Neuroscience in Nazi Europe part I: eugenics, human experimentation, and mass murder.
The Nazi regime in Germany from 1933 to 1945 waged a veritable war throughout Europe to eliminate neurologic disease from the gene pool. Fueled by eugenic policies on racial hygiene, the Nazis first undertook a sterilization campaign against "mental defectives," which included neurologic patients with epilepsy and other disorders, as well as psychiatric patients. From 1939-41 the Nazis instead resorted to "euthanasia" of many of the same patients. Some neuroscientists were collaborators in this program, using patients for research, or using extracted brains following their murder. Other reviews have focused on Hallervorden, Spatz, Schaltenbrand, Scherer, and Gross, but in this review the focus is on neuroscientists not well described in the neurology literature, including Scholz, Ostertag, Schneider, Nachtsheim, and von Weizsäcker. Only by understanding the actions of neuroscientists during this dark period can we learn from the slippery slope down which they traveled, and prevent history from repeating itself.


[Effect of long-term ambulatory hypotensive treatment on the structural and functional status of the myocardium].
Changes in myocardial function and the possibility of a regression of left-ventricular hypertrophy were examined in patients with stable hypertension during a year of effective hypotensive treatment. Ninety-seven patients with essential hypertension, stage IIB (by Myasnikov's classification) and aged 35 to 56 years, were studied. Echography was conducted before the onset of treatment and after one year of regular hypotensive therapy. A marked hypotensive effect was noted in the course of treatment. Left-ventricular myocardial weight declined in 69% of patients, remained unchanged in 18.6% and increased in 12.4% despite the hypotensive effect of treatment. The reduction of left-ventricular hypertrophy was associated with no basic changes of myocardial pump function or contractility.


Circulating liver enzymes and risks of chronic diseases and mortality in the prospective EPIC-Heidelberg case-cohort study.
Elevated liver enzyme concentrations in blood are indicative of liver diseases and may provide an early signal for being at risk for other chronic diseases. Our study aimed to assess the relationships of alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), alanine aminotransferase (ALT), aspartate transaminase (AST) and the De Ritis ratio (AST/ALT) with incidence and mortality of cardiovascular diseases (CVD) and the four most common cancers, that is, breast, prostate, colorectal and lung. We analysed a case-cohort sample of the prospective European Prospective Investigation into Cancer and Nutrition-Heidelberg cohort, including cancer (n=1632), cancer mortality (n=761), CVD (n=1070), CVD mortality (n=381) and a random subcohort (n=2739) with an average follow-up duration of 15.6 years. Concentrations of liver enzymes were measured in prediagnostic blood samples and Prentice-weighted Cox regression models were used to estimate HRs with 95% CIs. High ALP levels were associated with increased risk for lung cancer and all-cause mortality (highest vs lowest quartile, multivariable adjusted HR=2.39 (95% CI 1.30 to 4.39), HR=1.31 (95% CI 1.02 to 1.67)), high AST levels with all-cause mortality (HR=1.45 (95% CI 1.15 to 1.82)), and a high De Ritis ratio with prostate cancer risk, all-cause and cancer mortality (HR=1.61 (95% CI 1.10 to 2.36), HR=1.60 (95% CI 1.25 to 2.04), HR=1.67 (95% CI 1.26 to 2.23)). Using cut-points for liver enzyme levels above normal, we observed positive associations for all-cause mortality with ALP, GGT and AST, and assigning a combined risk score resulted in positive associations with all-cause and cause-specific mortality. Measurements of serum liver enzymes, as routinely performed in health check-ups, may support the identification of individuals at increased risk for all-cause mortality. Further prospective studies are needed to verify our first results on individual cancers and on a combined risk score.


Increased circulating FGF21 level predicts the burden of metabolic demands and risk of vascular diseases in adults with type 2 diabetes.
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by chronic hyperglycemia and metabolic stress, involved in the stepwise development of cardiovascular complications. Fibroblast growth factor 21 (FGF21) is a novel hepatokine involved in regulating glucose and lipid metabolism, and has been linked to the prediction, treatment, and improvement of prognosis in multiple cardiovascular diseases (CVDs). The aim of this study is to explore the relationship between FGF21 levels and vascular diseases (VDs) including carotid atherosclerosis (CAS) and hypertension (HP) in patients with T2DM. Baseline serum FGF21 was determined in a cross-sectional study of 701 patients with T2DM and 258 healthy control. The morbidity of CAS was increased in T2DM patients with HP as compared with those without (p < 0.001). The average serum FGF21 level of healthy was [123.9 (67.2-219.3)]. Baseline FGF21 was significantly higher in those who developed CAS or HP than in those who did not [305.9 (177.2-508.4) vs. 197.2 (129.7-308.3) pg/mL, p < 0.001]. In addition, an elevated serum FGF21 was observed in T2DM patients with HP and CAS than that of T2DM patients with CAS or HP [550.5 (312.6-711.3) vs. 305.9 pg/mL, p < 0.001]. Serum FGF21 levels were positively correlated with body mass index and carotid intima media thicknes (p < 0.05), the association remained significant after adjusting for age and T2DM duration. Furthermore, the multinomial logistic regression showed that serum FGF21 was independently associated with CAS and HP in patients with T2DM after adjustment for demographic and traditional VDs risk factors (p < 0.001). Baseline FGF21 is elevated in VDs during diabetes, changes of serum FGF21 levels were appropriately matched to metabolic stress. FGF21can be used as an independent predictor for diagnosing VDs and predicting prognosis.


Lipid Droplet Formation and Lipophagy in Fatty Liver Disease.
Lipid droplets (LDs) are key sites of neutral lipid storage that can be found in all cells. Metabolic imbalances between the synthesis and degradation of LDs can result in the accumulation of significant amounts of lipid deposition, a characteristic feature of hepatocytes in patients with fatty liver disease, a leading indication for liver transplant in the United States. In this review, the authors highlight new literature related to the synthesis and autophagic catabolism of LDs, discussing key proteins and machinery involved in these processes. They also discuss recent findings that have revealed novel genetic risk factors associated with LD biology that contribute to lipid retention in the diseased liver.


Evaluation of a ginkgo biloba extract (EGb 761) in functional tests for monoamine oxidase inhibition.
A standardized extract of ginkgo biloba (EGb 761) was evaluated in functional tests for monoamine oxidase (MAO) inhibition in mice: l-dihydroxyphenylalanine (CAS 59-92-7,1-DOPA) potentiation, tryptamine (CAS 61-54-1) potentiation, 5-hydroxytryptophan (CAS 4350-07-6,5-HTP) potentiation and phenylethylamine (CAS 64-04-0) potentiation. The doses investigated (25, 50 and 100 mg/kg p.o once daily for 5 days) were those known to possess anti-stress properties in other animal models. In contrast to the reference substances investigated (nialamide (CAS 51-12-7), clorgyline (CAS 17780-75-5) and 1-deprenyl (CAS 14611-52-01), EGb 761 did not exhibit any activity indicative of MAO inhibition. It was concluded that MAO inhibition was not the mechanism primarily responsible for EGb 761's anti-stress activity.


IMPACT probability of poor outcome and plasma cytokine concentrations are associated with multiple organ dysfunction syndrome following traumatic brain injury.
Traumatic brain injury (TBI) is a major cause of morbidity and mortality. Multiple organ dysfunction syndrome (MODS) occurs frequently after TBI and independently worsens outcome. The present study aimed to identify potential admission characteristics associated with post-TBI MODS. The authors performed a secondary analysis of a recent randomized clinical trial studying the effects of erythropoietin and blood transfusion threshold on neurological recovery after TBI. Admission clinical, demographic, laboratory, and imaging parameters were used in a multivariable Cox regression analysis to identify independent risk factors for MODS following TBI, defined as maximum total Sequential Organ Failure Assessment (SOFA) score > 7 within 10 days of TBI. Two hundred patients were initially recruited and 166 were included in the final analysis. Respiratory dysfunction was the most common nonneurological organ system dysfunction, occurring in 62% of the patients. International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) probability of poor outcome at admission was significantly associated with MODS following TBI (odds ratio [OR] 8.88, 95% confidence interval [CI] 1.94-42.68, p < 0.05). However, more commonly used measures of TBI severity, such as the Glasgow Coma Scale, Injury Severity Scale, and Marshall classification, were not associated with post-TBI MODS. In addition, initial plasma concentrations of interleukin (IL)-6, IL-8, and IL-10 were significantly associated with the development of MODS (OR 1.47, 95% CI 1.20-1.80, p < 0.001 for IL-6; OR 1.26, 95% CI 1.01-1.58, p = 0.042 for IL-8; OR 1.77, 95% CI 1.24-2.53, p = 0.002 for IL-10) as well as individual organ dysfunction (SOFA component score ≥ 1). Finally, MODS following TBI was significantly associated with mortality (OR 5.95, 95% CI 2.18-19.14, p = 0.001), and SOFA score was significantly associated with poor outcome at 6 months (Glasgow Outcome Scale score < 4) when analyzed as a continuous variable (OR 1.21, 95% CI 1.06-1.40, p = 0.006). Admission IMPACT probability of poor outcome and initial plasma concentrations of IL-6, IL-8, and IL-10 were associated with MODS following TBI.


MukEF Is required for stable association of MukB with the chromosome.
MukB is a bacterial SMC(structural maintenance of chromosome) protein required for correct folding of the Escherichia coli chromosome. MukB acts in complex with the two non-SMC proteins, MukE and MukF. The role of MukEF is unclear. MukEF disrupts MukB-DNA interactions in vitro. In vivo, however, MukEF stimulates MukB-induced DNA condensation and is required for the assembly of MukB clusters at the quarter positions of the cell length. We report here that MukEF is essential for stable association of MukB with the chromosome. We found that MukBEF forms a stable complex with the chromosome that copurifies with nucleoids following gentle cell lysis. Little MukB could be found with the nucleoids in the absence or upon overproduction of MukEF. Similarly, overproduced MukEF recruited MukB-green fluorescent protein (GFP) from its quarter positions, indicating that formation of MukB-GFP clusters and stable association with the chromosome could be mechanistically related. Finally, we report that MukE-GFP forms foci at the quarter positions of the cell length but not in cells that lack MukB or overproduce MukEF, suggesting that the clusters are formed by MukBEF and not by its individual subunits. These data support the view that MukBEF acts as a macromolecular assembly, a scaffold, in chromosome organization and that MukEF is essential for the assembly of this scaffold.


[Clinical Neurophysiology: past, present, future].
Clinical Neurophysiology is a medical speciality whose aim is the study of the nervous and muscular system for diagnostic, prognostic and therapeutic purposes. This article analyses the basic objective pursued by this discipline, the techniques it employs and its recognition as a medical speciality. The article briefly reviews its definition and scope, how it is structured at present and the future possibilities it offers.


