Fe(III) distribution varies substantially within and between atherosclerotic plaques.
Vulnerable atherosclerotic plaques are structurally weak and prone to rupture, presumably due to local oxidative stress. Redox active iron is linked to oxidative stress and the aim of this study was to investigate the distribution of Fe(III) in carotid plaques and its relation to vulnerability for rupture. Atherosclerotic plaques from 10 patients (three asymptomatic and seven symptomatic) were investigated. Plaque vulnerability was classified using ultrasound and immunohistochemistry and correlated to Fe(III) measured by electron paramagnetic resonance spectroscopy. Large intra-plaque Fe(III) variations were found. Plaques from symptomatic patients had a higher Fe(III) concentration as compared with asymptomatic plaques (0.36 ± 0.21 vs. 0.06 ± 0.04 nmol Fe(III)/mg tissue, P < 0.05, in sections adjoining narrowest part of the plaques). All but one plaque from symptomatic patients showed signs of cap rupture. No plaque from asymptomatic patients showed signs of cap rupture. There was a significant increase in cap macrophages in plaques from symptomatic patients compared with asymptomatic patients (31 ± 11% vs. 2.3 ± 2.3%, P < 0.01). Fe(III) distribution varies substantially within atherosclerotic plaques. Plaques from symptomatic patients had significantly higher concentrations of Fe(III), signs of cap rupture and increased cap macrophage activity.


Identifying What Is Known About Improving Operating Room to Intensive Care Handovers: A Scoping Review.
The purpose is to provide a descriptive overview of relevant material exploring improvement of handovers from the operating room (OR) to intensive care unit (ICU). An online search (MEDLINE, Cochrane, EMBASE, CINAHL, and Joanna Briggs), including gray literature and relevant reference lists, was completed. In all, 4574 unique citations were screened and 155 full-text reviews performed; 65 articles were included in the final analysis. The majority of articles discuss an ideal structure for handover (n = 63; 97%); 43 (66%) articles mentioned strategies for implementing such an approach. Only 21 (32%) explicitly described formal quality improvement (QI) methods. Few explored project sustainability and impact of a structured handover on patient safety outcomes (n = 15, 23%). Published literature suggests that there is a significant gap in evidence of measured patient outcomes from standardization of OR to ICU handover processes. Identifying formal QI strategies used to sustain standardized handover processes will allow accurate measurement of patient outcomes.


Analysis of mechanisms involved in reduced susceptibility to ciprofloxacin in Salmonella enterica serotypes Typhi and Paratyphi A isolates from travellers to Southeast Asia.
Owing to multidrug resistance, quinolones and third-generation cephalosporins are currently used as key antibiotics to combat Salmonella organisms. Therapy failure due to reduced ciprofloxacin susceptibility has been reported in endemic areas, but also in imported disease. Different bacterial resistance mechanisms may result in reduced ciprofloxacin susceptibility. In this study, the presence and expression of different resistance mechanisms resulting in reduced minimum inhibitory concentrations (MICs) for ciprofloxacin were evaluated in 23 blood-culture-derived Salmonella enterica serotypes Typhi and Paratyphi A organisms from ill-returned travellers to Asia. The presence of mutations in the quinolone resistance-determining region (QRDR) of the gyrA gene as well as an activated efflux pump and plasmid-mediated quinolone resistance genes was determined. Resistance selection during therapy and the clonal relatedness of all isolates were established. Efflux pump inhibition did not appear to affect the MICs of ciprofloxacin and activity of the efflux pump appeared to be specific for nalidixic acid. Repeated exposure of the isolates to ciprofloxacin did not result in a significant increase in the MICs for ciprofloxacin. Repetitive sequence-based polymerase chain reaction (rep-PCR) profiles identified five different genotypes, but no correlation with resistance was observed. However, a significant relation was found with geographic region; reduced ciprofloxacin susceptibility was only found in travellers returning from India and Pakistan. All isolates with reduced ciprofloxacin susceptibility had a mutation at position 83 in the QRDR region of the gyrA gene. Plasmid-mediated quinolone resistance was not found. These findings confirm that the reduced ciprofloxacin MIC in S. Typhi and S. Paratyphi A is solely due to an amino acid substitution in the QRDR 'cluster' of the gyrA gene.


Evaluation of the blood compatibility of materials, cells, and tissues: basic concepts, test models, and practical guidelines.
Medicine today uses a wide range of biomaterials, most of which make contact with blood permanently or transiently upon implantation. Contact between blood and nonbiological materials or cells or tissue of nonhematologic origin initiates activation of the cascade systems (complement, contact activation/coagulation) of the blood, which induces platelet and leukocyte activation. Although substantial progress regarding biocompatibility has been made, many materials and medical treatment procedures are still associated with severe side effects. Therefore, there is a great need for adequate models and guidelines for evaluating the blood compatibility of biomaterials. Due to the substantial amount of cross talk between the different cascade systems and cell populations in the blood, it is advisable to use an intact system for evaluation. Here, we describe three such in vitro models for the evaluation of the biocompatibility of materials and therapeutic cells and tissues. The use of different anticoagulants and specific inhibitors in order to be able to dissect interactions between the different cascade systems and cells of the blood is discussed. In addition, we describe two clinically relevant medical treatment modalities, the integration of titanium implants and transplantation of islets of Langerhans to patients with type 1 diabetes, whose mechanisms of action we have addressed using these in vitro models.


Methamphetamine body stuffers: an observational case series.
We describe the demographics, characteristics, treatment, and clinical course of methamphetamine body stuffers. We also determine the clinical characteristics of methamphetamine body stuffers who have severe outcomes. A 6.5-year descriptive nonconcurrent observational case series evaluated methamphetamine body stuffers about whom the Oregon Poison Center was consulted by their primary physicians. Poison center charts were supplemented by completed hospital charts (for 95% of patients). Six hundred forty-eight patients with methamphetamine exposure were identified and reviewed, and 55 charts met the criteria for "methamphetamine body stuffer." We found the following characteristics of methamphetamine body stuffers: mean age 29 years (range 16 to 57 years), men in 44 of 55 cases (80%), mean time to arrival 2.7 hours after ingestion, with a median of 1 hour after ingestion. Ninety-seven percent (53/55) stuffed methamphetamine orally (2/55 rectally). Methamphetamine was most frequently swallowed in baggies, but 25% were unpackaged. The median dose ingested was 3.5 g of methamphetamine in 1 package. Outcome-based analysis revealed 29% (16/55) of patients had severe outcomes, as defined by end-organ toxicity, with agitation requiring intubation the most common severe outcome. There was 1 death reported. Toxicity did not appear to be related to the amount of methamphetamine or number of packets. Patients with severe outcomes had higher mean initial pulse rates and temperatures. Eighty-eight percent (14/16) of patients with severe outcomes had a presenting pulse rate greater than 120 beats/min or a temperature greater than 38 degrees C versus 18% (7/39) patients with a benign outcome. Twenty-four radiographic studies were obtained; none detected packets. Methamphetamine body stuffers have similar demographics to those of body stuffers of other stimulants, but tended to ingest fewer baggies with larger masses, and had a higher percentage of severe outcomes (29%) than previously reported with other stimulants. Increases in presenting pulse rate and temperature (pulse rate >120 beats/min or >38.0 degrees C) are common in patients who will develop end-organ damage.


