that the methods used throughout all stages of the process are conducted in a rigorous and transparent way. The process should be documented in sufficient detail to enable the review to be replicated by others, and this explicit approach increases the reliability of the findings. Unlike a systematic review, a scoping study does not often lead to the statistical pooling of quantitative evidence from various studies, as is often done in meta-analyses of systematic review data. While a scoping study uses an analytical framework or thematic construction to present the evidence, there is no attempt made to present the weight or quality of evidence in relation to particular policies or interventions [27, 28].
The scoping review framework published by Arksey and O'Malley in 2005 includes 5 required stages which were followed in the present study. Many other scoping reviews have subsequently used this framework as a guideline .
The research team, consisting of academic and government researchers with expertise in the areas of foodborne illness and public health, jointly determined how to synthesize the cost of foodborne illness literature through a series of in-person meetings. The government researchers also contributed as potential end-users of the information obtained from a review in this area. The goals were to identify the different component costs that have been included when determining the cost of foodborne illnesses, and to identify the data sources used to calculate these estimates.
Two comprehensive electronic databases were chosen for the literature search. The MEDLINE (PubMed) database was used to identify studies from the human medical literature whereas studies from the animal health literature were located in the AGRICOLA database. Prior to the searches, 15 studies were identified by the research team as being highly relevant to a review in this area. The identification of these studies following relevance screening was used to verify the comprehensiveness of the search. Broad keyword searches were performed between October 27th and November 1st 2012 to identify studies that addressed the COI of any infectious disease, including foodborne illnesses (Table 1). Search terms were selected by extensive review of the terminology used in the titles and abstracts of the 15 studies of known relevance. No restrictions were placed on date, country, or language of publication during the searches. A broad search approach (i.e., using infectious disease keywords) was used initially. This allowed for later refinement of the data extraction process to address the specific research question for the study reported herein. The 'peer-reviewed' filter was unchecked in the AGRICOLA search. All of the search results were imported into RefWorks Reference Management Software (ProQuest LLP, 2012), and duplicate citations were removed using the close and exact-match functions.
aKeywords in each column (Foodborne, Communicable, Cost) were combined with the Boolean operator 'OR' and then each of the combined categories were further combined with the operator 'AND' in the database searches.
Prior to screening, reviewers were provided with instructional documents that outlined the objectives of the review and how the results would be presented (i.e., using empty shell tables). The 15 studies of known relevance were also provided to the reviewers. Subsequently, titles and abstracts of 250 test studies were independently screened by two reviewers, and also by a member of the research team. The 250 test studies were selected at random from those identified by the literature searches. Any disagreements during the testing stage were discussed by all 3 of the reviewers, and differences were resolved by consensus. Two levels of relevance screening were performed. Each level was based on reviews of the title and abstract only, with the second level of screening also serving as a categorization step. Both levels of screening were performed independently by two reviewers. The first round of screening, which included all citations from the database searches, identified studies that described the COI of any infectious (communicable) disease, including foodborne illnesses, while excluding cost-effectiveness studies for specific interventions. A standardized relevance screening tool was created in Microsoft Excel (Version 2007). A Cohen's kappa coefficient was calculated to establish a minimum level of agreement between each reviewer following the first relevance screening round. If the level of agreement was found to be poor (i.e., raised concerns among the reviewers), a third reviewer would have been used and the first round of relevance screening would be repeated.
Studies selected after the first round of screening underwent a second level of screening, whereby each of the infectious and foodborne disease COI studies were further classified into those that described the cost of foodborne illnesses in humans, foodborne illnesses in animals, infectious diseases in humans, infectious diseases in animals, a combination of any of these categories, none of these categories (the study did not describe the cost of an infectious or foodborne illness), and as studies in which relevance could not be determined using the title and abstract. Following the second level of relevance screening, the study focused on the COI of foodborne diseases in humans only, and all other categories of studies were excluded. Results from each level of screening were compared between reviewers and conflicts resolved by consensus through an open discussion.
Citations describing the cost of foodborne illnesses in humans (with or without other infectious illnesses) and citations where relevance could not be determined using the title and abstract were retrieved in full text. A standardized data-charting form was created in Microsoft Excel (Version 2007). Training for data extraction was performed using instruction forms and 7 full text studies. Data extraction was conducted by two independent researchers, and the completed forms were compared for comprehensiveness. Therefore, if one researcher extracted data that the other had omitted, the study was re-examined by both reviewers, and differences in extracted data were resolved by consensus.
The data-charting form had two sections, the first for gathering descriptive information on the relevant studies (Table 2) and the second for gathering the data of interest: the individual and societal level component costs included in the studies and the data sources for those estimations (Tables 3 and 4). Descriptive data included information on the title of the study, whether it was available in English, whether it directly estimated COI due to one or more foodborne pathogens, and whether it described the component costs for the estimate. The year of publication, country of publication, and a list of foodborne pathogens included in the study were also collected. All component cost data were extracted at the level of detail reported in each study rather than using pre-determined categories for data extraction. Therefore, the specificity and detail in the extracted data were representative of the level of detail reported in the paper. The source of data for each component cost was also collected, detailing whether the data for the estimation came directly from a: survey, pre-existing databases, hospital records, an online calculator (e.g., Economic Research Service of the United States Department of Agriculture's foodborne illness cost calculator) , the literature, population statistics, census data, outbreak data, or expert opinion.
aNon-English study languages: Swedish (4), German (3), Italian (1), Danish (1), Russian (1).
bNon-relevant studies: Did not describe component costs (i.e., studies that were identified as relevant through both levels of screening, but did not provide the data of interest).
c Toxoplasma gondii (10), Cyptosporidium spp. (7), Cyclospora cayetanensis (5), Trichinella spp. (3), Giardia lamblia (3), Taenia spp. (1).
dNorovirus (9), Hepatitis A (6), Rotavirus (6), Astrovirus (4), Saprovirus (2), Adenovirus (1).
e Yersinia enterocolitica (8), Bacillus cereus (6), Brucella spp. (4), Streptococcus spp. (4), Mycobacterium bovis (1), Plesiomonas spp. (1).
aCounts represent the number of studies reporting each component cost category at the specified level of detail. Therefore, a study that is counted as including a higher-level category (e.g., treatment costs) cannot contribute a count to a lower-level category (e.g., drug costs) within the same grouping, and vice versa.
bD: Database, L: Literature, OC: Online calculator S: Survey, O: Outbreak data, C: Census, P: Population statistics, E: Expert opinion, M: Multiple, N/P: Not provided, N/A: Not applicable.
aCounts represent the number of studies reporting each component cost category at the specified level of detail. Therefore, a study that is counted as including a higher-level category (e.g., industry costs) cannot contribute a count to a lower-level category (e.g., product recall) within the same grouping, and vice versa.
The primary goal of this step was to refine the information extracted from the studies into manageable groupings, or themes. Two researchers independently grouped the component cost and source data extracted from each paper into themes and differences were resolved by consensus throughout the process. The grouped information was summarized in categories of individual level (direct and indirect) and societal level component costs.
Tables 3 and 4 display the categories of direct and indirect costs included at the individual level and the data sources used for each component cost category. The categories were created based on the level of detail provided in the study and thus, some categories represent more detailed sub-categories. Therefore, a study which included 'medical costs' did not explicitly describe any other direct costs included in their COI estimate. Similarly, all of the studies that were categorized as including a broad component cost category (e.g., treatment costs, personnel costs, hospital service costs) were not counted towards including a more specific component in those categories. However, studies may have ultimately included these more specific costs in their estimates, but the components were unknown due to a superficial level of reporting detail.
Data sources were grouped as follows: if the authors of a study stated that the literature was used for an estimate, the source of data was described as 'literature'. The original source of data in the cited literature may have been one of the other categories (e.g., a survey or pre-existing databases), however, the cited literature was not obtained to determine the actual data source. The same principle applied for databases, population statistics, outbreak data, or census data that may have been created using information from other data sources. This resulted in potential overlapping between data source categories, as only the immediate source of data was identified in the present study. Cost calculators often provide component cost estimates that have been amalgamated from a range of data sources, and are tools that can be used when estimating costs . Sources of component cost data could also be described as not provided (N/P), not applicable (N/A), or as 'multiple' , meaning numerous component costs and data sources were described without specifying which data sources were used for a particular component cost estimate.
Following duplicate removal, the MEDLINE (PubMed) and AGRICOLA database searches yielded 7633 references to be screened for relevance (Figure 1). Of these, 7394 were excluded as they did not describe the COI of any infectious or foodborne illnesses. All of the 15 studies identified by the research team as being highly relevant to a review in this area prior to the literature searches were identified by the employed search strategy. The Cohen's kappa coefficient was 0.89 for the first relevance screening round, indicating substantial agreement between the two reviewers . In the second round of screening, the remaining 239 references were classified into 1 of 7 categories based on the type of COI that was estimated (e.g., cost of foodborne illness in humans). Classifications for studies that fell into multiple categories, none of the categories, or studies where the relevance could not be determined were also used.
Scoping review flow chart. aStudies were excluded as they did not describe the COI of any infectious or foodborne illnesses. bTen non-English references were excluded (4 Swedish, 3 German, 1 Italian, 1 Danish, 1 Russian), as were an additional 14 studies that did not provide any information on component costs.
Following the second round of relevance screening, references that focused on foodborne illness in humans, a combination of categories, and those where relevance could not be determined from the title and abstract were selected (n = 108). Ten non-English references were identified and excluded, as were an additional 14 studies that did not provide any information on component costs. Therefore, 84 studies ultimately underwent data extraction. These studies described studies that directly estimated the cost of foodborne illnesses and studies that described component costs but did not provide an estimate.
The majority of the studies (n = 74, 88%) calculated the cost of a foodborne illness (or a group of foodborne illnesses) and described the component costs included in the estimates (Table 2). Ten studies described component costs, but did not directly calculate the cost of a foodborne illness. Papers in this latter category were foodborne illness prioritization studies, burden of foodborne illness reviews, and conceptual studies such as cost of foodborne illness frameworks. Although the objective of this group of studies was not to calculate the cost of a foodborne illness, they did describe component costs and were therefore included. Data source identification was not applicable (N/A) for these ten studies. Of the 74 COI studies, 36 (49%) estimated the cost of a single foodborne pathogen while 38 (51%) examined multiple pathogens. Among all included studies (n = 84), most (80%) were published in the last two decades (1992–2012) in North America (51%) and Europe (35%). The 10 most frequently estimated costs were those due to illnesses caused by bacterial foodborne pathogens, with non-typhoidal Salmonella spp. (n = 51, i.e., COI for this pathogen was reported in 51 of 74 studies estimating costs), shiga-toxin producing E. coli (n = 34), and Campylobacter spp. (n = 27) being the most commonly studied. Additional bacterial foodborne pathogens were included in multiple studies (refer to footnotes of Table 2), as well as foodborne viruses, protozoa, and parasites.
Among the 84 studies included in the review, 40 (48%) studies described both individual (direct and indirect) and societal level costs. Twenty-seven (32%) studies described individual level costs only, while 10 (12%) studies described direct costs exclusively. Three studies solely examined the societal costs associated with foodborne illness. The remaining studies described both societal and direct individual costs (n = 2) or societal and indirect individual costs (n = 2).
The direct individual level component costs most often included were broadly described as hospital services costs (n = 46) without explicitly describing which hospital service costs they estimated (e.g., emergency room costs, intensive care costs, surgical services costs, dialysis costs). Physician costs, a component of personnel costs, were commonly included (n = 31) along with drug costs (n = 29), a component of treatment costs. Other studies described these and other costs at a greater depth (e.g., prescription and over-the-counter costs as a component of drug costs), and there was substantial variation in the specificity and detail among studies when describing component costs. The most commonly reported indirect component cost was productivity losses due to sick leave from work (n = 42). A large number of studies included a cost estimate for 'productivity losses' without specifically stating which individual was experiencing the loss of output (e.g., the patient or caregiver) (n = 30). The value-of-life lost was estimated in 29 studies while costs broadly described as 'personal transportation' expenses were calculated in 20 studies.
Prior estimates published in the literature were the most commonly used source of individual level component cost data (used 108 times), followed by databases (84 times) and surveys (72 times). Multiple sources were listed for component cost estimates on 69 occasions. These studies included a description of multiple component costs and data sources without specifying which data sources were used for a particular component cost estimate. No data sources were provided for component cost estimates 34 times, and data sources were not applicable for 68 of the component costs. These component costs came from the 10 studies that did not directly estimate a cost of foodborne illness.
The societal level component costs that were most often included in cost of foodborne illness studies were outbreak investigation costs (a component of public health costs, n = 15), losses incurred by businesses (a component of industry cost, n = 13), costs associated with product recall (a component of industry costs, n = 11), and costs related to public health surveillance of foodborne illness (n = 11) (Table 4). Other societal costs included in some studies were legal costs and government related (regulatory) costs.
Similar to the individual costs, prior estimates published in the literature were the most commonly used source of component cost data for societal costs (used 57 times). Outbreak data, surveys, and pre-existing databases were used 25, 23, and 22 times respectively. Multiple sources were listed for 19 component costs. These studies described numerous component costs and data sources without specifying which data sources were used for a particular component cost estimate. No data sources were provided for component cost estimates 4 times, and data sources were not applicable on 49 occasions.
This scoping review explored component costs of foodborne illness and sources of data for the cost estimates. High variability in terms of the depth and breadth of individual and societal level cost components and the data sources being used in the published cost of foodborne illness literature was observed. Rather than being guided by a highly specific research question and particular study designs, a scoping review is guided by the broad requirement of identifying all relevant literature that pertains to the research question . Due to the potential usefulness of COI studies to inform decision makers, it is important that COI estimates are derived in a uniform, consistent, and transparent manner [12, 25, 26]. To address the issues of uniformity in cost inventories and transparency in data source usage, a better understanding of which cost components are included and how they are described in the published cost of foodborne illness literature is critical.
Most studies were based in North America and Europe, indicating that the results are more applicable to developed country contexts and may not represent foodborne illness component costs and data sources in developing nations. This may be due to a lack of resources to conduct COI studies or it may be a reflection of other infectious disease priorities for developing countries. The majority of the cost of foodborne illness studies identified have been published in the past two decades (1992–2012), which is a trend observed in all COI literature . The 10 most frequently estimated costs were those due to illnesses caused by bacterial foodborne pathogens. This was expected as these pathogens are cited as carrying a large burden in terms of the number of illnesses, hospitalizations, and deaths .
The primary results from this study are the reporting patterns of component costs in the cost of foodborne illness literature along with the sources of data for each estimate. In regards to the breadth of cost inventories, almost half of the studies (48%) included individual level costs (direct and indirect) and societal level costs in their estimates. This indicated that many studies are estimating a wide spectrum of costs associated with foodborne illnesses. Fewer studies included societal costs compared to individual costs. Societal level costs may be more difficult to calculate, as attributing costs incurred at the population level due to a particular illness might be more challenging than estimating a direct or indirect cost associated with an individual person . Additionally, societal costs may not be applicable given a study's perspective (e.g., a study estimating healthcare-related costs may omit societal costs). In the 84 studies included in the review, there was a high level of variability in the reporting detail of individual and societal level component costs. For instance, 16 studies broadly included 'medical costs' in their estimates as the only individual direct cost, while the remainder of studies estimating direct costs included more specific components of medical costs such as treatment costs, laboratory costs, personnel costs, hospital service costs, community services costs, and long-term care services costs. Numerous papers provided even greater detail, with studies delineating particular components in these broader categories. For example, specific treatment-related components such as drug and rehabilitation costs were described in certain studies. The variability in reporting detail can also be seen in the indirect individual and societal level costs, which indicates that although a greater level of specificity can be achieved when calculating component costs, certain studies elect to estimate costs more superficially. This is an issue because it does not allow the end-user of a COI study to fully understand which types of costs were included in an overall estimation. In turn, this makes the economic burden of an illness more difficult to interpret and understand and reduces the feasibility of meaningfully comparing two studies for the same disease.
The component costs presented in Tables 3 and 4 were aggregated from all of the relevant cost of foodborne illness studies identified during the review. However, certain costs may only be relevant for a particular pathogen or chronic sequelae. An example of this would be intensive care unit (ICU) costs incurred due to shiga-toxin producing E. coli infections, which may not be as relevant to other foodborne illnesses. A future study could determine which costs are pathogen-specific and which are commonly included across all foodborne illnesses. Additionally, of the 74 COI studies, 36 estimated the cost of a single foodborne pathogen while 38 examined multiple pathogens. Further research could determine if the component cost inclusion and reporting detail differs in single-versus multiple-pathogen studies, and to explore the implications of this factor when comparing or combining COI estimates.
A further consideration is the impact of data sources on a cost of foodborne illness estimate. A wide variety of data sources were used to estimate component costs of foodborne illness. Certain data sources may be more credible than others. For example, it could be argued that costs estimated by expert opinion are more subjective than estimates taken from hospital records. Future research could compare specific component cost estimates for a particular pathogen using varying data sources to determine the impact of using different sources of data. However, because there was an overlapping of data sources (e.g., an estimate taken from the literature may have come from a survey), data source variability may be less substantial than it appears, as only the immediate source of data was identified in the present study. Additionally, when a study reports a data source (e.g., the literature) without identifying the origin of the information, which may in fact be another data category (e.g., a survey, hospital records, pre-existing database), it does not allow the reader to easily evaluate the appropriateness or validity of the data source for the estimate. Also of concern is the number of component cost estimates that could not be linked to a particular source of data. For both individual and societal costs, multiple sources were listed for 88 component costs across 14 different studies. These studies described numerous component costs and data sources without specifying which data sources were used for a particular component cost estimate. Data sources were not provided for 38 individual and societal level component costs, meaning that an estimate was included without any explanation of where it came from or how it was deduced. These are issues of inadequate reporting that inhibits repeatability of these estimates.
Proponents of COI research have cited that one of the major strengths of these studies is the potential to compare one estimate to another [12, 25]. In an era where evidence-informed decision making is at the forefront, synthesizing the evidence from high quality studies is an important step in making an informed decision . Numerous studies dating back to 1982 have stressed that researchers should standardize their COI methodologies to improve the consistency and comparability of estimates [12, 13, 26]. These studies claim that if two otherwise comparable studies have included different components when estimating a cost of an illness, it would not be meaningful to compare them. If researchers continue publishing cost of foodborne illness studies while using different cost inventories (i.e., studies which contain a wide range of component costs reported with varying levels of detail), this trend of insular estimates with limited comparability will continue. Therefore, the research community engaging in COI studies may benefit from a discussion of minimum criteria for component cost and data source reporting. This scoping review illustrates the breadth of published cost inventories in the cost of foodborne illness literature and the depth to which they have been reported. By using this scoping review as evidence that there is a lack of standardization in cost inventories in the cost of foodborne illness literature, and to promote greater transparency and detail of data source reporting, there will be an increase in cost of foodborne illness research that can be interpreted and compared in a meaningful way.
During the literature search, a formal search of the grey (unpublished) literature was not conducted. However, the peer-reviewed filter was left unchecked during the AGRICOLA database search and relevant grey literature identified at this stage was included in the review. Also, by only searching a single animal health-related database (i.e., AGRICOLA), the number of studies identified as describing the cost of foodborne and infectious illnesses in animals may be an underestimation. However, we do not believe that this has biased the results, as the study reported herein focused on costs related to foodborne illnesses in humans only. Non-English language papers were excluded from the present study, and therefore, these results may only be applicable to English speaking countries. Lastly, an optional stage (step 6) in the Arksey and O'Malley scoping review framework is to involve potential end-users in the scoping review process. Although a consultation was not conducted per se, members of the research team, who are also end-users of the information, were directly involved in the identification of the research question and in outlining the goals of the review.
Individual and societal level costs have been included in a substantial number of foodborne illness cost estimates, indicating that many studies are using cost inventories that estimate a variety of types of costs. The depth and breadth of individual and societal level cost inventories in the cost of foodborne illness literature were highly variable. This scoping review can be used as evidence that there is a lack of standardization in cost inventories in the cost of foodborne illness literature, and to promote greater transparency and detail of data source reporting. It should be noted that certain costs may be pathogen specific and the results of the present study should be interpreted with that in mind. Lastly, the results illustrate that there are a wide variety of data sources available to estimate component costs of foodborne illness. Efforts should be made to select credible and current sources when determining the costs associated with foodborne illness, and to report the specific source of data for each component cost estimate. These suggestions will help address the issues of uniformity in component cost selection and reporting. By conforming to a more standardized cost inventory for cost of foodborne illness studies, and by reporting data sources in more detail, there will be an increase in cost of foodborne illness research that can be interpreted and compared in a meaningful way.
The authors thank Stephanie Seto for her involvement as a second reviewer during the scoping review process. Funding for this project was provided by the Canadian Institutes of Health Research/Public Health Agency of Canada (CIHR/PHAC) Applied Public Health Research Chair (awarded to JMS) and the Public Health Agency of Canada. Stipend funding for TM was provided by the Ontario Graduate Scholarship (OGS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
TM: Is a former graduate student at the University of Guelph and a PhD student in Epidemiology at McGill University. TM participated in the design of the study, carried out the scoping review methodology, interpreted the results, and drafted the manuscript. JMS: Is the Director of the Centre for Public Health and Zoonoses and a Professor in the Department of Population Medicine (University of Guelph). JMS participated in the design of the study, assisted in carrying out the scoping review, and assisted with data interpretation. MKT (Epidemiologist, Public Health Agency of Canada), AP (Associate Professor in the Department of Population Medicine, University of Guelph), and AF (Chief in the Risk Integration Synthesis and Knowledge Section, Public Health Agency of Canada) participated in the design of the study and provided feedback on the manuscript. All authors read and approved the final manuscript.
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Collagen is known to be a skin plumping agent and low levels are linked to an increase in sagging skin and wrinkles. However, the loss of collagen affects so much more than just skin; it is also crucial for bone and brain health too.
Bone consists of 70% minerals and 30% collagen, making collagen a vital organic aspect of bone giving it flexible strength. A lack of collagen and essential minerals can lead to brittle bones, aching muscles, joint pain and arthritis.
Collagen also supports brain activity and creates the scaffolding that protects the neurons from damage so good levels of collagen can help protect against neurodegenerative disorders such as Alzheimer's and Parkinson's disease.
The synthesis of collagen production can be impaired by a number of factors, particularly toxins. A poor diet high in sugary and processed foods and low in antioxidants such as vitamin C will increase toxins, as will smoking and environmental pollution. High levels of stress or a lack of exercise also cause collagen deterioration.
Non-organic cosmetics, skin care and cleaning materials can also increase exposure to pollutants, affecting collagen production.
A healthy diet is the best place to start in improving collagen levels as this will ensure a higher antioxidant intake. Organic fruit and vegetables will provide nutrients needed to support collagen, particularly Vitamin C which is crucial to collagen synthesis.
Sufficient protein is also essential in collagen production; nuts, seeds, pulses, vegetables, spirulina and protein powders are excellent sources.
Reducing stress can help and this can be improved with enjoyable hobbies, meditation, breathing exercises and yoga.
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Good oral health affects your long term oral health. Plaque and tartar build up on your teeth and below your gums. Long term build up can cause gum disease. Gum disease is a risk factor for illnesses such as diabetes, stroke, pneumonia and heart disease. Unhealthy gums can also cause bone loss in your jacausing teeth to become loose. Getting regular teeth cleanings by our trained dental hygienists can help prevent this.
A filling is recommended when your dentist detects a cavity. There are many filling materials available depending on the size of a cavity, however the most commonly used is a white filing material so that a natural appearance is achieved. Smaller cavities are can be filled directly inside the mouth in one convenient visit, where as larger cavities may require a different material and be completed in two visits. If a cavity is not repaired it will continue to grow and will become painful. This can lead to a root canal or tooth loss.
A crown is a restoration that provides full coverage of your tooth (think of it as a cap on your tooth) and is used to help strengthen a tooth that is prone to fracture either due to an existing crack, or a large existing filling. It is also useful in restoring teeth that have had a root canal. A crown is matched to the shade of the rest of your teeth in order to give a natural appearance. A crown aids in keeping the jaw and bite aligned, prevents shifting of other teeth, and bears the forces from biting and chewing.
A bridge is used to replace one or multiple teeth. It is usually anchored to the teeth on either side of the space. The teeth being used as anchors usually have crowns placed on top of them as well. A bridge commonly consists of a fake tooth (or teeth) in the centre and have crowns attached on either side. The entire bridge is cemented in place and the fake tooth (or teeth) sits on top of the gums to give the illusion of a real tooth, or multiple teeth emerging from the gums. Bridges come in various materials such as porcelain (matched to the shade of your existing teeth) or gold.
A veneer is a thin layer of porcelain that is attached to the front side of your tooth to improve esthetics such as spacing, alignment, and discolouration. They are usually made out of porcelain or white filling material in order to match the shade of your natural teeth.
How your teeth fit together can affect your oral health and function greatly. Teeth that do not fit together properly (due to crowding, spacing, early loss of teeth, etc) are harder to clean, are at risk for tooth decay and periodontal disease, and can cause stress on the chewing muscles leading to headaches, TMJ issues, as well as neck, shoulder, and back pain. Orthodontics (braces) can help alleviate all of this and at the same time give you a beautiful smile! We have an in house orthodontist to take care of all your needs whether it is providing conventional orthodontics, Invisalign, and so much more!
When bacteria enters your tooth by either deep cavities, cracks, or older fillings, it can reach the nerve inside your tooth and cause an infection. When the nerve of your tooth becomes infected a successful root canal lets you keep the tooth rather than having it removed. If left, an infected nerve can cause severe pain, swelling, and the infection can spread which can be extremely painful and dangerous. The infected nerve is cleaned, sealed, and filled therefore alleviating any pain.
Your natural teeth help you bite, chew, maintain your mouth and jawbone structure, and so much more. This is why it is a dentists first priority to save and repair your natural teeth. However, we understand that sometimes a tooth extraction is unavoidable. We will ensure that your extraction is as comfortable as can be and will guide you through every step of the procedure as well as post care instructions.
Dentures are used as replacements for people who are missing most or all of their teeth. They are made of a flesh coloured acrylic base which fits over the gums and artificial teeth are inserted into the base. In most cases they are removable and are taken out at night. There are two types of dentures – partial and complete. A partial denture rests on either a metal or acrylic framework and attaches to your existing teeth by metal clasps. A complete denture has an acrylic base and is used when you are missing all your teeth. In some cases, an immediate denture can be inserted directly after having teeth removed therefore never having to be without teeth. Implant supported dentures are also an option that provide a more stable, functional denture.
A dental implant can replace one or several teeth, and can also be used for full or partial removable, or permanent dentures. An implant is an artificial root made out of titanium metal that is placed in the jaw to mimic the root of a natural tooth. A crown is attached to the implant and matched to the shade of your teeth in order to look like a natural tooth. The implant acts as the anchor to hold the crown in place. An implant is the closest treatment option available which functions like a real tooth. Implants come in the form of single implants (to replace one tooth), an implant supported bridge (to replace several teeth), or an implant supported denture (to replace all or most of your teeth).
Most whitening agents contain bleach to help get rid of external stain on your teeth leaving you with a whiter, brighter smile. There are many different methods of teeth whitening, and it is important to consult with your dentist which method is best for you. We offer custom fitted whitening trays molded to your teeth and provide you with whitening kits to take home. Please remember bleaching should be done under the care of your dentist.
SPORTS GUARDS - A custom fitted sports guard protects your teeth from damage, reduces the chances of sustaining a face, neck, or head injury such as a concussion, as well as aids in talking and breathing. A custom fitted sports guard even fits over braces and other dental restorations. After taking molds of your teeth, the sports guard is made on site at our office. A custom fit ensures the very best protection and comfort while playing. If you have children who play contact sports, it is very important to have a custom fitted sports guard made for them.
You can't plan for an emergency. Whether your child falls and hits their tooth, you have an unexpected toothache, or anything in between, we offer same day dental pain and trauma management.
Copyright © 2018 Niverville Heritage Dental Corporation.
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There are numerous applications of nanostructured, functional thin films, but this work focused on biomedical applications, particularly antimicrobial surface coatings and drug delivery thin film using functionalized star polymers. In the first part of this study, star polymer-based antimicrobial surface coatings, prepared on glass substrates, were shown to reduce methicillin-resistant Staphylococcus aureus (MRSA) contamination 200-400% faster than the current industry standard, copper. Star polymer films showed no cytotoxic effect on human liver cells, red blood cells, or epidermal skin cells.
In the second part of the study, surface-based drug delivery thin films were prepared by using a layer-by-layer self-assembly method of complimentary amine- and carboxylic acid-functionalized star polymers, namely PS-DMAEMA and PS-[PEGM/PAA], respectively. Three model dyes, representing three different drugs, were loaded into the interstitial regions of the star polymers through self-assembly to form three different occlusion complexes. The layer-by-layer self-assembly of the occlusion complexes in phosphate-buffered saline (PBS) was monitored using surface plasmon resonance (SPR), and the layer growth was found to be uniform. Topographical analysis by atomic force microscopy (AFM) revealed granular morphology with a closely-packed arrangement of the star polymers.
Tek, Andy Theodora, "Star Polymer-Based Thin Film Materials for Biomedical Applications" (2013). Master's Theses. 4317.
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The term "malposition of great arteries" is commonly used for diagnosis and surgery in abnormal ventriculo-arterial connections with usual arrangement and two well developed ventricles. In these abnormalities the variability of the arterial relationships is considerable and all relationships from normal to side by side to antero posterior have to be expected.
Can we find other anatomical landmarks for the diagnosis and the subsequent corrective surgery?
We reviewed the specimens previously published and observations collected in three different institutions.
There is a gradual transition from Tetralogy of Fallot to double outlet right ventricle with subaortic ventricular septal defect to Taussig-Bing hearts to transposition of great arteries. In this transition the normal aortic-mitral continuity is progressively lost with gradual development of pulmonary- mitral continuity.
The key features determining the sequence of these abnormalities are the relationships between the outlet septum and the ventricular musculature. We may describe and group these malformations in function of the anticlockwise rotation of the outlet septum and the septomarginal trabeculation.
The term "malposition of great arteries" is a generic term which is of little help for diagnosis and surgery, therefore, it should be avoided.
We recommend a detailed description of the outlet septum and the septomarginal trabeculation in relation to the VSD. Careful attention to these structures dictates the diagnosis and the best surgical approach.
We are grateful to Prof. Robert H. Anderson for the invaluable help and discussions during this study.
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This depends how many zones you have, for example 1 zone could be your forehead, where as 2 zones could be your forehead and around your eyes. Please see our fees.
Repeat treatments are usually needed every 3-4 months over a twelve-month period. Clinical trials report that some patients who have had treatment over twelve months are requiring further treatments only once or twice a year.
Immediately after the injections there may be mild swelling or bruising which usually subsides within 24 to 48 hours. Application of ice for a few hours after treatment will help to reduce any swelling.
Most patients find that the injections cause only mild temporary discomfort. We are now using the latest needle called "the invisible needle" which is the thinnest needle available to date.
Generally, pain relief is not required for dermal filler procedures to correct lines and folds. Some people may experience some mild discomfort and a local anaesthetic cream may be applied to the area for a more comfortable treatment experience. We do recommend anaesthetic for lip fillers however this is optional and dependant on the patient's preference.
How will I look after this treatment?
There are some injection related reactions which may occur after any injection and normally resolve within a few days. These may include: redness, swelling, bruising, itching, pain and tenderness.
Immediately upon treatment, fillers help restore loss of volume & smooth etched-in lines and wrinkles, such as vertical lip lines above and around your lips.
Lips & dermal fillers are priced separately. Please see our fees.
This is dependent on the individual. There are many factors to consider, such as the structure of your skin, your lifestyle and age. The procedure can be repeated as often as you like, although most patients choose to have follow up treatment after 6-12 months to maintain a fresh and youthful appearance.
What's the difference between anti-wrinkle injections & fillers?
Anti-wrinkle injections are meant to prevent wrinkles from getting deeper by freezing muscles that cause wrinkles in the first place. Notice on each wrinkle there is a ridge and a valley. The goal of these injections is to target mainly the ridge, so that these ridges don't come closer and deepen wrinkles further.
By preventing movement of certain muscles, this also temporarily lowers the appearance of wrinkles. In summary: if you have wrinkles that are caused by you moving your face, you probably would be best served by anti-wrinkle injections.
Dermal fillers work more as an inlay into the crevices of wrinkles. The dermal fillers treatment literally fills in the valley that appears between wrinkles or any other indentations of the skin. Instead of treating moving parts of the face like anti-wrinkle injections, Dermal fillers treat the stagnant creases in our faces. So, if you have a lot of wrinkles and creases in your face when your face is relaxed, you may want to consider dermal fillers.
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To conduct a systematic review and network meta-analysis of randomized controlled trials (RCTs) with the aims of comparing relevant clinical outcomes (that is, visual analog scores (VAS), total and sub-Western Ontario and McMaster Universities Osteoarthritis index (WOMAC) scores, Lequesne algofunctional index, joint space width change, and adverse events) between diacerein, glucosamine, and placebo.
Medline and Scopus databases were searched from inception to 29 August 2014, using PubMed and Scopus search engines and included RCTs or quasi-experimental designs comparing clinical outcomes between treatments. Data were extracted from original studies. A network meta-analysis was performed by applying weight regression for continuous outcomes and a mixed-effect Poisson regression for dichotomous outcomes.
Thirty-one of 505 identified studies were eligible. Compared to placebo, glucosamine showed a significant improvement with unstandardized mean differences (UMD) in total WOMAC, pain WOMAC, function WOMAC, and Lequesne score of −2.49 (95% confidence interval (CI) −4.14, −0.83), −0.75 (95% CI: −1.18, −0.32), −4.78 (95% CI: −5.96, −3.59), and −1.03 (95% CI: −1.34, −0.72), respectively. Diacerein clinically improves visual analog scores, function WOMAC, and stiffness WOMAC with UMD values of −2.23 (95% CI: −2.82, −1.64), −6.64 (95% CI: −10.50, −2.78), and −0.68 (95% CI: −1.20, −0.16) when compared to placebo.
The network meta-analysis suggests that diacerein and glucosamine are equally efficacious for symptom relief in knee OA, but that the former has more side effects.