Biodegradation Kinetics of Fragrances, Plasticizers, UV Filters, and PAHs in a Mixture─Changing Test Concentrations over 5 Orders of Magnitude.
Biodegradation of organic chemicals emitted to the environment is carried out by mixed microbial communities growing on multiple natural and xenobiotic substrates at low concentrations. This study aims to (1) perform simulation type biodegradation tests at a wide range of mixture concentrations, (2) determine the concentration effect on the biodegradation kinetics of individual chemicals, and (3) link the mixture concentration and degradation to microbial community dynamics. Two hundred ninety-four parallel test systems were prepared using wastewater treatment plant effluent as inoculum and passive dosing to add a mixture of 19 chemicals at 6 initial concentration levels (ng/L to mg/L). After 1-30 days of incubation at 12 °C, abiotic and biotic test systems were analyzed using arrow solid phase microextraction and GC-MS/MS. Biodegradation kinetics at the highest test concentrations were delayed for several test substances but enhanced for the reference chemical naphthalene. Test concentration thus shifted the order in which chemicals were degraded. 16S rRNA gene amplicon sequencing indicated that the highest test concentration (17 mg C/L added) supported the growth of the genera Acidovorax, Novosphingobium, and Hydrogenophaga, whereas no such effect was observed at lower concentrations. The chemical and microbial results confirm that too high mixture concentrations should be avoided when aiming at determining environmentally relevant biodegradation data.


Cardiac resynchronization therapy pacemaker or cardiac resynchronization therapy defibrillator: what determines the choice?-findings from the ESC CRT Survey II.
The decision to implant a cardiac resynchronization therapy pacemaker (CRT-P) or a cardiac resynchronization therapy defibrillator (CRT-D) may be challenging. There are no clear guideline recommendations as no randomized study of cardiac resynchronization therapy (CRT) has been designed to compare the effects of CRT-P with those of CRT-D on patients' outcomes. In the CRT Survey II, we studied patient and implantation centre characteristics associated with the choice of CRT-P vs. CRT-D. Clinical practice data from 10 692 patients undergoing CRT implantation of whom 7467 (70%) patients received a CRT-D and 3225 (30%) received a CRT-P across 42 ESC countries were collected and analysed between October 2015 and January 2017. Factors favouring the selection of CRT-P implantation included age >75 years, female gender, non-ischaemic heart failure (HF) aetiology, New York Heart Association functional Class III/IV symptoms, left ventricular ejection fraction >25%, atrial fibrillation, atrioventricular (AV) block II/III, and implantation in a university hospital. In a large cohort from the CRT Survey II, we found that patients allocated to receive CRT-P exhibited particular phenotypes with more symptomatic HF, more frequent comorbidities, advanced age, female gender, non-ischaemic HF aetiology, atrial fibrillation, and evidence of AV block. There were substantial differences in the proportion of patients allocated to receive CRT-P vs. CRT-D between countries.


Proregenerative Microenvironment Triggered by Donor Mesenchymal Stem Cells Preserves Renal Function and Structure in Mice with Severe Diabetes Mellitus.
The aim of our work was to evaluate, in an animal model of severe diabetes mellitus, the effect of mesenchymal stem cells (MSCs) administration on diabetic nephropathy (DN) progression. After diabetes induction, one group of mice received the vehicle (DM) and other group received a single dose of MSCs (DM + MSCs). DM + MSCs mice showed a significant improvement in functional parameters of the kidney compared with untreated mice. While DM mice presented marked histopathological changes characteristics of advanced stages of DN (fibrosis, glomerulosclerosis, glomerular basement membrane thickening, capillary occlusion, decreased podocyte density, and effacement of foot processes), DM + MSCs mice showed only slight tubular dilatation. The renoprotection was not associated with an improvement in diabetic condition and very low number of donor cells was found in the kidney of DM + MSCs mice, suggesting that renoprotection could be mediated by paracrine effects. Indeed, DM + MSC mice presented increased renal proliferation index, decreased renal apoptotic index and the restoration of proregenerative factors, and anti-inflammatory cytokines levels. Moreover, macrophage infiltration and oxidative stress damage were also reduced in DM + MSCs mice. Our data demonstrate that MSC administration triggers a proregenerative microenvironment in DN kidney, which allows the preservation of the renal function even if diabetes was uncorrected.


Watch-and-wait approach versus surgical resection after chemoradiotherapy for patients with rectal cancer (the OnCoRe project): a propensity-score matched cohort analysis.
Induction of a clinical complete response with chemoradiotherapy, followed by observation via a watch-and-wait approach, has emerged as a management option for patients with rectal cancer. We aimed to address the shortage of evidence regarding the safety of the watch-and-wait approach by comparing oncological outcomes between patients managed by watch and wait who achieved a clinical complete response and those who had surgical resection (standard care). Oncological Outcomes after Clinical Complete Response in Patients with Rectal Cancer (OnCoRe) was a propensity-score matched cohort analysis study, that included patients of all ages diagnosed with rectal adenocarcinoma without distant metastases who had received preoperative chemoradiotherapy (45 Gy in 25 daily fractions with concurrent fluoropyrimidine-based chemotherapy) at a tertiary cancer centre in Manchester, UK, between Jan 14, 2011, and April 15, 2013. Patients who had a clinical complete response were offered management with the watch-and-wait approach, and patients who did not have a complete clinical response were offered surgical resection if eligible. We also included patients with a clinical complete response managed by watch and wait between March 10, 2005, and Jan 21, 2015, across three neighbouring UK regional cancer centres, whose details were obtained through a registry. For comparative analyses, we derived one-to-one paired cohorts of watch and wait versus surgical resection using propensity-score matching (including T stage, age, and performance status). The primary endpoint was non-regrowth disease-free survival from the date that chemoradiotherapy was started, and secondary endpoints were overall survival, and colostomy-free survival. We used a conservative p value of less than 0·01 to indicate statistical significance in the comparative analyses. 259 patients were included in our Manchester tertiary cancer centre cohort, 228 of whom underwent surgical resection at referring hospitals and 31 of whom had a clinical complete response, managed by watch and wait. A further 98 patients were added to the watch-and-wait group via the registry. Of the 129 patients managed by watch and wait (median follow-up 33 months [IQR 19-43]), 44 (34%) had local regrowths (3-year actuarial rate 38% [95% CI 30-48]); 36 (88%) of 41 patients with non-metastatic local regrowths were salvaged. In the matched analyses (109 patients in each treatment group), no differences in 3-year non-regrowth disease-free survival were noted between watch and wait and surgical resection (88% [95% CI 75-94] with watch and wait vs 78% [63-87] with surgical resection; time-varying p=0·043). Similarly, no difference in 3-year overall survival was noted (96% [88-98] vs 87% [77-93]; time-varying p=0·024). By contrast, patients managed by watch and wait had significantly better 3-year colostomy-free survival than did those who had surgical resection (74% [95% CI 64-82] vs 47% [37-57]; hazard ratio 0·445 [95% CI 0·31-0·63; p<0·0001), with a 26% (95% CI 13-39) absolute difference in patients who avoided permanent colostomy at 3 years between treatment groups. A substantial proportion of patients with rectal cancer managed by watch and wait avoided major surgery and averted permanent colostomy without loss of oncological safety at 3 years. These findings should inform decision making at the outset of chemoradiotherapy. Bowel Disease Research Foundation.


Treatment of ruptured abdominal aneurysms with stent grafts: a new gold standard?
Ruptured abdominal aortoiliac aneurysms, when treated with open surgical repair, have high morbidity and mortality rates. Since 1994, the authors have used endovascular approaches to treat this entity. Patients with presumed ruptured aortoiliac aneurysms were treated with restricted fluid resuscitation (hypotensive hemostasis), transport to the operating room, placement under local anesthesia of a brachial or femoral guide wire into the supraceliac aorta, and arteriography. If aortoiliac anatomy was suitable, an endovascular graft (stent-graft) repair was performed. If the anatomy was unfavorable, standard open repair was performed. Only if circulatory collapse occurred was a supraceliac balloon placed and inflated using the previously positioned guidewire. Of 35 patients treated in this manner, 29 underwent endovascular graft repair, and 6 required open repair. Four patients died within 30 days (operative mortality rate, 11%). Only 10 patients required supraceliac balloon control. Endovascular grafts, when combined with hypotensive hemostasis and other endovascular techniques including proximal balloon control, may improve treatment outcomes with ruptured abdominal aortoiliac aneurysms. The authors believe these techniques will become widely used for the treatment of ruptured aneurysms.


Non-small cell lung cancer.
Lung cancer stands as the most important malignant neoplasm in the United States because of its high prevalence, increasing incidence, high rate of mortality, and great potential for prevention through the control of cigarette smoking. The World Health Organization (WHO) classification of lung cancer identifies four major types: squamous cell carcinoma, adenocarcinoma, large cell carcinoma, and small cell carcinoma. These tumors are commonly divided into two groups based on differences in their biology and treatment: small cell (SCLC) and non-small cell carcinomas (NSCLC). This review analyzes NSCLC with a strong emphasis on the practical aspects of treatment. We give recommendations about smoking cessation and early diagnosis through screening of high-risk individuals. We review contemporary diagnostic and staging techniques in the context of the new international TNM system of staging. Subsequent discussions of treatment are based on this new staging system. We stress the pivotal role of surgery for the management of local disease, and in addition present the potential contributions of newer radiation therapy techniques. We examine chemotherapy in detail, including a review of the comparative activity of the available cytotoxic agents against NSCLC, the relative contribution of combination chemotherapy, and the role of surgical adjuvant treatment with either chemotherapy or immunotherapy. We advise that patients with NSCLC be treated under the aegis of modern clinical trials of new therapy whenever possible. When this is not possible, we recommend an individualized approach based on such factors as the patient's age, general state of health, cardiopulmonary status, psychosocial status, and personal system of values.