CD8+ T cells from SIV elite controller macaques recognize Mamu-B*08-bound epitopes and select for widespread viral variation.
It is generally accepted that CD8+ T cell responses play an important role in control of immunodeficiency virus replication. The association of HLA-B27 and -B57 with control of viremia supports this conclusion. However, specific correlates of viral control in individuals expressing these alleles have been difficult to define. We recently reported that transient in vivo CD8+ cell depletion in simian immunodeficiency virus (SIV)-infected elite controller (EC) macaques resulted in a brief period of viral recrudescence. SIV replication was rapidly controlled with the reappearance of CD8+ cells, implicating that these cells actively suppress viral replication in ECs. Here we show that three ECs in that study made at least seven robust CD8+ T cell responses directed against novel epitopes in Vif, Rev, and Nef restricted by the MHC class I molecule Mamu-B*08. Two of these Mamu-B*08-positive animals subsequently lost control of SIV replication. Their breakthrough virus harbored substitutions in multiple Mamu-B*08-restricted epitopes. Indeed, we found evidence for selection pressure mediated by Mamu-B*08-restricted CD8+ T cells in all of the newly identified epitopes in a cohort of chronically infected macaques. Together, our data suggest that Mamu-B*08-restricted CD8+ T cell responses effectively control replication of pathogenic SIV(mac)239. All seven regions encoding Mamu-B*08-restricted CD8+ T cell epitopes also exhibit amino acid replacements typically seen only in the presence of Mamu-B*08, suggesting that the variation we observe is indeed selected by CD8+ T cell responses. SIV(mac)239 infection of Indian rhesus macaques expressing Mamu-B*08 may therefore provide an animal model for understanding CD8+ T cell-mediated control of HIV replication in humans.


Axial morphology and 3D neurocranial kinematics in suction-feeding fishes.
Many suction-feeding fish use neurocranial elevation to expand the buccal cavity for suction feeding, a motion necessarily accompanied by the dorsal flexion of joints in the axial skeleton. How much dorsal flexion the axial skeleton accommodates and where that dorsal flexion occurs may vary with axial skeletal morphology, body shape and the kinematics of neurocranial elevation. We measured three-dimensional neurocranial kinematics in three species with distinct body forms: laterally compressed Embiotoca lateralis, fusiform Micropterus salmoides, and dorsoventrally compressed Leptocottus armatus The area just caudal to the neurocranium occupied by bone was 42±1.5%, 36±1.8% and 22±5.5% (mean±s.e.m.; N=3, 6, 4) in the three species, respectively, and the epaxial depth also decreased from E. lateralis to L. armatus Maximum neurocranial elevation for each species was 11, 24 and 37°, respectively, consistent with a hypothesis that aspects of axial morphology and body shape may constrain neurocranial elevation. Mean axis of rotation position for neurocranial elevation in E. lateralis, M. salmoides and L. armatus was near the first, third and fifth intervertebral joints, respectively, leading to the hypothesis of a similar relationship with the number of intervertebral joints that flex. Although future work must test these hypotheses, our results suggest the relationships merit further inquiry.


Do the right thing: neural network mechanisms of memory formation, expression and update in Drosophila.
When animals learn, plasticity in brain networks that respond to specific cues results in a change in the behavior that these cues elicit. Individual network components in the mushroom bodies of the fruit fly Drosophila melanogaster represent cues, learning signals and behavioral outcomes of learned experience. Recent findings have highlighted the importance of dopamine-driven plasticity and activity in feedback and feedforward connections, between various elements of the mushroom body neural network. These computational motifs have been shown to be crucial for long term olfactory memory consolidation, integration of internal states, re-evaluation and updating of learned information. The often recurrent circuit anatomy and a prolonged requirement for activity in parts of these underlying networks, suggest that self-sustained and precisely timed activity is a fundamental feature of network computations in the insect brain. Together these processes allow flies to continuously adjust the content of their learned knowledge and direct their behavior in a way that best represents learned expectations and serves their most pressing current needs.


Outcomes of a Digitally Delivered Low-Carbohydrate Type 2 Diabetes Self-Management Program: 1-Year Results of a Single-Arm Longitudinal Study.
Type 2 diabetes mellitus has serious health consequences, including blindness, amputation, stroke, and dementia, and its annual global costs are more than US $800 billion. Although typically considered a progressive, nonreversible disease, some researchers and clinicians now argue that type 2 diabetes may be effectively treated with a carbohydrate-reduced diet. Our objective was to evaluate the 1-year outcomes of the digitally delivered Low-Carb Program, a nutritionally focused, 10-session educational intervention for glycemic control and weight loss for adults with type 2 diabetes. The program reinforces carbohydrate restriction using behavioral techniques including goal setting, peer support, and behavioral self-monitoring. The study used a quasi-experimental research design comprised of an open-label, single-arm, pre-post intervention using a sample of convenience. From adults with type 2 diabetes who had joined the program and had a complete baseline dataset, we randomly selected participants to be followed for 1 year (N=1000; mean age 56.1, SD 15.7 years; 59.30% (593/1000) women; mean glycated hemoglobin A1c (HbA1c) 7.8%, SD 2.1%; mean body weight 89.6 kg, SD 23.1 kg; taking mean 1.2, SD 1.01 diabetes medications). Of the 1000 study participants, 708 (70.80%) individuals reported outcomes at 12 months, 672 (67.20%) completed at least 40% of the lessons, and 528 (52.80%) completed all lessons of the program. Of the 743 participants with a starting HbA1c at or above the type 2 diabetes threshold of 6.5%, 195 (26.2%) reduced their HbA1c to below the threshold while taking no glucose-lowering medications or just metformin. Of the participants who were taking at least one hypoglycemic medication at baseline, 40.4% (289/714) reduced one or more of these medications. Almost half (46.40%, 464/1000) of all participants lost at least 5% of their body weight. Overall, glycemic control and weight loss improved, especially for participants who completed all 10 modules of the program. For example, participants with elevated baseline HbA1c (≥7.5%) who engaged with all 10 weekly modules reduced their HbA1c from 9.2% to 7.1% (P<.001) and lost an average of 6.9% of their body weight (P<.001). Especially for participants who fully engage, an online program that teaches a carbohydrate-reduced diet to adults with type 2 diabetes can be effective for glycemic control, weight loss, and reducing hypoglycemic medications.


Identifying Obstructive Sleep Apnea in Administrative Data: A Study of Diagnostic Accuracy.
Health administrative (HA) databases are increasingly used to identify surgical patients with obstructive sleep apnea (OSA) for research purposes, primarily using diagnostic codes. Such means to identify patients with OSA are not validated. The authors determined the accuracy of case-ascertainment algorithms for identifying patients with OSA with the use of HA data. Clinical data derived from an academic health sciences network within a universal health insurance plan were used as the reference standard. The authors linked patients to HA data and retrieved all claims in the 2 yr before surgery to determine the presence of any diagnostic codes, diagnostic procedures, or therapeutic interventions consistent with OSA. The authors identified 4,965 patients (2003 to 2012) who underwent preoperative polysomnogram. Of these, 4,353 patients were linked to HA data; 2,427 of these (56%) had OSA based on diagnosis by a sleep physician or the apnea hypopnea index. A claim for a polysomnogram and receipt of a positive airway pressure device had a sensitivity, specificity, and positive likelihood ratio (+LR) for OSA of 19, 98, and 10.9%, respectively. An International Classification of Diseases, Tenth Revision, code for sleep apnea in hospitalization abstracts was 9% sensitive and 98% specific (+LR, 4.5). A physician billing claim for OSA (International Classification of Diseases, Ninth Revision, 780.5) was 58% sensitive and 38% specific (+LR, 0.9). A polysomnogram and a positive airway pressure device or any code for OSA was 70% sensitive and 36% specific (+LR, 1.1). No code or combination of codes provided a +LR high enough to adequately identify patients with OSA. Existing studies using administrative codes to identify OSA should be interpreted with caution.