Osteoarthritis (OA) is the most common chronic joint disease of the older patient. The primarily affected joints are the knee and hip. The progression of the disease is influential on quality of life. This included functional and social activities, body image, and emotional well-being. In non-operative treatment, pain reduction and improved function are the primary goals. Management of mild degree OA of the knee mainly consists of medical treatment and lifestyle modifications. Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed agents for pain management, but they increase the risk of gastrointestinal (GI) bleeding and vascular adverse events [1,2]. Therefore, second-line drugs such as symptomatic slow-acting drugs for OA (SYSADOA) which include glucosamine sulfate, glucosamine hydrochloride, chondroitin sulfate, hyaluronic acid, avocado soybean unsaponifiables (ASU), and diacerein are more commonly used. These drugs may improve patient symptoms as well as reduce cartilage degradation [3,4], also having decreased occurrence of GI adverse events when compared to NSAIDs. Two drugs are recommended by the European League Against Rheumatism guidelines 2003. These include an interleukin-1 (IL-1B) inhibitor (diacerein) and glucosamine. However, these drugs have a slow onset and a prolonged residual effect. The diacerein and glucosamine groups have the greatest amount of randomized controlled trial (RCT) studies and meta-analysis when compared to all other SYSADOA. The results of all the studies show that diacerein and glucosamine improve symptoms and decrease structural progression in OA of the knee when compared to NSAIDs and placebo. Previous systematic reviews [3-6] have shown that diacerein had higher efficacy in reducing pain and Lequesne index, but increased risk of diarrhea when compared to placebo [4,6]. Similar effects were observed in systematic reviews of the efficacy of glucosamine, which showed a significant reduction in pain when compared to placebo but no effect on minimal joint space narrowing or adverse events [3,5]. However, no RCTs directly compared the clinical efficacy and safety of diacerein with glucosamine. We therefore conducted a systematic review with a network meta-analysis of RCTs with the aim of comparing relevant clinical outcomes (that is, visual analog score, Western Ontario and McMaster Universities Osteoarthritis index (WOMAC) score, Lequesne algofunctional index, joint space width change, and adverse events) between diacerein, glucosamine, NSAIDs, and placebo. The main outcomes that were focused on in this study included pain, functional assessment, joint space width change, and safety issues of the medications.
The Medline and Scopus databases were used to identify relevant studies published in English from the date of inception to 29 August 2014. The PubMed and Scopus search engines were used to locate studies using the following search terms: (osteoarthritis, degenerative arthritis, adult, older person), (symptomatic slow acting drug for osteoarthritis; SYSADOA, diacerein, glucosamine), (pain, function, score, grade, WOMAC, Knee Society Score (KSS), motion, radiographic grading, X-ray, MRI, Kellgren-Lawrence), (clinical trial, RCT, randomized controlled trial). Search strategies for Medline and Scopus are described in Additional file 1. Relevant studies from the reference lists of identified studies and previous systematic reviews were also explored.
Identified studies were selected by one author (J.K.) and randomly checked by A.T. Titles and abstracts were initially screened; full papers were then retrieved if a decision could not be made from the abstracts. The reasons for ineligibility or exclusion of studies were recorded and described (Figure 1).
Compared clinical outcomes between glucosamine (either glucosamine sulfate or glucosamine hydrochloride) and diacerein, or each of these treatments with other comparators (for example, placebo, non-steroidal anti-inflammatory drugs).
Compared at least one of the following outcomes: pain score, function, patient/physician global assessments, range of motion, joint space width difference, and adverse events.
Had sufficient data to extract and pool: reported mean, standard deviation (SD), numbers of subjects according to treatments for continuous outcomes, and number of patients according to treatment for dichotomous outcomes.
Two reviewers (J.K. and T.A.) independently performed data extraction using standardized data extraction forms. General characteristics of the study (mean age, gender, body mass index, duration of OA, pain score, and functional scores at baseline) were extracted. The number of subjects, mean, and SD of continuous outcomes (pain by visual analog score (VAS), total and sub-WOMAC scores, and Lequesne algofunctional index) between the groups were extracted. Cross-tabulated frequencies between treatments and adverse events were also extracted. Any disagreements were resolved by discussion and consensus with a third party (A.T.).
Two authors (J.K. and T.A.) independently assessed risk of bias for each study. Six study quality domains were considered, including sequence generation, allocation concealment, blinding (participant, personnel, and outcome assessors), incomplete outcome data, selective outcome reporting, and other sources of bias . Disagreements between two authors were resolved by consensus and discussion with a third party (A.T.).
The outcome of interests were pain VAS, total and sub-WOMAC scores (pain, stiffness, and function), Lequesne algofunctional index, joint space width (minimum), and adverse events. Methods of measure for these outcomes were used according to the original studies. Briefly, this includes the VAS pain scale from 0 to 10; the WOMAC score that consists of pain (0 to 20), stiffness (0 to 8), and function (0 to 68) with total scores of 0 to 96 . The Lequesne algofunctional index measured pain (0 to 10), maximum distance walked (0 to 6), and activities of daily living (0 to 8) with total scores of 0 to 24 [9,8]. For joint space width change, lower values of these scores refer to better outcomes. Adverse events were considered as composite and separate outcomes of the following: a musculoskeletal disorder, respiratory disorder, genitourinary tract disorder or central nervous system disorder, and GI adverse effects.
Direct comparisons of continuous outcomes were measured at the end of each study between glucosamine versus placebo and diacerein versus placebo and were then pooled using an unstandardized mean difference (UMD). Heterogeneity of the mean difference across studies was checked using the Q statistic, and the degree was quantified using the I 2 statistic. If heterogeneity was present (P value <0.10 or the I 2 > 25%), the UMD was estimated using a random effects model; otherwise, a fixed-effects model was applied.
For dichotomous outcomes, a relative risk (RR) of adverse reactions of treatment comparisons at the end of each study was estimated and pooled. Heterogeneity was assessed using the same method as mentioned previously. If heterogeneity was present, the DerSimonian and Laird method was applied for pooling; otherwise, the fixed-effects model by inverse variance method was applied. Meta-regression was applied to explore the source of heterogeneity (for example, mean age, percentage of females, bone mass index (BMI), Kellgren-Lawrence grading, duration of OA) if data was available. Publication bias was assessed using contour-enhanced funnel plots [11,12] and Egger tests .
For indirect comparisons, network meta-analyses were applied to assess all possible effects of treatment measured at different times if summary data were available for pooling [14-16]. A linear regression model weighted by inverse variance was applied to assess the treatment effects with adjustment for study effects and time for continuous outcomes. For adverse events, a mixed-effect Poisson regression was applied to assess treatment effects . Summary data was expanded to individual patient data using the "expand" command in STATA. Treatment was considered as a fixed-effect, whereas the study variable was considered as a random-effect in a mixed-effect model. The pooled RR and its 95% confidence intervals (CIs) were estimated by exponential coefficients of treatments. All analyses were performed using STATA version 12.0 . A P value <0.05 was considered statistically significant, except for the test of heterogeneity where P value < 0.10 was used.
Among 505 identified studies and 2 referred studies, 31 studies [18-48] were eligible for data extraction. Reasons for ineligibility are described in Figure 1. Characteristics of the 31 studies [18-44,46-48,45] are described in Table 1.
AR = adverse event, BMI = body mass index, D = diacerein, GH = glucosamine hydrochloride, GS = glucosamine sulfate, JSW = joint space width, VAS = visual analog score.
Among 23 glucosamine studies [26-44,1-4], the comparators included placebo, NSAIDs, and both placebo and NSAIDS in 17 studies [39,30,29,33,43,31,42,41,32,38,26,27,35,37,4,1,2], 4 studies [40,36,34,48,28], and 2 studies [28,44], respectively. All studies used glucosamine sulfate, except for one study which used glucosamine hydrochloride. Among eight diacerein studies, five studies [21,23,19,22,18], two studies [25,20], and 1 study had comparators as placebo, NSAIDs, and both NSAIDs and placebo, respectively. Most studies (24/27) included OA of the knee and the rest were OA of the hip. Mean age, body mass index (BMI), and duration of OA varied from 42 to 69 years, 24.0 to 32.6 kg/m2, and 1.6 to 13 years, respectively. Percentage of females in each study ranged from 5.1% to 88%. Duration of treatment ranged from 4 weeks to 3 years. Various outcomes were compared between the treatment groups (Figure 1).
Risk of bias assessment is described in Additional file 2.
Data used for direct comparisons for all treatments and outcomes were measured at the end of each study, as described in Table 1. Pooling according to outcomes was performed if there were at least two studies for each comparison, as clearly described below.
Among eight studies [25,39,34,21,23,40,42,47], five studies compared glucosamine pain VAS with comparators of placebo [39,42,2] and NSAIDs [34,40], respectively. Three studies compared diacerein with placebo [21,23] and NSAIDs . Most studies assessed pain using the VAS at 4 weeks to 3 years. Data for the mean and SD of VAS scores are described in Additional file 3. The mean VAS was −0.90 (95% CI: −1.67, −0.14) units significantly lower in glucosamine than in NSAIDs (Table 2). The mean VAS score was about −1.44 (95% CI: −3.01, 0.12) units lower in glucosamine than in placebo, but this was not significant. The pooled effects of diacerein versus placebo from three studies (n = 103 vs. 98) displayed no heterogeneity (I 2 = 0%) with an UMD of −2.23 (95% CI: −2.82, −1.64). The effect of diacerein versus NSAIDs was not statistically different with an UMD of 0.149 (95% CI: −0.29, 0.59). There was no evidence of publication bias for both pooled effect estimates.
*Statistically significant difference (P < 0.05). CI = confidence interval, NSAIDs = non-steroidal anti-inflammatory drugs, RR = relative risk, UMD = unstandardized mean difference, VAS = visual analog score, WOMAC = Western Ontario and McMaster Universities Osteoarthritis index.
As described in Table 2, the total WOMAC scores were compared as change from baseline and the actual scores measured at the end of each study. Among six studies [38,27,35,30,29,33] with total WOMAC score changes, the effects displayed no heterogeneity (I 2 = 0%) with an UMD of −2.49 (95% CI: −4.14, −0.83). The actual total WOMAC scores from two studies [31,29] were not statistically significant with an UMD of 5.67 (95% CI: −11.26, 22.61). The actual total WOMAC scores and change in sub-WOMAC scores (pain, stiffness, and function) were also compared (Table 2). Compared with placebo, glucosamine resulted in a significantly greater change in WOMAC pain scores with an UMD of −0.75 (95% CI: −1.18, −0.32). In addition, mean functional and stiffness WOMAC scores were significantly lower in the diacerein groups when compared to the NSAIDs and placebo groups (6.64 (95% CI: −10.50, −2.78) and −0.68 (95% CI: −1.20, −0.16)).
Only glucosamine resulted in a significantly greater change of Lequesne score when compared to placebo (UMD = −1.030 (95% CI: −1.34, −0.72)) (Table 2). However, glucosamine did not result in a significant change in joint space when compared to placebo with an UMD of 0.008 (95% CI: −0.232, 0.248).
Compared with a placebo control, composite adverse events were 1.12 (95% CI: 1.02, 1.23) and 5.58 (95% CI: 2.14, 14.59) times significantly higher in glucosamine and diacerein than in placebo (Table 2). When considering only GI adverse events, the pooled RR of glucosamine was 0.99 (95% CI: 0.82, 1.19) when compared with placebo and 0.393 (95% CI: 0.157, 0.588) when compared with NSAIDs. Conversely, diacerein respectively had 2.00 (95% CI: 0.69, 5.74) and 1.37 (95% CI: 0.89, 2.10) times more GI effects than placebo and NSAIDs, but this data was not statistically significant.
Data from eight studies [39,34,40,42,21,23,25,2] were included in pooling of indirect comparisons of the VAS scores (Additional file 4). Mean VAS scores measured at 4 to 24 weeks after receiving treatments were fitted as the dependent variable in a mixed linear regression model.
The VAS score was lowest in the diacerein group with an overall mean of 3.28 (95% CI: 2.25, 4.30) followed by the glucosamine (3.30, 95% CI: 2.61, 4.01), NSAIDs (3.31, 95% CI: 2.13, 4.50), and placebo groups (5.05, 95% CI: 3.79, 6.32). The regression analysis suggested that all active treatments resulted in a significant difference in VAS score when compared to placebo (Table 3). Multiple comparisons suggested no difference in effects between active treatments (Figure 2).
*Statistically significant difference (P < 0.05). CI = confidence interval, GI = gastrointestinal, NSAIDs = non-steroidal anti-inflammatory drugs, RR = relative risk, VAS = visual analog score, WOMAC = Western Ontario and McMaster Universities Osteoarthritis index.
Network meta-analysis of treatment effect on VAS.
Data from four studies [31,29,20,22] were included in pooling of indirect comparisons of the actual total WOMAC scores (Additional file 4). The mean total WOMAC scores were lower in the diacerein and NSAID groups, but higher in glucosamine compared to placebo, but this was not statistically significant (Table 3). Multiple comparisons suggested no difference in effects between active treatments.
Data from six studies [31,28,29,20,22,4] were included in the network meta-analysis of pain WOMAC scores (Additional file 4). Fitting the regression analysis using placebo as the reference suggested that pain WOMAC scores were lower in both the diacerein and NSAIDs groups. In contrast, the pain score was higher in the glucosamine group compared with placebo, but this was not statistically significant (Table 3).
Data from eight studies [20,22,18,31,28,29,4,25] were included in pooling of indirect comparisons of WOMAC function scores (Additional file 4). The regression analysis suggested that mean WOMAC function scores of diacerein, NSAIDs, and glucosamine were lower than placebo, but these results were not statistically significant (Table 3). Multiple comparisons indicated that diacerein and NSAIDs resulted in lower scores than glucosamine, but these results also were not statistically significant.
Data from six studies [20,22,18,31,28,29] were included in pooling of indirect comparisons of the WOMAC stiffness scores (Additional file 4). The regression analysis suggested that mean WOMAC stiffness scores were lower in diacerein, NSAIDs, and glucosamine groups when compared to placebo (Table 3). There was no significant difference between the three active treatments.
Three studies [21,36,37] compared mean changes of Lequesne scores after receiving treatments at 4 to 24 weeks (Additional file 4). The regression analysis suggested that mean Lequesne change in the glucosamine group was lower than the placebo group. There was no significant difference between the glucosamine and diacerein groups.
Data from five studies [33,38,43,41,19] were used for the network meta-analysis of joint space width change. Change of joint space width after receiving glucosamine and diacerein had no statistically significant difference when compared to placebo (Table 3). Multiple comparisons indicated that diacerein was superior to glucosamine at −0.2 mm (95% CI: −0.27, −0.14).
Sixteen studies [39,37,31,42,41,32,38,26,27,35,28,30,29,43,47,48] reported overall adverse events between treatment groups (Additional file 5). Compared to glucosamine, NSAIDs was 2.07 (95% CI: 1.47, 2.91) times and diacerein was 1.80 (95% CI: 1.27, 2.55) times more likely to have adverse events (Figure 3). Diacerein had approximately 13% (RR = 0.87; 95% CI: 0.62, 1.22) lower risk than NSAIDs, but this was not statistically significant (Table 3). Considering only GI adverse events showed similar results to overall adverse events.
Network meta-analysis of treatment effect on drug adverse effect.
This review compared effects of glucosamine, diacerein, NSAIDs, and placebo for the treatment of osteoarthritis of the knee. Relevant clinical outcomes that were pooled included VAS pain score, total and sub-WOMAC scores, joint space width, and adverse events.
The second-line drugs for OA knee in the SYSADOA group include glucosamine sulfate, glucosamine hydrochloride, chondroitin sulfate, hyaluronic acid, ASU, and diacerein. This study included both glucosamine sulfate and glucosamine hydrochloride because the results of previous meta-analysis of both preparations show that they have no statistically significant difference . Chondroitin sulfate [50-52], hyaluronic acid , and ASU were not included in this review because there were too few studies to pooled outcomes with network meta-analysis.
The clinical results of our study were consistent to previous meta-analyses [6,4,5,3] in which glucosamine and diacerein statistically improved pain scores (VAS and WOMAC) and function scores (WOMAC) when compared to placebo. However, we have added more evidence of multiple active treatment comparisons. There were no statistically significant differences between the three groups in pain VAS, total WOMAC, sub-WOMAC scores, and Lequesne functional scores. Although glucosamine showed greater improvement in joint space width when compared to diacerein, glucosamine and diacerein did not show a clinically relevant effect in joint space narrowing when compared to placebo. Both glucosamine and diacerein increased risk of adverse events when compared with placebo. However, glucosamine had a lower risk of adverse events when compared to diacerein. In the subgroup of gastrointestinal adverse events, patients who took diacerein had an approximately 86.9% and 99.6% increased risk of GI adverse events when compared to glucosamine and placebo, respectively. Glucosamine and diacerein can reduce pain VAS and improve function (WOMAC). Glucosamine and diacerein showed no differences in adverse effects when compared to NSAIDs. In conclusion, this study demonstrated that either glucosamine or diacerein can be selected for the treatment of pain associated with knee osteoarthritis. Diacerein has a higher risk of adverse GI events when compared to glucosamine. Both glucosamine and diacerein cannot decrease risk of adverse effects, and they both do not have a clinically relevant effect in delaying progression of joint space narrowing in OA of the knee.
The small number of studies that evaluated each particular pair of treatments limits performing a direct meta-analysis. A network meta-analysis circumvents this problem by creating indirect comparisons between active treatments that can identify the most effective therapy. In this case, diacerein was the best therapy for improvement of pain VAS scores. Glucosamine is the best therapy in terms of having less adverse effects when compared to diacerein but not when compared to placebo controls. None of the RCTs had compared combined treatments with an active control.
The strengths of this study were that a network meta-analysis was applied to increase the power of the tests and reduce type I errors [14-16]. We applied a regression model taking into account study effects to assess treatment effects. The network meta-analysis "borrows" treatment information from other studies and increases the total sample size. As a result, treatment effects that could not be detected in direct meta-analysis could be identified. All possible treatment comparisons are mapped and displayed (Additional file 6). Although our pooled estimates were heterogeneous, the regression model with cluster effect takes into account variations at the study level.
None of RCTs compared dual therapy with monotherapy of SYSADOA. In relation to the SYSADOA mechanism, diacerein inhibits IL-1b effects and reduces synthesis of cartilage-specific macromolecules. In addition, diacerein also decreases IL-1b-stimulated secretion of metalloproteinases and aggrecanases, thereby preventing breakdown of cartilage by these enzymes . Glucosamine, an amino sugar, is a building block of the glycosaminoglycan, which is a part of the cartilage structure. The SYSADOA group should be able to support effects of each other and may yield better clinical improvement than monotherapy. Further RCTs that compare dual vs. monotherapy SYSADOA are necessary to determine if this may enhance treatment effects.
This investigation demonstrates the potency of diacerein and glucosamine in the treatment of osteoarthritis of the knee. Glucosamine shows significant improvements in pain score but does not decrease risk of adverse effects and does not have a clinically relevant effect in slowing progression of joint space narrowing in OA knee. Diacerein has a higher risk of adverse GI events when compared to glucosamine. Diacerein also does not decrease risk of adverse effects and has no clinically relevant effect in delaying progression of joint space narrowing in OA of the knee. When compared to diacerein, glucosamine is the better treatment choice for OA of the knee.
All authors declare that no funding source or any sponsor was involved in the study design, collection, analysis, and interpretation of the data; in the writing of the manuscript; and in the submission to submit the manuscript for publication. This study is a part of Dr.Jatupon Kongtharvonskul 's training in Ph.D. program for Clinical Epidemiology, Faculty of Medicine Ramathibodi Hospital and Faculty of Graduate Studies, Mahidol University, Bangkok, Thailand.
Additional file 1: Search Strategies.
Additional file 2: Table S2. Risk of bias assessment.
Additional file 3: Table S3. Direct comparison of means VAS, WOMAC (total, pain, stiffness, and function), Lequesne actual, and difference score according to treatment.
Additional file 4: Table S4. Sample size, mean, and SD between treatment groups for studies included in a network meta-analysis.
Additional file 5: Table S5. Frequency of overall adverse events between treatment groups.
Additional file 6: Table S6. Summarization all treatment effects for osteoarthritis patients.
JK contributed to the conception and design, analysis and the interpretation of the data, the drafting of the article, the critical revision of the article for important intellectual content, the final approval of the article, and the collection and assembly of data. TA contributed to the collection and assembly of the data. MM contributed to the conception and design, the drafting of the article, the critical revision of the article for important intellectual content, and the final approval of the article. JA contributed to the conception and design, the drafting of the article, the critical revision of the article for important intellectual content, and the final approval of the article. PW contributed to the conception and design, the drafting of the article, the critical revision of the article for important intellectual content, and the final approval of the article. AT contributed to the conception and design, the analysis and interpretation of the data, the drafting of the article, the critical revision of the article for important intellectual content, the final approval of the article, the statistical expertise, and the collection and assembly of the data. All authors read and approved the final manuscript.
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Spinal fluid test may predict Alzheimer's
October 17th, 2013 Posted by Stephanie Desmon-JHU
"But we wondered if we could measure something in the cerebral spinal fluid when people are cognitively normal, to give us some idea of when they will develop difficulty," Marilyn Albert says. "The answer is yes." (Credit: iStockphoto)
Tests on brain and spinal fluid could soon mean earlier treatment for Alzheimer's disease—years before the first symptoms of memory loss, researchers report.
Such an early warning test would allow action to prevent or halt the progression of Alzheimer's while high-risk patients are still cognitively normal.
Medications designed to stop Alzheimer's brain damage have so far failed in clinical trials, possibly, many researchers say, because they are given to patients who already have symptoms and too much damage to overcome.
"When we see patients with high blood pressure and high cholesterol, we don't say we will wait to treat you until you get congestive heart failure," says Marilyn Albert, professor of neurology at the Johns Hopkins University School of Medicine. "Early treatments keep heart disease patients from getting worse, and it's possible the same may be true for those with pre-symptomatic Alzheimer's."
"But it has been hard to see Alzheimer's disease coming, even though we believe it begins developing in the brain a decade or more before the onset of symptoms," she adds.
Cognitive 'forecast'
Albert was primary investigator of a study of proteins in cerebrospinal fluid, published in the journal Neurology. The clear, colorless fluid, also called CSF, protects the brain and spinal cord.
Albert's team used CSF collected for BIOCARD, the Biomarkers for Older Controls at Risk for Dementia project. The samples were taken between 1995 and 2005, from 265 middle-aged healthy volunteers. Three-quarters of the study group had a close family member with Alzheimer's disease, putting them at higher than normal risk of developing the disorder. Annually during the collection years and again beginning in 2009, researchers gave the subjects neuropsychological tests and a physical exam.
They found that particular baseline ratios of two proteins—phosphorylated tau and beta amyloid—found in CSF could forecast mild cognitive impairment (often a precursor to Alzheimer's) more than five years before symptom onset.
They also found that the rate of change in the ratio over time was also predictive. The more tau and the less beta amyloid found in the spinal fluid, the more likely the development of symptoms, the study found. And, Albert says, the more rapidly the ratio of tau to beta amyloid goes up, the more likely the eventual development of symptoms.
Researchers have known that these proteins were in the spinal fluid of patients with advanced Alzheimer's disease.
"But we wondered if we could measure something in the cerebral spinal fluid when people are cognitively normal, to give us some idea of when they will develop difficulty," Albert says. "The answer is yes."
Alzheimer's disease disrupts critical metabolic processes that keep neurons healthy. These disruptions cause neurons to stop working, lose connections with other nerve cells, and finally die. The brains of people with Alzheimer's have an abundance of two abnormal structures—amyloid plaques and "tangles" made of tau.
Albert says researchers believe that the relative amount of beta-amyloid in the spinal fluid decreases as Alzheimer's progresses because it is getting trapped in the plaques and therefore isn't entering the fluid.
Though the BIOCARD study has been going on for nearly two decades, this is some of the first predictive data to come out of it, Albert says, owing to the length of time it takes for even high-risk middle-aged people to progress to dementia.
Only 53 of the original patients have progressed to mild cognitive impairment or dementia, giving a sample size just large enough to draw some preliminary conclusions. These first symptoms include memory disruptions such as repeating oneself, forgetting appointments, and forgetting what others have said.
Albert cautions that the biomarker ratio at this point is not accurate enough to precisely predict whether a particular individual is progressing to dementia, and further analysis of information about the group over time is needed.
If the initial findings are confirmed, however, they not only could guide the use of early treatments with drugs that become available, but also may also help test new drugs by seeing if they alter the rate at which the proteins change over time, Albert says.
The National Institute on Aging supported the research. Albert serves on scientific advisory boards for Eli Lilly, Eisai, Genentech, Biogen, and AgeneBio, and receives research support from GE Healthcare.
Source: Johns Hopkins University
Original Study DOI: 10.1212/01.wnl.0000435558.98447.17
Simple 'APEX' blood test may detect Alzheimer's
Does poor sleep in your 50s warn of Alzheimer's?
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In 2017, Group sales rose 5% to CHF 53.3 billion. Core operating profit grew 3% and Core EPS increased 5%, reflecting the good underlying business performance. On an IFRS basis net income decreased 9% at CER. The IFRS result includes charges for the impairment of goodwill and intangible assets and the amortisation of intangible assets.
Sales in the Pharmaceuticals Division increased 5% to CHF 41.2 billion. Recently launched medicines Ocrevus, Tecentriq and Alecensa contributed CHF 1.4 billion of new sales. This represents 65% of the division's growth. Perjeta also continued its strong sales increase. This growth was partially offset by lower sales of Tarceva, and Avastin. In the US, sales increased 10%, led by Ocrevus, Tecentriq, Xolair, and MabThera/Rituxan. In Europe, sales declined 2%, mainly due to lower MabThera/Rituxan sales driven by competition from biosimilars. In the International region, sales grew 4%, led by the Latin America and Asia–Pacific subregions. In Japan, sales increased 3%, with the main growth driver being Alecensa.
Diagnostics Division sales increased 5% to CHF 12.1 billion. Centralised and Point of Care Solutions (+7%) was the main contributor, led by the growth of its immunodiagnostics business (+13%). In regional terms, growth was driven by Asia–Pacific (+15%), with continued strong growth in China (+21%). Sales increased 2% in EMEA2, 10% in Latin America, and were stable in North America.
In 2017, the US FDA approved two new medicines, namely Ocrevus for the treatment of relapsing and primary progressive forms of multiple sclerosis and Hemlibra for people with haemophlia A with factor VIII inhibitors.
Health authorities also approved a number of line extensions for existing products including the US approvals of Perjeta for adjuvant (after surgery) treatment of HER2-positive early breast cancer at high risk of recurrence, in combination with Herceptin and chemotherapy as well as full approval of Perjeta for neoadjuvant use.
Additional line extensions granted by the FDA in the fourth quarter were Alecensa for first-line treatment in ALK-positive non-small cell lung cancer (NSCLC), Zelboraf in Erdheim-Chester disease, Gazyva for untreated advanced follicular lymphoma and Avastin for Glioblastoma in adult patients whose cancer has progressed after prior treatment.
In the EU, approval was granted for Alecensa as a monotherapy for the first-line treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive, advanced NSCLC. In January 2018, EMA approved Ocrevus for the treatment of both the relapsing and the primary progressive forms of multiple sclerosis and Hemlibra was granted a positive opinion by the CHMP.
In 2017, results of several key clinical studies were announced, including studies from key areas: Roche announced that the phase III IMpower150 study met its co-primary endpoint of PFS. The study demonstrated that the combination of Tecentriq and Avastin plus chemotherapy (paclitaxel and carboplatin) provided a statistically significant reduction in risk of disease worsening or death compared to Avastin plus chemotherapy in the first-line treatment of people with advanced non-squamous non-small cell lung cancer.
The phase III IMmotion151 study met its co-primary endpoint of investigator-assessed PFS and demonstrated that the combination of Tecentriq and Avastin provided a statistically significant reduction in the risk of disease worsening or death (PFS) in people whose disease expressed the PD-L1 (programmed death-ligand 1: Expression ≥1%) protein compared with sunitinib for the first-line treatment of people who have advanced or metastatic renal cell carcinoma.
Roche announced positive results from the phase III Haven 3 study evaluating Hemlibra in adults and adolescents (aged 12 years or older) with haemophilia A without factor VIII inhibitors. The study met its primary endpoint, showing a statistically significant and clinically meaningful reduction in the number of treated bleeds over time in people receiving Hemlibra prophylaxis every week compared to those receiving no prophylaxis.
The study also met key secondary endpoints, including a statistically significant reduction in the number of treated bleeds over time with Hemlibra prophylaxis dosed every two weeks compared to no prophylaxis.
Positive interim results were announced from the phase III Haven 4 study evaluating Hemlibra prophylaxis dosed once every four weeks in adults and adolescents (aged 12 years or older) with haemophilia A with and without inhibitors to factor VIII. At this interim analysis after a median of 17 weeks of treatment, Hemlibra prophylaxis showed a clinically meaningful control of bleeding.
The randomised phase II GO29365 study met its primary endpoint. The study compared polatuzumab vedotin in combination with bendamustine plus MabThera/Rituxan (BR) against BR alone in people with relapsed or refractory diffuse large B-cell lymphoma. The study demonstrated that the addition of polatuzumab vedotin to BR increased complete response (CR) rates from 15% to 40% at the end of treatment.
First results from the pivotal phase III Murano study evaluating Venclexta/Venclyxto plus MabThera/Rituxan compared to bendamustine plus MabThera/Rituxan (BR) for the treatment of people with relapsed or refractory chronic lymphocytic leukaemia (CLL) were reported. The results showed that treatment with Venclexta/Venclyxto plus MabThera/Rituxan significantly reduced the risk of disease progression or death (progression-free survival; PFS, as assessed by investigator) by 83% compared with BR. Venclexta/Venclyxto is being developed by AbbVie and Roche and is jointly commercialised by AbbVie and Genentech, a member of the Roche Group, in the US and commercialised by AbbVie outside of the US.
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Biopsy-negative giant cell arteritis: Does anti-CD83 immunohistochemistry advance the diagnosis?
BACKGROUND: In situ maturation of adventitial dendritic cells (DC) with expression of CD83 has been proposed as an early event in the pathogenesis of giant cell arteritis (GCA), preceding the appearance of an inflammatory infiltrate. The aim of this study was to evaluate the added value of anti-CD83 staining of temporal artery biopsy (TAB) specimens in patients with biopsy-negative temporal arteritis.
METHODS: Fourteen patients with TAB performed in our medical center since 2001 and considered negative for GCA due to the absence of any inflammatory infiltrate were identified by a computerized search of patient records. Their paraffin-embedded TAB specimens were retrieved, reprocessed, and stained with anti-CD83 monoclonal antibody (Serotec, 1:40). Three TAB specimens of patients with biopsy-proven GCA served as positive controls and three specimens of popliteal and/or tibial arteries of patients with atherosclerotic peripheral vascular disease were used as negative controls. Follow-up of the patients was confirmed by personal contact with their rheumatologists and analysis of their hospital charts.
RESULTS: Follow-up was available for 12 of 14 patients. Five of these patients were considered to have biopsy-negative GCA: they satisfied the ACR classification criteria, were successfully treated with glucocorticosteroids, and had a follow-up of at least 10 months with no alternative diagnosis established. Anti-CD83 staining was negative in all but one patient who demonstrated a single CD83-positive cell adjacent to the internal elastic membrane. Positive anti-CD83 staining of the inflammatory infiltrate throughout the arterial wall was observed in all patients with biopsy-proven GCA (positive controls). Negative controls did not show any CD83-positive cells.
CONCLUSIONS: In this pilot study, anti-CD83 immunohistochemical staining of paraffin-embedded specimens did not improve the yield of TAB in patients with suspected GCA.
20704489 - Nasolacrimal duct obstruction: clinicopathologic analysis of 205 cases.
6243209 - Myeloid bodies in patients without clinical fabry's disease.
6623659 - Coagulation disorders in patients with tumors of the uterus.
Departments of Internal Medicine Bnai Zion Medical Center and Bruce Rappoport Faculty of Medicine, Technion, Haifa, Israel.
Previous Document: Economic evaluation of assistance to HIV patients in a Spanish hospital.
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The results highlight the importance of evaluating and monitoring cognitive function in individuals with recent critical illness or major infections, especially if they are already at risk for dementia.
Low-dose naproxen increases frequency of adverse health effects and does not reduce progression of presymptomatic Alzheimer disease in cognitively intact persons at risk.
Low scam awareness is associated with an increased risk for Alzheimer disease and mild cognitive impairment among older adults.
Antiepileptic drug (AED) use may increase the risk for pneumonia in patients with Alzheimer disease.
Use of the orally administered β-site amyloid precursor protein-cleaving enzyme 1 inhibitors, verubecestat and atabecestat, does not prevent clinical progression to Alzheimer disease.
Gerontologists, practicing ethicists, policymakers, and health practitioners should consider the structural conditions of long-term care that both foster aggression and constrain prevention efforts, according to this commentary.
After adjusting for the competing risk of death without dementia, smoking is not associated with an increased risk for dementia.
Patients with poor cognitive function have significantly lower levels of Alzheimer disease-related biomarkers in the vitreous humor.
Avanir announced data from the phase 3 clinical program that evaluated AVP-786 (deudextromethorphan hydrobromide/quinidine sulfate) for the treatment of moderate-to-severe agitation in patients with Alzheimer dementia.
Memantine monotherapy was associated with a 7% lower risk for any cardiovascular event compared with both acetylcholinesterase inhibitor monotherapy and combination therapy, according to a new study.
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What are the Kleine-Levin Syndrome (KLS) Symptoms?
KLS symptoms can vary widely from patient to patient, making the illness difficult to diagnose and cope with. Not all KLS sufferers experience the same set of symptoms and a patients symptoms may change and evolve throughout the course of the illness. Episodes can range from mild to severe.
KLS started out mild for me and then worsened. At this time, KLS is becoming lighter again. I don't get every symptom with each episode but, I have experienced all of the mentioned symptoms during episodes. The dream like feeling and the memory loss are the most difficult symptoms for me. It is hard to function and not know if your experiences are really happening or if you are dreaming. The dream like feeling and child like behavior are common to nearly every episodic occurrence of mine while many of the other symptoms can come and go during the episodes.
Regression: Wanting to sleep in parent's bed; childlike behavior; young voice; holding stuffed animal.
Memory Loss: Not knowing what day it is when waking up from an episode; Not remembering doing something or saying something.
Anxieties/Fears: During episodes feeling as if someone is going to break into the house or a crime is going to be committed; having nightmarish thoughts; wondering if I am dead or alive. After episode ends, these psychological and emotional symptoms of the disorder are not present.
Head Pain or Headache: The head pain is not a classical migraine, but it is quite severe and causes me to vomit at times. It is a difficult pain to describe.
KLS Patients need reassurance that the episode will end and they will get better.