Neurosteroid analogues. 4. The effect of methyl substitution at the C-5 and C-10 positions of neurosteroids on electrophysiological activity at GABAA receptors.
A series of analogues of the neuroactive steroids 3 alpha-hydroxy-5 alpha-pregnan-20-one and 3 alpha-hydroxy-5 beta-pregnan-20-one were studied to elucidate the mode of binding of 5 alpha-and 5 beta-reduced steroids to steroid binding sites on GABAA receptors. Analogues which were either 3 alpha-hydroxy-20-ketosteroids or 3 alpha-hydroxysteroid-17 beta-carbonitriles and which contained various methyl group substitution patterns at C-5 and C-10 were prepared. Evaluations utilized whole-cell patch clamp electrophysiological methods carried out on cultured rat hippocampal neurons, and the results obtained with the rigid 17 beta-carbonitrile analogs were analyzed using molecular modeling methods. The molecular modeling results provide a rationale for the observation that the configuration of the hydroxyl group at C-3 is a greater determinant of anesthetic potency than the configuration of the A,B ring fusion at C-5. The electrophysiological results identify steric restrictions for the space that can be occupied in 5 alpha- and 5 beta-reduced steroid modulators of GABAA receptors in the regions of space proximate to the steroid C-5, C-10, and possibly C-4 positions. This information is useful for the development of nonsteroidal analogues that can modulate GABAA receptors via interactions at steroid binding sites.


Navigating the poverty of heroin addiction treatment and recovery opportunity in Kenya: access work, self-care and rationed expectations.
Drawing on the analyses of qualitative interview accounts of people who inject heroin in Kenya, we describe the narration of addiction treatment access and recovery desire in conditions characterised by a 'poverty of drug treatment opportunity'. We observe the performance of addiction recovery narrative in the face of heavy social constraints limiting access to care. Fee-based residential rehabilitation ('rehab') is the only treatment locally available and inaccessible to most. Its recovery potential is doubted, given normative expectations of relapse. Treating drug use is a product of tightly bounded agency. Individuals enact strategies to maximise their slim chances of treatment access ('access work'), develop self-care alternatives when these fail to materialise and ration their care expectations. The use of rehab as a primary means of respite and harm reduction rather than recovery and the individuation of care in the absence of an enabling recovery environment are key characteristics of drug treatment experience. The recent incorporation of 'harm reduction' into policy discourses may trouble the primacy of recovery narrative in addiction treatment and in how treatment desires are voiced. The diversification of drug treatments in combination with social interventions enabling their access are fundamental.


Identification of spirocyclic or phosphate substituted quinolizine derivatives as novel HIV-1 integrase inhibitors: a patent evaluation of WO2016094197A1, WO2016094198A1 and WO2016154527A1.
Highly active antiretroviral therapy (HAART) has been widely adopted to control the HIV-1 infection successfully. HIV-1 integrase (IN) inhibitors are primary drugs in HAART regimens targeting integration step in the HIV-1 life cycle. However, due to the emergence of viral resistance and cross-resistance amongst drugs, there is a pressing need for new and potent IN inhibitors. This review covers the three patents describing spirocyclic and phosphate substituted quinolizine derivatives as novel HIV-1 IN inhibitors for the discovery of new anti-HIV-1 drug candidates. Areas covered: This review is focused on spirocyclic and phosphate substituted quinolizine derivatives bearing the same metal chelation scaffold as novel HIV-1 IN inhibitors. Expert opinion: Generally, privileged structure-based optimizations have emerged as an effective approach to discover newly antiviral agents. More generally, due to the similar Mg2+ catalytic active centers of endoribonucleases, some divalent metal ion chelators were found to be versatile binders targeting multiple metalloenzymes. Therefore, privileged structure-based scaffold re-evolution is an important tactic to identify new chemotypes, to explore unknown biological activities, or to provide effective ligands for multiple targets by modifying the existing active compounds.


Serological and spatial analysis of alphavirus and flavivirus prevalence and risk factors in a rural community in western Kenya.
Alphaviruses, such as chikungunya virus, and flaviviruses, such as dengue virus, are (re)-emerging arboviruses that are endemic in tropical environments. In Africa, arbovirus infections are often undiagnosed and unreported, with febrile illnesses often assumed to be malaria. This cross-sectional study aimed to characterize the seroprevalence of alphaviruses and flaviviruses among children (ages 5-14, n = 250) and adults (ages 15 ≥ 75, n = 250) in western Kenya. Risk factors for seropositivity were explored using Lasso regression. Overall, 67% of participants showed alphavirus seropositivity (CI95 63%-70%), and 1.6% of participants showed flavivirus seropositivity (CI95 0.7%-3%). Children aged 10-14 were more likely to be seropositive to an alphavirus than adults (p < 0.001), suggesting a recent transmission period. Alphavirus and flavivirus seropositivity was detected in the youngest participants (age 5-9), providing evidence of inter-epidemic transmission. Demographic variables that were significantly different amongst those with previous infection versus those without infection included age, education level, and occupation. Behavioral and environmental variables significantly different amongst those in with previous infection to those without infection included taking animals for grazing, fishing, and recent village flooding. Experience of recent fever was also found to be a significant indicator of infection (p = 0.027). These results confirm alphavirus and flavivirus exposure in western Kenya, while illustrating significantly higher alphavirus transmission compared to previous studies.


Podiatric physicians' perspectives on their role in promoting self-care in high-risk patients with diabetes.
Foot self-care is key in preventing morbidity in high-risk diabetic patients. Motivational interviewing (MI) is an approach to encourage behavior change by patients that can be used in medical settings. The goal was to explore how podiatric physicians promote self-care in such patients and whether they use MI techniques. We conducted a 19-question online survey of US-based practicing podiatric physicians. Most answers were on a 5-point scale. The MI index was the sum of answers to five relevant questions. Of 843 podiatric physicians, 86% considered foot self-care to be very important for high-risk diabetic patients, and 90% felt that it was their role to discuss foot self-care with them; 49% felt that they had training and were successful in promoting behavior change, but most were definitely (38%) or possibly (46%) interested in learning more. Only 24% of respondents scored at least 15 of 20 on the MI index. Higher MI scores were associated with more face time and more time discussing foot self-care but were not related to podiatric physicians' age, sex, geographic location, percentage of time in surgery, or years in practice. Reported barriers to counseling were lack of reimbursed time and poor patient engagement. Most podiatric physicians view self-care behavior among high-risk diabetic patients and their role in promoting it as very important; most feel already proficient, but only a few demonstrate MI skills; most are willing to learn more. Success in behavioral counseling, such as MI, is likely to require more time and may be encouraged by a move from fee-for-service to outcome-based reimbursement.


Measurement of the mutation rates of animal viruses: influenza A virus and poliovirus type 1.
Epidemiologic and genetic evidence suggests that influenza A viruses evolve more rapidly than other viruses in humans. Although the high mutation rate of the virus is often cited as the cause of the extensive variation, direct measurement of this parameter has not been obtained in vivo. In this study, the rate of mutation in tissue culture for the nonstructural (NS) gene of influenza A virus and for the VP1 gene in poliovirus type 1 was assayed by direct sequence analysis. Each gene was repeatedly sequenced in over 100 viral clones which were descended from a single virion in one plaque generation. A total of 108 NS genes of influenza virus were sequenced, and in the 91,708 nucleotides analyzed, seven point changes were observed. A total of 105 VP1 genes of poliovirus were sequenced, and in the 95,688 nucleotides analyzed, no mutations were observed. We then calculated mutation rates of 1.5 X 10(-5) and less than 2.1 X 10(-6) mutations per nucleotide per infectious cycle for influenza virus and poliovirus, respectively. We suggest that the higher mutation rate of influenza A virus may promote the rapid evolution of this virus in nature.


Conferring an adhesion layer with mineralization-inducing capabilities for preparing organic-inorganic hybrid microcapsules.
In this study, a novel approach to prepare organic-inorganic hybrid microcapsules was developed by conferring an adhesion layer with mineralization-inducing capabilities under mild conditions. The wall of hybrid microcapsules consisted of two layers: an organic layer (adhesion layer) and an inorganic layer (biomineral layer). The organic layer was formed through rapid oxidative self-polymerization of dopamine into polydopamine (PDA) on a CaCO3 (PSS-doped) template surface. Then cysteamine was grafted onto the adhesion layer to induce the formation of titania, thus, constructing the biomineral layer. Notably, cysteamine acted as a bridge between the two layers to enhance the interfacial stability: (1) the -SH groups of cysteamine can react with the catechol groups of PDA to form covalent bonds through Michael addition or Schiff base reaction; (2) the -NH2 groups of cysteamine can induce the formation of titania. The hybrid microcapsules (PDA/cysteamine/Ti microcapsules) acquired much higher mechanical stability than pure PDA microcapsules. At 20% (w/v) PSS solution, 65% of PDA microcapsules were deformed, whereas, at 40% (w/v) PSS solution, only ∼6% of PDA/cysteamine/Ti microcapsules were deformed. Finally, catalase (CAT) was physically encapsulated in the microcapsule lumen. The immobilized CAT exhibited good recycling stability and high storage stability. Besides biocatalysis, the hybrid microcapsules may find applications in biomedical and biosensing fields.


Long-term effect of subthalamic nucleus deep brain stimulation on freezing of gait in Parkinson's disease.
Subthalamic nucleus deep brain stimulation (STN DBS) is effective against freezing of gait (FOG) in Parkinson's disease (PD); however, whether this effect persists over the long term is debated. The aim of the current study was to investigate the long-term effect of STN DBS on FOG in patients with PD. Data on 52 cases in which PD patients received bilateral STN DBS were obtained from a prospective registry. The authors blindly analyzed FOG incidence and its severity from the videotapes of a 5-m walking task at the baseline and at the 1-, 2-, and 5- or 7-year follow-up visits. They also compared the axial score from the Unified Parkinson's Disease Rating Scale (UPDRS) part III, UPDRS part II (UPDRS-II) item 14, and the FOG questionnaire (FOG-Q). Postoperatively, video-based FOG analysis and the axial score were evaluated under 4 conditions (off-medication/off-stimulation, off-medication/on-stimulation, on-medication/off-stimulation, and on-medication/on-stimulation), and UPDRS-II item 14 and the FOG-Q score were evaluated under 2 conditions (off-medication/on-stimulation and on-medication/on-stimulation). During the off-medication state, the on-stimulation condition improved FOG outcomes, except for video-based FOG severity, up to the last follow-up compared with the baseline. Video-based FOG outcomes and the axial score during the off-medication state were improved with the on-stimulation condition up to the last follow-up compared with the off-stimulation condition. During the on-medication state, the on-stimulation condition did not improve any FOG outcome compared with the baseline; however, it improved video-based FOG outcomes up to the 2-year follow-up and the axial score up to the last follow-up compared with the off-stimulation condition. Our findings suggest that STN DBS has a long-term effect on FOG in the off-medication state. However, STN DBS did not show a long-term effect on FOG in the on-medication state, although it had a short-term effect until the 2-year follow-up.