Body composition in sport: interobserver reliability of a novel ultrasound measure of subcutaneous fat tissue.
Very low body mass, extreme mass changes, and extremely low per cent body fat are becoming increasingly common in many sports, but sufficiently reliable and accurate field methods for body composition assessment in athletes are missing. Nineteen female athletes were investigated (mean (SD) age: 19.5 (± 3.3) years; body mass: 59.6 (± 7.6) kg; height: 1.674 (± 0.056) m; BMI: 21.3 (± 2.3) kg/m(2)). Three observers applied diagnostic B-mode-ultrasound (US) combined with the evaluation software for subcutaneous adipose tissue measurements at eight ISAK sites (International Society for the Advancement of Kinanthrometry). Regression and reliability analyses are presented. US measurements and evaluation of subcutaneous adipose tissue (SAT) thicknesses (including fibrous structures: D(included); n=378) resulted in an SE of estimate SEE=0.60 mm, R(2)=0.98 (p<0.001), limit of agreement LOA=1.18, ICC=0.968 (0.957-0.977). Similar values were found for D(excluded): SEE=0.68 mm, R(2)=0.97 (p<0.001). D(included) at individual ISAK sites: at biceps, R(2)=0.87 and intraclass-correlation coefficient ICC=0.811 were lowest and SEE=0.79 mm was highest. Values at all other sites ranged from R(2): 0.94-0.99, SEE: 0.42-0.65 mm, and ICC: 0.917-0.985. Interobserver coefficients ranged from 0.92 to 0.99, except for biceps (0.74, 0.83 and 0.87). Evaluations of 20 randomly selected US images by three observers (D(included)) resulted in: SEE=0.15 mm, R(2)=0.998(p<0.001), ICC=0.997 (0.993, 0999). Subject to optimal choice of sites and certain standardisations, US can offer a highly reliable field method for measurement of uncompressed thickness of the SAT. High accuracy and high reliability of measurement, as obtained with this US approach, are essential for protection of the athlete's health and also for optimising performance.


Genetic variants associated with risk of Alzheimer's disease contribute to cognitive change in midlife: The Atherosclerosis Risk in Communities Study.
Alzheimer's disease (AD) is the most common form of dementia and is characterized by impairment in memory, behavioral changes, and gradual loss of autonomy. Since there is a long latent period prior to diagnosis, the aim of this study was to determine whether twenty single nucleotide polymorphisms identified in genome-wide association analyses of AD are associated with cognitive change in 8,320 white and 2,039 African-American middle-aged adults enrolled in the prospective Atherosclerosis Risk in Communities (ARIC) study. Cognition was evaluated using the Delayed Word Recall Test (DWRT; verbal memory), Digit Symbol Substitution Test (DSST; processing speed), and Word Fluency Test (WFT; executive function). General linear models were used to assess mean differences in 6-year change in test scores among individuals categorized by genotype after adjusting for age, gender, and years of education. Addition of the minor allele for rs670139 (MS4A4E), rs9331896 (CLU), and rs12155159 (NME8) was nominally associated with change on the DWRT, DSST, and WFT, respectively, in whites. The ZCWPW1 (rs1476679) and CDS33 (rs3865444) variants were nominally associated with change on the DWRT and WFT in African-Americans. For rs670139 and rs9331896 the association was only significant in individuals bearing at least one APOE ϵ4 allele in stratified analyses. An unweighted genetic risk score aggregating the risk alleles for 15 polymorphisms was not associated with change in cognitive function. Although the AD-associated genetic variants appear to have small effects on early cognitive change, replication will be required to establish whether there is a discernible influence on cognitive status in midlife. © 2016 Wiley Periodicals, Inc.


Behavior and psychological functioning of young children of HIV-positive mothers in South Africa.
Adults with HIV are living longer due to earlier diagnosis and increased access to antiretroviral medications. Therefore, fewer young children are being orphaned and instead, are being cared for by parents who know they are HIV positive, although they may be asymptomatic. Presently, it is unclear whether the psychological functioning of these young children is likely to be affected or, alternatively, whether it is only when a mother is ill, that children suffer adverse effects. We, thus, aimed to compare the behavior and psychological functioning of young children (aged 6-10 years) of HIV-positive and HIV-negative mothers. We also aimed to examine the association between HIV status disclosure and child outcomes. This study uses cross-sectional data from the baseline assessment of a randomized controlled trial conducted in Tshwane, South Africa. Participants (n=509) and their children were recruited from area health clinics. Among the 395 mothers with HIV, 42% reported symptoms of HIV disease. Multivariate linear regression models suggested that after adjusting for socio-demographic characteristics, children of HIV-positive mothers had significantly greater externalizing behaviors than children of HIV-negative mothers. Importantly, children whose mothers were symptomatic had greater internalizing and externalizing behaviors compared with children of HIV-negative mothers, but this was not true for children of asymptomatic mothers. Additionally, among children of HIV-positive mothers, those who had been told their mothers were sick compared with children who had been told nothing had less internalizing and externalizing behaviors and improved daily living skills. This study, therefore, provides evidence that maternal HIV disease can affect the behaviors of young children in South Africa but, importantly, only when the mothers are symptomatic from their disease. Furthermore, results suggest that disclosure of maternal illness but not HIV status was associated with improved behavior and psychological functioning among young children.


Aging and the saturation of colors. 1. Colorimetric purity discrimination.
Colorimetric purity (Pc) discrimination functions were measured for 21 color-normal observers (11 younger and 10 older observers with mean ages of 30 and 74 years, respectively). On each two-alternative-forced-choice trial, observers saw two flashes of light, a broadband white light [CIE(x, y) = (0.33, 0.35)] and a mixture of broadband and monochromatic light (420-680 nm). The observer's task was to choose the flash that had a chromatic component. Foveally viewed, circular, 1.2 degrees-diameter stimuli were presented as 1.5-s flashes with 3-s interstimulus intervals in Maxwellian view. Stimuli [250 trolands (td) and 10 td] were equated on the basis of individual heterochromatic flicker photometry functions. Measured Pc discrimination sensitivity was lower in the older group than in the younger group at both light levels, and the performance difference between the age groups was approximately constant across the spectrum. The difference between discrimination at 10 and 250 td was relatively small for the younger group but larger for the older group, indicating a selective performance decrement for older observers at low light levels. The data were modeled as a sum of differential responses from S-cone and L/M-cone chromatic channels. The model and the data indicate similar age-related losses of sensitivity in the two channels, perhaps secondary to receptorial sensitivity losses.


Social mixing with other children during infancy enhances antibody response to a pneumococcal conjugate vaccine in early childhood.
Children who have siblings and/or who attend day care have higher rates of nasopharyngeal colonization with pneumococci than lone children do. Pneumococcal colonization is usually asymptomatic but is a prerequisite for invasive disease. We studied the effect of social mixing with other children on immunity to a pneumococcal vaccine. One hundred sixty children aged 1 year were immunized with a 7-valent conjugate pneumococcal vaccine. A blood sample was obtained before and 9 to 11 days after the vaccine. The concentration and avidity of antibody against vaccine pneumococcal serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F) were studied in relation to pneumococcal carriage rate and measures of social mixing. Children with increased social mixing had higher antibody concentrations against serotypes 4, 9V, 14, and 23F than lone children did. The least-carried serotype, serotype 4, was the one of the most immunogenic. This contrasts with serotype 6B, the most common nasopharyngeal isolate but the least immunogenic. Social mixing in infancy enhances the immune response to a Streptococcus pneumoniae polysaccharide-protein conjugate vaccine at 1 year of age. Exposure to pneumococci in the first year of life may induce immunological priming. An alternative explanation is that differences in immunological experience, such as increased exposure to respiratory viral infections in early childhood, alters the response to vaccines perhaps by affecting the balance between Th1 and Th2 cytokines. The low immunogenicity of serotype 6B polysaccharide might make conditions more favorable for carriage of the 6B organism and explain why 6B pneumococci were more frequently isolated than other serotypes.