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Seroprevalence of Hepatitis B Virus Infection among an Afro-descendant Community in Brazil
Ana RC Motta-Castro, Clara FT YoshidaI +, Elba RS LemosI, Jaqueline M OliveiraI, Rivaldo V Cunha, Lia L Lewis-XimenezI, Pedro H CabelloI, Kátia MB LimaII, Regina MB MartinsIII
Hemonúcleo do Hospital Universitário, Universidade Federal de Mato Grosso do Sul, Campo Grande, MS, Brasil
IDepartamentos de Virologia e Genética, Instituto Oswaldo Cruz-Fiocruz, Av. Brasil 4365, 21045-900 Rio de Janeiro, RJ, Brasil
IICoordenadoria de Imunizações, Secretaria de Saúde do Estado Mato Grosso do Sul, Campo Grande, MS, Brasil
IIIInstituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiânia, Goiânia, GO, Brasil
Furnas dos Dionísios is an Afro-Brazilian black community whose descendants were mainly fugitive slaves that established themselves in the State of Mato Grosso do Sul (MS), Brazil. The population is comprised mainly of low socioeconomic individuals who are engaged in agricultural activities. The objective of this study was to investigate the prevalence of hepatitis B (HB) and its correlation with epidemiological data obtained from the community. The studied population totaled 260 individuals with ages varying from 1 to 79 years (median 20). One hundred thirty-three (51.2%) were females and 127 (48.8%) were males. A high prevalence for anti-HBc was observed (42.7%), with present infection detected in 9.2% of the subjects who were also HB surface antigens (HBs Ag) positive; 27.3% were anti-HBc and anti-HBs reactive, and 6.2% had anti-HBc as only marker. The prevalence for anti-HBc was proportional to age, reaching its highest peak in age categories greater than 50. No serological marker was detected in children under the age of 2 years, however anti-HBc was present in 12 subjects with ages between 2 and 14 years, of these 8 (7.4%) were HBsAg positive. Among individuals over the age of 15 years, 99 were anti-HBc reactive, of these 16 (10.5%) were also HBsAg positive, thus suggesting an increased prevalence of HBV carriers among children and adolescents. The risk factors observed in this community that were significantly associated with anti-HBc positivity were age (over 20 years) and having an anti-HBc positive mother. Both HBeAg and anti-HBe were detected in 44.4% of the samples tested. HBsAg subtypes found in the studied population were adw2 (77.7%) and ayw2 (23.3%). While intrafamilial transmission was most likely responsible for HBV infection among children, other routes such as sexual contact might be considered for individuals with ages over 15 years.
seroprevalence
Afro-descendants
Hepatitis B virus (HBV) is believed to infect more than 350 million individuals throughout the world and its prevalence varies widely in different geographic regions. The relationship between chronic HBV infection and cirrhosis/hepatocarcinoma has been presented by many authors, giving this infection an important cause of morbimortality and of major concern to public health
(Kew 1998, Hilleman 2001).
Epidemiological studies carried out in different parts of the world show that the characteristics of the population, such as sanitary conditions, lifestyle, hygiene, risk and socioeconomic factors are related to large variations in the frequency and prevalence of HBV infection (Karim et al. 1991).
The HBsAg subtypes present typical geographic distribution that probably reflects the local of its origins and the migration of infected individuals. The HBsAg subtypes are important epidemiological markers to investigate the prevalence, transmission, and migration of HBV (Couroucé-Pauty & Soulier 1983, Teles et al. 1999).
Africa, considered a region of high endemicity, owns the second greater number of chronically infected individuals with HBV. Of an approximate 470 millions of people that live in that continent, more than 5 million are chronic carriers and about 12.5 will eventually die from hepatic illnesses induced by HBV, presenting a mortality risk of 25% (Kiire 1996).
The importance of studying HBV infection in isolated Afro-descendant communities is based on the absence of epidemiological data on Afro-descendant populations in Brazil; the high prevalence of HBsAg in African countries (5 to 20%); and the strong association between intrafamilial transmission of HBV and factors related to frequent and repeated exposure to the virus. Thus, the objectives of the present study were to investigate the prevalence of the HBV serological markers and the association of demographic variables and risk factors in the afro-descendant community of Furnas dos Dionísios, State of Mato Grosso do Sul (MS), Brazil. These findings may allow to obtain seroepidemiological data to aid in effective decisions for controlling and preventing HBV infection.
CASUISTICS AND METHODS
This study was conducted in the Afro-descendant community of Furnas dos Dionísios, founded in 1885 and pertaining to the District of Rio Verde and the city of Jaraguari, MS, which is located northward from Campo Grande, capital of the State of MS, Central Brazil.
A total of 430 Afro-descendants living in the community of Furnas dos Dionísios were invited to participate in the study, and 260 (60.5%) individuals consented in participating. The study took place between October 1999 and March 2000 and these 260 participants were identified to belong to 64 families.
The population, in general, had low socioeconomic and educational levels, poor health conditions, and lacked sanitation and sewage disposal. The economy was based on subsistence agriculture.
A standardized form was used to collect data on individual characteristics and risk factors for HBV infection such as: history of sexually transmitted diseases (STD), multiple partners, condom use, household contacts with HBV infected subject, history of blood transfusion, dental treatment, surgery, acupuncture, tattoos, intravenous drug use and sharing razor blade.
Serological tests - Serum samples were tested by enzyme-linked immunosorbent assay (ELISA) to detect the following serological markers for HBV infection: hepatitis B surface antigen (HBsAg), antibodies against HBsAg (anti-HBs) and antibodies against hepatitis B core antigen (anti-HBc) (Hepanostika Organon Teknika B.V., Boxtel, Holland). HBsAg positive samples were further tested for IgM anti-HBc, hepatitis B e antigen (HBeAg) and antibodies against HBeAg (anti-HBe) (Hepanostika Uni-form Organon Teknika B.V.) and submitted to the determination of the HBsAg subtypes (Fiocruz, Brazil).
Data analysis - A descriptive analysis was performed by calculating means, medians and frequencies. Prevalence and 95% confidence intervals (95% CI) were calculated. Chi-squared test or Chi-square for trend test were performed to evaluate risk factors associated with HBV infection. Crude and adjusted odds ratio with 95% CI were calculated to determine the strength of association between variables by uni and multivariate analysis using STATA 6 (State Corporation, College Station, Texas, USA). Statistical significance was assessed at the 0.05 probability level in all analyses.
The ages of the study population varied from 1 to 79 years, with a mean age of 25. More than 50% of the population consisted of individuals whose ages were less than 20 years. As for gender, 133 (51.2%) were females and 127 (48.8%) were males (Table I). This population did not differ in relation to age and gender (c2 = 14.72; p = 0.257).
To assess the prevalence of HBV serological markers in the study community, 260 individuals were analyzed (Fig. 1). Anti-HBc, considered the most representative marker for HBV exposure, was detected in 111 individuals, resulting in HBV prevalence infection of 42.7% (CI 95%: 36.8-48.8). All of these were negative for IgM anti-HBc, indicating the absence of acute or recent infection in this population. HBsAg was observed in 24 (9.2%) subjects. Detection of both anti-HBc and anti-HBs was found in 71 (27.3%) individuals, and suggests past infection with conferred immunity. Anti-HBc alone was detected in 16 (6.2%) subjects. Only 2% of the subjects were previously vaccinated and were anti-HBs positive. The remaining population (55.3%) lacked serological markers for HBV infection and was, thus, susceptible to HBV.
The Fig. 2 shows a progressive increase in prevalence of anti-HBc with age. The highest prevalence (100%) was observed in ages 51 to 60 years, followed by a slight reduction (94.4%) among those older than 60. A significant trend of anti-HBc positivity in relation to age was found in the study population (c2 for trend = 95.27; p < 0.001).
When the population was stratified in two age groups: 0-14 and 15-79 years old (Table II), anti-HBc was detected in 12 subjects under 14 years, of these 8 (7.4%) were HBsAg positive. Among individuals over the age of 15 years, 99 were anti-HBc reactive, of these 16 (10.5%) were HBsAg positive.
Serological tests for detecting HBeAg and anti-HBe markers were performed in 18 (75%) of the 24 HBsAg reactive serum samples, and a positivity of 44.4% was observed for each of these markers. Two (11.2%) were negative for both markers.
In order to evaluate the HBV subtypes distribution among this Afro-descendant community, subtyping was performed on HBsAg positive samples. Eighteen of 24 (75%) could be subtyped. Subtype adw2 (77.7%) was predominant, followed by ayw2 (22.3%).
Analysis of all risk factors studied showed that age over 20 years, history of STD, sexual contact with anti-HBc positive partner, anti-HBc positive mother, previous blood transfusion, dental treatment and history of surgery were significantly associated with HBV seropositivity by univariate analysis (Table III). However, multivariate analysis revealed that only age over 20 years and having a seropositive mother were significantly associated with HBV infection in this population.
The present investigation showed an elevated prevalence (42.7%) of HBV infection in Afro-descendants from Furnas dos Dionísios, MS, Central Brazil. This was lower than those observed in West Africa, where prevalence rates ranging from 56 to 98% were reported (Kiire 1996), but higher than that obtained in Gambia (33%) (VallMayans et al. 1990). On the other hand, Tabor et al. (1985), while studying a population with similar characteristics of this investigation, found rates of 42 to 65% for HBV in five regions in Zambia, Africa. Nevertheless, there is no data in other Afro-Brazilian black communities to make a comparative analysis.
A significant trend of HBV seropositivity in relation to age was observed. The positivity for anti-HBc was low in 0 to 10-year-old children and increased with age to a gradual and cumulative elevation. The highest prevalence (100%) was seen in individuals between 51 and 60 years old.
HBsAg, a marker which indicates present infection, was detected in 9.2% of the subjects. This suggests the area under study as a region of high endemicity. Similar findings (10 to 20%) were reported in regions of high endemicity in Africa. Also, other studies showed elevated prevalence rates as 19% in rural populations of Equatorial Africa (Richard-Lenoble et al. 1995), 9 to 20% in the adult population of Western Africa, and 14.6% in Mozambique (Kiire 1996).
In addition, when the population under study was stratified in two age groups: 0-14 and 15-79 years old, a high prevalence for HBsAg (7.4%) was found in children and adolescents. According to Szmuness et al. (1973), HBsAg is rarely detected in children and adolescents in low endemic areas, differently from high endemic areas, where detection is frequent.
The determination of HBsAg subtypes has an important value as an epidemiological marker. Through subtypes, infection source can be identified and migratory chains can be analyzed (Couroucé-Pauty & Soulier 1983, Gaspar & Yoshida 1987, Teles 1999). In this study, subtypes were identified in 75% of the HBsAg positive samples, with a predominance of adw2 (77.7%) followed by ayw2 (22.3%). Adw2 was the most frequent HBsAg subtype found in Brazil and Africa (Couroucé-Pauty & Soulier 1983, Gaspar & Yoshida 1987). In addition, the detection of ayw2 subtype in HBsAg positive members of one family or adw2 in other three families suggests the intrafamilial transmission of HBV (date not shown).
Although the number of subjects under the age of 2 years was small, all of these were HBV seronegative (data not shown), the absence of HBV carriers in this age group strongly indicates horizontal transmission of the virus in this community. It is believed that the transmission of HBV is greatly influenced by social features (Martinson et al. 1998). In this investigation, the low socioeconomic level of the population, poor hygienic conditions, precarious household and clusters of individuals per habitation are characteristics that, probably, increased dissemination of HBV infection in this community. Similar socio-demographic characteristics were observed in a study of HBV intrafamilial transmission in the South Africa (Karim et al. 1991). Still in Africa, lower rates of HBsAg have been observed in children in urban areas when compared to those of the country. Rural areas may promote HBV infection due to the low socioeconomic status, the precarious personal hygiene with considerable chances of transmission through skin injuries with infected fluids, secretions and saliva, sharing personal objects (as razor blade and toothbrush), insects bites and so on (Kiire 1996). A study conduct in a town of the state of São Paulo, Brazil, in which risk factors were evaluated, showed that individuals from rural areas with worse social conditions are at higher risk for HBV infection (Passos et al. 1993).
In addition, seroepidemiologic studies established that the transmission of HBV is relatively common between individuals and patients chronically infected that share the same household (Heathcote 1974, Hadziyannis 1975), or crowed living rooms, and have poor hygiene (Karim et al. 1991). According to Szumuness et al. (1973), serological evidences of intrafamilial transmission is greater in non-caucasian families and also depends on the size of the family and cluster of individuals in household.
The associations observed in the univariate analysis between positivity for anti-HBc and sexual contact with a seropositive partner for HBV, as well as history of STD, agree with the literature that has demonstrate the sexual transmission of the HBV (Rosenblum et al. 1992). Studies on heterosexual transmission of HBV demonstrated that Afro-descendants have a higher prevalence of HBV infection than Caucasian, and probably the virus is transmitted mainly through sexual contact (Alter et al. 1986). Parenteral exposure factors (history of blood transfusion, dental treatment and surgery procedures) also showed an association with HBV infectionby univariate analysis. Although many studies have demonstrated that sharing of sharp objects is a risk factor for the HBV exposure (Vallmayans et al. 1990, Karim et al. 1991, Koff et al. 1997), sharing of razor blade was not significantly associated with HBV infection in the study population.
After the multivariate analysis, being over 20 years of age and having seropositive mother remained significantly associated with HBV infection. Individuals born to anti-HBc seropositive mothers had a 5.4-fold (IC 95%: 2.1-14.1) greater risk for HBV exposure than those born to anti-HBc negative mothers, and suggests mother-to-infant transmission as an important role in this community. In spite of these findings, there were no positive child under 2 years of age and there were only two HBsAg positive mothers.
Although it was observed that the risk of HBV infection in subjects exposed to intrafamilial contact was greater among those whose mothers were seropositive, sexual transmission among individuals over the age of 15 years should not be discarded. In endemic regions, intrafamilial transmission of HBV has been shown to be an important route of the virus dissemination in households with low socioeconomic status (Karim et al. 1991, Passos et al. 1993).
We therefore conclude that elevated prevalence of HBV infection found in Furnas dos Dionísios suggests this region to be classified as one of high endemicity. Considering yet, the results obtained, preventive measures, such as educating and vaccinating the susceptible population are of fundamental importance to control HBV infection in this community and are presently being put into practice by Immunization Program of the Secretary of Health of the state of Mato Grosso do Sul.
To Cleber Ferreira Ginuino for collecting patient's samples and Marli Sidoni for performing HBsAg subtyping.
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This study was supported by CNPq and Capes.
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Biguino B., Olmedo E., Ferreira A., Zacarias N., Lamas L., Favareto L., Palma C., Borges C., Teles-Machado A., Dias J., Castellanos P., Brito A.C. (2022)
Evaluation of SMOS L4 Sea Surface Salinity Product in the Western Iberian Coast
Remote Sensing, 14, 2, 423. DOI: 10.3390/rs14020423. (BibTeX: biguino.etal.2022)
Resumen: Ver
Salinity is one of the oldest parameters being measured in oceanography and one of the most important to study in the context of climate change. However, its quantification by satellite remote sensing has been a relatively recent achievement. Currently, after over ten years of data gathering, there are still many challenges in quantifying salinity from space, especially when it is intended for coastal environments study. That is mainly due to the spatial resolution of the available products. Recently, a new higher resolution (5 km) L4 SMOS sea surface salinity (SSS) product was developed by the Barcelona Expert Center (BEC). In this study, the quality of this product was tested along the Western Iberian Coast through its comparison with in situ observations and modelled salinity estimates (CMEMS IBI Ocean Reanalysis system). Moreover, several parameters such as the temperature and depth of in situ measurements were tested to identify the variables or processes that induced higher errors in the product or influenced its performance. Lastly, a seasonal and interannual analysis was conducted considering data between 2011 to 2019 to test the product as a potential tool for long-term studies. The results obtained in the present analysis showed a high potential of using the L4 BEC SSS SMOS product in extended temporal and spatial analyses along the Portuguese coast. A good correlation between the satellite and the in situ datasets was observed, and the satellite dataset showed lower errors in retrieving coastal salinities than the oceanic model. Overall, the distance to the coast and the closest rivers were the factors that most influenced the quality of the product. The present analysis showed that great progress has been made in deriving coastal salinity over the years and that the SMOS SSS product is a valuable contribution to worldwide climatological studies. In addition, these results reinforce the need to continue developing satellite remote sensing products as a global and cost-effective methodology for long-term studie
Palabras clave: surface salinity, SMOS, coastal ocean, CMEMS IBI Ocean reanalysis system, climate change
Campuzano F., Santos F., Simionesei L., Oliveira A.R., Olmedo E., Turiel A., Fernandes R., Brito D., Alba M., Novellino A., Neves R. (2022)
Framework for Improving Land Boundary Conditions in Ocean Regional Products
Journal of Marine Science and Engineering, 10, 852 DOI: 10.3390/jmse10070852. (BibTeX: campuzano.etal.2022)
The coupling of coastal or regional ocean models to hydrological models or observed data is currently an uncommon practice in operational oceanography. Though hydrological models are regarded as a powerful and useful tool for estimating the quantity and quality of freshwater running in a watershed, they fail to provide accurate results for river flow reaching the coastal area due to water-management activities occurring within the river catchment, activities such as human consumption, irrigation, storage, etc. For this reason, many coastal and regional ocean models continue to impose surface zero-salinity discharges as land boundary conditions for representing such a dynamic boundary. Moreover, river flows are based in climatologies, thus neglecting seasonal and interannual variability. To achieve those objectives, this study proposes an integrated methodology ranging from watershed models to validation in the coastal area and passing through methods and proxies for integrating the freshwater flows into regional ocean models. The main objective of this study is to explore the results obtained by using more sophisticated land boundary conditions based on the capacities of state-of-the-art hydrologic models combined with observation networks. In addition to the evaluation of the source of river-flow data, this work also explores the use of estuarine proxies based on simple modelling grids. The estuarine proxies enable the incorporation of the mixing processes that take place in estuaries into the land fluxes and obtain the plume momentum. The watershed, estuarine proxies, and ocean were modelled using the MOHID Water modelling system and evaluated in western Iberia waters. The modelling results served to illustrate the sea surface salinity extension of the Western Iberia Buoyant Plume (WIBP) during an extreme event in March 2018.
Palabras clave: freshwater discharges; operational oceanography; sea surface salinity; IBI region; land boundary; estuarine proxy; water continuum; numerical models
Cazzaniga I., Zibordi G., Mélin F., Kwiatkowska E., Talone M., Dessailly D., Gossn J.I., Müller D. (2022)
Evaluation of OLCI Neural Network radiometric water products
IEEE Geoscience and Remote Sensing Letters, 19, 1-5. DOI: 10.1109/LGRS.2021.3136291. (BibTeX: cazzaniga.etal.2022)
Radiometric water products from the Neural Network (NNv2) in the Alternative Atmospheric Correction (AAC) processing chain of Ocean and Land Colour Instruments (OLCI) were assessed over different marine regions. These products, not included among the operational ones, were custom produced from the Copernicus Sentinel-3 OLCI Baseline Collection 3. The assessment benefitted of in situ reference data from the Ocean Color component of the Aerosol Robotic Network (AERONET-OC) from sites representative of different water types. These included clear waters in the Western Mediterranean Sea, optically-complex waters characterized by varying concentrations of total suspended matter and chromophoric dissolved organic matter (CDOM) in the northern Adriatic Sea, and optically-complex waters characterized by very high concentrations of CDOM in the Baltic Sea. The comparison of the water-leaving radiances 𝑳𝑾𝑵 derived from OLCI data on board Sentinel-3A and Sentinel-3B with those from AERONET OC confirmed consistency between the products from the two satellite sensors. However, the accuracy of satellite data products exhibited dependence on the water type. A general underestimate of 𝑳𝑾𝑵 was observed for clear waters. Conversely, overestimates were observed for data products from optically-complex waters with the worst results obtained for CDOM-dominated waters. These findings suggest caution in exploiting NNv2 radiometric products, especially for highly absorbing and clear waters.
Palabras clave: Remote Sensing, Ocean Color, Validation
Gabarró C., Fabregat P., Hernández-Maciá F., Jove R., Salvador J., Spreen G., Thielke L., Dadic R., Huntemann M., Kolabutin N., Nomura D., Hannula H.R., Schneebeli M. (2022)
First results of the ARIEL L-band radiometer on the MOSAiC Arctic Expedition during the late summer and autumn period
Elementa: Science of the Anthropocene, 10, 1 DOI: 10.1525/elementa.2022.00031. (BibTeX: gabarro.etal.2022)
Arctic sea ice is changing rapidly. Its retreat significantly impacts Arctic heat fluxes, ocean currents, and ecology, warranting the continuous monitoring and tracking of changes to sea ice extent and thickness. L-band (1.4 GHz) microwave radiometry can measure sea ice thickness for thin ice 1 m, depending on salinity and temperature. The sensitivity to thin ice makes L-band measurements complementary to radar altimetry which can measure the thickness of thick ice with reasonable accuracy. During the Multidisciplinary drifting Observatory for the Study of Arctic Climate (MOSAiC) expedition, we deployed the mobile ARIEL L-band radiometer on the sea ice floe next to research vessel Polarstern to study the sensitivity of the L-band to different sea ice parameters (e.g., snow and ice thickness, ice salinity, ice and snow temperature), with the aim to help improve/validate current microwave emission models. Our results show that ARIEL is sensitive to different types of surfaces (ice, leads, and melt ponds) and to ice thickness up to 70 cm when the salinity of the sea ice is low. The measurements can be reproduced with the Burke emission model when in situ snow and ice measurements for the autumn transects were used as model input. The correlation coefficient for modeled Burke brightness temperature (BT) versus ARIEL measurements was approximately 0.8. The discrepancy between the measurements and the model is about 5%, depending on the transects analyzed. No explicit dependence on snow depth was detected. We present a qualitative analysis for thin ice observations on leads. We have demonstrated that the ARIEL radiometer is an excellent field instrument for quantifying the sensitivity of L-band radiometry to ice and snow parameters, leading to insights that can enhance sea ice thickness retrievals from L-band radiometer satellites (such as Soil Moisture Ocean Salinity (SMOS) and Soil Moisture Active Passive (SMAP)) and improve estimates of Arctic sea-ice thickness changes on a larger scale
Palabras clave: Radiometry, Arctic, Emissivity, Sea ice, SMOS
Gimeno J., Jorba À., Nicolás B., Olmedo E. (2022)
Numerical computation of high-order expansions of invariant manifolds of high-dimensional tori
SIAM Journal on Applied Dynamical Systems, 21, 3, 1832-1861. DOI: 10.1137/21M1458363. (BibTeX: gimeno.etal.2022)
In this paper we present a procedure to compute reducible invariant tori and their stable and unstable manifolds in Poincar´e maps. The method has two steps. In the first step we compute, by means of a quadratically convergent scheme, the Fourier series of the torus, its Floquet transformation,and its Floquet matrix. If the torus has stable and/or unstable directions, in the second step we compute the Taylor-Fourier expansions of the corresponding invariant manifolds up to a given order. The paper also discusses the case in which the torus is highly unstable so that a multiple shooting strategy is needed to compute the torus. If the order of the Taylor expansion of the manifolds is fixed and N is the number of Fourier modes, the whole computational effort (torus and manifolds) increases as OpN log Nq and the memory required behaves as OpNq. This makes the algorithm very suitable to compute high-dimensional tori for which a huge number of Fourier modes are needed. Besides, the algorithm has a very high degree of parallelism. The paper includes examples where we compute invariant tori (of dimensions up to 5) of quasi-periodically forced ODEs. The computations are run in a parallel computer and its efficiency with respect to the number of processors is also discussed.
Palabras clave: Parametrization method, Quasi-periodic Floquet Theory, Jet transport, and Parallel computing
González-Gambau V., Olmedo E., Turiel A., González-Haro C., García-Espriu A., Martínez J., Alenius P., Tuomi L., Catany R., Arias M., Gabarró C., Hoareau N., Umbert M., Sabia R., Fernández D. (2022)
First SMOS Sea Surface Salinity dedicated products over the Baltic Sea
Earth System Science Data, 14, 2343-2368. DOI: 10.5194/essd-14-2343-2022. (BibTeX: gonzalezgambau.etal.2022)
This paper presents the first Soil Moisture and Ocean Salinity (SMOS) Sea Surface Salinity (SSS) dedicated products over the Baltic Sea. The SSS retrieval from L-band brightness temperature (TB) measurements over this basin is really challenging due to important technical issues, such as the land–sea and ice–sea contamination, the high contamination by radio-frequency interference (RFI) sources, the low sensitivity of L-band TB at SSS changes in cold waters, and the poor characterization of dielectric constant models for the low SSS range in the basin. For these reasons, exploratory research in the algorithms used from the level 0 up to level 4 has been required to develop these dedicated products. This work has been performed in the framework of the European Space Agency regional initiative Baltic+ Salinity Dynamics. Two Baltic+ SSS products have been generated for the period 2011–2019 and are freely distributed: the Level 3 (L3) product (daily generated 9 d maps in a 0.25◦ grid; https://doi.org/10.20350/digitalCSIC/13859, González-Gambau et al., 2021a) and the Level 4 (L4) product (daily maps in a 0.05◦ grid; https://doi.org/10.20350/ digitalCSIC/13860, González-Gambau et al., 2021b), which are computed by applying multifractal fusion to L3 SSS with SST maps. The accuracy of L3 SSS products is typically around 0.7–0.8 psu. The L4 product has an improved spatiotemporal resolution with respect to the L3 and the accuracy is typically around 0.4 psu. Regions with the highest errors and limited coverage are located in Arkona and Bornholm basins and Gulfs of Finland and Riga. The impact assessment of Baltic+ SSS products has shown that they can help in the understanding of salinity dynamics in the basin. They complement the temporally and spatially very sparse in situ measurements, covering data gaps in the region, and they can also be useful for the validation of numerical models, particularly in areas where in situ data are very sparse.
Grieco G., Stoffelen A., Verhoef A., Vogelzang J., Portabella M. (2022)
Analysis of Data-Derived SeaWinds Normalized Radar Cross-Section Noise
Remote Sensing, 14, 21, 5444. DOI: 10.3390/rs14215444. (BibTeX: grieco.etal.2022)
The normalized standard deviation (Kp) of the noise that affects scatterometer Normalized Radar Cross-Sections (σ0s) plays a key role in the ocean and more in particular coastal wind retrieval procedures and the a posteriori quality control. This paper presents a method based on SeaWinds measurements to estimate Kps. The method computes the standard deviation of the differences between the full-resolution (slice) σ0s and the footprint (egg) σ0. The results are compared to the median of Kps provided with SeaWinds σ0s, showing some non-negligible differences. Kps estimated on non-homogeneous surfaces are larger than those estimated on sea, whereas no differences are appreciated in the provided Kps, which is likely due to the ability of this methodology to account for the effect of the scene variability in the estimates. The presence of inter-slice biases is demonstrated with a trend with the antenna azimuth angle. A multi-collocation slice cross-calibration procedure is suggested for the retrieval stage. Finally, a theoretical model of the distribution of σ0s is proposed and used to validate Kps. The results prove the efficacy of this model and that the provided Kps seem to be largely underestimated at low-wind regimes.
Palabras clave: SeaWinds; normalized radar cross-section noise; wind
Isern-Fontanet J., Capet X., Turiel A., Olmedo E., González-Haro C. (2022)
On the Seasonal Cycle of the Statistical Properties of Sea Surface Temperature
Geophysical Research Letters, 49 DOI: 10.1029/2022GL098038. (BibTeX: isernfontanet.etal.2022)
The contribution of ocean fronts to the properties and temporal evolution of Sea Surface Temperature (SST) structure functions have been investigated using a numerical model of the California Current system. First, the intensity of fronts have been quantified by using singularity exponents. Then, leaning on the multifractal theory of turbulence, we show that the departure of the scaling of the structure functions from a straight line, known as anomalous scaling, depends on the intensity of the strongest fronts. These fronts, at their turn, are closely related to the seasonal change of intensity of the coastal upwelling characteristics of this area. Our study points to the need to correctly reproduce the intensity of the strongest fronts and, consequently, properly model processes such as coastal upwelling in order to reproduce SST statistics in ocean models.
King G.P., Portabella M., Lin W., Stoffelen A. (2022)
Correlating extremes in wind divergence with extremes in rain over the Tropical Atlantic
Remote Sensing, 14, 5, 1147. DOI: 10.3390/rs14051147. (BibTeX: king.etal.2022)
Air–sea fluxes are greatly enhanced by the winds and vertical exchanges generated by mesoscale convective systems (MCSs). In contrast to global numerical weather prediction models, space-borne scatterometers are able to resolve the small-scale wind variability in and near MCSs at the ocean surface. Downbursts of heavy rain in MCSs produce strong gusts and large divergence and vorticity in surface winds. In this paper, 12.5 km wind fields from the ASCAT-A and ASCAT-B tandem mission, collocated with short time series of Meteosat Second Generation 3 km rain fields, are used to quantify correlations between wind divergence and rain in the Inter-Tropical Convergence Zone (ITCZ) of the Atlantic Ocean. We show that when there is extreme rain, there is extreme convergence/divergence in the vicinity. Probability distributions for wind divergence and rain rates were found to be heavy-tailed: exponential tails for wind divergence (P∼e −αδ with slopes that flatten with increasing rain rate), and power-law tails for rain rates (P∼(R ∗ ) −β with a slower and approximately equal decay for the extremes of convergence and divergence). Co-occurring points are tabulated in two-by-two contingency tables from which cross-correlations are calculated in terms of the odds and odds ratio for each time lag in the collocation. The odds ratio for extreme convergence and extreme divergence both have a well-defined peak. The divergence time lag is close to zero, while it is 30 min for the convergence peak, implying that extreme rain generally appears after (lags) extreme convergence. The temporal scale of moist convection is thus determined by the slower updraft process, as expected. A structural analysis was carried out that demonstrates consistency with the known structure of MCSs. This work demonstrates that (tandem) ASCAT winds are well suited for air–sea exchange studies in moist convection
Palabras clave: air–sea interaction; scatterometer winds; ASCAT; Meteosat Second Generation; ocean wind divergence; tropical convection; mesoscale convective systems; compound extremes; heavytailed PDFs
Latasa M., Scharek R., Anxelu X., Morán G., Gutiérrez-Rodríguez A., Emelianov M., Salat J., Vidal M., Estrada M. (2022)
Dynamics of phytoplankton groups in three contrasting situations of the open NW Mediterranean Sea revealed by pigment, microscopy, and flow cytometry analyses
Progress in Oceanography, 201, 102737 DOI: 10.1016/j.pocean.2021.102737. (BibTeX: latasa.etal.2022)
A detailed study of phytoplankton composition and dynamics was carried out during three contrasting situations (cruises F1, F2, and F3) in the northwestern (NW) Mediterranean Sea. Haptophytes, diatoms, and green algae dominated in F1, during the spring bloom, with high nutrients and high phytoplankton biomass. In F2, the postbloom situation with a still weak stratification and lower nutrient concentrations, we found a high spatial variability. Stations were clearly dominated by either Synechococcus, haptophytes or cryptophytes; with Syn echococcus reaching the highest abundance (4 × 105 cells mL− 1, 60% of the integrated chlorophyll a) reported to date for the open Mediterranean Sea. Cryptophytes accumulated close to the surface in very shallow mixed layer stations. In late summer, F3 revealed a fully developed stratification with low nutrients and a marked deep chlorophyll maximum (DCM). Prochlorococcus was present only during this cruise, mainly in deep layers together with haptophytes and pelagophytes, while haptophytes and Synechococcus dominated the upper mixed layer. Flow cytometry (FCM) and pigment-based abundance estimates for Prochlorococcus, Synechococcus and cryptophytes were well correlated, as happened also between small picoeukaryotes (FCM) and green algae (pigments), and between large picoeukaryotes (FCM) and haptophytes (pigments). Dinoflagellate abundance by microscopy and by pigments did not agree well, probably due to the presence of heterotrophic forms or because they con tained pigments other than peridinin, the standard dinoflagellate marker. The decrease in size of the FCM large picoeukaryotes group with depth was presumably related to the increasing contribution of pelagophytes, with smaller cells than haptophytes, the other main component of this fraction. Cell size increase of Prochlorococcus and Synechococcus with depth suggests vertical segregation of genotypes or photoadaptation. The groups' ecological preferences are presented with respect to depth and nutrient concentrations. Synechococcus and cryptophytes occupied shallow layers; diatoms, green algae and Prochlorococcus showed a tendency for deep layers and pelagophytes for even deeper layers, while haptophyte and dinoflagellate allocations were less clear. As for nutrients, the maximum relative contributions of green algae and especially diatoms occurred when dissolved inorganic phosphorus (DIP) concentrations were highest, of Prochlorococcus, dinoflagellates and pelagophytes when lowest, and of Synechococcus and cryptophytes when DIP concentrations were low but not minimal. The contribution of haptophytes did not show a relationship with DIP concentration. These results from individual groups stand as significant exceptions to the general relationship between phytoplankton cell size and nutrient availability.
Palabras clave: HPLC CHEMTAX Spring bloom Synechococcus bloom Ecological preferences Size distribution
Lin W., Portabella M. (2022)
Characterizing global sea surface local wind variability from ASCAT data
IEEE Transactions on Geoscience and Remote Sensing, 60, 1-10. DOI: 10.1109/TGRS.2022.3228317. (BibTeX: lin.portabella.2022)
Recent advances in the sea surface wind quality control of the Advanced Scatterometer (ASCAT) show that spatial wind variability within a resolution cell of 25 km 25 km, namely the subcell wind variability, is highly correlated with the ASCAT quality indicators, such as the wind inversion residual (maximum likelihood estimator, MLE) and the singularity exponent (SE) derived from singularity analysis. This opens up opportunities for quantifying the instantaneous spatial wind variability over the global sea surface. In this paper, it is assumed that the spatial wind variability is linearly proportional to the temporal variation of buoy sea surface winds time-series following the Taylor's hypothesis. As such, the moored buoy winds with 10-minute sampling are used to examine the subcell wind variability. Then the sensitivity of ASCAT quality indicators to the subcell wind variability is evaluated. The results indicate that although SE is more sensitive than MLE in characterizing the wind variability, they are mainly complementary in flagging the most variable winds. Consequently, an empirical model is derived to relate the buoy wind vector variability to the ASCAT MLE and/or SE values. Although the overall procedure is based on the one-dimensional temporal analysis and such empirical model cannot fully represent the two-dimensional spatial variability, it leads for the first time to the development of an ASCAT-derived local wind variability product. The empirical method presented here is straightforward and can be applied to other scatterometer systems.
Palabras clave: Advanced Scatterometer (ASCAT), wind variability, maximum likelihood estimator (MLE), singularity exponent (SE), subcell
Liu S., Lin W., Portabella M., Wang Z. (2022)
Characterization of tropical cyclone intensity using the HY-2B scatterometer wind data
Remote Sensing, 14, 4, 1035. DOI: 10.3390/rs14041035. (BibTeX: liu.etal.2022)
The estimation of tropical cyclone (TC) intensity using Ku-band scatterometer data is challenging due to rain perturbation and signal saturation in the radar backscatter measurements. In this paper, an alternative approach to directly taking the maximum scatterometer-derived wind speed is proposed to assess the TC intensity. First, the TC center location is identified based on the unique characteristics of wind stress divergence/curl near the TC core. Then the radial extent of 17-m/s winds (i.e., R17) is calculated using the wind field data from the Haiyang-2B (HY-2B) scatterometer (HSCAT). The feasibility of HSCAT wind radii in determining TC intensity is evaluated using the maximum sustained wind speed (MSW) in the China Meteorological Administration best-track database. It shows that the HSCAT R17 value generally better correlates with the best-track MSW than the HSCAT maximum wind speed, therefore indicating the potential of using the HSCAT data to improve the TC nowcasting capabilities.