A randomized trial of 5-hydroxytryptamine4-receptor agonist, YKP10811, on colonic transit and bowel function in functional constipation.
YKP10811, a selective agonist of the serotonin 5-hydroxytryptamine-4 receptor, increases gastrointestinal (GI) motility. We investigated the safety and effects of YKP10811 on GI and colonic transit and bowel movements (BMs) in patients with functional constipation in a randomized, double-blind, placebo-controlled study. Patients with functional constipation, based on the Rome III criteria, were assigned randomly to groups given YKP10811 10 mg (n = 15), 20 mg (n = 16), 30 mg (n = 15), or placebo (n = 11) daily for 8 days. Transit of solids was measured by validated scintigraphy at baseline and on days 7 to 9. Patients kept diaries on days 1 to 9, recording time to first BM, number of BMs/day, and stool consistency (based on the Bristol Stool Form Scale). To evaluate safety, we collected data on adverse events and clinical laboratory test and electrocardiograms results. The primary efficacy end points were determined from an intent-to-treat analysis assessing colonic transit at 24 hours and the half-time (t1/2) of gastric emptying, using analysis of covariance models. Secondary efficacy end points included measures of colonic transit (geometric center at 4 and 24 hours), small-bowel transit (based on colon filling at 6 hours), t1/2 of ascending colon emptying, and bowel functions. We used the Dunnett test to compare the effects of each dose with placebo. A per-protocol analysis (PPA) assessed the t1/2 of gastric emptying and time to first BM using proportional hazards models. Fifty-five participants completed the study. YKP10811 was associated with a significant acceleration in colon filling at 6 hours (P < .05), t1/2 of ascending colon emptying, and colonic transit at 24 and 48 hours, as well as increased stool consistency over 8 days (based on intent-to-treat analysis). In general, the 10-mg and 20-mg doses were the most effective in accelerating colonic transit. No serious adverse events were observed. YKP10811, a selective agonist of the serotonin receptor 5-hydroxytryptamine-4, accelerates GI and colonic transit and improves bowel functions in patients with functional constipation, compared with placebo. ClinicalTrial.Gov: NCT01523184.


A group programme for postnatally distressed women and their partners.
A group programme for postnatally distressed women and their partners is described. The programme consists of eight sessions, including one session for the couple. The concerns of the women centre around their anxieties and feelings towards their partners, their own mothers and their infants. Psychotherapeutic and cognitive-behavioural strategies are employed to assist them in dealing with these concerns. The concerns of the men centre around their attempts to provide emotional and practical support to their partner. Invariably such support results in an increase in tension between the partners, and the programme helps the men to understand why this happens. Formal measures show a decrease in maternal distress over time and an increase in their level of self-esteem. About half of the men show elevated levels of distress.


[Effect of penicillin and the habitat medium in the body of bacterial carriers on the intercellular bonds in populations of the meningococcus and pertussis microbe].
The relationship of the bacterial cells in populations and their adhesion activity is at present one of the research priorities in microbiological studies. The stimulating effect of penicillin on the development of morphologically different intercellular bonds (IB) in populations of the pertussis causative agent and first of all derivatives or evaginates of the cell wall membranes was observed. Morphologically similar systems and polytubular IB were detected in populations of meningococcal strains isolated from carriers having no signs of the disease. Correlation between the after-effect of penicillin and the presence of the causative agent in bacterial carriers was shown. Unknown systems of interlacing tubular structures not directly bound with the cells, the walls of which were single contour membranes were determined in the meningococcal populations treated with penicillin. IB were observed in the population in the form of transpopulation cords. Morphologically different IB playing the role of specialized organelles might be considered as factors of the functional unity of the bacterial population as a multicellular system.


Robotic-assisted laparoscopic cryo-partial nephrectomy: a novel technique using cryoablation in lieu of hilar clamping in a porcine model.
Laparoscopic and robotic-assisted partial nephrectomy has become an increasingly viable approach for the resection of renal tumors. There are several technical limitations in performing laparoscopic partial nephrectomy, the most significant being the inability to easily obtain cold ischemia which allows for an extended operative time. In this study, we evaluated the feasibility and efficacy of cryoablation as an alternative to hilar clamping to maintain hemostasis during robotic-assisted laparoscopic partial nephrectomy in a porcine model. Twelve female swine underwent nine open and eight robotic-assisted laparoscopic partial nephrectomies using modified cryoablative methods to create hemostasis. Renal perfusion imaged with indocyanine green (ICG) and histological analysis was assessed immediately after the procedure and at 3 weeks post-operatively. With two freeze/thaw cycles, all nine open and eight robotic-assisted laparoscopic partial nephrectomies were successfully completed without the need for hilar clamping. The mean blood loss for the open and robotic-assisted groups was 230.6 and 99.4 ml, respectively. In all cases, maintenance of renal perfusion was confirmed by the presence of a renal pulse and intraoperative ICG imaging immediately and 3 weeks post-operatively. The histological anatomy was well preserved in the resected segment following cryo-resection. After 21 days following cryo-resection, histological analysis demonstrated normal viable tissue with minimal scarring in the remaining kidney. The use of cryoablation created a zone of hemostasis without compromising the vascularity of the remaining kidney, while preserving the renal cytoarchitecture of the segment remove for pathological analysis. Further studies will help to delineate its usefulness in laparoscopic partial nephrectomy.


Control of expression of the herpes simplex virus thymidine kinase gene in biochemically transformed cells.
A series of cell lines was constructed by transformation of murine LTK- cells with a family of deletion mutants of the herpes simplex virus (HSV) thymidine kinase (tk) gene. These mutants, differing in the extent of 5' sequence flanking the coding region for tk, varied in the frequency with which they were able to convert tk- cells to the tk+ phenotype. Converted cell lines were analysed for tk DNA sequences, tk mRNA sequences, the 5' terminus of tk-specific transcripts and for their ability to respond to a signal provided in trans by infecting tk- virus (transactivation). The results of these analyses reveal that transformation efficiency correlates inversely with the extent of 5' flanking information. Thus mutants retaining less than 109 bp of 5' sequences transform less efficiently than those that retain at least 109 bp. Cell lines established by transformation with mutants retaining the proximal 109 bp contain relatively few copies of tk DNA whereas those which arose as a result of transformation with mutant DNA containing less than 109 bp generally contained multiple copies of tk DNA. Analyses of tk-specific transcripts revealed that cell lines derived from plasmids that transformed efficiently synthesized an mRNA which was indistinguishable by its size or 5' end from infected cell mRNA. Cell lines established by plasmids that were inefficient at transformation accumulated truncated mRNAs that initiated at aberrant start sites. The presence of the 5' 109 bp block was required for transformants to increase the level of tk mRNA and enzyme when infected with a tk- deletion mutant of HSV. We also show that transactivation does not alter the initiation site of the tk mRNA synthesized by transformants.


Multibreed genome wide association can improve precision of mapping causative variants underlying milk production in dairy cattle.
Genome wide association studies (GWAS) in most cattle breeds result in large genomic intervals of significant associations making it difficult to identify causal mutations. This is due to the extensive, low-level linkage disequilibrium within a cattle breed. As there is less linkage disequilibrium across breeds, multibreed GWAS may improve precision of causal variant mapping. Here we test this hypothesis in a Holstein and Jersey cattle data set with 17,925 individuals with records for production and functional traits and 632,003 SNP markers. By using a cross validation strategy within the Holstein and Jersey data sets, we were able to identify and confirm a large number of QTL. As expected, the precision of mapping these QTL within the breeds was limited. In the multibreed analysis, we found that many loci were not segregating in both breeds. This was partly an artefact of power of the experiments, with the number of QTL shared between the breeds generally increasing with trait heritability. False discovery rates suggest that the multibreed analysis was less powerful than between breed analyses, in terms of how much genetic variance was explained by the detected QTL. However, the multibreed analysis could more accurately pinpoint the location of the well-described mutations affecting milk production such as DGAT1. Further, the significant SNP in the multibreed analysis were significantly enriched in genes regions, to a considerably greater extent than was observed in the single breed analyses. In addition, we have refined QTL on BTA5 and BTA19 to very small intervals and identified a small number of potential candidate genes in these, as well as in a number of other regions. Where QTL are segregating across breed, multibreed GWAS can refine these to reasonably small genomic intervals. However, such QTL appear to represent only a fraction of the genetic variation. Our results suggest a significant proportion of QTL affecting milk production segregate within rather than across breeds, at least for Holstein and Jersey cattle.


Expression of E-cadherin in pig kidney.
E-cadherin is a cell adhesion molecule that plays an important role in maintaining renal epithelial polarity and integrity. The purpose of this study was to determine the exact cellular localization of E-cadherin in pig kidney. Kidney tissues from pigs were processed for light and electron microscopy immunocytochemistry, and immunoblot analysis. E-cadhedrin bands of the same size were detected by immunoblot of samples from rat and pig kidneys. In pig kidney, strong E-cadherin expression was observed in the basolateral plasma membrane of the tubular epithelial cells. E-cadherin immunolabeling was not detected in glomeruli or blood vessels of pig kidney. Double-labeling results demonstrated that E-cadherin was expressed in the calbindin D28k-positive distal convoluted tubule and H(+)-ATPase- positive collecting duct, but not in the aquaporin 1-positive, N-cadherin-positive proximal tubule. In contrast to rat, E-cadherin immunoreactivity was not expressed at detectable levels in the Tamm-Horsfall protein-positive thick ascending limb of pig kidney. Immunoelectron microscopy confirmed that E-cadherin was localized in both the lateral membranes and basal infoldings of the collecting duct. These results suggest that E-cadherin may be a critical adhesion molecule in the distal convoluted tubule and collecting duct cells of pig kidney.


[Selection of resistant peanut genotypes to Anticarsia gemmatalis Hübner (Lepidoptera: Noctuidae) supported by multivariate analysis].
The velvetbean caterpillar Anticarsia gemmatalis Hübner attacks peanut leaves, and the use of resistant varieties has directly contributed to ecological and economic aspects of pest control. The aim of this work was to select resistant peanut genotypes to A. gemmatalis using cluster analyses (dendogram obtained by Ward's methods and K-means) and Principal Components analysis for data interpretation. The evaluated genotypes were: IAC 5, IAC 8112, IAC 22 and IAC Tatu ST with upright growth habit, and IAC 147, IAC 125, IAC Caiapó and IAC Runner 886 with runner growth habit, and soybean genotype BR 16 as a susceptible control. The biological parameters: leaf consumption, larval (4 masculine instar) and pupal (24h old) weight, larval and pupal development time and adult longevity were evaluated at laboratory conditions. The genotypes IAC 147 and IAC Runner 886 were resistant to A. gemmatalis in both cluster tests, grouping apart from most of the other genotypes. Both dendrogram and K-means methods provided satisfactory biological explanation, and they can be complementary used together with Principal Component and vice-versa. These results suggest that cluster analyses may be an important statistical tool in the selection of host plant resistance.