Treatment of stage I-III periodontitis-The EFP S3 level clinical practice guideline.
The recently introduced 2017 World Workshop on the classification of periodontitis, incorporating stages and grades of disease, aims to link disease classification with approaches to prevention and treatment, as it describes not only disease severity and extent but also the degree of complexity and an individual's risk. There is, therefore, a need for evidence-based clinical guidelines providing recommendations to treat periodontitis. The objective of the current project was to develop a S3 Level Clinical Practice Guideline (CPG) for the treatment of Stage I-III periodontitis. This S3 CPG was developed under the auspices of the European Federation of Periodontology (EFP), following the methodological guidance of the Association of Scientific Medical Societies in Germany and the Grading of Recommendations Assessment, Development and Evaluation (GRADE). The rigorous and transparent process included synthesis of relevant research in 15 specifically commissioned systematic reviews, evaluation of the quality and strength of evidence, the formulation of specific recommendations and consensus, on those recommendations, by leading experts and a broad base of stakeholders. The S3 CPG approaches the treatment of periodontitis (stages I, II and III) using a pre-established stepwise approach to therapy that, depending on the disease stage, should be incremental, each including different interventions. Consensus was achieved on recommendations covering different interventions, aimed at (a) behavioural changes, supragingival biofilm, gingival inflammation and risk factor control; (b) supra- and sub-gingival instrumentation, with and without adjunctive therapies; (c) different types of periodontal surgical interventions; and (d) the necessary supportive periodontal care to extend benefits over time. This S3 guideline informs clinical practice, health systems, policymakers and, indirectly, the public on the available and most effective modalities to treat periodontitis and to maintain a healthy dentition for a lifetime, according to the available evidence at the time of publication.


Trade-offs during the development of primary and secondary sexual traits in a horned beetle.
Resource allocation trade-offs during development affect the final sizes of adult structures and have the potential to constrain the types and magnitude of evolutionary change that developmental processes can accommodate. Such trade-offs can arise when two or more body parts compete for a limited pool of resources to sustain their growth and differentiation. Recent studies on several holometabolous insects suggest that resource allocation trade-offs may be most pronounced in tissues that grow physically close to each other. Here we examine the nature and magnitude of developmental trade-offs between two very distant body parts: head horns and genitalia of males of the horned scarab beetle Onthophagus taurus. Both structures develop from imaginal disklike tissues that undergo explosive growth during late larval development but differ in exactly when they initiate their growth. We experimentally ablated the precursor cells that normally give rise to male genitalia at several time points during late larval development and examined the degree of horn development in these males compared to that of untreated and sham-operated control males. We found that experimental males developed disproportionately larger horns. Horn overexpression was weakest in response to early ablation and most pronounced in males whose genital disks were ablated just before larvae entered the prepupal stage. Our results suggest that even distant body parts may rely on a common resource pool to sustain their growth and that the relative timing of growth may play an important role in determining whether, and how severely, growing organs will affect each other during development. We use our findings to discuss the physiological causes and evolutionary consequences of resource allocation trade-offs.


Heparin-binding serum protein(s) is required for the protection of sialyltransferase released during the incubation of rat jejunal slices.
Incubation of rat jejunal slices in Krebs-Ringer bicarbonate buffer (KRB) required the presence of heat-inactivated horse serum (HHS) in order to show time-dependent release of sialyltransferase into the medium. Sialyltransferase activity could not be detected in the medium when KRB alone or KRB supplemented with either albumin or glycerol was used in the incubations. The viability of the jejunal slices for up to 4 h of incubation was determined by studying the incorporation of glucosamine and leucine into acid-insoluble proteins. Supplementation of KRB with HHS had no beneficial effect on the rate of incorporation of leucine and glucosamine into proteins. KRB medium obtained after different periods of incubation contained higher trypsin-like activity than KRB medium containing HHS. Various antiproteases present as supplements to KRB resulted in the release of sialyltransferase activity from the jejunal slices. Among these antiproteases, alpha 1-proteinase inhibitor (alpha 1-PI) was the most effective. Also, HHS added to KRB immediately following incubation resulted in partial restoration of sialyltransferase activity in the medium, suggesting the presence of anti-proteolytic factors in HHS. The addition of increasing concentrations of heparin to incubations containing HHS caused a decrease in the medium sialyltransferase activity. The heparin-binding fraction (HBF) from HHS, when added to incubations, was able to protect the sialyltransferase released into medium. However, HHS depleted of its heparin-binding fraction by heparin-agarose affinity chromatography was unable to protect the sialyltransferase. HBF was separated into high- and low-molecular-mass fractions (fractions A and B respectively) by gel-filtration chromatography. The capacity to protect the released sialyltransferase was contained in fraction B. Fraction A contained multiple bands on SDS/PAGE and did not protect the enzyme. Fraction B contained a major protein band on the gel which corresponded to the migration of a similar band in human alpha 1-PI. HBF as well as fraction B isolated from HHS showed anti-trypsin-like activity. The results presented indicate that HHS contains a heparin-binding protein(s) similar to human alpha 1-PI which plays a role in the protection of sialyltransferase released from jejunal slices.


Cholera public health surveillance in the Republic of Cameroon-opportunities and challenges.
In Cameroon, cholera has periodically resurfaced since it was first reported in 1971. In 2003, Cameroon adapted the Integrated Disease Surveillance and Response (IDSR) strategy to strengthen surveillance in the country. This study was an in-depth description and assessment of the structure, core and support functions, and attributes of the current cholera surveillance system in Cameroon. It also discussed its strengths and challenges with hope that lessons learned could improve the system in Cameroon and in other countries in Africa implementing the IDSR strategy. Semi-structured key informant interviews, peer reviewed articles, and government record review were conducted in the Far North and Centre Regions of Cameroon. We used the matrix and conceptual framework from the World Health Organization (WHO) and Centers for Disease Control and Prevention, WHO Regional Office for Africa Technical Guidelines to frame the study. Site visits included the WHO country office, the ministry of public health (MoPH), two Regional Public Health Delegations (RPHDs), eight health districts (HDs) and health facilities (HFs) including two labs. Cholera surveillance is passive but turns active during outbreaks and follows a hierarchical structure. Cholera data are collected at HFs and sent to HDs where data are compiled and sent to the RPHD in paper format. RPHDs de-identify, digitalize, and send the data to the MoPH via internet and from there to the WHO. The case definition was officially changed in 2010 but the outdated definition was still in use in 2013. Nationally, there are 3 laboratories that have the ability to confirm cholera cases; the lack of laboratory capacity at HFs hampers case and outbreak confirmation. The absence of structured data analysis at the RPHD, HD, and HF further compounds the situation, making the goal of IDSR of data analysis and rapid response at the HD very challenging. Feedback is strongest at the central level (MoPH) and non-existent at the levels below it, with only minimal training and supervision of staff. In 2012, mobile phone coverage expanded to all 183 HDs and to HFs in 2014 in the Far North and North Regions. The phones improved immediate reporting and outbreak control. Further, the creation of cholera command and control centers, and introduction of laptops at all RPHDs are major strengths in the surveillance system. Completeness and timeliness of reporting varied considerably among levels. Significant milestones in the hierarchical structure towards integration and achieving early detection and rapid response in cholera surveillance are in effective use; however, some challenges exist. The surveillance system lack labs at HFs and there is no data analysis at HD level. Thus, the goal of IDSR-strategy of early detection, data analysis, and rapid response at the HD level is a challenge. Both human and material resources are needed at the HD level to achieve this goal.