Palabras clave: scatterometer; tropical cyclone; wind radii; intensity; HY-2 satellite
Lloret J., Turiel A., Solé J., Berdalet E., Sabatés A., Olivares A., Gili J.M., Vila-Subirós J., Sardá R. (2022)
Unravelling the ecological impacts of large-scale offshore wind farms in the Mediterranean Sea
Science of The Total Environment, 824, 153803 DOI: 10.1016/j.scitotenv.2022.153803. (BibTeX: lloret.etal.2022)
The need for alternative energy systems like offshore wind power to move towards the Green Deal objectives is unde niable. However, it is also increasingly clear that biodiversity loss and climate change are interconnected issues that must be tackled in unison. In this paper we highlight that offshore wind farms (OWF) in the Mediterranean Sea (MS) pose serious environmental risks to the seabed and the biodiversity of many areas due to the particular ecological and socioeconomic characteristics and vulnerability of this semi-enclosed sea. The MS hosts a high diversity of species and habitats, many of which are threatened. Furthermore, valuable species, habitats, and seascapes for citizens\' health and well-being coexist with compounding effects of other economic activities (cruises, maritime transport, tourism ac tivities, fisheries and aquaculture) in a busy space on a narrower continental shelf than in other European seas. We argue that simply importing the OWF models from the northern European seas, which are mostly based on large scale projects, to other seas like the Mediterranean is not straightforward. The risks of implementing these wind farms in the MS have not yet been well evaluated and, considering the Precautionary Principle incorporated into the Marine Strategy Framework Directive and the Maritime Spatial Planning Directive, they should not be ignored. We propose that OWF development in the MS should be excluded from high biodiversity areas containing sensitive and threatened species and habitats, particularly those situated inside or in the vicinity of Marine Protected Areas or areas with valuable seascapes. In the absence of a clearer and comprehensive EU planning of wind farms in the MS, the trade-off between the benefits (climate goals) and risks (environmental and socioeconomic impacts) of OWF could be unbalanced in favor of the risks
Palabras clave: Offshore energy Marine protected areas, environmental impacts, biodiversity Maritime spatial planning, seascape Renewable energy Mediterranean Sea
Marín-Beltrán I., Demaria F., Ofelio C., Serra L.M., Turiel A., Ripple W.J., Mukul S.A., Costa M.C. (2022)
Scientists\' warning against the society of waste
Science of The Total Environment, 811, 151359 DOI: 10.1016/j.scitotenv.2021.151359. (BibTeX: marinbeltran.etal.2022)
The metabolism of contemporary industrialized societies, that is their energy and material flows, leads to the overconsumption and waste of natural resources, two factors often disregarded in the global ecological equation. In this Discussion article, we examine the amount of natural resources that is increasingly being consumed and wasted by humanity, and propose solutions to reverse this pattern. Since the beginning of the 20th century, societies, especially from industrialized countries, have been wasting resources in different ways. On one hand, the metabolism of industrial societies relies on non-renewable resources. On the other hand, yearly, we directly waste or mismanage around 78% of the total water withdrawn, 49% of the food produced, 31% of the energy produced, 85% of ores and 26% of non-metallic minerals extracted, respectively. As a consequence, natural resources are getting depleted and ecosystems polluted, leading to irreversible environmental changes, biological loss and social conflicts. To reduce the anthropogenic footprint in the planet, and live in harmony with other species and ourselves, we suggest to shift the current economic model based on infinite growth and reduce inequality between and within countries, following a degrowth strategy in industrialized countries. Public education to reduce superfluous consumption is also necessary. In addition, we propose a set of technological strategies to improve the management of natural resources towards circular economies that, like ecosystems, rely only upon renewable resources.
Martínez J., Gabarró C., Turiel A., González-Gambau V., Umbert M., Hoareau N., González-Haro C., Olmedo E., Arias M., Catany R., Bertino L., Raj R.P., Xie J., Sabia R., Fernández D. (2022)
Improved BEC SMOS Arctic Sea Surface Salinity product v3.1
Earth System Science Data, 14, 1, 307–323. DOI: 10.5194/essd-14-307-2022. (BibTeX: martinez.etal.2022)
Measuring salinity from space is challenging since the sensitivity of the brightness temperature (TB) to sea surface salinity (SSS) is low (about 0.5 K psu−1 ), while the SSS range in the open ocean is narrow (about 5 psu, if river discharge areas are not considered). This translates into a high accuracy requirement of the radiometer (about 2–3 K). Moreover, the sensitivity of the TB to SSS at cold waters is even lower (0.3 K psu−1 ), making the retrieval of the SSS in the cold waters even more challenging. Due to this limitation, the ESA launched a specific initiative in 2019, the Arctic+Salinity project (AO/1-9158/18/I-BG), to produce an en hanced Arctic SSS product with better quality and resolution than the available products. This paper presents the methodologies used to produce the new enhanced Arctic SMOS SSS product (Martínez et al., 2019) . The product consists of 9 d averaged maps in an EASE 2.0 grid of 25 km. The product is freely distributed from the Barcelona Expert Center (BEC, http://bec.icm.csic.es/, last access: 25 January 2022) with the DOI number https://doi.org/10.20350/digitalCSIC/12620 (Martínez et al., 2019). The major change in this new product is its improvement of the effective spatial resolution that permits better monitoring of the mesoscale structures (large than 50 km), which benefits the river discharge monitoring.
Martínez J., García-Ladona E., Ballabrera-Poy J., Isern-Fontanet J., González-Motos S., Allegue J.M., González-Haro C. (2022)
Atlas of surface currents in the Mediterranean and Canary–Iberian–Biscay waters.
Journal of Operational Oceanography DOI: 10.1080/1755876X.2022.2102357. (BibTeX: martinez.etal.2022b)
Sea surface currents probably are the most relevant essential ocean variable affecting diverse societal challenges concerning the marine environmental (as, for example, safe and efficient navigation, marine pollution and ecological connectivity). This work introduces a climatological Atlas (monthly resolution) of currents in the Mediterranean and Canary–Iberian–Biscay basins, based on today's state of the art reanalyses of the ocean circulation. The focus is on surface and subsurface reanalyses (here understood as z 0.5 and z 15 m, respectively) provided by the Copernicus Marine Environment Monitoring Service (CMEMS). The climatological values are computed from the median of the empirical probability density functions and the Atlas also includes the variance matrix and a bimodality index to have quantitative information on their variability. For both domains, the subsurface climatological fields are reasonably consistent with circulation schemes proposed in the previous literature but clearly improving the time and space resolution of the emerging patterns. For the Canary–Iberian–Biscay domain, the monthly climatological surface currents capture accurately the characteristic seasonal signal and its transition between a favourable and non-favourable upwelling regime. In the Mediterranean basin, differences between the near-surface and the 15 m velocity fields suggest a non- negligible role of winds over the variability of the uppermost ocean layer, specially in the Eastern Mediterranean basin. This is, up to our knowledge, the first time that such near-surface climatological patterns are computed. It has been found that, in general, the resulting patterns agree with surface drifter trajectories. In several regions, interannual variability foster bimodal and multimodal probability distributions. The Atlas has been conceived with the purpose of providing a first quantitative assessment on the surface circulation, thus being a complementary tool of real-time ocean forecasting systems. The Atlas is distributed following the FAIR principles and is accompanied with a digital version, with enhanced visualization capabilities for both research and assessment
Palabras clave: Currents, climatology, atlas, Mediterranean, Atlantic, Iberian; Canary, Biscay
Miracca-Lage M., González-Haro C., Campagnoli-Napolitano D., Isern-Fontanet J., Simionatto-Polito P. (2022)
Can the Surface Quasi-Geostrophic (SQG) Theory Explain Upper Ocean Dynamics in the South Atlantic?
Journal of Geophysical Research: Oceans, 127 DOI: 10.1029/2021JC018001. (BibTeX: miraccalage.etal.2022)
Satellite altimeters provide quasi-global measurements of sea surface height, and from those the vertically integrated geostrophic velocity can be directly estimated, but not its vertical structure. This study discusses whether the mesoscale (30–400 km) dynamics of three regions in the South Atlantic can be described by the surface quasi-geostrophic (SQG) theory, both at the surface and in depth, using outputs from an ocean general circulation model. At these scales, the model surface eddy kinetic energy (EKE) spectra show slopes close to k−5/3 (k−3) in winter (summer), characterizing the SQG and quasi-geostrophic (QG) turbulence regimes. We use surface density and temperature to (a) reconstruct the stream function under the SQG theory, (b) assess its capability of reproducing mesoscale motions, and (c) identify the main parameters that improve such reconstruction. For mixed layers shallower than 100 m, the changes in the mixed-layer depth contributes nine times more to the surface SQG reconstruction than the EKE, indicating the strong connection between the quality of the reconstruction and the seasonality of the mixed layer. To further explore the reconstruction vertical extension, we add the barotropic and first baroclinic QG modes to the surface solution. The SQG solutions reproduce the model density and geostrophic velocities in winter, whereas in summer, the interior QG modes prevail. Together, these solutions can improve surface correlations (>0.98) and can depict spatial patterns of mesoscale structures in both the horizontal and vertical domains. Improved spatial resolution from upcoming altimeter missions poses a motivating scenario to extend our findings into future observational studies.
Nicolaus M., Perovich D.K., Spreen G., Granskog M.A., von Albedyll L., Angelopoulos M., Anhaus P., Arndt S., Belter H.J., Bessonov V., , Brauchle J., Calmer R., Cardellach E., Cheng B., , Dadic R., Damm E., de Boer G., Demir O., Dethloff K., Divine D.V., Fong A.A., Fons S., Frey M.M., Fuchs N., Gabarró C., , Goessling H.F., Gradinger R., Haapala J., Haas C., , Hannula H.R., Hen.dricks S, Herber A., Heuzé C., , Hoyland K.V., Huntemann M., Hutchings J.K., Hwang B., , Jacobi H.W., Jaggi M., Jutila A., Kaleschke L., Katlein C., , Krampe D., Kristensen S.S., Krumpen T., Kurtz N., , Lange B.A., Lei R., Light B., Linhardt F., Liston G.E., , Macfarlane A.R., Mahmud M., Matero I.O., Maus S., , Naderpour R., Nandan V., Niubom A., Oggier M., Oppelt N., Pätzold F., Perron C., Petrovsky T., Pirazzini R., Polashenski C., , Raphael I.A., Regnery J., Rex M., Ricker R., Riemann-Campe K., Rinke A., Rohde J., Salganik E., Scharien R.K., Schiller M., , Semmling M., Shimanchuk E., Shupe M.D., Smith M.M., , Sokolov V., Stanton T., Stroeve J., Thielke L., , Tonboe R.T., Tavri A., Tsamados M., Wagner D.N., , Webster M., Wendisch M. (2022)
Overview of the MOSAiC expedition: Snow and sea ice
Elementa: Science of the Anthropocene, 10, 1 DOI: 10.1525/ elementa.2021.000046. (BibTeX: nicolaus.etal.2022a)
Year-round observations of the physical snow and ice properties and processes that govern the ice pack evolution and its interaction with the atmosphere and the ocean were conducted during the Multidisciplinary drifting Observatory for the Study of Arctic Climate (MOSAiC) expedition of the research vessel Polarstern in the Arctic Ocean from October 2019 to September 2020. This work was embedded into the interdisciplinary design of the 5 MOSAiC teams, studying the atmosphere, the sea ice, the ocean, the ecosystem, and biogeochemical processes.The overall aim of the snow and sea ice observations during MOSAiC was to characterize the physical properties of the snow and ice cover comprehensively in the central Arctic over an entire annual cycle. This objective was achieved by detailed observations of physical properties and of energy and mass balance of snow and ice. By studying snow and sea ice dynamics over nested spatial scales from centimeters to tens of kilometers, the variability across scales can be considered. On-ice observations of in situ and remote sensing properties of the different surface types over all seasons will help to improve numerical process and climate models and to establish and validate novel satellite remote sensing methods; the linkages to accompanying airborne measurements, satellite observations, and results of numerical models are discussed. We found large spatial variabilities of snow metamorphism and thermal regimes impacting sea ice growth. We conclude that the highly variable snow cover needs to be considered in more detail (in observations, remote sensing, and models) to better understand snow-related feedback processes.The ice pack revealed rapid transformations and motions along the drift in all seasons. The number of coupled ice–ocean interface processes observed in detail are expected to guide upcoming research with respect to the changing Arctic sea ice
Olivar M.P., Castellón A., Sabatés A., Sarmiento-Lezcano A., Emelianov M., Bernal A., Yang Y., Proud R., Brierley A.S. (2022)
Variation in mesopelagic fish community composition and structure between Mediterranean and Atlantic waters around the Iberian Peninsula
Frontiers in Marine Science DOI: 10.3389/fmars.2022.1028717. (BibTeX: olivar.etal.2022)
Mesopelagic fish populations are characterised by high species richness and abundance, and have been identified as important contributors to the active carbon fluxes in the open ocean. We report variability in communities of mesopelagic fish between five zones around the Iberian Peninsula, i.e. Balears and Alboran in the Mediterranean, and Cadiz, Lisboa and Galicia in the Atlantic. Day and night samples were collected from 7 layers of the water column with a midwater trawl fitted with a multisampler. Temperature and salinity regimes were very different on the Mediterranean and Atlantic sides of the peninsula, with much higher values through the entire water column in the Mediterranean, characterized by a strong pycnocline. The highest productivity was observed off Lisboa, where Chlorophyll a concentrations were two orders of magnitude higher than in any other zone. Samples from the western Mediterranean held 22 fish species, while 67 were found in the Atlantic. The lowest diversity and the highest dominance were observed in Balears, and the highest diversity in Cadiz zone. In all zones, but particularly in those in the Mediterranean, mesopelagic populations were dominated by a high number of small fish with low individual biomasses. The species Benthosema glaciale, Cyclothone pygmaea and Ceratoscopelus maderensis were common in the Mediterranean populations, whereas in the Atlantic, Cyclothone microdon/ livida, Valenciennellus tripunctulatus, Ceratoscopelus warmingii and Benthosema suborbitale were the most common species. Temperature and salinity (both at surface and in the mesopelagic zone) were the main environmental factors explaining variability in assemblage composition. A persistent (day-night) deep scattering layer was observed using the vessel based echosounder in all zones, and was comprised primarily of the gonostomatid Cyclothone spp. Night-time echosounder observations of scattering layers near the surface were observed in Balears, Alboran, Cadiz and Lisboa, where night surface net collections indicated that Myctophidae, Stomiidae and Phosichthyidae migration extended to the upper 100 m. Sternoptychids and the gonostomatid Sigmops elongatus seldom reached the upper 100 m in their night vertical migrations. Night stratified hauls of 30 m resolution carried out in the epipelagic zone showed that abundances maxima of migratory fish coincided with the location of the Chlorophyll a maxima.
Palabras clave: diversity, bristlemouths, lanternfishes, vertical migration, deep scattering layers
Olmedo E., Turiel A., González-Gambau V., González-Haro C., García- Espriu A., Gabarró C., Portabella M., Corbella I., Martín-Neira M., Arias M., Catany R., Sabia R., Oliva R., Scipal K. (2022)
Increasing stratifcation as observed by satellite sea surface salinity measurements
Scientific Reports, 12, 6279 DOI: 10.1038/s41598-022-10265-1. (BibTeX: olmedo.etal.2022)
Changes in the Earth's water cycle can be estimated by analyzing sea surface salinity. This variable reflects the balance between precipitation and evaporation over the ocean, since the upper layers of the ocean are the most sensitive to atmosphere–ocean interactions. In situ measurements lack spatial and temporal synopticity and are typically acquired at few meters below the surface. Satellite measurements, on the contrary, are synoptic, repetitive and acquired at the surface. Here we show that the satellite-derived sea surface salinity measurements evidence an intensification of the water cycle (the freshest waters become fresher and vice-versa) which is not observed at the in-situ near-surface salinity measurements. The largest positive differences between surface and near-surface salinity trends are located over regions characterized by a decrease in the mixed layer depth and the sea surface wind speed, and an increase in sea surface temperature, which is consistent with an increased stratification of the water column due to global warming. These results highlight the crucial importance of using satellites to unveil critical changes on ocean–atmosphere fluxes.
Ortigosa I., Bardaji R., Carbonell A., Carrasco O., Castells-Sanabra M., Figuerola R., Hoareau N., Mateu J., Piera J., Puigdefabregas J., Salvador J., Simon C., Vallès-Casanova I., Pelegrí J.L. (2022)
Barcelona Coastal Monitoring with the "Patí a Vela", a Traditional Sailboat Turned into an Oceanographic Platform
Journal of Marine Science and Engineering, 10, 591 DOI: 10.3390/jmse100505. (BibTeX: ortigosa.etal.2022)
Shelf waters near large cities, such as Barcelona, are affected not only by meteorological episodes but also by anthropogenic influence. Scientists usually use data from on-site coastal platforms to analyze and understand these complex water ecosystems because remote sensing satellites have low spatiotemporal resolution and do not provide reliable data so close to the coast. However, platforms with conventional oceanographic instrumentation are expensive to install and maintain. This study presents the scientific adaptation and initial measurements from a "patí a vela", which is a very popular unipersonal catamaran in Barcelona. This versatile sailing vessel has been adapted to contain several low-cost sensors and instruments to measure water properties. Here, we describe the setup of a multi-parameter prototype, and then focus on results obtained using a low-cost temperature profiler. First, the temperature data are compared and validated with another conventional oceanographic instrument used in monthly oceanographic cruises. Then, field measurements between July and November 2021 are used to explore the relationship between air and water temperature in the Barcelona coastal area, showing the seasonal evolution of the temperature profile. We conclude that citizen sampling from fully sustainable sailing boats may turn into an effective strategy to monitor the urban coastal waters.
Palabras clave: scientific sailing boat; low-cost sensors; temperature-depth profiler; citizen science
Ostrovskii A.G., Emelianov M.V., Kochetov O.Y., Kremenetskiy V.V., Shvoev D.A., Volkov S.V., Zatsepin A.G., Korovchinsky N.M., Olshanskiy V.M., Olchev A.V. (2022)
Automated Tethered Profiler for Hydrophysical and Bio-Optical Measurements in the Black Sea Carbon Observational Site
Journal of Marine Science and Engineering, 10, 322 DOI: 10.3390/jmse10030322. (BibTeX: ostrovskii.etal.2022)
Biogeochemical cycles of carbon transformation throughout the euphotic zone of the sea are controlled by physical processes, e.g., daily thermocline, variation in solar irradiance, thermohaline convection, and intermittent mixing. These processes should be regularly observed with sufficient time resolution at fixed geographical locations. This study provides a brief overview of the carbon observational site in the Northeastern Black Sea. The focus is on the design of a new tethered profiler Winchi for the inner continental shelf part of the site. The profiler hull and two outriggers comprise an open trimaran platform that is positively buoyant and tends to maintain a horizontal position in the water. The lower end of the winch wire is secured to the bottom anchor. By unwinding/winding the wire, the profiler ascends/descends while measuring the depth profiles of marine environment parameters ranging from the seafloor to air–sea interface. After surfacing, the profiler determines its location using the Global Positioning System (GPS) and transmits data to (and from) a server on land through the Global System for Mobile Communications (GSM). Initial field tests with the Winchi profiler at the Northeastern Black Sea shelf exhibited promising results. We report these early tests to demonstrate the use of Winchi.
Palabras clave: greenhouse gases; carbon flux; tethered profiler; winch; real-time data transmission; Black Sea
Polverari F., Portabella M., Lin W., Saap J.W., Stoffelen A., Jelenak Z., Chang P.S. (2022)
On High and Extreme Wind Calibration Using ASCAT
IEEE Transactions on Geoscience and Remote Sensing, 60 DOI: 10.1109/TGRS.2021.3079898. (BibTeX: polverari.etal.2022)
Accurate high and extreme sea surface wind observations are essential for the meteorological, ocean, and climate applications. To properly assess and calibrate the current and future satellite-derived extreme winds, including those from the C-band scatterometers, building a consolidated high and extreme wind reference data set is crucial. In this work, a new approach is presented to assess the consistency between moored buoys and stepped-frequency microwave radiometer (SFMR)- derived winds. To overcome the absence of abundant direct collocations between these two data sets, the reprocessed Advanced Scatterometer (ASCAT)-A winds at the 12.5-km resolution, from 2009 to 2017, have been used to perform an indirect SFMR/buoy winds' intercomparison. The ASCAT/SFMR analysis reveals an ASCAT wind underestimation for winds of above 15 m/s. SFMR measurements are calibrated using GPS drop-wind-sondes (dropsondes) data and averaged along-track to represent ASCAT spatially. On the other hand, ASCAT and buoy winds are in good agreement up to 25 m/s. The buoy high-wind quality has been confirmed using a triple collocation approach. Comparing these results, both SFMR and buoy winds appear to be highly correlated with ASCAT at the high-wind regime; however, they show a very different wind speed scaling. An SFMR-based recalibration of ASCAT winds is proposed, the so-called ASCAT dropsonde-scale winds, for use by the extreme wind operational community. However, further work is required to reconcile dropsonde (thus, SFMR) and buoy wind measurements under extreme wind conditions
Palabras clave: High and extreme wind speeds, microwave radiometry, ocean wind reference, spaceborne scatterometry
Polverari F., Sapp J.W., Portabella M., Stoffelen A., Jelenak Z., Chang P.S. (2022)
On dropsonde surface-adjusted winds and their use for the Stepped Frequency Microwave Radiometer wind speed calibration
IEEE Transactions on Geoscience and Remote Sensing, 60 DOI: 10.1109/TGRS.2022.3189310. (BibTeX: polverari.etal.2022a)
The airborne Stepped Frequency Microwave Radiometer (SFMR) provides measurements of 10-m ocean- surface wind speed in high and extreme wind conditions. These winds are calibrated using the surface-adjusted wind estimates from the so-called dropsondes. The surface-adjusted winds are obtained from layer-averaged winds scaled to 10-m altitude to eliminate the local surface variability not associated with the storm strength. The SFMR measurements and, consequently, the surface-adjusted dropsonde winds represent a possible reference for satellite instrument and model calibration/validation at high and extreme wind conditions. To this end, representativeness errors that those measurements may introduce need to be taken into account to ensure that the storm variability is correctly resolved in satellite retrievals and modelling. In this work, we compare the SFMR winds with the dropsonde surface-adjusted winds derived from the so-called WL150 algorithm, which uses the lowest 150-meter layer between 10 m to 350 m. We use nine years of data from 2009 to 2017. We focus on the effects of the layer altitude and thickness. Our analysis shows that the layer altitude has a significant impact on dropsonde/SFMR wind comparisons. Moreover, the averaged winds obtained from layers thinner than the nominal 150 m and closer to the surface are more representative of the SFMR surface wind speed than the WL150 speeds. We also find that the surface-adjusted winds are more representative of 10-km horizontally averaged SFMR winds. We conclude that for calibration/validation purposes, the WL150 algorithm can introduce noise and the use of actual 10-m dropsonde measurements should be further investigated.
Palabras clave: Calibration, dropsondes, ocean surface high and extreme wind reference, tropical cyclones, microwave radiometry
Portal G., Vall-llosera M., Piles M., Jagdhuber T., Camps A., Pablos M., López-Martínez C., Das N.N., Entekhabi D. (2022)
Impact of Incidence Angle Diversity on SMOS and Sentinel-1 Soil Moisture Retrievals at Coarse and Fine Scales
IEEE Transactions on Geoscience and Remote Sensing, 60, 1, 18. DOI: 10.1109/TGRS.2022.3187467. (BibTeX: portal.etal.2022)
Incidence angle diversity of space-borne radiometer1 and radar systems operating at low microwave frequencies needs2 to be taken into consideration to accurately estimate soil mois-3 ture (SM) across spatial scales. In this study, the single channel4 algorithm (SCA) is first applied to Soil Moisture and Ocean5 Salinity (SMOS) brightness temperatures at vertical polarization6 (TBV ) to estimate SM at coarse resolution (25 km) and develop a7 land cover-specific and incidence angle (32.5◦ , 42.5◦, and 52.5◦ )-8 adaptive calibration of single scattering albedo (ω) and soil9 roughness (h s ) parameters. These effective parameters are used10 together with fine-scale multiangular Sentinel-1 backscatter in a11 single-pass active–passive downscaling approach to estimate TBV12 at fine scale (1 km) for each SMOS incidence angle. These TBV s13 are finally inverted to obtain the corresponding high-resolution14 SM maps. Results over the Iberian Peninsula for year 2018 show15 an increasing trend of ω and a decreasing trend of h s with16 SMOS incidence angle, with almost no variability of ω across17 land cover types. The active–passive covariation parameter is18 shown to increase with SMOS incidence angle and decrease with19 Sentinel-1 incidence angle. Coarse and fine TBV maps from the20 three SMOS incidence angles show similar distributions (mean differences below 0.38 K). Resulting high-resolution SM maps 22 have maximum differences in mean and standard deviation of 23 0.016 and 0.015 m3 /m3 , respectively, and compare well with 24 in situ measurements. Our results indicate that model-based 25 microwave approaches to estimate SM can be adequately adapted 26 to account for the incidence angle diversity of planned missions, 27 such as Copernicus Microwave Imaging Radiometer (CIMR), 28 Radar Observing System for Europe in L-band (ROSE-L), and 29 Sentinel-1 next generation.
Palabras clave: Active–passive microwave, incidence angle, radiometry, signal covariation, spatial disaggregation.
Salvador X., Fernández-Vilert R., Moles J. (2022)
Sea slug night fever: 39 new records of elusive heterobranchs in the western Mediterranean (Mollusca: Gastropoda)
Journal of Natural history, 56, 5-8, 265-310. DOI: 10.1080/00222933.2022.2040630. (BibTeX: salvador.etal.2022)
Citizen (or community) science has provided copious and valuable information about charismatic marine taxa such as heterobranch gastropods, thus contributing enormously to the known geographic distribution of many sea slug species. This study reports new records of elusive sea slugs in the coastal western Mediterranean (especially on the Catalan and French Mediterranean coasts) and contributes to new ecological information regarding their phenology, diet and behaviour. Out of 39 species reported here, 23 are new records for the Catalan coast (NE Spain), three are new records of pelagic pteropods for the Spanish Iberian coast, and eight are new records for the French Mediterranean coast. With 25 species found active at night, this study highlights the importance of sampling at night and in shallow, often under-sampled waters with high species diversity. Shallow waters usually have less diving activity and are harder to survey with heavy scuba equipment. We believe that the high-quality photos herein and the related species information will enable researchers, divers and the community to find and recognise these rare species in the Mediterranean basin.
Palabras clave: marine heterobranchs; new records; uncommon species; Mediterranean Sea; byodiversity
Umbert M., Hoareau N., Salat J., Salvador J., Guimbard S., Olmedo E., Gabarró C. (2022)
The contribution of the Vendée Globe Race to improved ocean surface information: A validation of the remotely sensed salinity in the sub-Antarctic zone.
Journal of Marine Science and Engineering, 10, 8 DOI: 10.3390/jmse10081078. (BibTeX: umbert.etal.2022b)
The Vendée Globe is the world's most famous solo, non-stop, unassisted sailing race. The Institute of Marine Sciences and the Barcelona Ocean Sailing Foundation installed a MicroCAT on the One Ocean One Planet boat. The skipper, Dídac Costa, completed the round trip in 97 days, from 8 November 2020 to 13 February 2021, providing one measurement of temperature and conductivity every 30 s during navigation. More than half of the ship's route was in the sub-Antarctic zone, between the tropical and polar fronts, and it passed through areas of oceanographic interest such as Southern Patagonia (affected by glacier melting), the Brazil–Malvinas confluence, the Southern Pacific Ocean, and the entire Southern Indian Ocean. This sailing race gave a rare opportunity to measure in-situ sea surface salinity in a region where satellite salinity measurements are not reliable. Due to the decreased sensitivity of brightness temperature to salinity in cold seas, retrieving sea surface salinity at high latitudes remains a major challenge. This paper describes how the data are processed and uses the data to validate satellite salinity products in the sub-Antarctic zone. The sailing race measurements represent surface information (60 cm depth) not available from drifters or Argo floats. Acquiring measurements using round-the-world sailing races would allow us to analyse the evolution of ocean salinity and the impact of changes in the ice extent around Antarctica.
Palabras clave: sea surface temperature; sea surface salinity; ocean circumnavigation; ships of opportunity; SMOS validation; sub-Antarctic zone
Vázquez A.J., Elosegui P., Lonsdale C.J., Crew G.B., Fish V.L., Ruszczyk C.A. (2022)
Model-based Performance Characterization of Software Correlators for Radio Interferometer Arrays
Publications of the Astronomical Society of the Pacific, 134, 1040, 12pp. DOI: https://doi.org/10.1088/1538-3873/ac8dc2. (BibTeX: vazquez.etal.2022)
Correlation for radio interferometer array applications, including Very Long Baseline Interferometry (VLBI), is a multidisciplinary field that traditionally involves astronomy, geodesy, signal processing, and electronic design. In recent years, however, high-performance computing has been taking over electronic design, complicating this mix with the addition of network engineering, parallel programming, and resource scheduling, among others. High- performance applications go a step further by using specialized hardware like Graphics Processing Units (GPUs) or Field Programmable Gate Arrays (FPGAs), challenging engineers to build and maintain high-performance correlators that efficiently use the available resources. Existing literature has generally benchmarked correlators through narrow comparisons on specific scenarios, and the lack of a formal performance characterization prevents a systematic comparison. This combination of ongoing increasing complexity in software correlation together with the lack of performance models in the literature motivates the development of a performance model that allows us not only to characterize existing correlators and predict their performance in different scenarios but, more importantly, to provide an understanding of the trade-offs inherent to the decisions associated with their design. In this paper, we present a model that achieves both objectives. We validate this model against benchmarking results in the literature, and provide an example for its application for improving cost-effectiveness in the usage of cloud resources.
Viudez A. (2022)
Exact solutions of time-dependent oscillations in multipolar spherical vortices
Journal of Fluid Mechanics, 949, A-13 DOI: 10.1017/jfm.2022.754. (BibTeX: viudez.2022a)
Exact solutions of the time-dependent three-dimensional nonlinear vorticity equation for Euler flows with spherical geometry are provided. The velocity solution is the sum of a multipolar oscillatory function and a rigid cylindrical motion with swirl. The multipolar oscillation is a velocity mode whose radial and angular dependencies are given by the spherical Bessel functions and vector spherical harmonics, respectively. The local frequency of the velocity oscillations equals the angular speed of the rigid flow times the angular azimuthal wavenumber of the oscillating flow. The unsteady motion corresponds to inertial oscillations in multipolar flows with spatial azimuthal waves (non-vanishing azimuthal wavenumber) in the presence of a background flow with constant axial vorticity. In these nonlinear solutions, the curl of the Lamb vector has a linear dependence with the oscillation velocity, a property that makes it possible for the oscillating motion to satisfy different linear wave equations. Based on these inviscid time-dependent velocity modes, new exact solutions to the time-dependent Navier–Stokes equation are also provided.
Palabras clave: waves in rotating fluids, Navier–Stokes equations, vortex dynamics
Viúdez A. (2022)
Multipolar spherical and cylindrical vortices
Journal of Fluid Mechanics, 936, A13 DOI: 10.1017/jfm.2022.73. (BibTeX: viudez.2022)
Multipolar spherical solutions to the three-dimensional steady vorticity equation are provided. These solutions are based on the separation of radial and angular contributions in terms of the spherical Bessel functions and vector spherical harmonics, respectively. In this set of multipolar vortex solutions, the Hicks–Moffatt swirling vortex is categorized as a vortex of degree l = 1 and therefore as a vortex dipole. This swirling vortex is the three-dimensional dipole in spherical geometry equivalent to the two-dimensional Lamb–Chaplygin dipole in polar geometry. The three-dimensional dipole solution admits two linearly superposable solutions. The first one is a Trkalian flow and the second one is a cylindrical solid-body rotation with swirl. The higher l > 1 multipolar vortices found are either vanishing-helicity vortices or Trkalian flow vortices. The multipolar Trkalian flows admit two circular polarizations given by the sign of the wavenumber k. It is also found that piecewise vortex solutions, consisting of interior rotational and exterior potential flow domains, satisfying velocity continuity conditions at the vortex boundary, are possible in the general multipolar Trkalian spherical vortex. A particular polarized dipole solution in three-dimensional cylindrical geometry, consisting as well in the superposition of a Trkalian flow and a rigid motion, is also analysed. This swirling vortex may be interpreted as the three-dimensional dipole in cylindrical geometry equivalent to the two-dimensional Lamb–Chaplygin dipole in polar geometry.
Palabras clave: vortex flows
On the superposition of multipolar spherical and cylindrical oscillations in swirling rigid flow
European Journal of Mechanics B/Fluids, 98, 247-252. DOI: 10.1016/j.euromechflu.2022.12.011. (BibTeX: viudez.2022b)
It is shown that a superposition of an arbitrary number of multipolar spherical and cylindrical oscillations in a cylindrical rigid flow with swirl is an exact solution to the time-dependent nonlinear vorticity equation. The oscillations are normal modes whose fundamental frequency and radial wavenumber are given by the angular speed and scaled inverse pitch, respectively, of the rigid flow.