Multiplex analysis of age-related protein and lipid modifications in human Bruch's membrane.
Aging of the human retina is characterized by progressive pathology, which can lead to vision loss. This progression is believed to involve reactive metabolic intermediates reacting with constituents of Bruch's membrane, significantly altering its physiochemical nature and function. We aimed to replace a myriad of techniques following these changes with one, Raman spectroscopy. We used multiplexed Raman spectroscopy to analyze the age-related changes in 7 proteins, 3 lipids, and 8 advanced glycation/lipoxidation endproducts (AGEs/ALEs) in 63 postmortem human donors. We provided an important database for Raman spectra from a broad range of AGEs and ALEs, each with a characteristic fingerprint. Many of these adducts were shown for the first time in human Bruch's membrane and are significantly associated with aging. The study also introduced the previously unreported up-regulation of heme during aging of Bruch's membrane, which is associated with AGE/ALE formation. Selection of donors ranged from ages 32 to 92 yr. We demonstrated that Raman spectroscopy can identify and quantify age-related changes in a single nondestructive measurement, with potential to measure age-related changes in vivo. We present the first directly recorded evidence of the key role of heme in AGE/ALE formation.


Work loss and activity impairment due to extended nausea and vomiting in patients with breast cancer receiving CINV prophylaxis.
Chemotherapy-induced nausea and vomiting (CINV)'s impact on work loss remains poorly described. We evaluated associations between the duration of CINV episodes, CINV-related work loss (CINV-WL), and CINV-related activity impairment (CINV-AI) in patients with breast cancer receiving highly emetogenic chemotherapy. We analyzed data from a prospective CINV prophylaxis trial of netupitant/palonestron and dexamethasone for patients receiving an anthracycline and cyclophosphamide (AC) for breast cancer (NCT0340371). Over the observed CINV duration (0-5 days), we analyzed patient-reported CINV-WL and CINV-AI for the first two chemotherapy cycles. We categorized patients as having either extended (≥ 3 days) or short (1-2 days) CINV duration and quantified its impact on work using the Work Productivity and Activity Impairment Questionnaire (WPAI). Overall, we captured data for 792 cycles in 402 women, including 136 (33.8%) employed patients with 35.3% reporting CINV. Of those with CINV, patients reported CINV-WL in 26 cycles and CINV-AI in 142 cycles. Of those with CINV, 55.3% of extended CINV cycles experienced CINV-WL compared to 16.7% of short CINV cycles (p < 0.001). The relative risk of CINV-WL between extended and short CINV was 3.32 (p < 0.01) for employed patients. The mean difference in CINV-AI scores (higher = worse) between extended and short duration CINV was 5.0 vs. 3.0 (p < 0.001). Extended (≥ 3 days) CINV was associated with more than triple the risk of CINV-WL and higher CINV-AI compared with short CINV.


Nontechnical skill training and the use of scenarios in modern surgical education.
Nontechnical skills are being increasingly recognized as a core reason of surgical errors. Combined with the changing nature of surgical training, there has therefore been an increase in nontechnical skill research in the literature. This review therefore aims to: define nontechnical skillsets, assess current training methods, explore assessment modalities and suggest future research aims. The literature demonstrates an increasing understanding of the components of nontechnical skills within surgery. This has led to a greater availability of validated training methods for its training, including the use of didactic teaching, e-learning and simulation-based scenarios. In addition, there are now various extensively validated assessment tools for nontechnical skills including NOTSS, the Oxford NOTECHS and OTAS. Finally, there is now more focus on the development of tools which target individual nontechnical skill components and an attempt to understand which of these play a greater role in specific procedures such as laparoscopic or robotic surgery. Current evidence demonstrates various training methods and tools for the training of nontechnical skills. Future research is likely to focus increasingly on individual nontechnical skill components and procedure-specific skills.


Chromophobe renal cell carcinoma: analysis of 53 cases.
To discuss the pathological and clinical characteristics, treatments and prognosis of chromophobe renal cell carcinoma (CRCC). We developed a database that contained 1,870 patients who were diagnosed with renal cell carcinoma (RCC) and who underwent surgery in our hospital between 2002 and 2010. Afterward, the clinical and pathological data of 53 CRCC cases were extracted and analyzed. The mean age of the 53 patients at diagnosis was 50.2 years (range, 21-88 years), and the ratio of male to female was 1:1. All tumors were unilateral and a majority of them (69.8%) were discovered incidentally. The mean tumor size was 5.8 ± 3.2 cm (range, 2-20 cm). Stage T1, T2, and T3 tumors, in accordance with 2004 TNM classification, accounted for 75.5, 13.2 and 11.3% of all cases, respectively. By histologic grading, 11.3, 73.6 and 15.1% of the tumors were G1, G2, and G3, respectively. Forty-one (77.4%) patients underwent radical nephrectomy, 12 (22.6%) underwent partial nephrectomy. Forty-five (84.9%) patients with follow-up results were alive after a mean follow-up of 34 months (range, 4-79 months). Tumor metastasis was discovered in 2 patients: one tumor metastasis was found in the liver 4 months postoperation, and the other was found in the lumbar vertebrae 47 months postoperation. No local recurrence was found. The overall survival rate was 100%. CRCC is an uncommon subtype of RCC, with a favorable prognosis. Chinese patients are seemingly younger at diagnosis. Prediction of prognosis is still difficult.


Nanoscale characterization of PM2.5 airborne pollutants reveals high adhesiveness and aggregation capability of soot particles.
In 2012 air pollutants were responsible of seven million human death worldwide, and among them particulate matter with an aerodynamic diameter of 2.5 micrometers or less (PM2.5) are the most hazardous because they are small enough to invade even the smallest airways and penetrate to the lungs. During the last decade the size, shape, composition, sources and effect of these particles on human health have been studied. However, the noxiousness of these particles not only relies on their chemical toxicity, but particle morphology and mechanical properties affect their thermodynamic behavior, which has notable impact on their biological activity. Therefore, correlating the physical, mechanical and chemical properties of PM2.5 airborne pollutants should be the first step to characterize their interaction with other bodies but, unfortunately, such analysis has never been reported before. In this work, we present the first nanomechanical characterization of the most abundant and universal groups of PM2.5 airborne pollutants and, by means of atomic force microscope (AFM) combined with other characterization tools, we observe that fluffy soot aggregates are the most sticky and unstable. Our experiments demonstrate that such particles show strong adhesiveness and aggregation, leading to a more diverse composition and compiling all possible toxic chemicals.


"What's up with price controls?" Stakeholders' views on the regulation of pharmaceutical pricing in Malaysia.
Escalating costs have made the accessibility of drugs one of the biggest challenges faced by the Malaysian government. The government agreed to regulate drug prices by means of external reference pricing, but its proposed policy had a setback owing to much opposition from the pharmaceutical industry. The policy did gain support from the public and from non-governmental organisations because it ensured easy access to affordable medicines. Comments from public consultations with key stakeholders were used to explore stakeholders' perceptions of the external reference pricing policy. A total of 140 comments were analysed for this study. Stakeholders' views were classified as being from the Socioeconomic, industrial, and government sectors. To summarise, the government must carefully manage and consider stakeholders' views to ensure a sound policy. Using Mendelow's stakeholder mapping, this study mapped out stakeholders' views in a systematic approach. The classification of different stakeholders' views and recommendations led to suggestions for reviewing current practices in pharmaceutical pricing regulations in the Malaysian healthcare system. The analyses can be extended to other countries that face similar concerns.


Support Interventions for Family Members of Adults with Mental Illness: A Narrative Literature Review.
The aim of this review was to describe research related to support interventions for adult family members of people with mental illness and the significance that support may have. The results indicate the importance of flexible and individualized forms of support from both professionals and people with personal experience as a family member of someone with mental illness. In many cases, the intervention studies revealed that family members' burden decreased, their knowledge of the disease and treatment increased, and their ability to cope with the situation was improved. The results highlight the importance of support both from professionals and peers.


Exploring the mechanism of fluorescence quenching in proteins induced by tetracycline.
The binding of the antibiotic tetracycline hydrochloride (TC) to three proteins was investigated by steady-state, time-resolved, and circular dichroism spectroscopy. The tryptophan (Trp) amino acid residues were used as an intrinsic fluorophore to decipher the structure-function relationship. As monitored by CD spectroscopy, the addition of TC causes the protein to alter some of its helical content although such changes are only marginal. The gradual decrease in fluorescence intensity of Trp can be ascribed to static quenching which takes place by the interaction of the drug with the protein. Besides Trp quenching, there is evidence of fluorescence resonance energy transfer (FRET) in all three proteins with different values of efficiency of energy transfer. Various quenching/binding and thermodynamic parameters associated with such drug-protein interactions have been estimated. The results thus obtained can provide guidelines to synthetic chemists to design and synthesize target-oriented drugs.


Studies on the mechanism of action of rabbit anti-mouse thymocyte serum. I. Induction of suppressor cells.
Treatment of B6AF1 (C57BL/6 x A/Jax) mice with either rabbit anti-mouse thymocyte serum (ATS) or with both ATS and sheep red blood cells (SRBCs) resulted in the generation of splenic suppressor cells within 5 days. Suppressor activity was determined by injecting secondary syngeneic recipients with both donor cells and SRBCs. Five days later the SRBCs hemolytic effect of their spleen cells was determined. Suppressor cells were found in either whole spleen or enriched T cell suspensions from mice treated with ATS and SRBCs and in only enriched T cell suspensions from mice treated with ATS alone. These results support the possibility that ATS induces a population of suppressor cells and that these cells may be responsible in part for the immune suppression noted after treatment with ATS.


Immune reconstitution inflammatory syndrome in the CNS of HIV-infected patients.
To describe challenges in diagnosis and management of patients with clinical syndromes of immune reconstitution inflammatory syndrome (IRIS) involving the CNS. The authors describe three patients with clinically distinct neurologic manifestations of IRIS with HIV infection who presented as diagnostic and therapeutic challenges. One patient with cryptococcal meningitis developed acute cerebellitis with mass effect and brainstem compression. Corticosteroid therapy was associated with complete resolution of the cerebellar lesion but the patient developed VZV encephalitis. Another patient with progressive multifocal leukoencephalopathy developed subacute progression of focal neurologic deficits associated with contrast enhancing lesions on brain MRI. This patient had spontaneous resolution of the lesion but was left with residual deficits. One patient developed a progressive dementing syndrome and deterioration over several months resulting in coma during combination antiretroviral therapy. A brain biopsy in this latter patient showed massive infiltration of T lymphocytes predominantly of the CD8 subtype. This patient had a significant improvement with corticosteroids and change in antiretroviral regimen although she was left with residual cognitive impairment. Immune reconstitution inflammatory syndrome should be suspected in patients who show clinical or radiologic deterioration following initiation of antiretroviral therapy accompanied with improvement in CD4 cell count and viral load. Some patients may respond to a brief course of treatment with corticosteroids.