The natural history of cerebral cavernous malformations.
To determine the natural history of brain cavernous malformations, the authors entered patients referred to their center into a prospective registry between 1987 and 1993. All patients underwent magnetic resonance imaging, which showed the typical appearance of this lesion, and conservative management was recommended in all. Patients or their referring physicians were contacted for follow-up data. The purpose of the study was to define the rate of symptomatic hemorrhage and to determine the outcome in those patients who had suffered seizures. Follow-up data were available for 122 patients with a mean age at entry of 37 years (range 4-82 years). The malformation was located in the brainstem in 43 cases (35%), the basal ganglia/thalamus in 20 (17%), and a hemispheric area in 59 (48%). Fifty percent of patients had never had a symptomatic hemorrhage, 41% had one bleed, 7% had two, and 2% had three. Seizures were reported in 23% of patients and headaches in 15%. Lesions were solitary in 80% of patients and multiple in 20%. The retrospective annual hemorrhage rate (61 bleeds/4550.6 patient-years of life) was 1.3%. The mean prospective follow-up period was 34 months. There were nine bleeds during this time, six with new neurological deficits. In patients without a prior bleed, the prospective annual rate of hemorrhage was 0.6%. In contrast, patients with prior hemorrhage had an annual bleed rate of 4.5% (p = 0.028). Patient sex (p = 0.97) or the presence of seizures (p = 0.11), headaches (p = 0.06), or solitary versus multiple lesions (p = 0.15) were not significant predictors of later hemorrhage. There was no difference in the rate of bleeds between brain locations. Four patients with seizures became seizure-free and four patients without seizures later developed seizures; only one patient developed intractable seizures. Fourteen had radiosurgery. No patient died in the follow-up period. This study indicates that conservative versus operative management strategies may need to be redefined, especially in patients who present with hemorrhage and who appear to have a significantly increased risk of subsequent rehemorrhage.


Assessment of cytologic evaluation of preputial epithelial cells as a diagnostic test for detection of adrenocortical disease in castrated ferrets.
To determine whether results of cytologic evaluation of preputial epithelial cells correspond to results of a serum endocrine hormone assay and clinical signs associated with adrenocortical disease in castrated ferrets. 13 clinically normal ferrets and 8 ferrets with signs of adrenocortical disease. Blood and preputial lavage samples were collected from each ferret. Serum samples were submitted to the University of Tennessee Veterinary Diagnostic Laboratory for performance of an endocrine hormone assay. Differential epithelial cell counts were performed on preputial lavage samples to determine the percentage of cornified cells. Results of cytologic evaluation were compared with results of the endocrine hormone assay and clinical status of ferrets. The percentage of cornified preputial epithelial cells was not significantly correlated with serum 17B-estradiol or androstenedione concentration but was significantly correlated with serum 17-hydroxyprogesterone concentration (r = 0.60). The percentage of cornified preputial epithelial cells was higher in ferrets with clinical signs of adrenocortical disease (mean +/- SD, 71.3 +/- 16.9%) than in clinically normal ferrets (55.5 +/- 19.0%). Cornification of preputial epithelial cells was correlated with an increase in serum 17-hydroxyprogesterone concentration as well as clinical signs of adrenocortical disease in castrated ferrets. Additional investigation is needed to elucidate the mechanism of preputial epithelial cell cornification in castrated ferrets.


Long-term survival and function after cardiac transplantation.
Cardiac transplantation now permits prolonged survival for some patients with otherwise fatal heart disease. This report summarizes the hemodynamic and clinical characteristics of 25 patients who have survived five or more years after cardiac replacement. The average age of the patients at the time of operation was 40 +/- 10 (SD) years; 23 were men. The average duration of survival is 6.7 years, and ranges from five to 10.5 years. Annual cardiac catheterization and clinical follow-up were performed to assess systolic cardiac function, coronary anatomy, and quality of extended rehabilitation. We found that among these long-term survivors, the left ventricular ejection fraction remained constant (0.59 +/- 0.08 one year postoperatively, 0.57 +/- 0.09 at most recent study, p = ns). Segmental wall motion measured by fluoroscopic examination of midwall intramyocardial markers also remained normal. Four of 21 (19%) patients with complete longitudinal studies developed significant graft coronary artery disease. Clinical evaluation revealed that the long-term survivors required fewer than one unscheduled admission to the hospital per year. Sixteen of 25 patients (64%) were gainfully employed, and 22 of 25 (88%) enjoyed substantial benefit in terms of extended rehabilitation. These 25 long-term survivors represent 27% of 92 patients transplanted between 1968 and 1975. The actuarial survival rate at five years, of patients transplanted since 1975, is 40 +/- 5%. This increase in survival rate reflects improved techniques of early postoperative management. Cardiac transplantation now offers prolonged survival with good quality of life for selected patients with terminal heart disease.


The evolution of land plant hemoglobins.
This review discusses the evolution of land plant hemoglobins within the broader context of eukaryote hemoglobins and the three families of bacterial globins. Most eukaryote hemoglobins, including metazoan globins and the symbiotic and non-symbiotic plant hemoglobins, are homologous to the bacterial 3/3-fold flavohemoglobins. The remaining plant hemoglobins are homologous to the bacterial 2/2-fold group 2 hemoglobins. We have proposed that all eukaryote globins were acquired via horizontal gene transfer concomitant with the endosymbiotic events responsible for the origin of mitochondria and chloroplasts. Although the 3/3 hemoglobins originated in the ancestor of green algae and plants prior to the emergence of embryophytes at about 450 mya, the 2/2 hemoglobins appear to have originated via horizontal gene transfer from a bacterium ancestral to present day Chloroflexi. Unlike the 2/2 hemoglobins, the evolution of the 3/3 hemoglobins was accompanied by duplication, diversification, and functional adaptations. Duplication of the ancestral plant nshb gene into the nshb-1 and nshb-2 lineages occurred prior to the monocot-dicot divergence at ca. 140 mya. It was followed by the emergence of symbiotic hemoglobins from a non-symbiotic hemoglobin precursor and further specialization, leading to leghemoglobins in N₂-fixing legume nodules concomitant with the origin of nodulation at ca. 60 mya. The transition of non-symbiotic to symbiotic hemoglobins (including to leghemoglobins) was accompanied by the alteration of heme-Fe coordination from hexa- to penta-coordination. Additional genomic information about Charophyte algae, the sister group to land plants, is required for the further clarification of plant globin phylogeny.