Palabras clave: exact solucions, vortex flows, waves in swirling flow
Wang S., Yang X., Portabella M., Yuen K.V., Zhang M., Du Y. (2022)
A SAR-Based Parametric Model for Tropical Cyclone Tangential Wind Speed Estimation
IEEE Journal of Selected Topics in Applied Earth Observations and Remote Sensing, 15, 8806-8818. DOI: 10.1109/JSTARS.2022.3213822. (BibTeX: wang.etal.2022)
The tangential wind speed increases from the center to the eyewall of tropical cyclones (TC) along the radial direction and begins to decay when it extends outward. The tangential wind profile model is one of the most effective and widely used methods to reconstruct the TC radial wind speed. This article proposes a parametric tangential wind profile (TWP) model based on high- spatial-resolution synthetic aperture radar (SAR) imagery. The new model functions are piecewise with maximum tangential wind speed as a threshold, and all of them are designed as nonlinear. Notably, the derivative at the segmentation threshold is zero to ensure a smooth transition of the estimated wind speed profile. With the SAR-derived azimuth-averaged wind speed, we can determine the model parameters and get the tangential wind speed. The TWP model outperforms the commonly used single-modified Rankine vortex (SMRV) model, as it better resolves the tangential wind profile shape as depicted by both SAR-derived winds and hurricane hunter stepped-frequency microwave radiometer derived winds. A comprehensive analysis of the TWP model parameters is carried out by fitting tangential winds for 620 hurricane hunter flights. Interestingly, the tangential wind profiles for major hurricanes show a similar shape. The proposed TWP model can be used for improved TC characterization and forecasting purposes
Palabras clave: Parametric modeling, synthetic aperture radar (SAR), Tangential wind speed, tropical cyclone (TC)
Woods S.M., Daskolia M., Joly A., Bonnet P., Soacha K., Liñán S., Woods T., Piera J., Ceccaroni L. (2022)
How Networks of Citizen Observatories Can Increase the Quality and Quantity of Citizen-Science-Generated Data Used to Monitor SDG Indicators
Sustainability, 14, 4078 DOI: 10.3390/su14074078. (BibTeX: woods.etal.2022)
There is a growing acknowledgement that citizen observatories, and other forms of citizen- generated data, have a significant role in tracking progress towards the Sustainable Development Goals. This is evident in the increasing number of Sustainable Development Goals' indicators for which such data are already being used and in the high-level recognition of the potential role that citizen science can play. In this article, we argue that networks of citizen observatories will help realise this potential. Drawing on the Cos4Cloud project as an example, we highlight how such networks can make citizen-generated data more interoperable and accessible (among other qualities), increasing their impact and usefulness. Furthermore, we highlight other, perhaps overlooked, advantages of citizen observatories and citizen-generated data: educating and informing citizen scientists about the Sustainable Development Goals and co-creating solutions to the global challenges they addres
Palabras clave: citizen science; citizen observatory; Sustainable Development Goals; interoperability; co-design; education
Zhao X., Lin W., Portabella M., Wang Z., He Y. (2022)
Effects of rain on CFOSAT scatterometer measurements
Remote Sensing of Environment, 274, 113015 DOI: 10.1016/j.rse.2022.113015. (BibTeX: zhao.etal.2022)
The Ku-band scatterometer onboard China France Oceanography Satellite (CFOSAT) observes the sea surface with two conically scanning fan beams. Compared to the prior Ku-band pencil beam scatterometers, this innovative observing mechanism provides more independent backscatter measurements at varying incidence and azimuth angles, as such it brings challenges for the sea surface wind inversion, particularly under rainy conditions. In this paper, the rain effects on the CFOSAT SCATterometer (CSCAT) are investigated using the collocated numerical weather prediction (NWP) wind data and the Global Precipitation Measurement (GPM) microwave imager (GMI) rain data. Similar to the prior Ku-band or C-band scatterometers, the sensitivity of CSCAT radar backscatter to rain substantially varies with wind speed, radar polarization and incidence angle. However, due to the complex observation geometries, rain effects on the CSCAT retrieved winds is more complex than that of prior scatterometers, which may lead to a remarkable underestimation of CSCAT wind speed at high winds and heavy rain conditions. A simple simulation method is used to clarify the relation between the retrieved wind speed and the dependency of radar rain effects on the incidence angle. It is found that the backscatter measurements at low incidence angles, which are generally underestimated at high winds and heavy rainy condi tions, have a larger influence on the wind inversion minimization, leading to much lower retrieved wind speeds than those of ECMWF and the pencil beam scatterometer (e.g., Haiyang-2B scattometer). Under low and mod erate rain conditions though, a more compensated effect between low and high incidence angle measurements is found, leading to generally unbiased CSCAT high winds, in contrast to the generally underestimated pencil-beam scatterometer winds.
Palabras clave: CFOSAT Scatterometer Backscatter Rain effects Wind quality
Zibordi G., Talone M., Mélin F. (2022)
Uncertainty Estimate of Satellite-Derived Normalized Water-Leaving Radiance
IEEE Geoscience and Remote Sensing Letters, 19, 1502905, 1-5. DOI: 10.1109/LGRS.2021.3134876. (BibTeX: zibordi.etal.2022)
The quantification of uncertainties affecting satel lite ocean color products is a fundamental step to ensure their compliance with mission and science requirements. This work investigated a methodology relying on the use of in situ radiometric data with known uncertainties to determine those affecting matching satellite data. By exploiting in situ radiometric data from the Ocean Color component of the Aerosol Robotic Network (AERONET-OC), an advanced method was applied to radiometric data products from the Ocean and Land Color Instruments onboard the Sentinel-3A satellite (OLCI-A) and the Visible Infrared Imager Radiometer Suite onboard the Suomi National-Polar Orbiting Partnership satellite (VIIRS-S). The results from the analysis support the relevance of the method proposed.
Palabras clave: Ocean color, remote sensing, uncertainties
Zibordi G., Kwiatkowska E., Mélin F., Talone M., Cazzaniga I., Dessailly D., Gossn J.I. (2022)
Assessment of OLCI-A and OLCI-B radiometric data products across European seas
Remote Sensing of Environment, 272, 112911. DOI: 10.1016/j.rse.2022.112911. (BibTeX: zibordi.etal.2022a)
The Ocean and Land Color Instruments (OLCI) operated onboard the Copernicus Sentinel-3 satellites are providing globally distributed Ocean Color Radiometry (OCR) data products of relevance for environmental and climate applications. This work summarizes results on the assessment of fundamental OCR data from the Operational Baseline 3 Collection OL_L2M.003.01 of OLCI-A and OLCI-B onboard Sentinel-3A and Sentinel-3B, respectively. Evaluated products are the satellite derived normalized water-leaving radiance LWN(λ), aerosol optical depth at 865 nm τa(865) and Ångstrom ¨ exponent α determined in the near-infrared spectral region. The analyses were performed relying on in situ reference data from the Ocean Color component of the Aerosol Robotic Network (AERONET-OC) from sites representative of diverse water types. The comparison of OLCI-A and OLCI-B with AERONET-OC LWN(λ) for oligotrophic/mesotrophic waters shows cross-mission consistent spectral median percent differences (i.e., biases) varying within ±6% at the blue-green center-wavelengths. The analysis of data from regions characterized by optically complex waters, however, displays systematic negative biases for both OLCI-A and OLCI-B further increasing for waters dominated by chromophoric dissolved organic matter, thus suggesting a dependence of the atmospheric correction on water type. The direct inter-comparison of OLCI-B and OLCI-A LWN(λ) from the Tandem Phase characterized by Sentinel-3B and Sentinel-3A flying 30 s apart on the same orbit, shows spectral median percent differences lower than ±1% in the 412–560 nm interval, of approximately +5% at 620 and 665 nm, and − 7% at 400 nm. However, outside the Tandem Phase, the inter comparison of OLCI-B and OLCI-A data products indicates large and systematic differences explained by a notable dependence on the viewing angle. The evaluation of τa(865) and α across different geographic regions exhibits overestimated values between +48 and + 79% for the former and underestimated values between − 28% and − 41% for the latter. A complementary evaluation of OCR data products from the Visible Infrared Imager Radiometer Suite on board the Suomi National Polar-orbiting Partnership (VIIRS-S), proposed as a further in direct term of reference for OLCI-A and OLCI-B data, shows large underestimates of LWN(λ) with respect to the in situ reference data in the various water types at 410 nm. Nevertheless, opposite to OLCI-A and OLCI-B data products, absolute differences between VIIRS-S and in situ reference data do not reveal any large or systematic dependence on water type and satellite viewing angle. Overall results suggest the need for further developing the OLCI-A and OLCI-B atmospheric correction, possibly improving the capability to identify aerosol types and to model scattering processes.
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OtherPractice
Management of impetigo and cellulitis
Simple considerations for promoting appropriate antibiotic use in skin infections
Lynette Kosar and Tessa Laubscher
Canadian Family Physician August 2017, 63 (8) 615-618;
Lynette Kosar
Information Specialist for the RxFiles Academic Detailing Program for the Saskatoon Health Region in Saskatchewan and Assistant Clinical Professor in the College of Pharmacy at the University of Saskatchewan in Saskatoon.
For correspondence: [email protected]
Tessa Laubscher
Clinical Associate Professor of Academic Family Medicine at the University of Saskatchewan.
CFPlus
For years health care providers have been encouraged to judiciously use antibiotics in their practices. It is an important message, and programs have been developed to focus solely on promoting appropriate antibiotic use. While these initiatives are valuable, simple steps without a formalized program can have a positive effect on rational antimicrobial use. This article will review the evidence on antibiotics for the treatment of impetigo and cellulitis, and answer questions about the role of topical antibiotics, if antibiotics are required after incision and drainage of an abscess, and when empiric coverage for community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is recommended.
Charles is a 6-year-old boy seen in the clinic with "infected" mosquito bites on his face and limbs. He has no fever and feels well. He has no medical history of note and no known allergies. On examination he looks well; there are numerous excoriated papules on all his limbs and 5 discreet small patches of erythematous skin covered with yellow crusting on his chin and arms that he reports are itchy.
Bringing evidence to practice
Impetigo, the most common skin infection in young children, can occur when there is a disruption in the skin due to minor trauma (eg, insect bites, scratches).1 Yellow- or honey-crusted lesions are a classic sign of nonbullous impetigo, which accounts for 70% of impetigo cases.1,2 Nonbullous impetigo is most often caused by group A streptococcus, but might also be caused by S aureus or a combination of both.2
Can topical antibiotics be used to treat impetigo?
Clinical practice guidelines recommend a topical antibiotic for 5 to 7 days when treating uncomplicated impetigo infections with limited and localized lesions.2–4 A 2012 Cochrane review, which included 68 randomized controlled trials (RCTs) and 5578 patients, compared various treatment options for impetigo.5 The authors concluded that topical antibiotics (eg, mupirocin, fusidic acid) were as effective as oral antibiotics (eg, cephalosporins, macrolides), based on 22 RCTs involving 884 patients.5 Topical mupirocin was slightly superior to oral erythromycin (relative risk of 1.07, 95% CI 1.01 to 1.13) in 10 of these studies, with 581 patients.5 It was noted that studies were lacking in individuals with more extensive impetigo.5 There was also no evidence to support the combined use of a topical and an oral antibiotic for impetigo.5 One small RCT with 49 patients compared a topical antibiotic with a topical antibiotic plus an oral antibiotic and failed to show a benefit with dual therapy.5 Regarding which topical antibiotic to use, mupirocin and fusidic acid had similar efficacy based on 4 RCTs with 440 patients.5
In addition to being as effective as oral antibiotics, topical antibiotics have less systemic absorption and therefore less risk of adverse events.1 Topical therapy also reduces the risk of antimicrobial resistance compared with oral therapy1; however, resistance still occurs with overuse, and topical antibiotics should be reserved for skin infections, like impetigo, and not for noninfectious scratches or rashes.
Back to Charles
You prescribe a topical antibiotic for Charles because his impetigo lesions are limited and localized to the face and arms. You select 2% mupirocin ointment to be applied sparingly to the lesions 3 times daily for 5 days, as you are not aware of any local resistance to this antibiotic. You explain to his mother that the crusts do not need to be removed before applying the antibiotic4; however, you advise her that removing the crusts by soaking in warm water or using warm compresses might relieve skin itch. You encourage Charles to avoid scratching the lesions to minimize spreading the infection and to wash his hands frequently. You also instruct his mother to cover the lesions with bandages if he continues to scratch.
Two weeks later Charles returns to the clinic. The impetigo lesions initially resolved, but he is still scratching mosquito bites and his mother noticed new infected areas of skin yesterday. He now has several new patches of impetigo on his arms and legs with a 4 ×6-cm area of cellulitis on the dorsum of his left forearm. He is afebrile and looks well. His current weight is 25 kg.
Most of the limited evidence on impetigo focuses on uncomplicated infections.2 Based on clinical experience, clinical practice guidelines suggest oral antibiotics for the following2–4:
lesions that are unresponsive to topical antibiotics (ie, no improvement after 24 to 48 hours);
recurrent or widespread (ie, numerous or large) lesions;
infections that occur during an outbreak;
patients with constitutional symptoms suggesting bacteremia or a fever;
patients with lymphadenopathy, with valvular heart disease, or who are immunocompromised; and
patients who are younger than 1 month old.
Topical antibiotic therapy was appropriate when Charles first presented. However, with spreading of the infection, more extensive lesions, and cellulitis, an oral antibiotic is now preferred. You prescribe 325 mg of cephalexin 4 times daily (50 mg/kg daily), which will empirically cover group A streptococcus, the most common pathogen in impetigo and nonpurulent cellulitis.
As noted above, Charles does not have any medication allergies. However, if his mother reported a nonsevere penicillin allergy (eg, delayed rash during or after use of amoxicillin), cephalexin would still be an appropriate option. If the penicillin reaction was severe (eg, anaphylaxis), erythromycin or clindamycin could be used. Clinical response to erythromycin or clindamycin should be monitored owing to potential resistance concerns.3,4 The RxFiles document on β-lactam allergies is available from CFPlus.*
Mark is a 28-year-old man who presents with pain and swelling of his left lower leg. This evolved after scraping his leg while moving equipment at the local gym a few days ago. Mark is generally healthy; he takes no medications and has no allergies. He is mildly febrile with a temperature of 37.8°C; his pulse is 90 beats/min and his blood pressure is 122/68 mm Hg. On examination you note moderate swelling of his left lower leg and a small scabbed lesion on the lateral calf with surrounding skin erythema, warmth, and induration. Beneath the lesion is an area of fluctuation suggestive of an abscess about 3 cm in diameter.
Whereas group A streptococcus is the predominant causative bacteria in nonpurulent skin infections, purulent skin infections (eg, cutaneous abscess, purulent cellulitis) are often caused by S aureus.2 Categorizing skin infections as purulent versus nonpurulent helps tailor antibiotic therapy to the most likely organisms.2 Consideration of empiric coverage for CA-MRSA is primarily limited to purulent skin infections2 (Table 1).6,7
Empiric antibiotic selection for nonpurulent and purulent cellulitis
Are antibiotics needed after incision and drainage of an abscess?
Incision and drainage is recommended for all abscesses,2–4 as antibiotics penetrate pus poorly. Studies have shown that at least 75% of uncomplicated abscesses resolve after incision and drainage without antibiotics.8,9 A 2014 meta-analysis of 4 RCTs involving 589 patients found no difference in clinical cure rates when incision and drainage plus antibiotics was compared with incision and drainage alone (88.1% vs 86%, odds ratio of 1.17, 95% CI 0.7 to 1.95).9 More recently, an RCT of 1265 patients who underwent incision and drainage for uncomplicated skin abscesses compared high-dose (2 double-strength tablets twice daily) trimethoprim-sulfamethoxazole (TMP-SMX) for 7 days with placebo.8 The median abscess size was 2 × 2.5 cm, and approximately 45% of the S aureus isolates were methicillin-resistant S aureus (MRSA).8 The investigators found a modest improvement in clinical cure rates with the antibiotic (80.5% vs 73.6%, 95% CI 2.1 to 11.7) at days 14 to 21, which resulted in a number needed to treat of 14.8 The number needed to harm for antibiotic-related gastrointestinal adverse events was 15.8 There was no difference in the rate of invasive infections.8 The RxFiles trial summary of this study is available from CFPlus.*
Clinical practice guidelines suggest using an oral antibiotic for abscesses that are "complicated"2–4—for example, abscesses2–4
that are large (ie, greater than 5 cm) or not resolving;
with extensive cellulitis or rapid progression;
in areas where incision and drainage is difficult (eg, face, hands, genitalia);
in patients with systemic symptoms; or
in patients with substantial comorbidities, immuno-suppression, or extremes of age.
Cephalexin3 and cloxacillin3,4 are considered first-line options for purulent skin infections caused by methicillin-susceptible S aureus (Table 1).6,7 The Infectious Disease Society 2014 guideline on skin and soft tissue infections recommends 5 days of antibiotics, but notes therapy should be extended if the infection has not improved within this time period (strong recommendation, high level of evidence).2 The recommendation is based on a small RCT of 121 patients with uncomplicated cellulitis that compared 5 versus 10 days of antibiotic therapy.10 The rate of clinical success was the same for both treatment arms (98%) at 14 and 28 days after study enrolment.10
Back to Mark
In view of Mark's fever, clinical signs and symptoms of purulent cellulitis, and absence of CA-MRSA risk factors (Box 1), you prescribe 500 mg of cephalexin 4 times daily for 5 days. In addition, you perform incision and drainage of the abscess. You instruct him to return if he does not see improvement within a few days, if he has ongoing fever, or if he notes rapid progression with reaccumulation of pus or worsening redness or pain in his calf. You also provide him with a medical certificate to stay home from work and emphasize the importance of elevating his left lower leg to optimize wound healing.
Box 1. Risk factors for community-associated MRSA
Factors that increase the risk of community-associated MRSA include the following:
history of MRSA colonization or recent MRSA infection
previous hospitalization for a skin and soft tissue infection
age younger than 2 y or older than 65 y
antibiotic use in the past 6 mo
recent invasive procedures (eg, dialysis)
intravenous drug use
penetrating trauma
being an athlete, particularly one who plays contact sports
living in a correctional facility
being military personnel
homeless persons
residing in an endemic area for community-associated MRSA
MRSA—methicillin-resistant Staphylococcus aureus.
When is empiric coverage for CA-MRSA recommended?
In 2015, approximately 20% of S aureus isolates in Canada were MRSA, and fewer than half of these were community-associated strains.11 However, there are regional differences across the country, and health care providers are encouraged to be familiar with their local resistance patterns.11,12 Based on the latest Canadian Antimicrobial Resistance Surveillance System report, three-quarters of the MRSA isolates were nonblood isolates and approximately half of these were from skin and soft tissue infections.12 Skin infections often respond to antibiotics that do not cover MRSA, even if the patient has risk factors for CA-MRSA (Box 1).4 Thus, empiric therapy with a β-lactam is reasonable; however, coverage for CA-MRSA should be considered if the patient does not respond to the β-lactam or develops systemic symptoms (eg, fever), or if you have high suspicion of CA-MRSA.
If MRSA coverage is required for skin infections, the preferred antibiotics are TMP-SMX and doxycycline.3,4 Depending on local antibiogram data, clindamycin is often considered a third-line agent owing to concerns with group A streptococcus and MRSA resistance to clindamycin from overuse,3,4,7,* and owing to potential inducible resistance in MRSA from macrolide use.2 According to the 2015 Canadian Antimicrobial Resistance Alliance, 12% of CA-MRSA isolates were resistant to clindamycin, while 100% of isolates were sensitive to TMP-SMX and doxycycline.11 Clindamycin has also been associated with a 4-fold increased risk (relative risk of 3.92, 95% CI 1.15 to 136.43) of community-acquired Clostridium difficile diarrhea.13 In a small RCT of 524 patients with uncomplicated skin infections (which included purulent cellulitis and abscesses), there was no statistically significant difference in clinical cure rates between TMP-SMX and clindamycin, which was assessed 7 to 10 days after the end of treatment.14 Approximately one-third (32%, n = 167) had a positive culture for MRSA, of which 4% were resistant to clindamycin (3.5% in the TMP-SMX group and 4.5% in the clindamycin group).14 All abscesses underwent incision and drainage.14
How would the approach to empiric treatment change if Mark were a member of a competitive wrestling team and resided in a community known to have high rates of CA-MRSA?
Initial treatment with incision and drainage of his abscess and antibiotic therapy would remain unchanged; however, it would be beneficial to send a wound swab to assess for MRSA.4 It would be appropriate to select an antibiotic with activity against CA-MRSA, such as TMP-SMX or doxycycline.3,4 Clindamycin should be reserved for individuals with allergies to these agents. If there were concern about a mixed group A streptococcus and S aureus infection, treatment could be initiated with cephalexin plus TMP-SMX or doxycycline.
Integrating simple considerations for the management of skin infections into practice can facilitate judicious antibiotic use. Topical antibiotics are recommended for limited and localized uncomplicated impetigo. If the lesions are itchy, educating the patient and caregiver on measures to reduce scratching might help reduce the spread of impetigo. For cellulitis, stratification of treatment based upon the presence or absence of purulence, and subsequently the most likely pathogen, will assist with antibiotic selection. Empiric coverage for both group A streptococcus and S aureus is not required. Limit antibiotics with CA-MRSA coverage to patients with risk factors for CA-MRSA and, if required, consider TMP-SMX or doxycycline over clindamycin owing to resistance and safety concerns. All abscesses should be incised and drained, and uncomplicated abscesses might not require antibiotics.
We thank Dr Shaqil Peermohamed, Clinical Assistant Professor and infectious disease consultant in the Department of Medicine at the University of Saskatchewan in Saskatoon and Physician Lead for the Saskatoon Health Region's Antimicrobial Stewardship Program; Justin Kosar, Pharmacist Lead for the Saskatoon Health Region's Antimicrobial Stewardship Program; and Loren Regier, Program Coordinator for the RxFiles Academic Detailing Program in Saskatoon, for their contributions.
This article is eligible for Mainpro+ certified Self-Learning credits. To earn credits, go to www.cfp.ca and click on the Mainpro+ link.
La traduction en français de cet article se trouve à www.cfp.ca dans la table des matières du numéro d'août 2017 à la page e366.
RxFiles and contributing authors do not have any commercial competing interests. RxFiles Academic Detailing Program is funded through a grant from Saskatchewan Health to Saskatoon Health Region; additional "not for profit; not for loss" revenue is obtained from sales of books and online subscriptions. No financial assistance was obtained for this publication.
↵* The RxFiles document on β-lactam allergies, the trial summary, and the newsletter on antibiotics for skin infections are available at www.cfp.ca. Go to the full text of this article online and click on the CFPlus tab.
Copyright© the College of Family Physicians of Canada
Hartman-Adams H,
Banvard C,
Juckett G
. Impetigo: diagnosis and treatment. Am Fam Physician 2014;90(4):229-35.
Stevens DL,
Bisno AL,
Chambers HF,
Dellinger EP,
Goldstein EJ,
Gorbach SL,
. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis 2014;59(2):e10-52. Erratum in: Clin Infect Dis 2014;60(9):1448. Epub 2015 Feb 26.
Bugs and drugs [smartphone application]. Edmonton, AB: Alberta Health Services; 2017. Available from: www.bugsanddrugs.ca. Accessed 2017 Jun 27.
Anti-infective guidelines for community acquired infections. Toronto, ON: MUMS Guideline Clearinghouse; 2013. Anti-infective Review Panel.
Koning S,
van der Sande R,
Verhagen AP,
van Suijlekom-Smit LW,
Morris AD,
Butler CC,
. Interventions for impetigo. Cochrane Database Syst Rev 2012;(1):CD003261.
Gilbert D,
Chambers H,
Ellopoulous G,
Pavia A,
Black D,
. The Sanford guide to antimicrobial therapy 2017. 47th ed. Sperryville, VA: Antimicrobial Therapy, Inc; 2017.
RxFiles
. Antibiotics & common infections. ABX-2: uncomplicated cystitis and skin. Stewardship, effectiveness, safety & clinical pearls. Saskatoon, SK: RxFiles; 2017. Available from: www.rxfiles.ca/rxfiles/uploads/documents/ABX-2-Newsletter-Cystitis-and-SSTI.pdf. Accessed 2017 Jun 4.
Talan DA,
Mower WR,
Krishnadasan A,
Abrahamian FM,
Lovecchio F,
Karras DJ,
. Trimethoprim-sulfamethoxazole versus placebo for uncomplicated skin abscess. N Engl J Med 2016;374(9):823-32.
Singer AJ,
Thode HC Jr.
. Systemic antibiotics after incision and drainage of simple abscesses: a meta-analysis. Emerg Med J 2014;31(7):576-8. Epub 2013 May 18.
Hepburn MJ,
Dooley DP,
Skidmore PJ,
Ellis MW,
Starnes WF,
Hasewinkle WC
. Comparison of short-course (5 days) and standard (10 days) treatment for uncomplicated cellulitis. Arch Intern Med 2004;164(15):1669-74.
Canadian Antimicrobial Resistance Alliance [website]. Winnipeg, MB: Canadian Antimicrobial Resistance Alliance; Available from: www.can-r.com. Accessed 2017 Jun 9.
Canadian Antimicrobial Resistance Surveillance System—report 2016. Ottawa, ON: Public Health Agency of Canada; 2016. Available from: www.canada.ca/en/public-health/services/publications/drugs-health-products/canadian-antimicrobial-resistance-surveillance-system-report-2016.html. Accessed 2017 Jun 9.
Vardakas KZ,
Trigkidis KK,
Boukouvala E,
Falagas ME
. Clostridium difficile infection following systemic antibiotic administration in randomised controlled trials: a systematic review and meta-analysis. Int J Antimicrob Agents 2016;48(1):1-10. Epub 2016 Apr 27.
Miller LG,
Daum RS,
Creech CB,
Young D,
Downing MD,
Eells SJ,
. Clindamycin versus trimethoprim-sulfamethoxazole for uncomplicated skin infections. N Engl J Med 2015;372(12):1093-103.
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Microcephaly (my-kroh-SEF-uh-lee) is a rare neurological condition in which an infant's head is significantly smaller than the heads of other children of the same age and sex. Sometimes detected at birth, microcephaly usually is the result of the brain developing abnormally in the womb or not growing as it should after birth.
Microcephaly can be caused by a variety of genetic and environmental factors. Children with microcephaly often have developmental issues. Generally there's no treatment for microcephaly, but early intervention with supportive therapies, such as speech and occupational therapies, may help enhance your child's development and improve quality of life.
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The primary sign of microcephaly is:
A head size significantly smaller than that of other children of the same age and sex
Head size is measured as the distance around the top of the child's head (circumference). Using standardized growth charts, the measurement is compared with other children's measurements in percentiles.
Some children just have small heads, whose measurement falls as low as the first percentile. In children with microcephaly, head size measures significantly below average, possibly even below the first percentile for your baby's age and sex.
A child with more severe microcephaly may also have a backward-sloping forehead.
Chances are your doctor will detect microcephaly at the baby's birth or at a regular well-baby checkup. However, if you think your baby's head is smaller than normal or isn't growing as it should, talk to your doctor.
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Microcephaly usually is the result of abnormal brain development, which can occur in the womb (congenital) or during infancy. Microcephaly may be genetic. Other causes may include:
Craniosynostosis. The premature fusing of the joints (sutures) between the bony plates that form an infant's skull keeps the brain from growing. Treating craniosynostosis (kray-nee-o-sin-os-TOE-sis) usually means your infant needs surgery to separate the fused bones. If there are no underlying problems in the brain, this surgery allows the brain adequate space to grow and develop.
Chromosomal abnormalities. Down syndrome and other conditions may result in microcephaly.
Decreased oxygen to the fetal brain (cerebral anoxia). Certain complications of pregnancy or delivery can impair oxygen delivery to the fetal brain.
Infections passed to the fetus during pregnancy. These include toxoplasmosis, cytomegalovirus, German measles (rubella), chickenpox (varicella) and Zika virus.
Exposure to drugs, alcohol or certain toxic chemicals in the womb. Any of these put your baby at risk of brain abnormalities.
Severe malnutrition. Not getting adequate nutrition during pregnancy can affect your baby's development.
Uncontrolled phenylketonuria (fen-ul-kee-toe-NU-ree-uh), also known as PKU, in the mother. PKU is a birth defect that hampers the body's ability to break down the amino acid phenylalanine.
Some children with microcephaly are of normal intelligence and development, even though their heads will always be small for their age and sex. But depending on the cause and severity of the microcephaly, complications may include:
Developmental delays, such as in speech and movement
Difficulties with coordination and balance
Dwarfism or short stature
Facial distortions
Learning your child has microcephaly can raise questions about future pregnancies. Work with your doctor to determine the cause of the microcephaly. If the cause is genetic, you and may want to talk to a genetics counselor about the risk of microcephaly in future pregnancies.
By Mayo Clinic Staff
Hay WW, et al. Neurological assessment and neurodiagnostics. In: Current Diagnosis & Treatment: Pediatrics. 22nd ed. New York, N.Y.: McGraw-Hill Education; 2014. http://www.accessmedicine.com. Accessed Feb. 18, 2015.
Boom JA. Microcephaly in infants: Etiology and evaluation. http://www.uptodate.com/home. Accessed Feb. 18, 2015.
Microcephaly information page. National Institute of Neurological Disorders and Stroke. https://www.ninds.nih.gov/Disorders/All-Disorders/Microcephaly-Information-Page. Accessed April 1, 2018.
Hoecker JL (expert opinion). Mayo Clinic, Rochester, Minn. Feb. 20, 2015.
Nielsen-Saines K. Congenital Zika virus infection: Clinical features, evaluation, and management of the neonate. https://www.uptodate.com/contents/search. Accessed April 1, 2018.
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Series "Processes and Food Production Equipment"
Vitamin composition and biological value of altai dairy drink chegen Nadtochii L.A. , Arsenyeva T.P., Bukachakova L.Ch.
The process control system of heat treatment food Balubash V.A., Aleshichev S.E., Dobryakov V.A.
Substantiationof shelf stable functional ingredients from Jerusalem artichokeproduction technological parameters Baranenko D.A., Borisova I.I.
Role of baсterial cultures in formation of taste and aromatic of sour-cream butter Bodnarchuk O.V., Kigel N.F., Gukova Ya.F., Eresko G.O.
Experimental study of vertical autoclave temperature field Bredikhin S.A. , Skotnikov D.A.
Design and construction of resource-saving installations for the processing of slurries of citrus in the ultrasound Verboloz E.I., Raspopov К.S. , Amirova E.R.
Benefits of production of strudels without addition of preservative Domorackyi S. S., Gryazon D.Y.
Oscillatory mode of drying shredded carrots by infrared radiation* Demidov S.F., Voronenko B.A., Pelenko V.V., Demidov A.S., Elovik D.K.
Drying leaves and shredded celery by infrared radiation Demidov S.F., Voronenko B.A., Pelenko V.V., Demidov A.S., Dergunov M.V.
Fermenting fish trimmings using enzyme-based drug transglutaminase Domorackaya M.V. , Domorackyi S. S.
The study of the influence of the mass fraction of green tea extract on the organoleptic characteristics of curd product Evstigneeva T.N., Mikhailova A.V., Yakovleva R.V.
Studying of influence of ultrasound on some production phases of flour confectionery in the convection steamer Ivanova M.A. , Rekuto N.V.
Pectin and its impact on consumer properties of fruit sugar confectionery Koldina T.V., Vitovtov A.A.
Study of features of probiotic cultures fermentation mixture of milk and serum containing extracts of berries Krasnikova Ludmila Vasilievna, Zhukova A.D.
Rheological characteristics ofabnormallyviscous foodproducts and othermedia Krupoderov А.U., Nikolaev L.K., Кузнецов А.В.
The usage of protein stimulants of by-products of meat processing for the needs of natural grassland Kutsakova V. E., Kremenevskaya M.I., Dobryagin R.V., Kalinina O.A., Pavlova A.I.
The choice of varieties of hops for the technology of dry hopping Matveeva N.A. , Titov A.A.
Research and intensification of dynamic crushing fruit lemon beverage with pulp Minaeva L.V. , Alexeev G.V.
Features change the hue of a boiled sausage products arising under the influence of betulin Murashev S.V., Petukhova D.B., Svetlichnaya V.D.
Stability of iron-porphyrin complexes red colo and properties of the ligand Paramonova A.P., Murashev S.V.
Mathematical model of the separation of meat and bone meat raw materials high-energy water jets Murashov I.D. , Petrakov S.A. , Zhuravleva D.A.
Scaling of the device with opposite twirled streams the inert carrier for drying an agar agar Kutsakova V. E., Namliyev Yu.V., Panina T.S., Fedorova A.M.
Investigation of the method of reception of liquid fof smoking on the basis acoustically generated aerosol Nikonova A.S. , Ivaney A.A.
Analytical and experimental evaluation of the effect of the friction torque kinematic pair knife-lattice performance shredder Pelenko V.V., Zuev N.A., Ольшевский Р.Г., Ivanenko V.P., Krysin A.G.
The chemical composition of fennel storage frozen Prokofjev A.A., Stepanova N.Y.
The nutritional value of mint and lemon balm in fresh and frozen Prokofjev P.A., Stepanova N.Y.
Improving the efficiency of purification and deodorization gas emissions in columns packed with polymer-type nozzle Shpilin D.I., Pronin V.A.
Development and production of cheese products with vegetable components Rudakova A.Yu. , Zabodalova L.A.,, Serova O. P.
Antioxidant activity of vegetable raw materials in processes of freezing and vacuum dehydration Semenov G. V., Budantsev E.V., Krasnova I.S.
Verification of computer simulation of a flow of a coolant in a buffer tank of cooling system Timofeyevsky A.L., Borozdkin S.V. , Saifullin T.I.
Extraction of garlicphytoncides for meat products microbiological stability increase during refrigerated storage Khlibov N.A., Baranenko D.A.
Blancmange with radioprotective fillers Kukushkina O.M. , Arsenyeva T.P.
Systematic approach to the analysis of process water-heat and enzymatic treatment of the grain material in the production technology of edible ethanol. 1. Analysis of the block "Medium" Alexander G. Novoselov, Chebotar A.V., Gulyaeva Yu. N.
Approaches of the ill-defined logic in study biotechnology for rational use food resource Egoshina E.V., Alexeev G.V., Verboloz E.I., Basheva E.P., Borovkov M.I.
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Single-Layer WEBs: Intrasaccular Flow Disrupters for Aneurysm Treatment—Feasibility Results from a European Study
J. Caroff, C. Mihalea, J. Klisch, C. Strasilla, A. Berlis, T. Patankar, W. Weber, D. Behme, E.A. Jacobsen, T. Liebig, S. Prothmann, C. Cognard, T. Finkenzeller, J. Moret and L. Spelle
American Journal of Neuroradiology October 2015, 36 (10) 1942-1946; DOI: https://doi.org/10.3174/ajnr.A4369
J. Caroff
aFrom the Interventional Neuroradiology NEURI Center (J.C., C.M., J.M., L.S.), Beaujon Hospital, Clichy, France
ORCID record for J. Caroff
C. Mihalea
bDepartment of Neurosurgery (C.M.), University of Medicine and Pharmacy "Victor Babes," Timisoara, Romania
J. Klisch
cDepartment of Neuroradiology (J.K., C.S.), Helios General Hospital, Erfurt, Germany
C. Strasilla
A. Berlis
dDepartment of Diagnostic and Interventional Neuroradiology (A.B.), Klinikum Augsburg, Augsburg, Germany
T. Patankar
eMRI Department (T.P.), Leeds Teaching Hospitals National Health Service Trust, Leeds, UK
W. Weber
fInterventional Neuroradiology (W.W.), Ruhr University Medical Center, Bochum, Germany
D. Behme
gDepartments of Radiology and Neuroradiology (D.B.), Klinikum Vest, Recklinghausen, Germany
E.A. Jacobsen
hInterventional Neuroradiology (E.A.J.), Oslo University Hospital, Oslo, Norway
T. Liebig
iInterventional Neuroradiology (T.L.), Universitatsklinik Koeln, Köln, Germany
S. Prothmann
jAbteilung für Diagnostische und Interventionelle Neuroradiologie (S.P.), Klinikum rechts der Isar, Technische Universität München, München, Germany
C. Cognard
kInterventional Neuroradiology (C.C.), Centre Hospitalier Universitaire Hôpital Purpan, Toulouse, France
T. Finkenzeller
lInterventional Neuroradiology (T.F.), Klinikum Nürnberg Süd, Nürnberg, Germany.
J. Moret
L. Spelle
BACKGROUND AND PURPOSE: The safety and efficiency of the dual-layer Woven EndoBridge (WEB) device has already been published. However, this international multicenter study sought to evaluate the safety of single-layer devices, which are the newest generation of the WEB intrasaccular flow-disrupter family. They have been designed to offer smaller-sized devices with a lower profile to optimize navigability and delivery, which may, in turn, broaden their range of use.