A cross-cultural clinical comparison between subjects with obsessive-compulsive disorder from the United States and Brazil.
Although OCD is a global problem, the literature comparing, in a direct and standardized way, the manifestations across countries is scarce. Therefore, questions remain as to whether some important clinical findings are replicable worldwide, especially in the developing world. The objective of this study was to perform a clinical comparison of OCD patients recruited in the United States (U.S.) and Brazil. Our sample consisted of 1187 adult, treatment-seeking OCD outpatients from the U.S. (n=236) and Brazil (n=951). With regards to the demographics, U.S. participants with OCD were older, more likely to identify as Caucasian, had achieved a higher educational level, and were less likely to be partnered when compared to Brazilians. Concerning the clinical variables, after controlling for demographics the two samples presented largely similar profiles. Brazilian participants with OCD, however, endorsed significantly greater rates of generalized anxiety disorder and post-traumatic stress disorder, whereas U.S. subjects were significantly more likely to endorse a lifetime history of addiction (alcohol-use and substance-use disorders). This is the largest direct cross-cultural comparison to date in the OCD field. Our results provide much needed insight regarding the development of culture-sensitive treatments.


Less Well-Known Consequences of the Long-Term Use of Opioid Analgesics: A Comprehensive Literature Review.
The adverse effects of short-term opioid analgesics are well known and acknowledged; however, the spectrum of the sequelae of long-term use seems less clear. Some effects may remain undetected but still have the potential to cause harm and reduce patients' quality of life. To review the literature on the adverse effects of long-term opioid therapy. We performed a quasi-systematic search, analyzing articles published in the MEDLINE database between January 2000 and March 2021 that identified adverse effects of opioids used for chronic pain treatment. Growing evidence indicates that there are multiple serious adverse effects of opioid treatment. Long-term opioid use may have significant effects on the endocrine, immune, cardiovascular, respiratory, gastrointestinal, and neural systems. Studies show that long-term opioid treatment increases the risk of fractures, infections, cardiovascular complications, sleep-disordered breathing, bowel dysfunction, overdose, and mortality. Opioids may potentially affect cancer development. Most consequences of the long-term use of opioids have been identified in studies of patients with non-malignant pain. Studies indicate that long-term use of opioids increases the risk of drug-related events in a significant number of patients. Clinicians should be aware of these complications associated with prescribing opioids, discuss them with patients, prevent complications, if possible, and diagnose them early and manage adequately. More human studies are needed to assess the risk, including trials with individual opioids, because they have different adverse effect profiles.


Initial investigations of a novel bioluminescence method for imaging dental demineralization.
In this in vitro study, a bioluminescent marker was investigated for its potential to illuminate the assessment of dental caries and dental erosion, which are significant clinical and public health problems, through its binding of those ions, notably Ca2+ , known to be released during the process of demineralization. The light output from the selected bioluminescent marker was investigated in several experiments, including: (a)contact with a range of Ca2+ ion concentrations; (b) treatment of extracted teeth with solutions of differing pH, followed by application of the bioluminescence marker to assess Ca2+ ion release; and (c) application of the marker to freshly extracted teeth with natural and artificially created caries lesions on occlusal and smooth surfaces to image the Ca2+ ion distribution. The results of: experiment (a) showed that the light output from the marker increases with increasing Ca2+ concentration and of experiment (b) showed increases in light being observed as increasingly acidic solutions were applied. The results of experiment (c) showed the bioluminescence images of the extracted teeth produced "demineralization maps" of the imaged surfaces. These results demonstrate the ability of a novel bioluminescence technology to image Ca2+ ions on tooth enamel surfaces which has potential in dental caries and dental erosion applications and provides the scientific basis for the ongoing development of that novel technology.


Selenium Deficiency Is Widespread and Spatially Dependent in Ethiopia.
: Selenium (Se) is an essential element for human health and livestock productivity. Globally, human Se status is highly variable, mainly due to the influence of soil types on the Se content of crops, suggesting the need to identify areas of deficiency to design targeted interventions. In sub-Saharan Africa, including Ethiopia, data on population Se status are largely unavailable, although previous studies indicated the potential for widespread Se deficiency. Serum Se concentration of a nationally representative sample of the Ethiopian population was determined, and these observed values were combined with a spatial statistical model to predict and map the Se status of populations across the country. The study used archived serum samples (n = 3269) from the 2015 Ethiopian National Micronutrient Survey (ENMS). The ENMS was a cross-sectional survey of young and school-age children, women and men. Serum Se concentration was measured using inductively coupled plasma mass spectrometry (ICPMS). The national median (Q1, Q3) serum Se concentration was 87.7 (56.7, 123.0) μg L-1. Serum Se concentration differed between regions, ranging from a median (Q1, Q3) of 54.6 (43.1, 66.3) µg L-1 in the Benishangul-Gumuz Region to 122.0 (105, 141) µg L-1 in the Southern Nations, Nationalities, and Peoples' Region and the Afar Region. Overall, 35.5% of the population were Se deficient, defined as serum Se <70 µg L-1. A geostatistical analysis showed that there was marked spatial dependence in Se status, with serum concentrations greatest among those living in North-East and Eastern Ethiopia and along the Rift Valley, while serum Se concentrations were lower among those living in North-West and Western Ethiopia. Selenium deficiency in Ethiopia is widespread, but the risk of Se deficiency is highly spatially dependent. Policies to enhance Se nutrition should target populations in North-West and Western Ethiopia.


Biologically rapid synthesis of silver nanoparticles by Sphingobium sp. MAH-11T and their antibacterial activity and mechanisms investigation against drug-resistant pathogenic microbes.
The present study highlights the biological synthesis of silver nanoparticles (AgNPs) using Sphingobium sp. MAH-11 and also their antibacterial mechanisms against drug-resistant pathogenic microorganisms. The nanoparticle synthesis method used in this study was reliable, facile, rapid, cost-effective and ecofriendly. The AgNPs exhibited the highest absorbance at 423 nm. The TEM image expressed spherical shape of AgNPs and the size of synthesized AgNPs was 7-22 nm. The selected area diffraction (SAED) pattern and XRD spectrum revealed the crystalline structure of AgNPs. The results of FTIR analysis disclosed the functional groups responsible for the reduction of silver ion to metal nanoparticles. The biosynthesized AgNPs showed strong anti-microbial activity against drug-resistant pathogenic microorganisms. Moreover, Escherichia coli and Staphylococcus aureus were used to explore the antibacterial mechanisms of biosynthesized AgNPs. Minimal inhibitory concentrations (MICs) of E. coli and S. aureus were 6.25 μg/mL and 50 μg/mL, respectively and minimum bactericidal concentrations (MBCs) of E. coli and S. aureus were 25 μg/mL and 100 μg/mL, respectively. Results exhibited that biosynthesized AgNPs caused morphological changes and injured the membrane integrity of strains E. coli and S. aureus. The AgNPs synthesized by Sphingobium sp. MAH-11 may serve as a potent antimicrobial agent for many therapeutic applications.


The effect of quercetin on diabetic nephropathy (DN): a systematic review and meta-analysis of animal studies.
Quercetin, a flavonoid possessing numerous biological activities, is reported to improve renal injury in diabetic animals. Here, the aim of this systematic review and meta-analysis is to assess the effect of quercetin on diabetic nephropathy and summarize its possible mechanisms. We searched in four databases PubMed, Web of Sciences (WOS), Cochrane and Embase from inception to May 2021 and ultimately included 20 animal studies in this review. A total of 12 outcome measurements including renal function indexes, oxidative stress biomarkers and inflammatory cytokines were extracted for meta-analysis using RevMan 5.4 software. Apart from creatinine clearance and uric acid with no significant difference, quercetin significantly decreased the levels of renal index, serum/plasma creatinine (SCr), blood urea nitrogen (BUN), urine protein, urine albumin, malondialdehyde (MDA), tumor necrosis factor (TNF)-α and interleukin (IL)-1β, and increased superoxide dismutase (SOD) and catalase (CAT) activity. In short, quercetin improves renal function and attenuates the renal oxidative stress level and inflammatory response in DN animal models. Its possible action mechanisms include anti-oxidation, anti-inflammation, anti-fibrosis, and regulation of renal lipid accumulation.


[Reactivity of the cortical neurons to acetylcholine in rats].
Activity of 55 neurons of the sensorimotor cerebral cortex of rats was recorded at iontophoretic application of acetylcholine. 36% of neurons exhibited an excitatory reaction, 30%--inhibitory-excitatory, 18%--inhibitory-excitatory-inhibitory and 16%--excitatory-inhibitory reactions; the type of reaction, in contrast to its expressiveness, did not depend on the the type of reaction, in contrast to its expressiveness, did not depend on the strength of phoresis current. Duration of the excitatory components entering reactions of all neurons formed a continuous series of values in the range of 1.4 to 16 s and had 2 maxima--at the 4-th and 8-th seconds. It is suggested that duration of this component of reaction reflects important functional properties of the nerve cell.


A safer alternative: Cannabis substitution as harm reduction.
Substitution is operationalised as a conscious choice made by users to use one drug instead of, or in conjunction with another based on: perceived safety, level of addiction potential, effectiveness in relieving symptoms, access and level of acceptance. Harm reduction is a set of strategies that aim to minimise problems associated with drug use while recognising that for some users, abstinence may be neither a realistic nor a desirable goal. In this paper, we aim for deeper understandings of older adult cannabis users' beliefs and substitution practices as part of the harm reduction framework. We present selected findings from our qualitative study of Baby Boomer (born 1946-1964) marijuana users in the San Francisco Bay Area. Although the sample consisted of primary cannabis users, many had personal experience with other drugs throughout their lifetimes. Data collection consisted of an audio-recorded, semi-structured in-depth life history interview followed by a questionnaire and health survey. Qualitative interviews were analysed to discover users' harm reduction beliefs and cannabis substitution practices. Study participants described using cannabis as a safer alternative for alcohol, illicit drugs and pharmaceuticals based on their perceptions of less adverse side effects, low-risk for addiction and greater effectiveness at relieving symptoms, such as chronic pain. Cannabis substitution can be an effective harm reduction method for those who are unable or unwilling to stop using drugs completely. More research is needed on cannabis as a safer alternative.