Expression of receptors for luteinizing hormone-releasing hormone (LH-RH) in prostate cancers following therapy with LH-RH agonists.
In addition to their expression on pituitary cells, receptors for luteinizing hormone-releasing hormone (LH-RH) are found on most prostate cancer cells. These tumoral LH-RH receptors mediate the direct cytotoxic effects of LH-RH analogs and are potential therapeutic targets. Although pituitary LH-RH receptors are downregulated following prolonged exposure to LH-RH agonists, there is no evidence that tumoral receptors behave in a similar manner. To better characterize expression of tumoral LH-RH receptors, specimens of prostate cancer from various cohorts of patients were analyzed. Surgical specimens were obtained from untreated patients with prostate cancer and from patients with metastatic castration-resistant prostate cancer previously treated with bilateral orchiectomy. To address the possibility of receptor downregulation, two additional cohorts of patients who had been previously treated with LH-RH agonists were included. One group received neoadjuvant therapy prior to prostatectomy, and the other group was treated for metastatic disease with LH-RH agonists and, at progression, required palliative resection of the prostate. Lymph node metastases from previously untreated patients were subjected to similar analysis. Expression of LH-RH receptors was found in most specimens. The relative expression of LH-RH receptor mRNA in untreated patients was greater in patients whose tumor had received a Gleason score <8. LH-RH receptor expression persisted despite prolonged exposure to LH-RH agonists. These findings support the concept of targeting cytotoxic LH-RH analogs to prostatic LH-RH receptors, using these receptors to gain entry into cancer cells to deliver a hybridized cytotoxic moiety for the treatment of prostate cancer.


Blockade of neurotransmission in Drosophila mushroom bodies impairs odor attraction, but not repulsion.
Olfaction can elicit a rich perceptual experience. It is not known, however, whether olfactory information is decomposed into various components and processed in distinct perceptual centers as in other sensory systems, such as vision, where neural representations of different visual sensations are segregated in different cortical regions, despite the fact that multiple structures of the primary olfactory cortex receive projections from the olfactory bulb. Here, we use Drosophila as a model to investigate whether different olfactory information may be processed in separate brain structures. Organizations of the peripheral olfactory system are remarkably similar from mammals to insects. As in vertebrates, the olfactory pathway in Drosophila follows similar convergence and divergence, and multiple high-order structures in the Drosophila brain, including the mushroom body (MB) and lateral horn (LH) of the protocerebrum, receive olfactory input. We specifically blocked neurotransmission in the MB while leaving the LH unaffected and examined its effect on olfactory avoidance and attraction behaviors. We show that blocking MB activity disrupted responses to attractive, but not repulsive, odors, and this finding suggests that attractive and repulsive olfactory information may be separately processed in higher olfactory centers of the Drosophila brain.


Regulatory considerations surrounding the deployment of Bt-expressing cowpea in Africa: report of the deliberations of an expert panel.
Cowpea (Vigna unguiculata spp unguiculata) is adapted to the drier agro-ecological zones of West Africa where it is a major source of dietary protein and widely used as a fodder crop. Improving the productivity of cowpea can enhance food availability and security in West Africa. Insect predation--predominately from the legume pod borer (Maruca vitrata), flower thrips (Megalurothrips sjostedti) and a complex of pod-sucking bugs (e.g., Clavigralla spp)--is a major yield-limiting factor in West African cowpea production. Dramatic increases in yield are shown when M. vitrata is controlled with insecticides. However, availability, costs, and safety considerations limit pesticides as a viable option for boosting cowpea production. Development of Bt-cowpea through genetic modification (GM) to control the legume pod borer is a promising approach to cowpea improvement. Cowpea expressing the lepidopteran-active Cry1Ab protein from Bacillus thuringiensis is being developed as a first generation Bt-cowpea crop for West Africa. Appropriate stewardship of Bt-cowpea to assure its sustainability under West African conditions is critical to its successful development. A first step in this process is an environmental risk assessment to determine the likelihood and magnitude of adverse effects of the Cry1Ab protein on key environmental protection goals in West Africa. Here we describe the results of an expert panel convened in 2009 to develop the problem formulation phase for Bt-cowpea and to address specific issues around gene flow, non-target arthropods, and insect resistance management.


Minimal-invasive thoracic surgery in pediatric patients.
During the last two decades, there was a tremendous development of video-assisted thoracoscopic surgery (VATS), especially in the field of video-assisted lung resections. This article describes the actually state of this surgical technique in the treatment of pediatric patients. The problems in practical application are illustrated as well as clinical results, like they are presented in literature.


Structuring targeted surveillance for monitoring disease emergence by mapping observational data onto ecological process.
An efficient surveillance system is a crucial factor in identifying, monitoring and tackling outbreaks of infectious diseases. Scarcity of data and limited amounts of economic resources require a targeted effort from public health authorities. In this paper, we propose a mathematical method to identify areas where surveillance is critical and low reporting rates might leave epidemics undetected. Our approach combines the use of reference-based susceptible-exposed-infectious models and observed reporting data; We propose two different specifications, for constant and time-varying surveillance, respectively. Our case study is centred around the spread of the raccoon rabies epidemic in the state of New York, using data collected between 1990 and 2007. Both methods offer a feasible solution to analyse and identify areas of intervention.


Radiological findings in edentulous Kenyan patients.
Seven hundred and seventy five files of edentulous patients seen at the Department of Dental Surgery, University of Nairobi were scrutinized for the presence or absence of routine radiographs prior to treatment. 180 (23.2%) had radiographs. 26% of the radiographs had 51 positive radiological findings. 17.3% were roots, 3.9% were unerupted teeth, 6.7% were radiopacities and 0.6% were radiolucencies. 52.9% of the radiological findings were in the mandible and 47.1% were in the maxilla. In the mandible, 44.4% of the radiological findings were in the anterior region and 55.6% were found posteriorly. 66.7% of the maxillary radiological findings were in the anterior region and 33.3% were found posteriorly. Since some of the positive radiological findings such as the retained roots and unerupted teeth might lead to infection, cysts or poor dentures fit, it is recommended that whenever possible, all edentulous patients be examined radiographically prior to treatment.


Short-chain dehydrogenase/reductase (SDR) relationships: a large family with eight clusters common to human, animal, and plant genomes.
The progress in genome characterizations has opened new routes for studying enzyme families. The availability of the human genome enabled us to delineate the large family of short-chain dehydrogenase/reductase (SDR) members. Although the human genome releases are not yet final, we have already found 63 members. We have also compared these SDR forms with those of three model organisms: Caenorhabditis elegans, Drosophila melanogaster, and Arabidopsis thaliana. We detect eight SDR ortholog clusters in a cross-genome comparison. Four of these clusters represent extended SDR forms, a subgroup found in all life forms. The other four are classical SDRs with activities involved in cellular differentiation and signalling. We also find 18 SDR genes that are present only in the human genome of the four genomes studied, reflecting enzyme forms specific to mammals. Close to half of these gene products represent steroid dehydrogenases, emphasizing the regulatory importance of these enzymes.


Climate-driven spatial dynamics of plague among prairie dog colonies.
We present a Bayesian hierarchical model for the joint spatial dynamics of a host-parasite system. The model was fitted to long-term data on regional plague dynamics and metapopulation dynamics of the black-tailed prairie dog, a declining keystone species of North American prairies. The rate of plague transmission between colonies increases with increasing precipitation, while the rate of infection from unknown sources decreases in response to hot weather. The mean annual dispersal distance of plague is about 10 km, and topographic relief reduces the transmission rate. Larger colonies are more likely to become infected, but colony area does not affect the infectiousness of colonies. The results suggest that prairie dog movements do not drive the spread of plague through the landscape. Instead, prairie dogs are useful sentinels of plague epizootics. Simulations suggest that this model can be used for predicting long-term colony and plague dynamics as well as for identifying which colonies are most likely to become infected in a specific year.