MATERIALS AND METHODS: Data from all consecutive patients treated with a single-layer WEB device, in 10 European centers from June 2013 to May 2014 were included. Clinical presentations, technical details, intra- and perioperative complications, and outcomes at discharge were recorded. Clinical and angiographic data at last follow-up were also analyzed when available.
RESULTS: Ninety patients with 98 WEB-treated aneurysms were included in this study. In 93 cases (95%), WEB placement was possible. Complete occlusion at the end of the procedure was obtained in 26 instances (26%). Additional treatment during the procedure (coiling and/or stent placement) was necessary in 12 cases (12.7%). Procedure-related complications occurred in 13 cases, leading to permanent neurologic deficits in 4 patients (4.4%). Early vascular imaging follow-up data were available for 44 patients (57%), with an average time interval of 3.3 months. Treatment-related morbidity and mortality rates at last follow-up were 2.2% and 1.1%, respectively.
CONCLUSIONS: In this study, the feasibility and safety of the single-layer WEB device was comparable with that of the double-layer. However, further studies are needed to evaluate long-term efficacies.
dual-layer
Woven EndoBridge
single-layer
single-layer sphere.
The Woven EndoBridge dual-layer device (WEB-DL; Sequent Medical, Aliso Viejo, California) is an intrasaccular flow-disruption device, initially developed to treat wide-neck bifurcation intracranial aneurysms. It has proved to be a highly feasible, safe,1⇓⇓–4 and efficient5 technique, particularly dedicated to the treatment of aneurysms challenging to treat with standard coiling.
The single-layer WEB (WEB-SL) device is the newest generation of the WEB family. Improved microbraiding technology allows a reduction in device size and profile, which optimizes navigability (through smaller catheters) and delivery. The purpose of this study was to evaluate the feasibility and safety of this new device, which has been available in Europe since 2013.
All patients with planned treatment with the WEB-SL device, in the 10 participating centers from June 2013 to May 2014, were consecutively included in this study. No exclusion criteria were used. The decision to use the WEB-single-layer device was made locally by the interventional teams and was based on aneurysm characteristics (size, wide-neck, bifurcation location, and so forth) in each case. It mostly corresponded to bifurcation aneurysms with aspect ratios of <1.2, in which adjunctive techniques to coiling would have been required.6 Informed consent was obtained from all patients.
WEB Devices
The WEB-SL and WEB-single-layer sphere (SLS) are the latest generation of WEB devices and became available for use in 2013 (Fig 1). The WEB-SL is barrel-shaped (similar to the WEB-DL) and the WEB-SLS is spheric. They are available in various diameters, from 4 to 11 mm and heights from 3 to 9 mm. Unlike the WEB-DL, the WEB-SL and SLS devices can contain from 144 wires in the 4-mm-diameter devices to 216 wires in the 11-mm-diameter devices. They present a lower profile and were designed for use with the VIA-27 and VIA-33 catheters (Sequent Medical), which are 3F and 3.4F (outer diameter), respectively. The VIA-33 is dedicated to the WEB-SL and SLS devices with diameters of 10 mm and above.
WEB-SL device family. A, The barrel-shaped WEB-SL, similar to the WEB-DL. B, The spheric WEB-SLS.
Treatment Technique
Endovascular treatment was performed with the patient under general anesthesia and systemic heparinization. By the end of the procedure, the heparin therapy was discontinued but not reversed. Antiplatelet medications were used pre- and postoperatively, depending on local protocols and angiographic results. In 94% of cases, VIA catheters were used for WEB delivery. The use of antiplatelet agents in the pre- and postoperative periods was decided locally and for each case by the operator. Even if the use of an antiplatelet agent is not mandatory with the WEB device, depending on local habits, some patients were premedicated with aspirin and clopidogrel in case of a strategy shift to stent-assisted coiling.
For each aneurysm, we collected the following data retrospectively: age, sex, aneurysm location and biometry (maximum diameter, neck size, aspect ratio), rupture status, the modified Rankin Scale score at the time of admission and discharge, modalities of treatment (WEB type and size, associated medication and treatment), intraoperative complications (aneurysm rupture, thromboembolic events, deployment failure, WEB protrusion or migration), and postoperative complications (delayed bleeding, thromboembolic events). Immediate postoperative DSA, 3D rotational angiography, and VasoCT (Philips Healthcare, Best, the Netherlands)7 images were collected, along with any available follow-up imaging data (DSA, CTA, MRA).
Data were self-reported by the different centers, but the principal investigators (J.C. and L.S.) performed a blinded review of the clinical and angiographic data, as an independent core laboratory not involved in patient care. Adverse events were adjudicated independently from operators. Permanent morbidity and mortality rates, subsequent to treatment, were evaluated at discharge and at follow-up when possible. Morbidity was defined as an mRS of >1. When the preoperative mRS was >1, morbidity was defined by any increase in the mRS score.
The principal investigators also independently assessed the degree of aneurysmal occlusion, by using a modified version of the Montreal 5-grade scale as previously published.8 The Beaujon Occlusion Scale Score is described as follows: 0 = no residual flow inside the aneurysm or the WEB, 0′ = opacification of the proximal recess of the WEB, 1 = residual flow inside the WEB, 2 = neck remnant, 3 = aneurysm remnant, and 1 + 3 = contrast media depicted inside and around the device (Fig 2).
WEB occlusion scale. Grade 0 indicates complete occlusion. Grade 0′ is similar but with opacification of the proximal recess, which may also be considered complete occlusion. Grade 1 signifies opacification inside the WEB. Grade 2 denotes a neck remnant. Grade 3 indicates an aneurysm remnant with contrast agent inside the sac between the wall and the WEB device.
Ninety patients (60 women and 30 men; age range, 26–83 years; median age, 55 years) with 98 WEB-treated aneurysms were included in this study. Of these, 65 aneurysms were unruptured (66%) (Fig 3). They were treated in 10 European centers with a median of 7.5 WEB implants per center.
A 65-year-old man was admitted for the treatment of an asymptomatic aneurysm. Preoperative DSA showed a 6-mm right MCA bifurcation aneurysm (A). B, 3D rotational angiography before treatment. C, VasoCT before detachment confirmed the correct positioning of the WEB-SL. D, After WEB-SL deployment, postoperative DSA showed partial occlusion and stagnation of contrast agent inside the aneurysm. The Beaujon Occlusion Scale Score is 3.
It was determined that 38 aneurysms were located along the middle cerebral artery (38.8%); 21, along the anterior communicating artery (21.4%); 19, along the basilar artery (19.4%); and 15, along the supraclinoid internal carotid artery (15.3%). Aneurysm size varied from 3.7 to 39 mm (mean, 8.9 ± 5.5 mm), neck size varied from 2.0 to 12.3 mm (mean, 5.2 ± 2.1 mm), and the aspect ratio, defined as depth/neck, varied from 0.6 to 7.6 mm (mean, 1.6 ± 1.0 mm).
Treatment Feasibility
The WEB-SL device was successfully deployed inside the aneurysmal sac in 93 cases (95%). Deployment failures were attributed to device migration during detachment in 1 instance, while there were difficulties in achieving satisfactory positioning of the WEB before detachment in the other 4 cases. Of those 5 aneurysms, 3 were successfully treated with stent-assisted coiling, 1 case required a WEB-DL, and simple coiling was used in 1 case.
The necessity of additional coiling had been anticipated preoperatively, to manage large or giant aneurysms in 4 patients and to ensure immediate occlusion of a daughter bleb, in a fifth patient with a ruptured aneurysm. In 7 cases (8.2%), unplanned additional treatment had been required. In 5 of these cases, stent deployment was needed because of WEB protrusion into the parent artery (Fig 4). In the remaining 2 cases, additional coiling was performed to complete aneurysm occlusion after WEB deployment because of the presence of aneurysm remnants.
A 59-year-old women was admitted for the treatment of an unruptured anterior communicating artery aneurysm. A, Preoperative DSA. B, After WEB-SL deployment, a protrusion occurred in the right A2 segment, leading to a significant stenosis (black arrow). The proximal marker is also depicted within the parent artery. C, A laser cut Enterprise stent (Codman & Shurtleff, Raynham, Massachusetts) was then delivered to restore the caliber of the artery. The Beaujon Occlusion Scale Score is 0. D, Final VasoCT confirmed satisfactory positioning of the stent without any protrusion of the WEB (arrows show the 2 radio-opaque markers of the WEB-SL).
Postdelivery, major protrusion occurred in 14 cases. It required balloon remodeling in 5 and additional stent placement in 5. In 3 other cases, it led to clot formation, successfully treated with abciximab infusion in 2 cases and with mechanical thrombectomy in 1. In the last case, 1 branch occlusion occurred, resulting in an ischemic infarction. In 29 cases, a protrusion of only the proximal marker was depicted at the level of the bifurcation. In those situations, a postoperative antiplatelet regimen was prescribed at the physician's discretion.
Platelet Antiaggregation Therapy
One or 2 platelet antiaggregation agents were administered preoperatively to 27 patients (30%), while 60 patients (67%) were still given at least 1 antiplatelet therapy at discharge, mostly because of slight device protrusion in the parent artery.
Complication Rate
Procedure-related complications occurred in 13 cases. We observed 6 intraoperative thromboembolic complications, 4 of which were successfully managed (2 treated by intra-arterial infusion of abciximab; 1, by stent deployment; and another, by performing a thrombectomy by using a Solitaire stent [Covidien, Irvine, California]). The other 2 patients had arterial occlusion and hemiplegia. One recovered partially and was mRS 1 at last follow-up, and the other was rated mRS 3.
We also observed 5 hemorrhagic complications. In 1 case, an aneurysmal rupture occurred due to a wire perforation but was immediately stopped after WEB delivery, and the patient remained asymptomatic. In another case, an occipital lobe parenchymal bleed occurred 4 days after the treatment of an anterior communicating artery aneurysm, and the patient still had hemianopsia at last follow-up. The patient had a history of uncontrolled hypertension and received double-antiplatelet therapy as a premedication.
The other 3 were ruptured cases, and early follow-up showed new parenchymal or subarachnoidal bleeding, which led to severe disability in 1 patient, seizures in the second patient, and death in the last patient. In the first one, an aneurysmal bleb was occluded by 1 coil, then the aneurysm itself was treated with a WEB, stagnation was obtained inside the sac, but 6 hours later a large parenchymal hematoma was depicted. In the second one, with a multilobulated anterior communicating artery aneurysm, only partial occlusion was obtained after WEB delivery. A nonoccluded part of the aneurysm, initially misjudged as a nonpotential source of bleeding, was secondarily coiled after rebleeding was revealed by seizures. The last case was one of major and diffuse SAH. Three potential ruptured aneurysms were discovered; 1 was treated with coils, and other 2, with the WEB-SL. Massive rebleeding predominantly located in the right Sylvian fissure occurred 3 hours after treatment, leading to death. The lesions that were most likely to be the cause of the recurrent fatal hemorrhage were probably 1 of the 2 right MCA aneurysms. One was treated with coils, and 1, with the WEB-SL. After treatment, those 3 patients were kept under at least 1 antiplatelet agent because of device protrusion.
A distal migration of the WEB device during removal, due to an incomplete detachment, was noted in 1 instance. It was impossible to recapture the device in the M1 segment. While we tried to recapture it, it finally migrated into an M2 branch in a nondeployed fashion without flow repercussions. The patient remained asymptomatic under double antiplatelet therapy, and no ischemic lesions were observed on imaging follow-up.
One patient was mRS 1 at discharge due to a postoperative iliac artery occlusion.
Data from early clinical follow-ups were available for 52 patients (58%), with an average time interval of 3.8 months. Treatment-related morbidity and mortality rates at last follow-up were 2.2% and 1.1%, respectively.
Immediate Results
Immediate angiographic evaluation showed 27 cases (28%) of complete occlusion, 2 neck remnants, and a stagnation of iodine contrast agent in the aneurysm in all other cases.
Angiographic Follow-Up
Short-term vascular imaging follow-ups were available in 69 cases (70%), including DSA data in 54 cases, and the average time interval to follow-up was 3.3 months. Satisfactory results (complete occlusion or small neck remnants) were achieved in 45 patients (65%). In 8 cases, contrast opacification agent was still observed inside the device at that time.
The work presented here is the largest WEB study undertaken to date, wherein WEB-SL devices were used to treat aneurysms that would normally be considered difficult to treat with traditional endovascular approaches. Most of the treated aneurysms were wide-neck (average, 5.1 mm), with unfavorable anatomy (average aspect ratio, 1.6). Brinjikji et al6 defined 2 thresholds based on the aspect ratio value, to define the possible strategy of endovascular treatments. They reported that in cases with a value below 1.2 (39% of cases in our study), adjunctive techniques are almost always necessary. Usually, an aspect ratio of >1.6 implied that adjunctive techniques were not required. In our study, 69% of cases presented a lower ratio than this.
Most lesions were bifurcation aneurysms (86%). Approximately 40% were middle cerebral artery aneurysms, 20% were anterior communicating artery aneurysms, and 20% were basilar tip aneurysms.
Within this study, 34% of cases were ruptured aneurysms, which is much higher than the percentage in other WEB series. In contrast to our previous observations, from investigation of a smaller cohort,8 3 patients had rebleeding after WEB treatment. At the end of the procedure, contrast agent stagnation was detected in the proximal part of those aneurysms, but complete occlusion was not yet achieved. After the endovascular treatment, those 3 patients were kept under at least 1 antiplatelet agent, and this could have influenced this relatively high rebleeding rate.
Despite the fact that aneurysm geometry was unfavorable in our study, the procedure-related complication rate was low (13%) and comparable with that obtained from the largest WEB-DL study (10.8%).1 The rupture rate during treatment was low (1%) and was, in fact, unrelated to WEB delivery but was caused by guidewire perforation during catheterization of the sac. Bleeding was controlled by rapid WEB delivery, and the patient remained asymptomatic.
Treatment-related morbidity and mortality rates at last follow-up were 2.2% and 1.1%, respectively. Finally, safety results from this WEB-SL study are similar to those in other published WEB-DL studies. Indeed those authors reported morbidity (mRS of >2) rates between 1.3% and 6.7% and mortality rates between 0% and 2.2%.1,3,5 These results are also comparable with those obtained from neurosurgical clipping of unruptured aneurysms (6.7% overall morbidity, 1.7% mortality)9 and non-WEB endovascular treatment of unruptured aneurysms (2.5% morbidity, 1.8% mortality).9
An antiplatelet premedication was used in 30% of cases (aspirin and clopidogrel) because if during a procedure, WEB treatment appears to be unsuitable, another alternative therapy can be stent-assisted coiling for these wide-neck aneurysms. In 67% of cases, at least 1 antiplatelet agent was still used at discharge. It was given either in cases of device protrusion in the parent artery or sometimes only because of proximal marker protrusion, though the need for antiplatelets in those situations is not mandatory.
This study was not intended for the evaluation of anatomic results subsequent to WEB-SL treatment. Early follow-up vascular imaging was available in a large number of cases (70%), and it consisted of DSA data in half of these cases. These data demonstrated a low rate of satisfactory results (65%), which could probably improve during follow-up because in some cases, stagnation was depicted inside the WEB and patients were still kept under antiplatelet therapy at that time. In a WEB-DL article5 with a short-term imaging follow-up (average length, 5.0 months), authors reported complete occlusion in 57% of cases; in our series, it was obtained in only 38% of cases. However, as with flow-diverter stents, delayed thrombosis should be expected. Therefore, results must be reviewed after longer time intervals.
This study has several limitations. First the number of treated cases for each center is low and mostly corresponds to an initial experience for the operators with this new device. The complications were self-reported. Angiographic outcome is now still limited, but it appeared important for us to report these preliminary results before analysis of long-term follow-up imaging to evaluate the efficiency of the WEB-SL device.
In this study, the feasibility and safety of the single-layer WEB device was comparable with that of the double-layer device. However, further studies are needed to evaluate long-term efficacies.
The authors thank Dr Francesco D'Argento from Policlinico A. Gemelli in Roma for his elegant work on the illustrations.
Disclosures: Joachim Klisch—RELATED: Consulting Fee or Honorarium: consultant to Sequent Medical.* Ansgar Berlis—RELATED: Consulting Fee or Honorarium: consultancy agreement for proctoring with Sequent Medical; UNRELATED: Consultancy: consultancy agreements for proctoring with Covidien and MicroVention; Payment for Lectures (including service on Speakers Bureaus): honorarium for lectures from Penumbra and Stryker. Tufail Patankar—UNRELATED: Travel/Accommodations/Meeting Expenses Unrelated to Activities Listed: travel expense paid by Sequent Medical to present Web data in Val d'Isère 2015; Other: proctor for Sequent Medical. Werner Weber—UNRELATED: Payment for Lectures (including service on Speakers Bureaus): Sequent Medical (lectures); Other: Sequent Medical (proctoring). Daniel Behme—RELATED: Consulting Fee or Honorarium: speaking honoraria, German Society of Neurosurgery meeting in Dresden 2014; Support for Travel to Meetings for the Study or Other Purposes: Sequent Medical; UNRELATED: Payment for Manuscript Preparation: Penumbra, Comments: Separator 3D Series; Travel/Accommodations/Meeting Expenses Unrelated to Activities Listed: Penumbra, Comments: Anatomy Biology Clinical correlations – Working group in Interventional Neuroradiology (ABC WIN) meeting in Val d'Isère 2014 and 2015. Eva Astrid Jacobsen—RELATED: Support for Travel to Meetings for the Study or Other Purposes: MicroVention, Comments: registration fee to Live Interventional Neuroradiology and Neurosurgery Course (LINNC) meeting in Paris 2014. Thomas Liebig—RELATED: Consulting Fee or Honorarium: proctoring and consulting for Sequent Medical; Support for Travel to Meetings for the Study or Other Purposes: Sequent Medical, Comments: reimbursement of traveling and meeting admission fees; UNRELATED: Consultancy: consulting for Acandis, MicroVention, and Stryker. Sascha Prothmann—UNRELATED: Consultancy: phenox, Bochum, Germany (proctor); Payment for Lectures (including service on Speakers Bureaus): Boston Scientific, Covidien, Comments: oral presentation (workshop) at Third Munich Aortic and Carotid conference 2013 (Boston Scientific), oral presentation (workshop) at European Society of Neuroradiology Annual Meeting, Frankfurt, 2013 (Covidien). Christophe Cognard—UNRELATED: Consultancy: Stryker, MicroVention, Codman, Covidien. Jacques Moret—UNRELATED: Board Membership: Covidien; Consultancy: Covidien, MicroVention. Laurent Spelle—UNRELATED: Consultancy: Stryker, Sequent Medical, Medtronic. *Money paid to the institution.
Indicates open access to non-subscribers at www.ajnr.org
Papagiannaki C,
Spelle L,
Januel AC, et al
. WEB intrasaccular flow disruptor—prospective, multicenter experience in 83 patients with 85 aneurysms. AJNR Am J Neuroradiol 2014;35:2106–11
Pierot L,
Liebig T,
Sychra V, et al
. Intrasaccular flow-disruption treatment of intracranial aneurysms: preliminary results of a multicenter clinical study. AJNR Am J Neuroradiol 2012;33:1232–38
Klisch J,
Cognard C, et al
. Endovascular WEB flow disruption in middle cerebral artery aneurysms: preliminary feasibility, clinical, and anatomical results in a multicenter study. Neurosurgery 2013;73:27–34; discussion 34–35
Mine B,
Collignon L, et al
. WEB device for endovascular treatment of wide-neck bifurcation aneurysms. AJNR Am J Neuroradiol 2013;34:1209–14
Gauvrit JY, et al
. WEB-DL endovascular treatment of wide-neck bifurcation aneurysms: short- and midterm results in a European study. AJNR Am J Neuroradiol 2014;35:432–38
Brinjikji W,
Cloft HJ,
Kallmes DF
. Difficult aneurysms for endovascular treatment: overwide or undertall? AJNR Am J Neuroradiol 2009;30:1513–17
Caroff J,
Mihalea C,
Neki H, et al
. Role of C-arm VasoCT in the use of endovascular WEB flow disruption in intracranial aneurysm treatment. AJNR Am J Neuroradiol 2014;35:1353–57
Dargento F, et al
. Woven EndoBridge (WEB) device for endovascular treatment of ruptured intracranial wide-neck aneurysms: a single-center experience. Neuroradiology 2014;56:755–61
Kotowski M,
Darsaut TE, et al
. Safety and occlusion rates of surgical treatment of unruptured intracranial aneurysms: a systematic review and meta-analysis of the literature from 1990 to 2011. J Neurol Neurosurg Psychiatry 2013;84:42–48
Received January 6, 2015.
Accepted after revision February 25, 2015.
You are going to email the following Single-Layer WEBs: Intrasaccular Flow Disrupters for Aneurysm Treatment—Feasibility Results from a European Study
J. Caroff, C. Mihalea, J. Klisch, C. Strasilla, A. Berlis, T. Patankar, W. Weber, D. Behme, E.A. Jacobsen, T. Liebig, S. Prothmann, C. Cognard, T. Finkenzeller, J. Moret, L. Spelle
American Journal of Neuroradiology Oct 2015, 36 (10) 1942-1946; DOI: 10.3174/ajnr.A4369
Comparison of Woven EndoBridge device sizing with conventional measurements and virtual simulation using the Sim&Size software: a multicenter experience
WEB Device Shape Changes in Elastase-Induced Aneurysms in Rabbits
Two-Center Experience in the Endovascular Treatment of Intracranial Aneurysms Using the Woven EndoBridge 17 Device Including Midterm Follow-Up Results: A Retrospective Analysis
Treatment of Wide-Neck Intracranial Aneurysms with the Woven EndoBridge Device Associated with Stenting: A Single-Center Experience
Factors that determine aneurysm occlusion after embolization with the Woven EndoBridge (WEB)
Two-Center Experience in the Endovascular Treatment of Ruptured and Unruptured Intracranial Aneurysms Using the WEB Device: A Retrospective Analysis
WEB Device: Ready for Ruptured Aneurysms?
Initial and mid-term results from 108 consecutive patients with cerebral aneurysms treated with the WEB device
Efficacy and Safety of the Woven EndoBridge (WEB) Device for the Treatment of Intracranial Aneurysms: A Systematic Review and Meta-Analysis
WEB as part of a multimodality treatment in complex, large, and partially thrombosed intracranial aneurysms: a single-center observational study of technical success, safety, and recurrence
Endovascular Treatment of Intracranial Aneurysms with the WEB Device: A Systematic Review of Clinical Outcomes
Flow-Diverter Stents for the Treatment of Saccular Middle Cerebral Artery Bifurcation Aneurysms
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Since several years ago, semiconductor materials the band gap of which is wide, including Gallium Nitride (GaN) & Silicon Carbide (SiC), have been very promising in the applications of fabricating devices of high power, high temperature and microwave frequency as the characteristics of high breakdown voltages & low thermal generation rates. However, the performance of devices made from these materials is strongly influenced by the ambient temperature. In order to analyze the temperature effects, an analytical physical model is adopted in this paper to determine the temperature-dependent characteristics, including current-voltage characteristic, current-temperature characteristic and saturation electron drift velocity-temperature characteristic, which are also simulated through MATLAB software. Based on these characteristics, the device performance can be anticipated and device structure can be optimized.
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QT interval prolongation effects of bedaquiline (BDQ) and delamanid (DLM) given together were no more than additive in a study looking at cardiac safety of the combined use of these drugs in people with multidrug resistant (MDR)-TB.
Data from the ACTG A5343 (DELIBERATE) trial were presented at CROI 2019.
BDQ and DLM are the first drugs from two new classes approved for TB in over 40 years. Both are recommended by WHO for treatment of MDR-TB by WHO.
Both drugs' metabolites prolong the QT interval. Peak QT effects are at 16–18 weeks for BDQ and 8 weeks for DLM. The cardiac safety of these drugs given together as part of a regimen to treat MDR-TB has not been previously studied.
DELIBERATE was a phase 2, randomised, open-label, three arm pharmacokinetic and safety trial. Adults with MDR-TB, receiving multidrug background treatment (MBT), were randomised 1:1:1 to receive BDQ, DLM or both (BDQ + DLM) for 24 weeks.
The primary objective was to compare mean change from baseline in QTcF (in ms; averaged over weeks 8–24) when BDQ and DLM are given together to the mean change when each drug is given alone.
People with QTcF >450 ms or CD4 count <100 cells/mm3 were excluded. Clofazamine was not permitted and moxifloxacin was switched to levofloxacin. HIV positive participants received dolutegravir-based ART.
Three electrocardiograms (ECG) were performed at baseline, every two weeks for 24 weeks, then week 28.
A core laboratory blinded to treatment arm calculated QTcF. The study defined grade 3 QTcF prolongation as >500ms or >480 ms with increase from baseline >60 ms. Grade 4 was life-threatening dysrhythmia.
Sites were in South Africa and Peru. Gary Maartens from the University of Cape Town presented these findings on behalf of the DELIBERATE investigators.
Eighty-four participants were enrolled. Most (75%) were men, median age was 35 years and 37% were HIV positive.
Mean baseline QTcF and standard deviations in the BDQ, DLM and BDQ + DLM arms were respectively: 398 (24), 404 (19) and 391 (14).
Of 74 participants with QTc data, mean change in QTcF from baseline in the respective arms was: 11.9 (95% CI 7.4 to 16.5), 8.6 (95% CI 4.0 to 13.2) and 20.7 (95% CI 16.1 to 25.4).
There were no Grade 3 or 4 QT interval prolongation events.
The investigators concluded that the combined effect on the QTcF interval of co-administration of BDQ and DLM is clinically modest and no more than additive.
The investigators also noted the caveat that this was a carefully-screened population not receiving other DR-TB drugs that have significant QT prolongation effects (clofazimine and moxifloxacin).
Dooley KE et al. QT effects of bedaquiline, delamanid or both in MDR-TB patients: The Deliberate trial.
CROI 2019. Seattle. 4–7 March 2019. Oral abstract 84LB.
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user: Erik_Spickard
Erik Spickard, PhD
www.rt.com www.rt.com
A scientific review of the science behind lockdown concludes the policy was a MISTAKE & will have caused MORE deaths from Covid-19
Erik_Spickard 09 Oct 2020
in Viral Feedback
Take Away: The new scientific paper confirms earlier modeling work and should not be interpreted as a detailed prediction for future deaths due to the ongoing pandemic.
The Claim: "A scientific review of the science behind lockdown concludes the policy was a MISTAKE & will have caused MORE deaths from Covid-19"
The Evidence: The scientific process involves replication and confirmation of experiments and studies. A new paper replicates and expands on an early modeling study of the COVID-19 pandemic in England (1). Their findings support the earlier results. However, there are limitations to the replication paper, which does not accurately reflect the current state of the pandemic response and does not make detailed predictions for a second wave of infections and deaths.
A recent expert response to the paper further explains (2):
"It needs to be stressed that all the simulations assume that interventions are only in place for 3 months (18th April – 18th July) and then completely relaxed. This gives rise to a strange set of scenarios where a second wave is allowed to progress in an uncontrolled manner."
"It is this that leads to the counter-intuitive headline finding "that school closures would result in more overall covid-19 deaths than no school closures" – actually what the authors find is that a short period of intense lock-down (including the closure of schools) leads to a large second wave if it is allowed to run with no controls. To be fair the authors do highlight this in the paper, but it is not in the reported press release." -Prof Matt Keeling, Professor of Populations and Disease, University of Warwick
(1) https://www.bmj.com/content/371/bmj.m3588
(2) https://www.sciencemediacentre.org/expert-reaction-to-reanalysis-of-model-used-for-imperial-report-9-and-impact-of-school-closures/
Epidemiology Scientific process Health policy Needs more context
Needs more context
Erik_Spickard
rt.com/op-ed/502867-lockdown-mistake-science-review/
lockdownsceptics.org lockdownsceptics.org
Lies, Damned Lies and Health Statistics – the Deadly Danger of False Positives – Lockdown Sceptics
Erik_Spickard 24 Sep 2020
The lowest value for false positive rate was 0.8%. Allow me to explain the impact of a false positive rate of 0.8% on Pillar 2. We return to our 10,000 people who've volunteered to get tested, and the expected ten with virus (0.1% prevalence or 1:1000) have been identified by the PCR test. But now we've to calculate how many false positives are to accompanying them. The shocking answer is 80. 80 is 0.8% of 10,000. That's how many false positives you'd get every time you were to use a Pillar 2 test on a group of that size.
Take Away: The exact frequency of false positive test results for COVID-19 is unknown. Real world data on COVID-19 testing suggests that rigorous testing regimes likely produce fewer than 1 in 10,000 (<0.01%) false positives, orders of magnitude below the frequency proposed here.
The Claim: The reported numbers for new COVID-19 cases are overblown due to a false positive rate of 0.8%
The Evidence: In this opinion article, the author correctly conveys the concern that for large testing strategies, case rates could become inflated if there is (a) a high false positive rate for the test and (b) there is a very low prevalence of the virus within the population. The false positive rate proposed by the author is 0.8%, based on the "lowest value" for similar tests given by a briefing to the UK's Scientific Advisory Group for Emergencies (1).
In fact, the briefing states that, based on another analysis, among false positive rates for 43 external quality assessments, the interquartile range for false positive rate was 0.8-4.0%. The actual lowest value for false positive rate from this study was 0% (2).
An upper limit for false positive rate can also be estimated from the number of tests conducted per confirmed COVID-19 case. In countries with low infection rates that have conducted widespread testing, such as Vietnam and New Zealand, at multiple periods throughout the pandemic they have achieved over 10,000 tests per positive case (3). Even if every single positive was false, the false positive rate would be below 0.01%.
The prevalence of the virus within a population being tested can affect the positive predictive value of a test, which is the likelihood that a positive result is due to a true infection. The author here assumes the current prevalence of COVID-19 in the UK is 1 in 1,000 and the expected rate of positive results is 0.1%. Data from the University of Oxford and the Global Change Data Lab show that the current (Sept. 22, 2020) share of daily COVID-19 tests that are positive in the UK is around 1.7% (4). Therefore, based on real world data, the probability that a patient is positive for the test and does have the disease is 99.4%.
Sources: (1) https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/895843/S0519_Impact_of_false_positives_and_negatives.pdf
(2) https://www.medrxiv.org/content/10.1101/2020.04.26.20080911v3.full.pdf+html
(3) https://ourworldindata.org/coronavirus-data-explorer?yScale=log&zoomToSelection=true&country=USA~DEU~IND~ITA~AUS~VNM~FIN~NZL~GBR®ion=World&testsPerCaseMetric=true&interval=smoothed&aligned=true&smoothing=7&pickerMetric=location&pickerSort=asc
(4) https://ourworldindata.org/coronavirus-data-explorer?zoomToSelection=true&country=USA~DEU~IND~ITA~AUS~VNM~FIN~NZL~GBR®ion=World&positiveTestRate=true&interval=smoothed&aligned=true&smoothing=7&pickerMetric=location&pickerSort=asc
Poorly Supported Molecular biology Diagnostics Statistics
Poorly Supported
lockdownsceptics.org/lies-damned-lies-and-health-statistics-the-deadly-danger-of-false-positives/
www.bbc.com www.bbc.com
Covid tests 'could be picking up dead virus'
He added that while it would not be possible to check every test to see whether there was active virus, the likelihood of false positive results could be reduced if scientists could work out where the cut-off point should be.
Take Away: This is an incorrect usage of the term "false positive." A positive PCR test result from a recovered infection is a valid and true positive.
Claim: PCR tests for SARS-CoV-2 give false positive results when there is no active virus.
Evidence: The diagnostic PCR tests currently in widespread use are designed to detect the presence of the SARS-CoV-2 viral RNA in a clinical sample. The RNA is only a part of the complete virus and is not infectious on its own. Research has shown that viral RNA can be detected in some samples up to 12 weeks after onset of symptoms (1). In other words, this is like testing if an oven is warmer than the room temperature - it could be hot even after it has been turned off.
By definition, in the context of SARS-CoV-2 PCR tests, a "false positive" means that a test result is deemed positive when in reality there was no viral RNA in the sample. If a person is recovering from an infection, gets tested, and then is given a positive test result, that is a true positive regardless of whether they are infectious or not.
Sources: 1) https://www.cdc.gov/coronavirus/2019-ncov/hcp/duration-isolation.html
Molecular biology Diagnostics PCR Needs more context
bbc.com/news/health-54000629
www.nytimes.com www.nytimes.com
Your Coronavirus Test Is Positive. Maybe It Shouldn't Be.
Take Away: Diagnostic tests are most useful when they are both sensitive and rapid. The sensitivity of SARS-CoV-2 PCR tests is not the issue, but rather the time it takes to get a result. Additionally, the "90%" statistic is likely misleading due to the data source and not generalisable to all testing results.
The Claim: The usual PCR diagnostic tests may be too sensitive and too slow, with up to 90% of positive cases due to trace amounts of virus.
The Evidence: Polymerase Chain Reaction (PCR)-based tests, which are currently in the most widespread use for detection of SARS-CoV-2 RNA, involves a molecular process that amplifies target DNA sequences in repeated temperature-dependent cycles. The amount of target DNA is measured after each cycle and the number of the cycle when the target can be reliably detected is often referred to as the cycle threshold (Ct). The Ct value is proportional to the amount of starting DNA in the sample and can be used to estimate the viral load of a patient. In some ways this is like a teacher making photocopies of a chapter from a textbook until they have enough for all their students.
However, Ct values are relative measurements and need to be directly compared to controls for every sample - a Ct value taken alone can be meaningless. For instance, consider an infected patient who is tested twice: the first time they are gently swabbed and the sample is relatively dilute, the second time they are vigorously swabbed and the sample is relatively concentrated. The resulting Ct values could be drastically different. Therefore, Ct values need to be considered carefully in the proper context for making medical or policy decisions. The FDA also recommends that a PCR result alone should not be used to determine infection status.
Positive results are indicative of the presence of SARS-CoV-2 RNA; clinical correlation with patient history and other diagnostic information is necessary to determine patient infection status. (1)
Current PCR test results are generally given as a binary positive/negative based on a cutoff value for Ct. The cutoff needs to be determined based on the performance of each individually developed SARS-CoV-2 test, of which there are currently over 160 that have been granted emergency use authorization by the FDA (2). Based on unpublished data from the CDC, setting a stringent Ct cutoff of 30 could return negative results in patients who are both infected and potentially infectious (3 Fig 5). Furthermore, a 30 cycle cutoff would return invalid results for samples which are too diluted. Based on the same CDC data, up to 30% of potentially infectious patients would get invalid results and need to be re-swabbed, thereby extending the time between getting infected and getting a positive result.
The period of time when RNA from SARS-CoV-2 can be detected (and a positive PCR test result returned) may extend up to 12 weeks after recovery, with Ct values trending higher over time (3,4). According to The New York Times article, they looked at Ct values from people who tested positive in Massachusetts in July and found 85-90% of results had Ct values greater than 30. The epidemiology of COVID-19 is highly time and region dependent. Massachusetts had a peak in COVID-19 hospitalizations on April 21 (5), which is 9-12 weeks prior to the testing data analyzed by The NY Times. Therefore, the detection of a large proportion of people with lingering viral RNA is not surprising. These results are likely not universal and can not be applied to other regions, especially where community spread is still significant.