Fatal Yersinia enterocolitica biotype 4 serovar O:3 sepsis after red blood cell transfusion.
Although posttransfusion bacterial sepsis is rare, this complication is associated with a high mortality rate. A fatal case of septic shock was observed in a 71-year-old patient following transfusion of contaminated red blood cells (RBCs) for refractory anemia. Yersinia enterocolitica was isolated from the patient's blood sample and the transfused RBCs. Both strains were of bioserotype 4/O:3 and had the same NotI pulsotype. High titers of antibodies against Y. enterocolitica were detected in the donor's plasma sample 1 month after blood donation. The donor reported abdominal discomfort 3.5 months before blood collection but had no clinical signs of intestinal infection at the time of donation. Y. enterocolitica has been identified with increased frequency as a causative agent of posttransfusion septic shock. This nationwide investigation of these cases led to an estimated incidence of one case per 6.5 million RBC units distributed in France. Although rare, this often fatal complication remains nonpreventable worldwide owing to the lack of practical means for screening RBCs before transfusion.


Long-term effectiveness and compliance of positional therapy with the sleep position trainer in the treatment of positional obstructive sleep apnea syndrome.
To investigate effectiveness, long-term compliance, and effects on subjective sleep of the Sleep Position Trainer (SPT) in patients with position-dependent obstructive sleep apnea syndrome (POSAS). Prospective, multicenter cohort study. Adult patients with mild and moderate POSAS were included. Patients were [corrected] asked to use the SPT for 6 mo. At baseline and after 1, 3, and 6 mo, questionnaires would be completed: Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), Functional Outcomes of Sleep Questionnaire (FOSQ), and questions related to SPT use. One hundred forty-five patients were included. SPT use and SPT data could not be retrieved in 39 patients. In the remaining 106 patients, median percentage of supine sleep decreased rapidly during SPT's training phase (day 3 to 9) to near-total avoidance of supine sleep. This decrease was maintained during the following months of treatment (21% at baseline versus 3% at 6 mo). SPT compliance, defined as more than 4 h of nightly use, was 64.4%. Regular use, defined as more than 4 h of usage over 5 nights/w, was 71.2%. Subjective compliance and regular use were 59.8% and 74.4%, respectively. Median ESS (11 to 8), PSQI (8 to 6), and FOSQ (87 to 103) values significantly improved compared with baseline. Positional therapy using the Sleep Position Trainer (SPT) effectively diminished the percentage of supine sleep and subjective sleepiness and improved sleep related quality of life in patients with mild to moderate position-dependent obstructive sleep apnea syndrome. SPT treatment appeared to have sustained effects over 6 months. SPT compliance and regular use rate were relatively good. Subjective and objective compliance data corresponded well. The lack of a placebo-controlled group limited the efficacy of conclusions. van Maamen JP, de Vries N. Long-term effectiveness and compliance of positional therapy with the Sleep Position Trainer in the treatment of positional obstructive sleep apnea syndrome.


Outcome of bilateral hip hemiarthroplasty for displaced fracture of the hip.
Our aim was to evaluate the outcome in patients with bilateral non-simultaneous hip fracture treated with hemiarthroplasty at our institution between 1997 and 2003. We looked for any important modification factor that could change the devastating functional and social results. Twenty-two patients with a mean age of 79 at the initial fracture and 82 at the subsequent fracture were evaluated; all were Garden grade III-IV. The second fracture happened a mean of 28 months after the first one. The outcome measurement was the incidence of hip pain, recovery of pre-injury level of ambulation and activities of daily living at a minimum follow-up of one year. Following the first hemiarthroplasty patients deteriorated in their walking capacity and other activities of daily life, and this happened to an even greater extent after the second operation. With respect to walking ability (measured in metres) we concluded that it improved if a modular hemiarthroplasty was used after both fractures (p<0.05) and that worse functional outcomes were observed when different kinds of hemiarthroplasties were used in the same patient.;


Development of Broth Microdilution MIC and Disk Diffusion Antimicrobial Susceptibility Test Quality Control Ranges for the Combination of Cefepime and the Novel β-Lactamase Inhibitor Enmetazobactam.
Third-generation cephalosporin resistance among Enterobacteriaceae, mediated by the spread of extended-spectrum β-lactamases (ESBLs), is a very serious medical concern with limited therapeutic options. Enmetazobactam (formerly AAI101) is a novel penicillanic sulfone β-lactamase inhibitor active against a wide range of ESBLs. The combination of enmetazobactam and cefepime has entered phase 3 development in patients with complicated urinary tract infections. Using the Clinical and Laboratory Standards Institute (CLSI) M23 tier 2 study design, broth microdilution MIC and disk diffusion quality control (QC) ranges were determined for cefepime-enmetazobactam. Enmetazobactam was tested at a fixed concentration of 8 μg/ml in the MIC assay, and a cefepime-enmetazobactam disk mass of 30/20 μg was used in the disk diffusion assay. Escherichia coli ATCC 25922, E. coli ATCC 35218, E. coli NCTC 13353, Klebsiella pneumoniae ATCC 700603, and Pseudomonas aeruginosa ATCC 27853 were chosen as reference strains. The CTX-M-15-producing E. coli NCTC 13353 isolate is recommended for routine testing to control for inhibition of ESBL activity by enmetazobactam. Broth microdilution MIC QC ranges spanned 3 to 4 doubling dilutions and contained 99.6% to 100.0% of obtained MIC values for the five reference strains. Disk diffusion yielded inhibition zone diameter QC ranges that spanned 7 mm and encompassed 97.1% to 100.0% of the obtained values. Quality control ranges were approved by the CLSI in 2017 (broth microdilution MIC) and 2019 (disk diffusion). The established QC ranges will ensure that appropriate assay performance criteria are attained using CLSI reference methodology when determining the susceptibility of clinical isolates to cefepime-enmetazobactam.


Non-specific elongation of cell cycle phases by cycloheximide in rat 3Y1 cells, and specific reduction of G1 phase elongation by simian virus 40 large T antigen.
Partial inhibition of protein synthesis by cycloheximide caused prolongation of G1, S and G2 phases in rat 3Y1 fibroblasts. In cells expressing simian virus 40 (SV40) large T antigen, by infection with SV40 in the previous generation, the prolongation of G1 phase in the presence of cycloheximide was suppressed. However, the prolongation of S and G2 phases in the presence of cycloheximide was not suppressed in cells expressing large T antigen, by infection with SV40 in the current generation. Similarly, when density-arrested cells (cells in G0 phase) were infected with SV40 (either wild-type strain or a mutant deleted in the unique coding region for small t antigen) and reseeded sparsely in the presence of cycloheximide, the cycloheximide-induced delay of entry into S phase was suppressed. In this case, the reduction in [35S]methionine incorporation, that in protein accumulation and that in cell volume increase, were not surmounted by SV40 infection. In T-antigen-negative cells, all the regions in G1 phase seemed to be sensitive to cycloheximide, i.e. they suffered elongation. These results suggest that, in comparison with cells that enter S phase by the action of growth factors, cells expressing large T antigen can enter S phase more efficiently through a quite different process.


Nerve growth factor deprivation results in the reactivation of latent herpes simplex virus in vitro.
Primary sympathetic neuronal cultures were maintained for up to 5 weeks after inoculation with herpes simplex virus (HSV) without evidence of viral infection. Upon deprivation of nerve growth factor, the cultures produced infectious HSV, indicating that the cultures harbored latent HSV. This study demonstrates a function of nerve growth factor in the maintenance of HSV latency.


Compared to sucrose, previous consumption of fructose and glucose monosaccharides reduces survival and fitness of female mice.
Intake of added sugar has been shown to correlate with many human metabolic diseases, and rodent models have characterized numerous aspects of the resulting disease phenotypes. However, there is a controversy about whether differential health effects occur because of the consumption of either of the two common types of added sugar-high-fructose corn syrup (fructose and glucose monosaccharides; F/G) or table sugar (sucrose, a fructose and glucose disaccharide). We tested the equivalence of sucrose- vs. F/G-containing diets on mouse (Mus musculus) longevity, reproductive success, and social dominance. We fed wild-derived mice, outbred mice descended from wild-caught ancestors, a diet in which 25% of the calories came from either an equal ratio of F/G or an isocaloric amount of sucrose (both diets had 63% of total calories as carbohydrates). Exposure lasted 40 wk, starting at weaning (21 d of age), and then mice (104 females and 56 males) were released into organismal performances assays-seminatural enclosures where mice competed for territories, resources, and mates for 32 wk. Within enclosures all mice consumed the F/G diet. Females initially fed the F/G diet experienced a mortality rate 1.9 times the rate (P = 0.012) and produced 26.4% fewer offspring than females initially fed sucrose (P = 0.001). This reproductive deficiency was present before mortality differences, suggesting the F/G diet was causing physiologic performance deficits prior to mortality. No differential patterns in survival, reproduction, or social dominance were observed in males, indicating a sex-specific outcome of exposure. This study provides experimental evidence that the consumption of human-relevant levels of F/G is more deleterious than an isocaloric amount of sucrose for key organism-level health measures in female mice.


Morphological aspects of Ebstein's anomaly in adults.
The essence of the Ebstein's malformation is that the tricuspid valve leaflets do not attach normally to the valve annulus, and the effective orifice is displaced downward into the right ventricular cavity at the junction of the inlet and trabecular components of the right ventricle. Only the septal and posterior leaflets are displaced and divide the right ventricle into two portions. The inlet portion is usually integrated functionally with the right atrium ("atrialized portion"), while the other, including the trabecular and outlet portions, constitutes the functional right ventricle. The proximal atrialized right ventricle often has a wall thinner than the distal functional right ventricle, due to partial congenital absence of myocardium. An atrial septal defect is present in more than one-third of hearts, and the majority of the remainder has a patent foramen ovale resulting in a right-to-left shunt. The downward displacement of the septal tricuspid valve leaflet is associated with discontinuity of the central fibrous body and septal atrioventricular ring, thus creating a potential substrate for accessory atrioventricular connections and ventricular pre-excitation making the patient at risk of sudden death. Angiography has demonstrated that a significant number of patients with Ebstein's anomaly also have morphofunctional abnormalities of the left ventricle, which may be explained by increased fibrosis in the left ventricular wall and ventricular septum as demonstrated by histological studies. Regarding embryology, the leaflets and tensile apparatus of the tricuspid valve are believed to be formed mostly by a process of delamination of the inner layers of the inlet zone of the right ventricle. The downward displacement of the leaflets in Ebstein's anomaly suggests that delamination from the inlet portion failed to occur.