Intravenous immunoglobulin, splenectomy, and antibiotic prophylaxis in Wiskott-Aldrich syndrome.
To assess the results of supportive treatment with intravenous immunoglobulin (IVIG) and antibiotic prophylaxis in combination with splenectomy in patients with Wiskott-Aldrich syndrome. Retrospective review of case records of 21 patients from March 1984 to February 1996. Thrombocytopenia was cured in 14 of 15 patients who had splenectomy, but it recurred intermittently in three. Mean platelet volume (MPV) was normal transiently in some patients, but all MPV values were subnormal 8-23 months after splenectomy. Antibiotic and IVIG prophylaxis may have contributed to the lack of a detectable increase in the number of severe acute bacterial infections in the 451 months after splenectomy. Four patients died in 2205 months of observation before and after splenectomy (median 82, range 16-248): two of cerebral B cell lymphoma, one of progressive multifocal leucoencephalopathy, and one with severe chronic chest disease of pneumonia. Adequate supportive treatment with IVIG and antibiotic prophylaxis together with splenectomy enables good survival and quality of life in the short and medium term in patients with Wiskott-Aldrich syndrome. Persistence of infection, bleeding, and vasculitic and allergic symptoms in a significant minority and the risk of development of lymphoma, however, suggest that bone marrow transplantation may be indicated if an HLA identical donor is available.


Experiences seeking, sourcing, and using abortion pills at home in the United States through an online telemedicine service.
A growing number of people in the United States seek to self-manage their abortions by self-sourcing abortion medications online. Prior research focuses on people's motivations for seeking self-management of abortion and experiences trying to obtain medications. However, little is known about the experiences of people in the U.S. who actually complete a self-managed abortion using medications they self-sourced online. We conducted anonymous in-depth interviews with 80 individuals who sought abortion medications through Aid Access, the only online telemedicine service that provides abortion medications in all 50 U.S. states. Through grounded theory analysis we identified five key themes: 1) participants viewed Aid Access as a "godsend"; 2) Fears of scams, shipping delays, and surveillance made ordering pills online a "nerve-racking" experience; 3) a "personal touch" calmed fears and fostered trust in Aid Access; 4) participants were worried about the "what ifs" of the self-managed abortion experience; and 5) overall, participants felt that online telemedicine met their important needs. Our findings demonstrate that online telemedicine provided by Aid Access not only provided a critical service, but also offered care that participants deemed legitimate and trustworthy.


Tissue transglutaminase is a negative regulator of monomeric lacritin bioactivity.
Molar accounting of bioactive fluids can expose new regulatory mechanisms in the growing proteomic focus on epithelial biology. Essential for the viability of the surface epithelium of the eye and for normal vision is the thin, but protein-rich, tear film in which the small tear glycoprotein lacritin appears to play a prominent prosecretory, cytoprotective, and mitogenic role. Although optimal bioactive levels in cell culture are 1 to 10 nM over a biphasic dose optimum, ELISA suggests a sustained tear lacritin concentration in the midmicromolar range in healthy adults. Here we identify a reconciling mechanism. Monoclonal anti-lacritin 1F5 antibody was generated, and applied together with a new anti-C-terminal polyclonal antibody to tear and tissue Western blotting. In vitro tissue transglutaminase (Tgm2) cross-linking was monitored and characterized by mass spectrometry. Blotting for lacritin in human tears or saliva surprisingly detected immunoreactive material with a higher molecular weight and prominence equal or exceeding the ∼23 to 25 kDa band of monomeric glycosylated lacritin. Exogenous Tgm2 initiated lacritin cross-linking within 1 minute and was complete by 90 minutes-even with as little as 0.1 nM lacritin, and involved the donors lysine 82 and 85 and the acceptor glutamine 106 in the syndecan-1 binding domain. Lacritin spiked into lacritin-depleted tears formed multimers, in keeping with ∼0.6 μM TGM2 in tears. Cross-linking was absent when Tgm2 was inactive, and cross-linked lacritin, unlike recombinant monomer, bound syndecan-1 poorly. Since syndecan-1 binding is necessary for lacritin mitogenic and cytoprotective activities, TGM2 cross-linking negatively regulates lacritin bioactivity.


Female reproductive strategies in orangutans, evidence for female choice and counterstrategies to infanticide in a species with frequent sexual coercion.
Intersexual conflicts over mating can engender antagonistic coevolution of strategies, such as coercion by males and selective resistance by females. Orangutans are exceptional among mammals for their high levels of forced copulation. This has typically been viewed as an alternative mating tactic used by the competitively disadvantaged unflanged male morph, with little understanding of how female strategies may have shaped and responded to this behaviour. Here, we show that male morph is not by itself a good predictor of mating dynamics in wild Bornean orangutans but that female conception risk mediated the occurrence and quality of male-female interactions. Near ovulation, females mated cooperatively only with prime flanged males who they encountered at higher rates. When conception risk was low, willingness to associate and mate with non-prime males increased. Our results support the hypothesis that, together with concealed ovulation, facultative association is a mechanism of female choice in a species in which females can rarely avoid coercive mating attempts. Female resistance, which reduced copulation time, may provide an additional mechanism for mate selection. However, coercive factors were also important as prime males were frequently aggressive to females and females used mating strategies consistent with infanticide avoidance.


A graphene-like membrane with an ultrahigh water flux for desalination.
An ultrathin nanoporous membrane which combines high water permeability and high salt rejection is the core of ultrafiltration technology. Recently, we reported the synthesis of a chemically robust and nanoporous two-dimensional conjugated aromatic polymer (2D-CAP) membrane. Due to its array of highly regular sub-nanometer pores and channels, the ultrathin 2D-CAP membrane can be potentially used in desalination. Herein, we used molecular dynamics simulations to analyze the transmembrane hydrodynamics of mono- and multi-layer 2D-CAP membranes as a function of layer number. The energy barriers to water and ions across these membranes were calculated to evaluate the potential of 2D-CAP to function as the ultimate RO membrane. Our simulation results show that the bilayer CAP membrane exhibits superior ion rejection (100%) and a water flux (1172 L m-2 h-1 bar-1) with a performance that is three orders of magnitude higher than the commercial reverse osmosis membrane, which is three times higher than the theoretically reported monolayer nanoporous MoS2 membrane (the state-of-the-art membrane reported for desalination). In addition, the 2D-CAP bilayer membrane is highly resistant to swelling even at a high water flux. The monolayer 2D-CAP membrane shows good ion selectivity between monovalent and divalent ions.


An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants.
Normal processing of the amyloid beta protein precursor (beta APP) results in secretion of a soluble 4-kilodalton protein essentially identical to the amyloid beta protein (A beta) that forms insoluble fibrillar deposits in Alzheimer's disease. Human neuroblastoma (M17) cells transfected with constructs expressing wild-type beta APP or the beta APP717 mutants linked to familial Alzheimer's disease were compared by (i) isolation of metabolically labeled 4-kilodalton A beta from conditioned medium, digestion with cyanogen bromide, and analysis of the carboxyl-terminal peptides released, or (ii) analysis of the A beta in conditioned medium with sandwich enzyme-linked immunosorbent assays that discriminate A beta 1-40 from the longer A beta 1-42. Both methods demonstrated that the 4-kilodalton A beta released from wild-type beta APP is primarily but not exclusively A beta 1-40. The beta APP717 mutations, which are located three residues carboxyl to A beta 43, consistently caused a 1.5- to 1.9-fold increase in the percentage of longer A beta generated. Long A beta (for example, A beta 1-42) forms insoluble amyloid fibrils more rapidly than A beta 1-40. Thus, the beta APP717 mutants may cause Alzheimer's disease because they secrete increased amounts of long A beta, thereby fostering amyloid deposition.