(1) https://www.fda.gov/media/135900/download
(2) https://www.fda.gov/medical-devices/coronavirus-disease-2019-covid-19-emergency-use-authorizations-medical-devices/vitro-diagnostics-euas
(3) https://www.cdc.gov/coronavirus/2019-ncov/hcp/duration-isolation.html
(4) Li N, Wang X, Lv T. Prolonged SARS-CoV-2 RNA Shedding: Not a Rare Phenomenon. J Med Virol 2020 Apr 29. doi: 10.1002/jmv.25952.
(5) https://www.bostonherald.com/2020/05/22/massachusetts-finally-seeing-downward-coronavirus-trends/
Molecular Biology Diagnostics PCR Needs more context Poorly supported
nytimes.com/2020/08/29/health/coronavirus-testing.html
www.conservativereview.com www.conservativereview.com
Horowitz: Mass testing results: Endless panic and false positives
If we are now going to hold our nation hostage because of this obsession over PCR (polymerase chain reaction) swab tests, we should at the very least make certain they're accurate. What happens when we have expedited and chaotic test results driving an epidemic curve rather than actual symptoms? You get what happened to Ohio Governor Mike DeWine last Thursday. He tested positive for the virus after experiencing absolutely no symptoms. But because he is such a VIP, he got a second, more accurate test that showed he was in fact negative for SARS-CoV-2. The same thing happened to Detroit Lions quarterback Matthew Stafford, who tested negative after receiving a false positive and was therefore allowed out of coronavirus prison.
Take away: Current polymerase chain reaction (PCR) testing technology is very sensitive and specific. Even for rapidly developed new tests for the novel coronavirus, SARS-CoV-2, available clinical data indicates they are highly accurate.
The claim: SARS-CoV-2 testing is unreliable and plagued by false positive results.
The evidence: Any diagnostic test has some degree of error that is typically very low for FDA approved products. For SARS-CoV-2 tests, which detect the presence of the virus that causes COVID-19, although rare, it is possible to get a positive result when you may not have been exposed or infected by the virus. In other words, a false positive. So how frequently do false positives occur?
There is no universal false positive rate for SARS-CoV-2 test results because there are dozens of different tests that have been developed and deployed, each with their own error rate. As of August 26, 2020, there are 146 commercial diagnostic tests that have received emergency use authorization from the FDA. Data from clinical performance testing submitted to the FDA indicates that PCR tests are highly accurate. For example, the specific PCR test mentioned by the author, Quest Diagnostics SARS-CoV-2 rRT-PCR, obtained 100% correct results in clinical evaluation studies (n = 60), and 100% true negative results in a random population of samples from before the pandemic (n = 72).
Additional considerations: In addition to PCR technology-based tests, which detect the viral RNA genome and require lab processing, there are antigen tests, which use antibodies to detect viral proteins and can be rapidly performed in point-of-care settings. Antigen tests are much easier to perform than PCR tests, but they can be less sensitive. For example, the LumiraDx SARS-CoV-2 Ag Test, when compared to PCR, has an overall agreement of 96.9%.
The author provides two anecdotes of high-profile personnel who obtained false positive test results. For the Ohio Governor, his initial positive was from an antigen test, not a PCR test. The NFL quarterback is part of a unique population that is presumed to be largely SARS-CoV-2 negative but is being tested frequently and repeatedly. This scenario increases the probability that a positive test result may be false. However, the NFL in early August said it has conducted over 75,000 tests, so unless there are many additional cases of false positives, this suggests that their testing methodology is over 99.99% accurate.
Poorly Supported Molecular biology Molecular diagnostics
conservativereview.com/news/horowitz-mass-testing-results-endless-panic-false-positives/
Molecular, Cellular, and Developmental Biologist. Viral Feedback Senior Moderator.
Annotations: 5
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This paper introduces Floasys, a Web-based platform to foster the collaboration among engineers involved in Computational Fluid Dynamics (CFD) simulations. The platform has been designed around the simulation data, i.e., fostering and stimulating sharing, re-use and aggregation of models, simulation results and engineers annotations. Floasys requirements come directly from an extensive requirements study that we conducted with two different teams in Automobiles (FCA), geographically distributed, who daily perform an intense activity of CFD simulations to design vehicle products. Collaborative requirements were gathered through stakeholders' interviews and a user survey. We describe, first, Functional and Non-Functional requirements as suggested by relevant literature (both in scientific and industrial setting) and by the user survey performed within FCA teams. Then, we show Floasys functionalities and its architecture, that is based on a centrally managed repository of simulation data. By enriching the repository with metadata annotations, Floasys provides all the desired functionalities to allow CFD analysts an easy and immediate access to simulation data and results performed within the teams so that they can leverage them to make the right design decisions. In this paper, we were able to (1) identify key collaborative requirements for CFD design, (2) address each of them with an integrated, extensible and modular architecture, (3) implement a working industrial prototype (currently under testing and evaluation in a real setting like FCA), and (4) identify the possible extensions to different contexts (like aeronautic, rail and naval sectors).
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Germano M, Meleleo D, Montorfano G, et al. Plasma, red blood cells phospholipids and clinical evaluation after long chain omega-3 supplementation in children with attention deficit hyperactivity disorder (ADHD). Nutr Neurosci. 2007;10(1-2):1-9.
Omega-3 and omega-6 long-chain polyunsaturated fatty acids (LCPUFAs), are crucial to brain development and function. Increasing evidence indicates that deficiencies or metabolic imbalances of these fatty acids might be associated with childhood developmental and psychiatric disorders including attention-deficit/hyperactivity disorder (ADHD).
Omega-3 are often lacking on modern diets. Moreover preliminary evidences suggest that supplementation with omega-3 LCPUFAs, might help in the management of the ADHD linked behavioural and learning difficulties. However, few studies published to date have involved different populations, study designs, treatments and outcome results. Thus, further researches are required to assess the durability of the treatment effects, to determine optimal composition and dosages of the supplement and to develop reliable ways to identify patients that might have some benefits from this kind of treatment, also because the study of LCPUFAs and their metabolism might offer new approaches to the early identification and management of ADHD.
In this paper, we provide new insight on the lipid pattern in plasma and red blood cells (RBC) phospholipids, together with evaluation of the arachidonic acid (AA)/eicosapentaenoic acid (EPA) ratio which seems to correlate with the improvement of the patients both from a biochemical and clinical point of view.
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May 30 NH DHHS COVID-19 update: 55 new positive cases with 13 in Manchester; 4 deaths reported
Saturday, May 30, 2020 NH Department of Transportation COVID-19 in NH: Latest news and updates, Government 0
For interactive version of cumulative case map click here.
CONCORD, NH – On Saturday, May 30, 2020, DHHS announced 55 new positive test results for COVID-19. There have now been 4,545 cases of COVID-19 diagnosed in New Hampshire. Several cases are still under investigation. Additional information from ongoing investigations will be incorporated into future COVID-19 updates.
Of those with complete information, there are four individuals under the age of 18 and the rest are adults with 60 percent being female and 40 percent being male. The new cases reside in Hillsborough County other than Manchester and Nashua (10), Merrimack (7), Rockingham (7), Belknap (2), Carroll (1), Grafton (1), and Strafford (1) counties, and in the cities of Manchester (13) and Nashua (12). The county of residence is being determined for one new case.
Nine new hospitalized cases were identified for a total of 449 (10 percent) of 4,545 cases. Seven of the new cases have no identified risk factors. Community-based transmission continues to increase in the State and has been identified in all counties. Most of the remaining cases have either had travel to domestic or international locations or have had close contact with a person with a confirmed COVID-19 diagnosis.
DHHS has also announced four additional deaths related to COVID-19.
2 male residents of Hillsborough County, 60 years of age and older
2 female residents of Hillsborough County, 60 years of age and older
For interactive map of current cases click here.
New Hampshire 2019 Novel Coronavirus (COVID-19) Summary Report
(data updated May 30, 2020, 9:00 AM)
NH Persons with COVID-19 (see 1 below) 4,545
Recovered 2,940 (65%)
Deaths Attributed to COVID-19 242 (5%)
Total Current COVID-19 Cases 1,363
Persons Who Have Been Hospitalized for COVID-19 449 (10%)
Current Hospitalizations 107
Total Persons Tested at Selected Laboratories, Polymerase Chain Reaction (PCR) (see 2 below) 70,280
Total Persons Tested at Selected Laboratories, Antibody Laboratory Tests (see 2 below) 11,468
Persons with Specimens Submitted to NH PHL 24,550
Persons with Test Pending at NH PHL (see 3 below) 1,208
Persons Being Monitored in NH (approximate point in time) 3,925
1 Includes specimens positive at any laboratory and those confirmed by CDC confirmatory testing.
2 Includes specimens tested at the NH Public Health Laboratories (PHL), LabCorp, Quest, Dartmouth-Hitchcock Medical Center, and those sent to CDC prior to NH PHL testing capacity.
3 Includes specimens received and awaiting testing at NH PHL. Does not include tests pending at commercial laboratories.
Number of Specimens Tested by Date of Report to NH DHHS
Polymerase Chain Reaction (PCR) Tests
Testing Laboratory 5/23 5/24 5/25 5/26 5/27 5/28 5/29 Daily Average
NH Public Health Laboratories 894 561 768 866 404 665 273 633
LabCorp 241 211 175 99 281 385 151 220
Quest Diagnostics 495 257 616 906 607 736 353 567
Dartmouth-Hitchcock Medical Center 165 191 72 66 86 188 238 144
Other NH Hospital Laboratory 80 26 138 178 184 261 n/a** 145
Other Laboratory* 16 9 38 11 9 39 45 24
Total 1,891 1,255 1,807 2,126 1,571 2,274 1,060 1,712
Antibody Laboratory Tests
LabCorp 37 12 0 0 2 58 30 20
Dartmouth-Hitchcock Medical Center n/a n/a n/a n/a 1 13 13 9
Other Laboratory* 7 8 5 0 1 6 28 8
Total 479 244 241 232 309 379 296 311
* Includes out-of-state public health laboratories, out-of-state hospital laboratories, and other commercial laboratories not
already listed in the table. ** Not available at the time of this report.
Police: Man with Trump flag on truck drives by protesters outside police station, pulls gun, gets arrested
Herman 'Herk' Streitburger, 100: Army Veteran and POW, known for his humor, his faith and his positive outlook
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The foil-air bearing (FAB) plays a key role in the development of high speed, economical and environmentally friendly oil-free turbomachinery. However, FABs are known to be capable of introducing undesirable nonlinear effects into the dynamic response of a rotor-bearing system. This necessitates a means for calculating the nonlinear response of rotor systems with FABs. Up to now, the computational burden introduced by the interaction of the dynamics of the rotor, air film and foil structure has been overcome by uncoupling these three subsystems, introducing the potential for significant error. This paper performs the time domain solution of a simple rotordynamic system without uncoupling the state variables. This solution is then used as a reference for the verification of two proposed novel methods for reducing the computational burden: (a) use of harmonic balance; (b) use of Galerkin transformation. The applicability and accuracy of these two methods is illustrated on a simple symmetric rotor-FAB system.
Pham H, Bonello P. Efficient Techniques for the Computation of the Nonlinear Dynamics of a Foil-Air Bearing Rotor System. ASME. Turbo Expo: Power for Land, Sea, and Air, Volume 7B: Structures and Dynamics ():V07BT30A011. doi:10.1115/GT2013-94389.
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Victor Snieckus's Special Issues, Vol. 88, No. 1, 2014
65 data found. 1 - 30 listed Next Last
Contents | Special issue | Vol 88, No. 1, 2014
Published online: 17th December, 2013
DOI: 10.3987/Contents-13-8801
Curriculum vitae | Special issue | Vol 88, No. 1, 2014, pp. -
DOI: 10.3987/COM-13-S(S)Portrait
■ Portrait
Victor Snieckus*
*Department of Chemistry, Queen's University, 90 Bader Lane K7L 3N6, Canada
FREE:PDF (185KB)
Foreword | Special issue | Vol 88, No. 1, 2014, pp. 1 - 4
DOI: 10.3987/COM-13-S(S)Foreword
■ Preface – Honoring the 77th Birthday of Professor Victor Snieckus
Gordon W. Gribble*
*6128 Burke Laboratory, Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755, U.S.A.
FREE:Full Text HTMLPDF (567KB)
Curriculum vitae | Special issue | Vol 88, No. 1, 2014, pp. 5 - 43
DOI: 10.3987/COM-13-S(S)CV
■ Curriculum Vitae – Victor Algirdas Snieckus
Publications | Special issue | Vol 88, No. 1, 2014, pp. 45 - 74
DOI: 10.3987/COM-13-S(S)Publications
■ Publications
Review | Special issue | Vol 88, No. 1, 2014, pp. 75 - 101
Published online: 11th July, 2013
DOI: 10.3987/REV-13-SR(S)1
■ Synthesis of Heterocycles via Nucleophilic Substitution of Hydrogen in Nitroarenes
Mieczysław Mąkosza* and Krzysztof Wojciechowski
*Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44/52, P.O.Box 58, PL-01-224 Warszawa 42, Poland
The main message of this review is that nucleophilic substitution of hydrogen in nitroarenes and other electron-deficient arenes is primary general process of wide scope and great value in organic synthesis, whereas conventional nucleophilic substitution of halogens, SNAr reaction, is just a secondary process. Nucleophilic substitution of hydrogen in electron-deficient arenes is a powerful tool in organic synthesis, effectively applicable to the synthesis of heteroaromatic compounds.
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Review | Special issue | Vol 88, No. 1, 2014, pp. 103 - 127
■ Additive Effects on Asymmetric Hydrogenation of N-Heteroaromatics
Takuto Nagano, Atsuhiro Iimuro, Kenta Yamaji, Yusuke Kita, and Kazushi Mashima*
*Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan
The multiplication of chiral information is one of the most important tasks in organic chemistry. Chiral catalysis is the most elegant way to achieve this and organic chemists developed a variety of catalytic asymmetric reaction systems, in which the addition of some chemicals effectively improves the performance of transition-metal-catalysis. In this review, we summarize development of additive effects in the asymmetric hydrogenation of N-heteroaromatic compounds based on interactions of additives with catalysts and substrates.
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Published online: 6th September, 2013
■ Hydrazines and Azo-Compounds in the Synthesis of Heterocycles Comprising N-N Bond
Svetlana Tšupova and Uno Mäeorg*
*TBD-Biodiscovery, Tiigi 61b, 50410 Tartu, Estonia
The synthesis of nitrogen containing heterocycles is of great importance in modern science, owing to their valuable biological properties, and endocyclic hydrazinocycles are no exception. There are methods that enable the transformation of amines to hydrazines, however the use of hydrazine derivatives and azo-compounds as starting materials is both logical and straightforward. In this review we aimed to summarize the methods that use simple hydrazines and azo-compounds for the synthesis of these heterocycles. We begin with simple stoichiometric alkylation of hydrazines and later on move to catalytic systems. Finally, we provide an overview of the advances in the field of azomethine imines chemistry.
Communication | Special issue | Vol 88, No. 1, 2014, pp. 175 - 178
Published online: 3rd April, 2013
DOI: 10.3987/COM-13-S(S)2
■ Synthesis and Characterization of Nickel Complex of 4-Amino-3-pyridinethiolate
Kouzou Matsumoto,* Maho Nishizawa, Yasukazu Hirao, Hiroyuki Kurata, and Takashi Kubo*
*Department of Chemistry, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-8531, Japan
A Ni(Hapt)2 complex, apt = 4-amino-3-pyridinethiolate, is isolated and characterized by X-ray crystallography, cyclic voltammetry, and UV-Vis spectroscopy.
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DOI: 10.3987/COM-13-S(S)30
■ N,N-Bond Formation in Intramolecular Cobalt-Catalyzed [2+2+2] Cyclizations of Alkynyl-Linked Bisnitriles, and the Preparation of Annulated Pyridazines
Cuifang Cai, Megan A. Audet, and John K. Snyder*
*Department of Chemistry, Boston University, 590 Commonwealth Ave RM 474, Boston, MA 02215, U.S.A.
Cobalt(I) catalyzed intramolecular [2 + 2 + 2] cyclization of bisnitriles linked through a central alkyne has led to a facile route to annulated pyridazines. Ring closure through N,N-bond formation allows the construction of annulated pyridazine scaffolds that can be utilized in further small molecule library syntheses.
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■ One-Pot Access to 3,3'-Bisindolylmethanes through the Intermolecular Pummerer Reaction
Takumi Abe, Toshiaki Ikeda, Tomoki Itoh, Noriyuki Hatae, Eiko Toyota, and Minoru Ishikura*
*Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan
A one-pot synthesis of 3,3'-bisindolylmethanes was developed through the intermolecular Pummerer reaction using indole as a nucleophile.
Published online: 31st July, 2013
■ Palladium-Catalyzed Borylation of Aryl Iodides with 2,3-Dihydro-1H-benzo[d][1,3,2]diazaboroles
Miki Murata,* Nobuyoshi Hirai, Michihiro Okuyama, Takeshi Namikoshi, and Shinji Watanabe
*Department of Materials Science and Engineering, Kitami Institute of Technology, Koen-cho 165, Kitami, Hokkaido 090-8507, Japan
The palladium-catalyzed borylation of aryl iodides with 2,3-dihydro-1H-benzo[d][1,3,2]diazaboroles was achieved. The mild reaction conditions employed allowed for the inclusion of a wide variety of functional groups in aryl iodides to be tolerated. Additionally, the borylated products can be transformed into the corresponding boronic acids or their esters under acidic conditions.
Supporting Info. (195KB)Full Text HTMLPDF (701KB)PDF with Links (889KB)
Published online: 7th August, 2013
■ Formation of 1,2-cis-α-Aryl-glycosidic Linkages Directly from 2-Acetamido-2-deoxy-D-glucopyranosyl Acetate by the Mixed Activating System Using Ytterbium(III) Triflate and Catalytic Boron Trifluoride Diethyl Etherate Complex
Takashi Yamanoi,* Masanobu Midorikawa, and Yoshiki Oda
*Research Department, The Noguchi Institute, 1-8-1, Kaga, Itabashi-ku, Tokyo 173-0003, Japan
We found that a mixed activating system using ytterbium(III) triflate and a catalytic boron trifluoride diethyl etherate complex efficiently promoted glycosidation of the 2-acetamido-3,4,6-tri-O-benzyl-2-deoxy-α-D-glucopyranosyl acetate in dichloromethane at room temperature to afford 2-acetamido-2-deoxy-D-glucopyranosides in good yields along with the formation of a considerable amount of α-isomers. Glycosylations of the aryl alcohols as the acceptors stereoselectively afforded aryl α-glycosides without producing any β-isomers.
Published online: 1st August, 2013
■ Preparation and Electrochemical Property of Octaethylphthalocyanine Fused with Four Diselenadithiafulvalene Units
Takeshi Kimura*
*Center for Instrumental Analysis, Iwate University, 4-3-5 Ueda, Morioka, Iwate 020-8551, Japan
3,6-Diethylphthalonitrile (3) fused with diselenadithiafulvalene (DSDTF) was prepared from 5,6-dibromo-4,7-diethylbenzotriselenole (1) and treated with lithium alkoxide to produce octaethylphthalocyanine (6) with four DSDTF units. The structure of the product was determined by 1H NMR and MALDI-TOF-MS. Electrochemical and optical properties of 6 and its nickel complex (6-Ni) were examined by cyclic voltammetry and UV-vis spectroscopy.
Paper | Special issue | Vol 88, No. 1, 2014, pp. 213 - 221
Published online: 28th March, 2013
■ Introduction of Heteroarene Functionality on the Bipedal-Thiol-Capped Gold Nanoparticle by Deprotonative C-H Coupling with Palladium Complex
Atsushi Sugie, Hiroki Yamauchi, Kei Miyamura, Kenta Kumazawa, Shota Tanaka, Kiyoshi Kanie, Atsushi Muramatsu, and Atsunori Mori*
*Chemical Science & Technology, Graduate School of Engineering, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan
Gold nanoparticle stabilized by adsorption of bipedal thiol whose end is modified with bromoarene is prepared to undergo palladium-mediated deprotonative C-H arylation reaction. Heteroarenes are introduced onto the organic moiety of the nanoparticle.
Supporting Info. (921KB)Full Text HTMLPDF (1.8MB)PDF with Links (1.1MB)
Published online: 20th June, 2013
■ Palladium-Catalyzed Tetraarylation of 5,15-Dialkylporphyrins with Aryl Bromides
Yutaro Yamamoto, Sumito Tokuji, Takayuki Tanaka, Hideki Yorimitsu,* and Atsuhiro Osuka*
*Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
Nickel complexes of 5,15-dialkylporphyrins are subjected to palladium-catalyzed direct arylation under the modified Fagnou conditions. The arylation takes place still exclusively at the four less hindered β positions although the meso-nonyl, hexyl, and propyl groups are considered to impose less steric hindrance than the meso-3,5-di-tert-butylphenyl group in the previous report.
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Published online: 31st May, 2013
■ Cu/HP20-Catalyzed Solvent-Free Huisgen Cycloaddition at Ordinary Temperatures
Yoshiaki Kitamura, Kazumi Taniguchi, Tomohiro Maegawa, Yasunari Monguchi, Yukio Kitade, and Hironao Sajiki*
*Laboratory of Organic Chemistry, Department of Pharmaceutical Sciences, Gifu Pharmaceutical University, 1-25-4 Daigakunishi, Gifu 501-1196, Japan
We have developed an environmentally friendly and highly efficient solvent-free Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction using a polymer-supported copper catalyst (Cu/HP20). Substrates poorly soluble in common organic solvents are also applicable to the present cycloaddition reaction without any solvents and provide the corresponding 1,4-triazole in high yields.
Published online: 28th May, 2013
■ Efficient Oxidative Spirolactamization by μ-Oxo Bridged Heterocyclic Hypervalent Iodine Compound
Toshifumi Dohi, Eisuke Mochizuki, Daisuke Yamashita, Keitaro Miyazaki, and Yasuyuki Kita*
*College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga, 525-8577, Japan
In this report, the authors have clarified that the μ-oxo bridged heterocyclic hypervalent iodine compound 1 shows a more effective reactivity in the oxidative dearomatizing spirolactamization compared to conventional PIDA (phenyliodine(III) diacetate). Besides the high reactivity, a new selectivity during the oxidations based on the steric discrimination of the nitrogen groups of the pre-spirocyclic substrates is demonstrated for the heterocyclic hypervalent iodine compound 1.
■ Synthesis and Optical Properties of 2,2'-Biimidazole and Benzo[d]imidazole Derivatives: Changing π-Conjugation by Photoexcitation
Shoji Matsumoto,* Yu Zhao, and Motohiro Akazome
*Department of Applied Chemistry and Biotechnology, Graduate School and Faculty of Engineering, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
1,1′,5,5′-Tetraaryl-2,2′-biimidazole and benzo[d]imidazole derivatives were synthesized. Symmetrical and unsymmetrical benzo[d]imidazole derivatives could be obtained by the Pd-catalyzed coupling reaction between 2-iodo-benzo[d]imidazole and the corresponding (benzo)imidazole anion. Hypsochromic shifts in absorption and fluorescence spectra of 1,1′,5,5′-tetraaryl-2,2′-biazole were observed by switching pyrrole rings for imidazole and benzo[d]imidazole rings, resulting in compounds with various Stokes shifts. Based on the (TD)DFT calculation, it was reasoned that changing the conformation of each single bond from a twisted to planar structure by photoexcitation led to larger Stokes shifts.
■ Palladium-Catalyzed Direct Arylation and Alkenylation of 3-(Indol-3-yl)propionic Acids through C–H Bond Cleavage
Daisuke Takeda, Koji Hirano, Tetsuya Satoh,* and Masahiro Miura*
*Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
The palladium-catalyzed direct arylation of 3-(indol-3-yl)propionic acids with aryl bromides proceeds through C–H bond cleavages to give C2-arylated product in good yields. The C2-alkenylation of the substrates can also be performed smoothly under appropriate oxidative conditions.
Supporting Info. (519KB)Full Text HTMLPDF (990KB)PDF with Links (1MB)
Published online: 5th July, 2013
■ New, Lithiation-Based Synthesis of Tofisopam, a 2,3-Benzodiazepine Type Anxiolytic Drug
Erika Molnárné Samu,* Gyula Lukács, Balázs Volk, and Gyula Simig
*Chemical Research Deivision, EGIS Pharmaceuticals PLC, 1106 Hungary, Budapest,
Keresztúri út 30-38, Hungary
The classical, widely-used synthesis of the anxiolytic drug tofisopam applies chromium(VI) oxide reagent for the synthesis of the diketone key intermediate. The chromium salts formed in the course of the reaction are strongly toxic compounds. In order to reduce the reagents contributing to the pollution of the environment, an alternative manufacturing process has been elaborated at our laboratory. Starting compound (3,4-dimethoxyphenyl)acetone was transformed to the ethylene ketal of (2-bromo-4,5-dimethoxyphenyl)acetone. Bromine-lithium exchange and introduction of a 3,4-dimethoxybenzoyl moiety resulted in the new key intermediate. Removal of the ketal protecting group and ring closure with hydrazine was carried out in one pot affording drug substance tofisopam.
■ Total Synthesis of the Benzo[c]phenanthridine Alkaloids, Terihanine and Isoterihanine, and Their Antitumor Activity
Yuhki Kurata, Tominari Choshi,* Yuhsuke Ishihara, Noriyuki Hatae, Takashi Nishiyama, and Satoshi Hibino*
*Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan
A new total synthesis of terihanine (2a) and isoterihanine (2b) was established by our new bond formation between the C4b and N5 positions of the benzo[c]phenanthridine ring based on a microwave-assisted thermal electrocyclic reaction of 2-cycloalkenylbenzaldoxime as an aza 6π-electron system. In addition, the antitumor activity of these synthesized compounds, including nitidine and nornitidine was evaluated in HCT-116 cells.
Published online: 2nd August, 2013
■ Synthetic Approaches to 3,3'-Biindolyl and 3,3'-Biindazolyl Derivatives
Azadeh Nakhai and Jan Bergman*
*Department of Biosciences and Nutrition, Unit for Organic Chemistry, Karolinska Institute, Novum Research Park, SE-141 57 Huddinge, Sweden
In this paper new syntheses of 3,3'-biindolyl and 3,3'-biindazolyl derivatives are described. Formation of 3,3'-biindolyl derivatives by oxidative coupling of N-acetylindole with TeCl4 gave a good yield, while attempt to use the same reaction conditions for synthesis of 3,3'-biindazolyl derivatives failed. However, conversion of 3-haloindazole derivatives to its trimethylstannane derivative, followed by palladium-catalyzed Stille cross-coupling reaction, resulted in formation of 3,3'-biindazolyl derivatives.
■ Synthesis, Properties, and Crystal Structure of DDQ-Adducts of Ethynylated 2H-Cyclohepta[b]furan-2-ones
Taku Shoji,* Mitsuhisa Maruyama, Erika Shimomura, Akifumi Maruyama, Shunji Ito, Masafumi Yasunami, Junya Higashi, Kozo Toyota, and Noboru Morita*
*Department of Chemistry, Faculty of Science, Shinshu University, Asahi, Matsumoto 390-8621, Japan
Ethynylated 2H-cyclohepta[b]furan-2-ones reacted with 2,3-dichrolo-5,6-dicyano-1,4-benzoquinone (DDQ) in a formal [2+2] cycloaddition reaction to afford the corresponding DDQ-adducts in good yields. The electronic properties of the DDQ-adducts were investigated by UV/Vis spectroscopy. One of the DDQ-adducts was revealed the molecular structure by X-ray crystallographic analysis. The redox behavior of the new compounds was examined by cyclic voltammetry (CV) and differential pulse voltammetry (DPV).
■ Diastereoselective Synthesis of 3-Fluoro-2-substituted Piperidines and Pyrrolidines
Paul N. Gichuhi, Masami Kuriyama, and Osamu Onomura*
*Department of Natural Product Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
A facile procedure for synthesis of trans-3-fluoro-2-substituted piperidines by utilizing electrophilic fluorination of cyclic enamines and Lewis acid mediated nucleophilic substitution has been developed. Also, optically active trans-2-allyl-3-fluorinated pyrrolidines have been prepared by utilizing nucleophilic fluorination of hydroxyl group of trans-hydroxy-L-proline and Lewis acid mediated diastereoselective allylation as key steps.
■ Diastereoselective Lithiation of N-Silyl-Protected (S)-Tetrahydro-1H-pyrrolo[1,2-c]imidazol-3(2H)-one
Costa Metallinos,* Seyed Iraj Sadraei, and Nadezda Zhukovskaya
*Department of Chemistry, Brock University, 500 Glenridge Ave., St. Catharines, Ontario, L2R 3K4, Canada
An L-proline-derived imidazolone protected with an N-triethylsilyl (N-TES) group undergoes diastereoselective lithiation–electrophile quench to give C5-substituted products with syn stereochemistry. Unlike the previous N-t-Bu analogues, the N-TES derivatives may be easily N-desilylated to give secondary ureas that serve as precursors to N-phenyl chiral bicyclic guanidines.
■ Isolation, Structure Characterization, and Synthesis of Stabilized 1,2,3,4-Tetrahydroisoquinoline Marine Natural Product from Potassium Cyanide Pretreated Thai Tunicate, Ecteinascidia thurstoni
Shinya Kimura, Waree Pangkruang, Masashi Yokoya, Amane Honda, Ploenthip Puthongking, Khanit Suwanborirux,* and Naoki Saito*
*Department of Medicinal Chemistry, Pharmaceutical Chemistry, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
A simple 1,2,3,4-tetrahydroisoquinoline marine natural product (2a) together with two known compounds (3 and 4) was isolated from a low polar fraction of the crude extract of KCN pretreated Thai tunicate Ecteinascidia thurstoni. The structure of 2a was determined by X-ray crystallographic analysis. We also reported an eight-step large-scale preparation of 2a from isovanillin (9).
■ The Ability of 1-Aryltriazole-Containing Nucleobases to Recognize a TA Base Pair in Triplex DNA
Yoshiyuki Hari,* Motoi Nakahara, Shin Ijitsu, and Satoshi Obika*
*Graduate School of Pharmaceutical Science, Osaka University, 1-6 Yamadaoka, Suita, Osaka 560-0871, Japan
Phosphoramidites bearing propargyl and (N-propargylcarbamoyl)methyl groups at the C1-position of deoxyribose were synthesized and introduced into oligonucleotides by using an automated DNA synthesizer. Copper-catalyzed alkyne-azide 1,3-dipolar cycloaddition of the oligonucleotides with various aryl azides led to triplex-forming oligonucleotides (TFOs) possessing the corresponding aryltriazole-containing nucleobases. The triplex-forming ability of TFOs with double-stranded DNA (dsDNA) was evaluated through UV-melting experiments, and it was demonstrated that m-hydroxy or m-ureido derivatives in the (1-aryltriazol-4-yl)methyl nucleobases likely interacted with a TA base pair in dsDNA.
■ Exploration of Fluoral Hydrazones Derived from Carbohydrazides for the Synthesis of Trifluoromethylated Heterocycles
Grzegorz Mlostoń,* Katarzyna Urbaniak, Natalia Jacaszek, Anthony Linden, and Heinz Heimgartner*
*Institute of Organic Chemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland
The reaction of fluoral hydrate with carbohydrazides in methanol in the presence of molecular sieves (4 Å) gave the desired N-acylated fluoral hydrazones (3a–f) in fair yields. Treatment of the latter with mercaptoacetic acid in benzene led to the corresponding 2-trifluoromethyl-1,3-thiazolidinone derivatives (4a–f), whereas the reaction with acetic anhydride gave 3-acetyl-2,3-dihydro-2-trifluoromethyl-1,3,4-oxadiazoles (5a–f). The structures of each type of product have been established by X-ray crystallography.
Published online: 23rd July, 2013
■ Hydrogen Bond Organocatalysis of Benzotriazole in Transamidation of Carboxamides with Amines
Thanh Binh Nguyen,* Ludmila Ermolenko, Marie-Elise Tran Huu Dau, and Ali Al-Mourabit
*Department of Chemistry, Institut de Chimie des Substances Naturelles, CNRS, 1, Avenue de la Terrasse, 91190 Gif-sur-Yvette, France
A new method of transamidation of carboxamides with amines catalyzed by benzotriazole has been developed.
Full Text HTMLPDF (1MB)PDF with Links (1.1MB)
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On April 24, a special election will determine whether Orcas Island will have a public hospital district. PHD commissioner candidates are set to be elected on the same day as the district.
Richard Fralick is running unopposed for hospital commissioner one; Pegi Groundwater is running unopposed for position two; Arthur (Art) Lange and Leif (mononymous) are running for position three; John Dann, Richard (R.J.) Myers, Diane Boteler and Bill Bangs are running for position four; and Patricia Miller is running unopposed for position five.
For more about the candidates, see our article about the first candidate forum.
The Sounder asked the candidates the following questions about the public hospital district.
If the hospital district is approved, how do you think funds should be distributed among the existing facilities?
I believe all existing primary care providers on Orcas Island should be able to request PHD support. As regards to support for the UW Medicine Orcas Island Clinic and the Orcas Family Health Clinic, a detailed financial analysis of both clinics must be completed. Obtaining patient census and visit data will be critical to the study. Once obtained, the information will be used to determine the correct level of assistance to be provided to each. Through negotiation and monetary incentives, I would encourage both clinics to work together to streamline delivery of services, sharing of overheads and capital equipment. Whether this would ultimately lead to consolidation of the practices cannot be predicted at this time. Depending on developing circumstances, such an outcome might become practicable.
How do you think urgent care and after-hours care should be addressed?
The cost of current levels of urgent and after-hours care must be quantified. A cost/benefit analysis for improving these services must then be made. After the level of assistance required to sustainably support primary care is determined, residual taxing capacity should be evaluated and a determination made as to whether or not these available funds should be collected and how they should be apportioned. Improvement of urgent and after-hours care is a priority. The long-term financial sustainability of the PHD must also be considered, particularly as it relates to debt service and a rainy-day reserve fund. The Board of Commissioners will then make a considered decision as to how much should be spent on each.
How can the district ensure that the funded facilities are meeting the needs of the public?
The PHD should use satisfaction metrics to ensure that funded facilities are meeting the needs of the community. Such metrics should be included in any contract for services, and there should be clearly spelled-out consequences for nonperformance up to and including loss of PHD funding.
Satisfaction metrics are obtained from the patients of the providers after an office visit. They are semi-subjective, typically provided by a survey filled out by the patient post-visit. They [should] measure satisfaction overall, access to care, communication, coordination, etc. I would not expect the board to see individual surveys but rather summaries showing overall perceptions/measures of the medical provider's performance.