Predator dispersal determines the effect of connectivity on prey diversity.
Linking local communities to a metacommunity can positively affect diversity by enabling immigration of dispersal-limited species and maintenance of sink populations. However, connectivity can also negatively affect diversity by allowing the spread of strong competitors or predators. In a microcosm experiment with five ciliate species as prey and a copepod as an efficient generalist predator, we analysed the effect of connectivity on prey species richness in metacommunities that were either unconnected, connected for the prey, or connected for both prey and predator. Presence and absence of predator dispersal was cross-classified with low and high connectivity. The effect of connectivity on local and regional richness strongly depended on whether corridors were open for the predator. Local richness was initially positively affected by connectivity through rescue of species from stochastic extinctions. With predator dispersal, however, this positive effect soon turned negative as the predator spread over the metacommunity. Regional richness was unaffected by connectivity when local communities were connected only for the prey, while predator dispersal resulted in a pronounced decrease of regional richness. The level of connectivity influenced the speed of richness decline, with regional species extinctions being delayed for one week in weakly connected metacommunities. While connectivity enabled rescue of prey species from stochastic extinctions, deterministic extinctions due to predation were not overcome through reimmigration from predator-free refuges. Prey reimmigrating into these sink habitats appeared to be directly converted into increased predator abundance. Connectivity thus had a positive effect on the predator, even when the predator was not dispersing itself. Our study illustrates that dispersal of a species with strong negative effects on other community members shapes the dispersal-diversity relationship. When connections enable the spread of a generalist predator, positive effects of connectivity on prey species richness are outweighed by regional extinctions through predation.


Reversible Thiol Oxidation Inhibits the Mitochondrial ATP Synthase in Xenopus Laevis Oocytes.
Oocytes are postulated to repress the proton pumps (e.g., complex IV) and ATP synthase to safeguard mitochondrial DNA homoplasmy by curtailing superoxide production. Whether the ATP synthase is inhibited is, however, unknown. Here we show that: oligomycin sensitive ATP synthase activity is significantly greater (~170 vs. 20 nmol/min-1/mg-1) in testes compared to oocytes in Xenopus laevis (X. laevis). Since ATP synthase activity is redox regulated, we explored a regulatory role for reversible thiol oxidation. If a protein thiol inhibits the ATP synthase, then constituent subunits must be reversibly oxidised. Catalyst-free trans-cyclooctene 6-methyltetrazine (TCO-Tz) immunocapture coupled to redox affinity blotting reveals several subunits in F1 (e.g., ATP-α-F1) and Fo (e.g., subunit c) are reversibly oxidised. Catalyst-free TCO-Tz Click PEGylation reveals significant (~60%) reversible ATP-α-F1 oxidation at two evolutionary conserved cysteine residues (C244 and C294) in oocytes. TCO-Tz Click PEGylation reveals ~20% of the total thiols in the ATP synthase are substantially oxidised. Chemically reversing thiol oxidation significantly increased oligomycin sensitive ATP synthase activity from ~12 to 100 nmol/min-1/mg-1 in oocytes. We conclude that reversible thiol oxidation inhibits the mitochondrial ATP synthase in X. laevis oocytes.


Self-collected vaginal sampling for the detection of genital human papillomavirus (HPV) using careHPV among Ghanaian women.
Detection of genital HPV DNA is recommended as an important strategy for modern cervical cancer screening. Challenges include access to services, the reliance on cervical samples taken by clinicians, and patient's preference regarding provider gender. The objective of this research was to determine the acceptability, feasibility and performance of alternative self-collected vaginal samples for HPV detection among Ghanaian women. A comparative frequency-matched study was conducted in a systematic (1:5) sample of women attending HIV and outpatient clinics in the Cape Coast Teaching Hospital, Ghana. Participants were instructed on self-collection (SC) of vaginal samples using the careHPV brush and a clinician-collected (CC) cervical sample was obtained using a similar brush. Paired specimens were tested for HPV DNA (14 high-risk types) by careHPV assay (Qiagen) and by HPV genotyping (Anyplex II, Seegene). Overall, 194 women of mean age 44.1 years (SD ± 11.3) were enrolled and 191 paired SC and CC results were analysed. The overall HPV detection concordance was 94.2% (95%CI: 89.9-97.1), Kappa value of 0.88 (p < 0.0001), showing excellent agreement. This agreement was similar between HIV positive (93.8%) and negative (94.7%) women. Sensitivity and specificity of SC compared to CC were 92.6% (95%CI: 85.3-97.0) and 95.9% (95%CI: 89.8-98.8) respectively. The highest sensitivity was among HIV positive women (95.7%, 95%CI: 88.0-99.1) and highest specificity among HIV negative women (98.6%, 95%CI: 92.4-100). Overall, 76.3% women found SC very easy/easy to obtain, 57.7% preferred SC to CC and 61.9% felt SC would increase their likelihood to access cervical cancer screening. The feasibility, acceptability and performance of SC using careHPV support the use of this alternative form of HPV screening among Ghanaian women. This could be a potential new affordable strategy to improve uptake of the national cervical cancer screening program.


Detection of Zika Virus and Human Papilloma Virus in Cervical Cytology Samples using Two Real Time PCR Based Techniques in Ecuadorian Women diagnosed with ASCUS.
Atypical Squamous Cells of Undetermined Significance(ASCUS) is the most reported result on pap smears. It is most commonly related to Human Papillomavirus (HPV) infections. However, other pathogens (EBV, Chlamydia) have been reported on cervical samples with abnormal results. Zika virus(ZIKV) has been found to induce cellular abnormalities on different tissues and its presence has been identified on genital secretions. Two real-time PCR has been made on cervical samples from the gynecological service of a third level hospital on Guayaquil-Ecuador. This work was part of a bigger study of ZIKV presence on different body fluids. From 89 samples obtained, 19 received an ASCUS result. From these 5 were positive for ZIKV and 5 were positive for HPV, there were no co infections. Given the presence of ZIKV RNA and the absence of HPV DNA on cervical samples diagnosed as ASCUS, it might be plausible that ZIKV could be a triggering factor for the induction of cellular changes observed on these cells.


Genetically distinct subsets within ANCA-associated vasculitis.
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a severe condition encompassing two major syndromes: granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis) and microscopic polyangiitis. Its cause is unknown, and there is debate about whether it is a single disease entity and what role ANCA plays in its pathogenesis. We investigated its genetic basis. A genomewide association study was performed in a discovery cohort of 1233 U.K. patients with ANCA-associated vasculitis and 5884 controls and was replicated in 1454 Northern European case patients and 1666 controls. Quality control, population stratification, and statistical analyses were performed according to standard criteria. We found both major-histocompatibility-complex (MHC) and non-MHC associations with ANCA-associated vasculitis and also that granulomatosis with polyangiitis and microscopic polyangiitis were genetically distinct. The strongest genetic associations were with the antigenic specificity of ANCA, not with the clinical syndrome. Anti-proteinase 3 ANCA was associated with HLA-DP and the genes encoding α(1)-antitrypsin (SERPINA1) and proteinase 3 (PRTN3) (P=6.2×10(-89), P=5.6×10(-12,) and P=2.6×10(-7), respectively). Anti-myeloperoxidase ANCA was associated with HLA-DQ (P=2.1×10(-8)). This study confirms that the pathogenesis of ANCA-associated vasculitis has a genetic component, shows genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis that are associated with ANCA specificity, and suggests that the response against the autoantigen proteinase 3 is a central pathogenic feature of proteinase 3 ANCA-associated vasculitis. These data provide preliminary support for the concept that proteinase 3 ANCA-associated vasculitis and myeloperoxidase ANCA-associated vasculitis are distinct autoimmune syndromes. (Funded by the British Heart Foundation and others.).


Diagnostic accuracy of quantitative PCR (Xpert MTB/RIF) for tuberculous pericarditis compared to adenosine deaminase and unstimulated interferon-γ in a high burden setting: a prospective study.
Tuberculous pericarditis (TBP) is associated with high morbidity and mortality, and is an important treatable cause of heart failure in developing countries. Tuberculous aetiology of pericarditis is difficult to diagnose promptly. The utility of the new quantitative PCR test (Xpert MTB/RIF) for the diagnosis of TBP is unknown. This study sought to evaluate the diagnostic accuracy of the Xpert MTB/RIF test compared to pericardial adenosine deaminase (ADA) and unstimulated interferon-gamma (uIFNγ) in suspected TBP. From October 2009 through September 2012, 151 consecutive patients with suspected TBP were enrolled at a single centre in Cape Town, South Africa. Mycobacterium tuberculosis culture and/or pericardial histology served as the reference standard for definite TBP. Receiver-operating-characteristic curve analysis was used for selection of ADA and uIFNγ cut-points. Of the participants, 49% (74/151) were classified as definite TBP, 33% (50/151) as probable TBP and 18% (27/151) as non TBP. A total of 105 (74%) participants were human immunodeficiency virus (HIV) positive. Xpert-MTB/RIF had a sensitivity and specificity (95% confidence interval (CI)) of 63.8% (52.4% to 75.1%) and 100% (85.6% to 100%), respectively. Concentration of pericardial fluid by centrifugation and using standard sample processing did not improve Xpert MTB/RIF accuracy. ADA (≥35 IU/L) and uIFNγ (≥44 pg/ml) both had a sensitivity of 95.7% (88.1% to 98.5%) and a negative likelihood ratio of 0.05 (0.02 to 0.10). However, the specificity and positive likelihood ratio of uIFNγ was higher than ADA (96.3% (81.7% to 99.3%) and 25.8 (3.6 to 183.4) versus 84% (65.4% to 93.6%) and 6.0 (3.7 to 9.8); P = 0.03) at an estimated background prevalence of TB of 30%. The sensitivity and negative predictive value of both uIFNγ and ADA were higher than Xpert-MT/RIF (P < 0.001). uIFNγ offers superior accuracy for the diagnosis of microbiologically confirmed TBP compared to the ADA assay and the Xpert MTB/RIF test.


Uncommon cause of acute pelvic pain: isolated torsion of hydrosalpinx.
Isolated torsion of hydrosalpinx is a rare cause of acute pelvic pain. Pre-operative diagnosis is very difficult because of non specific clinical presentation. Definitive diagnosis is always made at surgical exploration performed for suspected adnexal torsion and salpingectomy is performed in the majority of cases. A 34-year-old woman was admitted for acute pelvic pain with nausea and vomiting. Vaginal examination revealed a right adnexal tender mass and ultrasound revealed a well circumscribed right adnexal cystic mass. Surgical exploration has revealed torsion of a right hydrosalpinx and right salpingectomy was performed. Differential diagnosis between adnexal and tubal torsion is very difficult, however both should be managed by rapid surgical exploration which an allow precocious diagnosis and conservative treatment.