A community needs assessment should also be conducted by the PHD to determine if additional services should be added to those available.
I believe that the PHD should fund both primary care practices on Orcas to the extent required to ensure ongoing operations while carefully reviewing [its] financial operations to make sure that taxpayer dollars are not wasted. I think the PHD should also explore ways to reduce the duplicative overhead associated with having more than one practice on the island. For instance, if large pieces of new equipment need to be purchased, I believe the equipment should be owned by the PHD and its use shared by all primary care providers. Perhaps the PHD can find a way for all primary care providers to work out of the Medical Center building.
Our primary care providers already provide urgent care during office hours, but UW experienced some significant issues as they established their practice on Orcas. They seem to have resolved some problems and are working on solutions to others like courtesy blood draws. The PHD commission and superintendent should work with our medical providers to make sure that urgent care is available on a timely basis for all islanders. After-hours urgent care seems to be the larger issue. Both the Family Health Center and UW provide some form of after-hours urgent care, but that does not necessarily mean that a doctor is available to see a patient after hours if necessary. I believe the PHD should bring our EMS team and our primary care providers together to create a system that ensures that a doctor is available to meet with a patient after hours if medically necessary.
The PHD can require the medical practices to provide their quality metrics and patient complaint data to the PHD (in a manner that protects patient privacy and complies with HIPPA laws) as a condition of funding to make sure Orcas patients are receiving quality care. In addition, the PHD will carry out periodic public-needs assessments to make sure that the practices that receive PHD financial support are providing the medical services that Orcas residents want and are willing to support financially. The PHD meetings are open public meetings and will provide Orcas residents with an opportunity to speak to the commissioners about their vision of health care on Orcas.
All existing primary/urgent-care providers should be eligible to request PHD assistance. While the process of applying has to be decided by the elected commissioners, I would expect that each provider would make a specific request for assistance. The commissioners would carefully review in detail the specific request and the budgets of those making requests; negotiate the provision of specific services, their cost, metrics for measuring patient satisfaction; and [determine] how the PHD will monitor performance. The commissioners would then work with each provider to reach a mutually acceptable contract.
Patients needing treatment for urgent care problems during regular office hours should have quick access to a provider (a doctor, NP, PA, nurse) who would be able to make a determination that the patient needs to be seen "urgently." Once that determination is made, the patient should be able to see a provider quickly (depending on the nature of the presenting problem, that same day or the next day, if such delay is medically appropriate).
Regarding after-hours calls, patients should have access to a physically present provider when it is determined that that is medically appropriate. There may be a process of triage to make that determination, but being able to receive treatment from a physically present provider should be the end result when that is medically appropriate.
I do not believe we, as a community, can afford the cost of a fully staffed, 24/7 walk-in clinic. There is just not enough use to justify the considerable expense, but I believe that providers can be available when it is medically appropriate to see patients after-hours.
I would also like to see expanded clinic hours both during the week and on weekends wherever possible. It is estimated that such expanded hours would greatly reduce the number of after-hours calls.
There are, at least, two questions regarding "meeting the needs of the public": one, are services being provided at very high levels of patient satisfaction throughout the patient experience at the practices that are supported by the PHD? and two, are the practices providing the service that patients want and need? Number one focuses on the issues of quality and number two focuses on the issue of what types of services are wanted/needed.
The first issue would be addressed by including very specific metrics in the contract with each provider, measuring patient satisfaction on all the aspects of their medical experience. However, having data alone will not ensure that patients will be well served. There must also be clear consequences articulated in the contract for non-performance. There has to be some form of tangible accountability. Frankly, the only way the PHD can incentivize high levels of performance is with the provision or withholding of its funding.
The second issue can be addressed by surveying the members of our community to clearly understand what additional specific services folks want from their primary and urgent-care providers that are not being offered at that time and how much they would be willing to increase the levy to receive them. Certainly, it is very possible that some additional services might not require any additional cost.
Once the primary/urgent care needs have been met satisfactorily, the commissioners can then survey the members of our community to identify what other health care services they would like the PHD to support and how much they would be willing to increase the levy to receive them.
We have a long history of accounting too. Numbers were generated under a real-life "stress test" and can be taken as a very good approximation of financial need. This should be used as a baseline for future estimation.
"Urgent care" is an uninformed misnomer revealing the difficulty of oversight in health care. Without informed advocates, serious misunderstandings develop between professional providers and community debate. [For example:] caring for a sick relative is not a qualification as a community health care advocate; and EMS cannot replace ongoing professional care. On Orcas, we need to be much more careful in our choices about who represents our "needs." Having popularity or money cannot replace being qualified. Qualifications are verifiable facts and skills.
"After-hours medical care" is, for Orcas, the test of successful collaboration between our providers including EMS. It is a constant drain on resources, professional and financial, but it is only sparsely remunerated, so it becomes largely unrecoverable overhead, like having the heater on all the time.
This is an illustration of points one and two (above). What will deliver the best value to Orcas health care?
A successful collaboration between the community, its legitimate local advocates and the professional team. We have come to this critical juncture portending the loss of primary care on Orcas because of a pattern of complicity giving undue influence to those without sufficient standing, leading to abuses of governance, sapping our limited resources and destroying confidence in our providers thus rupturing the professional safety net, thus allowing our most vulnerable to fall through.
Financial stresses on the cusp of [Baby] Boomer senescence has merely exposed this metastatic cancer. No level of management restructuring or financial bailout will substitute for addressing this root cause finally.
Our ultimate goal should be a single, integrated practice at the existing clinic (Deye Lane) that meets the primary and urgent-care needs of our community at minimum cost. We have two separate practices and facilities that, in spite of skill, dedication and good intentions, are not yet meeting our needs and expectations. In the long term, we might not have either of the existing practices. In the short term, we need to negotiate minimum cost contracts to ensure continuity of care as we establish the vision for our future. I believe we can fund our immediate health care needs, including seven-day urgent care, with a tax rate of fewer than 50 cents per $1,000. We must insist on efficiency and collaboration with whoever receives public funds.
Our non-life-threatening urgent-care needs should be met both during and after normal clinic hours. We should be able to walk in during normal hours as well as receive same-day or next-morning urgent appointments, seven days a week. We should have 24/7 call-in access to either physician or nurse practitioner clinicians who can triage our issues so that we can be counseled to call 911, rely on self-care or receive a prompt appointment at our clinic. This can be provided seven days a week by having local doctors on-call on Saturday and Sunday. With four doctors, each needs only be on-call once every other weekend, and the cost to the taxpayer, assuming current market rates for a call, would be less than 2 cents per $1,000.
Any practice or facility funded by the PHD should agree to meet several conditions, including the acceptance of insurance and providing financial assistance. The practices should report on a number of quantitative measures of effectiveness, both for patient experience and for financial performance. These measures should include patient load, the number of visits per month, patient satisfaction, waiting times for routine appointments, and waiting times for urgent appointments. These measures should also include operating expenses per patient visit and expense recovery from all sources. All of these measures would be published on the district website for public review and comment. The district should also provide a complaint management system on its website for public comment and resolution. All such reports will factor into contract renegotiations.
Funds should be allocated based on the ability of each clinic to provide primary and urgent care to all islanders and participate in an after-hours urgent care system in collaboration with EMS. This evaluation would require a scientific needs assessment conducted over the first year of the district. Additionally, each clinic requesting funds would be required to provide detailed financial and patient visit information to support any subsidy request. The details of what information must be provided would be developed and published by the board with public input. The commissioners should also look at how clinics compare to other rural clinics in efficiency measures such as administrative costs, billing recovery from insurance companies, and staff-to-provider ratios.
How would you feel urgent care and after-hours care should be addressed?
Any subsidized clinic should have appointments available for patients with acute medical needs to be seen ideally the same day.
After-hours care first-contact could be by phone to island-savvy nurses. EMS would continue to evaluate acute illness and injuries. Physicians or providers would be available by phone to back up triage nurses, to discuss patients with EMS and to assure follow up care and to see patients needing acute treatment or evaluation.
The system should be accessible to all islanders and visitors with urgent health care needs without barriers based on primary care registration, insurance status or ability to pay. My hope would be to facilitate building a system for urgent and after-hours care easily accessible to all and appropriate in time and place of care.
We think we know what our essential health care needs are, primary and urgent care, but without a formal assessment, we are making ill-supported decisions. A scientifically designed and administered health-needs assessment should be done in the first months of the District that includes all islanders. Each clinic should be required to provide quarterly metrics to assess meeting those needs. Metrics should include specific measurements of care provided, such as the number of unique patients and encounters, timeliness of access to care and patient satisfaction and complaints. The district superintendent will be tasked with ensuring the accuracy of the reports and working with the board and the clinics to ensure identified needs are met.
I would distribute funds based upon patient volumes treated on a monthly basis to include after-hours care. Asking for any more detailed data could be fraught with inaccuracy.
I would stipulate funding of individual practices predicated upon developing an after-hours call network from the practices being subsidized.
The hospital district should receive a periodic report of patient volumes under active treatment. Additionally, HIPPA notwithstanding, the hospital district should be privy to information regarding patient complaints of providers and the ultimate resolution of those complaints by providers.
Answers were unavailable by press time.
RCW 70.44.140 spells out the requirements for how contracts can be awarded for services sought by a PHD. I anticipate that the initial desired services will be similar to what is currently provided by the existing facilities and that funds may be distributed to support their current models of operation. Collaborative solutions to address the biggest gaps in urgent care should also be evaluated. Customer satisfaction and economic metrics should be established and contracts should include penalties for failing to meet these metrics.
Metrics should evolve to measure the complexity and volume of visits and include incentives to achieve efficiencies within each practice and between practices. Industry metrics exist for compensating practitioners and measuring efficiency, which could be used to determine the level of reimbursement.
Both clinics currently offer some level of 24/7 after-hours and critical care support. The commissioners must evaluate the current services, including EMS, then clarify the gaps.
Collaboration between the main practices and EMS will be essential to the development of island appropriate service. I expect that the final solution might include a combination of one, limited expansion of regular hours of operation and limited hours on Saturdays; two, a more robust on-call system that offers over the phone triage to determine appropriate care; three, recognition by the community that a needs-based system, where an on-call medical practitioner deems what situations require immediate on-site after-hours service may be what is available; and four, some additional compensation to practitioners delivering that immediate on-site care.
This is a question of if the PHD is focused on delivering not only the right services but also are they being delivered in the right manner. I expect that the commission will conduct a health care needs assessment and gap analysis for the community in the early stages of the PHD. This will help establish the priorities as well as identify the biggest gaps in services to determine where the public's needs are not being met. This analysis, combined with the implementation and tracking of appropriate performance metrics for the participating clinics, should clarify if the services that are being delivered are meeting the needs of the public.
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High Specificity Malaria P.f. / Pan. Rapid Test Cassette / Kit in Blood
Large Image : High Specificity Malaria P.f. / Pan. Rapid Test Cassette / Kit in Blood
IMPN-402
Format: Cassette Accuracy: 99.2%
Feature: High Sensitivity, Specificity, And No Cross Reactivity Storage: 2-30℃
OEM: Available Certificate I: ISO13485,CE
The Malaria P.f./Pan Rapid Test Cassette (Whole Blood) is a rapid chromatographic immunoassay for the qualitative detection of four kinds of circulating plasmodium falciparum (P. falciparum (P.f.), P. vivax (P.v.), P. ovale (P.o.), and P. malariae (P.m.)) in whole blood
Malaria is caused by a protozoan which invades human red blood cells. 1 Malaria is one of the world's most prevalent diseases. According to the WHO, the worldwide prevalence of the disease is estimated to be 300-500 million cases and over 1 million deaths each year. Most of these victims are infants, young children. Over half of the world's population lives in malarious areas. Microscopic analysis of appropriately stained thick and thin blood smears has been the standard diagnostic technique for identifying malaria infections for more than a century. 2 The technique is capable of accurate and reliable diagnosis when performed by skilled microscopists using defined protocols. The skill of the microscopist and use of proven and defined procedures, frequently present the greatest obstacles to fully achieving the potential accuracy of microscopic diagnosis. Although there is a logistical burden associated with performing a time-intensive, labor-intensive, and equipment-intensive procedure such as diagnostic microscopy, it is the training required to establish and sustain competent performance of microscopy that poses the greatest difficulty in employing this diagnostic
The Malaria P.f./Pan Rapid Test Cassette(Whole Blood) is a rapid test to qualitatively detect the presence of P. falciparum - specific HRP-II and four kinds of circulating plasmodium falciparum(P. falciparum (P.f.), P. vivax (P.v.), P. ovale (P.o.), and P. malariae (P.m.)). The test utilizes colloid gold conjugate to selectively detect P.f-specific and Pan-malarial antigen (P.f., P.v., P.o. and P.m.) in whole blood.
1.Bring the pouch to room temperature before opening it. Remove the test cassette from the sealed pouch and use it as soon as possible.
2.Place the cassette on a clean and level surface.
For Whole Blood specimen:
·Use a pipette: To transfer 5 μl of whole blood to the specimen well, then add 3 drops of buffer (approximately 180 μl).
·Use a disposal specimen dropper: Hold the dropper vertically, draw the specimen up to the Fill Line as shown in illustration below (approximately 5 μl). Transfer the specimen to the specimen well, then add 3 drops of buffer (approximately 180 μl), and start the timer.
POSITIVE:* Two or Three distinct colored lines appear.P. falciparum or mixed malaria infection : one line appears in the control region, one line appears in Pan line region and one line appears in P.f. line region. P. falciparum infection: one line appears in the control region, and one line appears in
P.f .line region.
Non-falciparum Plasmodium species infection :one line appears in the control region and one line appears in Pan line region.
*NOTE: The color intensity of P.f. or Pan test lines may vary depending on the concentration of antigens, viz., HRP-II or Aldolase present in the specimen.
NEGATIVE: Only one colored line appears in the control region.
INVALID: Control line fails to appear. Insufficient specimen volume or incorrect procedural techniques are the most likely reasons for control line failure. Review the procedure and repeat the test with a new test device. If the problem persists, discontinue using the test kit immediately and contact your local distributor.
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Q: My error checking method for a certain user input is not working I have a method here that is supposed to check if a user has entered a "y", pertaining to the answer yes; or an "n" pertaining to the answer no. It reads in the letters entered by the user correctly, however it keeps saying that the user has not entered a "y" or an "n". If someone could let me know what I'm doing wrong that would be great. Here is the code I'm using :
String answer = "";
do {
while (answer.equals("")) {
answer = sc.nextLine();
}
if (!answer.equals("y") || !answer.equals("n")) {
System.out.println("Please enter a y, meaning yes; or an n, meaning no.");
answer = "";
}
} while (!answer.equals("y") || !answer.equals("n"));
A: The answer is pretty simple, change your || to &&. This is, because every input is not equal to n or y.
The corrected code should look like this:
String answer = "";
Scanner sc = new Scanner(System.in);
do {
while(answer.equals("")) {
answer = sc.nextLine();
}
if(!answer.equals("y") && !answer.equals("n")) {
System.out.println("Please enter a y, meaning yes; or an n, meaning no.");
answer = "";
}
}while (!answer.equals("y") && !answer.equals("n"));
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The worldwide trend of using botanical drugs and strategies for developing global drugs
Natural product drugs, or botanical drugs, are drugs composed of natural substances which have constituents with health-enhancing or medicinal activities. In Korea, government-led projects brought attention to botanical drugs invigorating domestic botanical drug industry. Foreign markets, as well, are growing bigger as the significance of botanical drugs stood out. To follow along with the tendency, Korea puts a lot of effort on developing botanical drugs suitable for global market. However, standards for approving drug sales vary by countries. And also, thorough standardization, certification, clinical studies and data of these will be required as well as data confirming safety and effectiveness. Meanwhile, as an international exchange in botanical drug market continues, the importance of plant resources was emphasized. Thus countries' ownership of domestic natural resources became vital. Not only establishing a systematic method to secure domestic plant resources, but also cooperation with other countries on sharing natural resources is essential to procure natural resources effectively. Korea started to show visible results with botanical drugs, and asthma/COPD treatment made out of speedwell is one example. Sufficient investment and government's active support for basic infrastructure for global botanical drugs will bring Korea to much higher level of botanical drug development.
INTRODUCTION Natural products, in a broad sense, is a generic term for plants, animals, minerals, microorganisms and their metabolites found in nature. In Korea, the term 'natural product drug' was defined-according to the enactment of 'Natural Product Drug R&D Acceleration Law' in 2000-as drugs researched and developed using substances from natural products that contain new constituents and efficacies. The U.S. coined the official term 'botanical drug' for natural products, referring to drugs manufactured with plant substances, including algae, microfungi (the term botanical drugs will be used for natural product drugs hereafter). While many vendors promote the use of botanical products as dietary supplements, only a select number of products have been approved by the U.S. Food and Drug Administration (FDA) for use as prescription drugs. The first botanical drug approved by the FDA was Veregen®, a treatment for genital and perianal warts that is derived from green tea (Camellia sinensis Kuntze). A number of years later, the FDA approved another New Drug Application (NDA) for the drug Fulyzaq™, an indicator drug for HIV-associated diarrhea extracted from the blood-red latex of the South American croton tree (Croton lechlerii Müll. Arg). In Europe, they use the term herbal medicinal product (HMP) to encompass all drugs that contain one of more kind of herbal substances in the herbal preparation. The Chinese developed TCM (Traditional Chinese medicine), a prescription of their traditional medicines, based on their own experiences of its usage, and eastern ideas.
DEVELOPMENT TRENDS OF BOTANICAL DRUGS In 2000, 'Natural Product Drug R&D Acceleration Law' was established as institutional support from the Korean government and, based on this law, the government and various institutes initiated a 5-year-plan of research and development of botanical drugs. Botanical drugs drew more interest from the public when botanical drugs were selected as one of the five tasks of a government-derived project. In the first half of 2011 alone, three products, including the Shinbaro Capsule from Greencross, Synatura Syrup from Ahn-gook, Motilitone from Dong-A were approved for marketing, and in 2012, the PMG Pharm's osteoarthritis treatment and Layla tablet, Yungjin's atopy cure, Utoma, was accepted as a botanical drug. In 2013, according to the data from UBIST, a program aggregating statistics on drugs, the Stillen tablet from Donga-ST raised more than 60 million dollars, Ahn-gook raised 30 million dollars with Synatura Syrup, 18 million dollars from Motilitone, and 36.4 million dollars from Joins Tablet, 6.7 million dollars from SK Chemical, 5.2 million dollars from Shinbaro Capsule, and 5.2 million dollars from Layla Tablet (5.2 million as prescription performance). These performances indicate a successful settlement of botanical drugs in the domestic market. Encouraged by these facts, pharmaceutical companies reinforced their developing processes of botanical drugs. Currently, 24 companies are researching and developing botanical drugs, and 23% of the investigational drugs in the pipeline are botanical drugs. These companies mainly focus on digestive system, metabolic and central nervous system diseases.
Meanwhile, the size of the global market, including medical supplies, functional foods for health etc. is estimated to be 1 trillion dollars and is growing annually by 8 to 10 percent. About half of the medical supplies currently on sale are botanical drugs, or extracts composed of single-element substances from natural products. Tamiflu (Oseltamivir) is one typical example. Tamiflu was discovered from a natural substance called star anise which is a Chinese native plant, and its sales from all over the world reached 3 billion dollars. Besides Tamiflu, Aspirin, Taxol, Ginkgo Biloba extract, and plantain extract were developed and put on sale, raising big profits. In 2004, FDA established an industrial guideline for botanical drugs (Botanical Drug Guidance), as an effort to take the initiative in the botanical drug market. As a result, the FDA approved 868 kinds of Semisynthetic substances that originated as natural products since 1982 and developed 20 kinds of an anticancer drug derived from natural substances until 2002 (Science Times, 2010. 8). Veregen Ointment 15% (Veregen® Phynova, warts treatment on pubic area, approved in 2006) made by Medigen, German Pharmaceutical, is one of the products that was approved by the FDA. This drug reached 4.5 million dollars in sales. Fulyzaq, the second botanical drug developed, is the first oral medication developed by Salix Pharmaceuticals using a proanthocyanidin polymer extracted from wild plants in the Amazon river basin, and this drug was approved for sales in 2012, as an orphan drug which relieves symptoms of diarrhea from AIDS patients. GW Pharmaceuticals, an English company, developed Sativex (Oromucosal Spray), a marijuana extract efficacious for rigidity due to multiple sclerosis. GW Pharm raised 11 million dollars with Sativex. China intends to found the world's biggest Chinese medication database. Sales of Chinese medication are 22.7% of the entire drug market and it is expected to grow at the same pace as the recorded high growth at an average of 35% annually over the past 5 years.
CHALLENGES IN DEVELOPING GLOBAL BOTANICAL DRUGS Although the global market of botanical drugs is expanding continuously, Korea's performance overseas is not quite satisfactory. Stillen, one of the representative botanical drugs in Korea, raised only 200 thousand dollars abroad after its release. Other domestically developed botanical drugs are no different when it comes to sales performance. Performances until now contrasts with the government's prediction that botanical drugs will be one of the major sources of income in Korea. Botanical drug approvals in the U.S There have been numerous attempts to bring botanical drugs to the market through FDA approval, including 500+ pre-IND meetings and IND applications, with limited success in reaching the final NDA stage. In fact, only two NDAs have been approved by the FDA so far. The authors suggest in this section three of the most commonly encountered complications that account for the low number of botanical drug NDAs submitted to the FDA for review. The FDA requires "adequate and well-controlled" multicenter clinical studies on any new drug candidate to document and support its safety and efficacy, and imposes the maximum level of scrutiny prior to approval. It is crucial for these efficacy studies to have a well-defined target population (according to the FDA protocol eligibility criteria), proper experimental controls (such as placebo or active treatment), appropriate outcome measures (agreed upon by the FDA), independent monitoring, and accurate analysis. Consequently, the single most common reason that any new drug candidate, including botanical drugs, fails to reach the NDA step is the failure to present statistically significant evidence for having efficacies of clinical relevance.
Unrealistic Goals and Expectations Unrealistic expectations are often set forth by drug sponsors with insufficient experience with a drug development program, for multiple reasons, and the resulting miscommunication could hinder the drug approval process. For one, the initial stages of IND development is relatively less strict, and this may falsely suggest to new drug sponsors that botanical drugs, compared to conventional synthetic drugs, are less rigorously evaluated by the FDA. Another reason for drug sponsors to have unrealistic expectations is the confusion that arises from the lack of internationally standardized regulatory requirements for botanicals. In other words, many non-U.S. botanical drug sponsors, especially those that have no experience in fielding a drug development operation in the U.S., are not aware of the practical differences in regulations between the U.S. and a foreign market. As an anecdote, some sponsors do not reconcile the fact that "raw data" (chemistry, nonclinical safety testing, or clinical study databases), instead of data summaries or "expert" opinion, is required by U.S. regulations.
Insufficient Funding It is possible that the development of botanical drugs in the IND stage suffers the loss of some or all project funding, which brings the project to a standstill. Several factors contribute to funding cuts: general economic climate; skepticism of investors; lack of patents (even if other forms of intellectual property are filed and secured); and/or inadequate project planning.
STRATEGIES FOR DEVELOPING 'GLOBAL BOTANICAL DRUGS.'
Development of novel botanical drugs using traditional medicinal plant sources Botanical drugs are, by nature, plant-derivative materials and their complexes. This makes them unfit for conventional "single-target/single-drug" development processes and thus have been largely disregarded in the field of medicine. However, it is widely understood in synthetic medicine that the single-drug "magic bullet" strategy is not adequate for treating chronic illnesses (e.g. cancers, immune disorders, mental illnesses, cardiovascular diseases, lifestyle diseases) due to their complex pathogenetic mechanisms, and that a "multi-target/multi-component" approach involving control over a number of target sites is more effective. Traditional herbal medicine, itself being a mixture of various components, corresponds to the "multi-target/multi-component" approach, with therapeutic effects that are clinically confirmed--albeit with no analytically defined mechanisms--through experience and knowledge accrued over a long history of treatment of chronic illnesses. The strategy for developing novel botanical drugs by reverse-engineering of traditional herbal medicine is called reverse pharmacology. Reverse pharmacology involves the study of active ingredients based on traditional herbal medicine and formulations as well as the subsequent development of drug candidates or formulations for preclinical and clinical research. This is deemed to be the most optimal strategy for the development of cures for chronic illnesses because it utilizes materials (traditional herbs) with proven safety and clinical efficacy, which allows the development process to be opposite that of the initial stages of synthetic drug development and therefore reduces the cost and duration of development compared to conventional synthetic drug development methods. Using knowledge from traditional Korean medicine in botanical drug development is also a reverse pharmacology approach with many successes reported worldwide, which prompted the reevaluation of traditional medicinal herbs and greatly spurred the research and development of botanical drugs.
Keeping pace with global standards of botanical drug development For Korean botanical drugs to successfully compete in global market, there are some conditions institutes and pharmaceuticals to keep in mind. Since the licensing procedure of new drugs varies by countries, it is reasonable to begin development procedure in accordance with such country's distinct regulations. Secondly, certification and standardization of botanical drugs, complex clinical studies, scientific data for sale approval are essential. For materials, specific origin of the medicine and securing bioequivalence is the most important and procuring bioequivalence is the most challenging part of drug development process. Equivalent production of the material is also a vital portion, scientification of plants, ecological environment, a record of cultivation should be conducted. If a company imports natural products as materials, they need to secure a reliable supply chain in terms of collection, cultivation, and importation for the seamless supply of medicine. The third requisite is safety and effectiveness. All countries, including the US, Europe, and China, set safety as the top priority. They accept oriental medicine texts of cases of drug usage abroad to some extent, but mainly, they request data on drug-drug interaction (DDI), mechanism of action (MOA) and pharmacokinetic (PK). Meanwhile, the Nagoya Protocol came into effect. There are articles related to ABS, agreement of access to genetic resources and benefit-sharing, in Nagoya Protocol which consequently acknowledges each country's ownership of its domestic natural resources. Therefore, biotechnology institutes and universities, especially those that are in the beginning process of developing botanical drugs, should be well informed about ABS articles. To sensibly deal with this issue, institutes should build a partnership with countries providing resources or such organizations. Also, they need to analyze regulation regarding access and benefit share in different countries and come up with counterplan for anticipated future problems. For counterplay, financial benefit sharing, technology transfer, co-ownership of patent and intellectual property may be possible.
Promoting infrastructure on securing plant resources Industrial value of plant resource in drug market is prominent. Traditional plant resources were not only the key material for drug development, but also a core resource in the market for botanical drug products since 85% of the world's traditional medication derive from plants. Korean, China, Japan, India, Germany, countries that have long developed traditional medicine and herbal medication, are striving to procure plant resources countrywide to develop botanical drugs using plant extract. Specific strategies among countries might differ, but the point is they all acknowledge the significance of plant resource. Korea has constructed their own method of securing plant resources. Korean Research Institute of Bioscience & Biotechnology (KRIBB) founded South Korea's first mass-distribution system named Korea Plant Extract Bank. Extract Bank provides researchers screening samples at the beginning of food and drug development phase, assisting researchers to acquire resources regardless of season, and holds vouchers of materials to provide the origin of the plantation, and subsidiaries preventing overexploitation of rare species. From 2000 to 2010, extract bank gathered 1,699 species of Korean native plants, which takes up 40% of entire Korean plant species, excluding garden plants and food crops, and made extracts with 5,164 samples separated by parts then offered them to researchers (total 416,829/2013. 12) as a part of supporting research of domestic natural substances. Meanwhile from 2006, in terms of extending a variety of resources, extract bank has launched 'International Biological Material Development Project' (2006–2016) and established 4 local centers near tropical/subtropics area (China, Indonesia, Costa Rica, Vietnam) where a broad range of life exists. Each year, through a formal agreement, extract bank assembles foreign resources (27,000 pieces of extract, 2015. 12) and establishes a database of basal activity(anti-inflammatory, cytotoxic, antioxidation, insecticide). After that, they give out foreign resources (1,600,000 pieces 2015. 09) to researchers and provide them information based on the database.
ENDEAVORS OF KOREAN PHARMACEUTICALS FOR GLOBALIZING DOMESTIC BOTANICAL DRUGS In spite of some challenges Korea had in globalizing domestic botanical drug products, some companies are starting to show visible results throughout the US and Europe. Korean government suggested 'Global Leading Natural Pharmaceutical Project' as a project to forge developing industries to the highest level and make internationally recognized drugs. With Donga-ST in charge, 10 pharmaceutical companies participated with the support of 16 industry-academic collaboration institutes. As a result, Donga-ST's new diabetic Neurotherapy treatment was approved by the US for clinical study phase I IND in April 2013, and recently got down to clinical trial. Motilitone is on standby for FDA's approval on phase II within the first half of 2014. COPD/asthma treatment from Yungjin Pharmaceutical completed phase I and is in the middle of phase II base on approval in 2014. For pharmaceuticals aiming Europe market, Greencross HS developed anticancer supplements and is in the process of phase I trials and SK Chemicals has set a goal of their asthma treatment to acquire authorization of Phase I trials in Europe. All of this medicine were developed is Korea and later got approval at clinical studies from institutes of Europe and the US, quantitatively/qualitatively comparable with botanical drugs made in developed countries. The KRIBB Natural Medicine Research Center developed asthma/COPD treatment, and the natural substance they used is speedwell genus (Pseudolysimachion genus) plants. Speedwell, according to Chinese medicine dictionary, is a kind of herb medicine used to treat loosen phlegm, chronic cough, and asthma/COPD. However, in Korea, there was no record of speedwells in 10 major books being utilized as herbal medicines, which means that the usage of speedwell was not extensively known to the traditional Korean medicine world. From the beginning of research, relying on the clinical effects referred to in old books, research center conducted clinical studies on animals, and they discovered active materials substantially effectively. Since 2006, these results were applied to patents in 12 countries. For the following study, selected mountain spike speedwells in which the aerial part is relatively larger has active components. Then, after identifying excellence for cultivation at the central inland area, they massively cultivated wild seeds proving phytoequivalence between wild type and cultivated type seeds. Afterward, they transferred such results, along with the patent to Yungjin Pharmaceuticals in May 2010, and July of the same year, KRIBB Natural Medicine Research Center was selected as supporting organization of pharmaceuticals on 'Global Botanical Drug Development Project.' For the past 3 years, Natural Medicine Research Center conducted studies on standardization of raw material medicine/herb medicine suitable for US guideline of clinical studies, and biological researchers on animal effectiveness/biomarker/MOA. Ultimately, KRIBB successfully supported Yungjin Pharmaceutical to complete phase I trials in the US.
CONCLUSION The International perspective of drug development recently has been rapidly changing. As the world's population is constantly aging, and lifestyle diseases and chronic diseases have become more prevalent, and more and more people pursue improved quality of life which focuses on preventing diseases, drug development shifted its focus towards treating aging, cancer, chronic diseases, and lifestyle related diseases. Consequently, traditional medication, which safety and clinical effects had been confirmed over a long period of time for treating diseases mentioned earlier, and botanical drugs which stand on the basis of traditional medication are expected to grow tremendously. However, Korea relies most of its resources on foreign countries, and it can be a hindrance in developing botanical drugs. To resolve this matter, externally, Korea needs to establish a systematic network with countries possessing such resources and internally, needs to build up well-organized infrastructure on procuring natural resources residing in Korea. Lately, global trend has been towards acknowledging country's claim on its biological resources, and in the close future, countries providing biological resources (including intellectual resources) may demand their share of profits produced by developing natural resources. This ongoing trend would be a serious limitation to Korea's development strategy with foreign resources, so Korea needs to prepare plans to resolve this matter. In addition, basic structures for the legal system, analyzing and standardizing system for improving quality and GAP cultivation management of domestic natural resources should be set up, and continuously supervised. Government's active support and companies' investment based on this structure will bring forward the days that Korea moves up to a higher level on developing botanical drugs.
Source: BMB Rep. 2017 Mar; 50(3): 111–116. Published online 2017 Mar 31.
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This allergy blood test project is meeting the need for better diagnosis and treatment for subtropical grass pollen allergy.
Grass pollens are the major outdoor aeroallergen globally and the primary illness caused by pollen exposure, allergic rhinitis, affects 500 million people worldwide. Whilst allergen specific immunotherapy "vaccines" are an effective treatment that reduces symptoms and progression to more severe disease (eg asthma), there are currently no standardized tests or treatments for subtropical grass pollens. Dr Davies' research has revealed primary sensitisation to pollen of subtropical grasses (eg Bahia and Johnson grass) in patients from subtropical regions. Importantly, her team has demonstrated that allergic responses of these patients show species-specific IgE and cellular immune recognition of the dominant allergen components of Bahia and Johnson grass pollens, indicating the need for better diagnosis and treatment for subtropical grass pollen allergy.
They have now discovered, using advanced molecular and bioinformatics techniques, all the allergen components of the Panicoideae subfamily of grasses.
The discovery of the complete allergen repertoire of Johnson grass pollen (awarded European Academy of Allergy and Clinical Immunology prize) was published in the top-ranked, field-leading Journal of Allergy and Clinical Immunology (JIF12). Application of these discoveries for specific tests and therapies have been protected by a series of patent applications, including one accepted for grant in Australia this year. With NHMRC Development Grant funding, extensive enabling in kind support and close collaboration with industry partners Sullivan Nicolaides Pathology (Queensland), Abacus ALS (Australia) and ThermoFisher (Sweden), the team has now developed an extremely sensitive and specific blood test for accurate diagnosis of Bahia grass pollen allergy (Area under the Receiver Operator Curve of 0.96). The test is based on measurement of specific IgE concentrations to the major allergen component of Bahia grass pollen, Pas n 1.
These research outcomes have the potential to improve the accuracy of diagnosis and efficacy of treatment for patients primarily allergic to subtropical grass pollens. This Pas n 1–IgE test, alone and in combination with further subtropical grass pollen allergen component tests under development, will enable a more quantitative, differential diagnosis of subtropical grass pollen allergy. These outcomes are intended to reduce the high medical and economic burden of healthcare and lost economic productivity attributed to allergic rhinitis and its adverse impact upon asthma.
Discussions are underway with the international leader in immunology diagnosis, regarding the commercial potential for clinical use of this test as a single point component resolved diagnostic and within a multi-allergen array platform to improve the specificity of allergy diagnosis in Australia and other regions with a subtropical climate (including a large US market). Further NHMRC Development funding is sought for component resolved therapies for subtropical grass pollens. Several global leaders in the business allergen immunotherapy are engaged in consultation, and collaborative research with Dr Davies' team, to resolve the need for optimised allergy vaccines targeting subtropical grass pollens.
Within the TRI, Dr Michelle Hill (UQ-DI) collaborates on proteomic identification of allergen components and Dr Ray Steptoe (UQ-DI) is establishing murine models of pollen induced allergic airway inflammation that will identify the allergen components required for an effective subtropical grass pollen allergy vaccine in future.
A multi-centre clinical survey is underway to determine effectiveness of blood test in diagnosing allergic reaction to subtropical grasses. Ultimate aim is to develop a vaccine to prevent the allergic reaction.
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