Comparative costs of the Mouse Inoculation Test (MIT) and Virus Isolation in Cell Culture (VICC) for use in rabies diagnosis in Brazil.
The decision to use laboratory animals rather than in vitro methods is frequently based on the financial costs involved, so the objective of our study was to compare the costs of performing the Mouse Inoculation Test (MIT) and Virus Isolation in Cell Culture (VICC) for use in rabies diagnosis in Brazil. Based on observations of laboratory routines at the Pasteur Institute, São Paulo, we listed the fixed cost (FC) and variable cost (VC) items necessary to perform both tests. Considering that 200 MITs are equivalent to 350 VICC assays, in terms of facilities and staff-hours needed per month, we calculated, for both tests, the average total cost per sample, the costs of the implementation of the laboratory structure, and the costs of routine use. With regard to absolute values, the total cost was mainly influenced by FC items, as they represented 60% of the cost for the MIT and 86% of the cost for VICC. A sample analysed by the MIT costs around 205% more than one analysed by using VICC. The MIT costs 74% and 406% more than VICC, when implementation costs and routine use per month, respectively, are taken into account. Our results can assist in the resolution of costing disputes that could hinder the replacement of animals for rabies diagnosis in Brazil. The method demonstrated here might also be useful for cost comparisons in other situations where animal use still continues when validated alternatives exist.


Quenching protein dynamics interferes with HIV capsid maturation.
Maturation of HIV-1 particles encompasses a complex morphological transformation of Gag via an orchestrated series of proteolytic cleavage events. A longstanding question concerns the structure of the C-terminal region of CA and the peptide SP1 (CA-SP1), which represents an intermediate during maturation of the HIV-1 virus. By integrating NMR, cryo-EM, and molecular dynamics simulations, we show that in CA-SP1 tubes assembled in vitro, which represent the features of an intermediate assembly state during maturation, the SP1 peptide exists in a dynamic helix-coil equilibrium, and that the addition of the maturation inhibitors Bevirimat and DFH-055 causes stabilization of a helical form of SP1. Moreover, the maturation-arresting SP1 mutation T8I also induces helical structure in SP1 and further global dynamical and conformational changes in CA. Overall, our results show that dynamics of CA and SP1 are critical for orderly HIV-1 maturation and that small molecules can inhibit maturation by perturbing molecular motions.


Apoptosis and the immune system.
Apoptosis is a physiological process of cell death that occurs as part of normal development and in response to a variety of physiological and pathophysiological stimuli. The effector mechanisms which carry out the death program are well preserved across species and evolution. Apoptosis is important in the immune system, and plays significant roles in the control of the immune response, the deletion of immune cells recognising self-antigens, and cytotoxic killing. Some of the molecular regulators of these processes, such as CD95 and bcl-2 family proteins are the subjects of intense research. Malfunctioning of the immune system may lead to increased or decreased cell death. Conversely, dysregulation of apoptotic pathways themselves may lead to a spectrum of human disease, including autoimmune disease and immunodeficiency.


Talking yourself out of exhaustion: the effects of self-talk on endurance performance.
The psychobiological model of endurance performance proposes that the perception of effort is the ultimate determinant of endurance performance. Therefore, any physiological or psychological factor affecting the perception of effort will affect endurance performance. Accordingly, this novel study investigated the effects of a frequently used psychological strategy, motivational self-talk (ST), on RPE and endurance performance. In a randomized between-group pretest-posttest design, 24 participants (mean ± SD age = 24.6 ± 7.5 yr, VO2max = 52.3 ± 8.7 mL·kg·min) performed two constant-load (80% peak power output) cycling time-to-exhaustion (TTE) tests, punctuated by a 2-wk ST intervention or a control phase. A group (ST vs Control) × test (pretest vs posttest) mixed-model ANOVA revealed that ST significantly enhanced TTE test from pretest to posttest (637 ± 210 vs 750 ± 295 s, P < 0.05) with no change in the control group (486 ± 157 vs 474 ± 169 s). Moreover, a group × test × isotime (0%, 50%, and 100%) mixed-model ANOVA revealed a significant interaction for RPE, with follow-up tests showing that motivational self-talk significantly reduced RPE at 50% isotime (7.3 ± 0.6 vs 6.4 ± 0.8, P < 0.05), with no significant difference in the control group (6.9 ± 1.9 vs 7.0 ± 1.7). This study is the first to demonstrate that ST significantly reduces RPE and enhances endurance performance. The findings support the psychobiological model of endurance performance and illustrate that psychobiological interventions designed to specifically target favorable changes in the perception of effort are beneficial to endurance performance. Consequently, this psychobiological model offers an important and novel perspective for future research investigations.


Use of photolithography to encode cell adhesive domains into protein microarrays.
Protein microarrays are rapidly emerging as valuable tools in creating combinatorial cell culture systems where inducers of cellular differentiation can be identified in a rapid and multiplexed fashion. In the present study, protein microarraying was combined with photoresist lithography to enable printing of extracellular matrix (ECM) protein arrays while precisely controlling "on-the-spot" cell-cell interactions. In this surface engineering approach, the micropatterned photoresist layer formed on a glass substrate served as a temporary stencil during the microarray printing, defining the micrometer-scale dimensions and the geometry of the cell-adhesion domains within the printed protein spots. After removal of the photoresist, the glass substrates contained micrometer-scale cell-adhesive regions that were encoded within 300 or 500 microm diameter protein domains. Fluorescence microscopy and atomic force microscopy (AFM) were employed to characterize protein micropatterns. When incubated with micropatterned surfaces, hepatic (HepG2) cells attached on 300 or 500 mum diameter protein spots; however, the extent of cell-cell contacts within each spot varied in accordance with dimensions of the photoresist stencil, from single cells attaching on 30 microm diameter features to multicell clusters residing on 100 or 200 microm diameter regions. Importantly, the photoresist removal process was shown to have no detrimental effects on the ability of several ECM proteins (collagens I, II, and IV and laminin) to support functional hepatic cultures. The micropatterning approach described here allows for a small cell population seeded onto a single cell culture substrate to be exposed to multiple scenarios of cell-cell and cell-surface interactions in parallel. This technology will be particularly useful for high-throughput screening of biological stimuli required for tissue specification of stem cells or for maintenance of differentiated phenotype in scarce primary cells.


Trauma systems in Kenya: a qualitative analysis at the district level.
Injury is a leading cause of death and disability in low- and middle-income countries. Kenya has a particularly high burden of injuries, accounting for 88.4 deaths per 100,000 population. Despite recent attempts to prioritize injury prevention in Kenya, trauma care systems have not been assessed. We assessed perceptions of formal and informal district-level trauma systems through 25 qualitative semi-structured interviews and 16 focus group discussions with Ministry of Health officials, district hospital administrators, health care providers, police, and community members. We used the principles of theoretical analysis to identify common themes of prehospital and hospital trauma care. We found prehospital care relied primarily on "good Samaritans" and police. We described hospital care in terms of human resources, infrastructure, and definitive care. The interviewers repeatedly emphasized the lack of hospital infrastructure. We showed the need to develop prehospital care systems and strengthen hospital trauma care services.


The action spectrum for induction of chronic actinic dermatitis is similar to that for sunburn inflammation.
The action spectrum for induction of the abnormal cutaneous response at 24 h in the photosensitivity disorder chronic actinic dermatitis (CAD) was determined in 15 patients and found to be the same in shape as that for normal sunburn in fair-skinned individuals at 24 h, as determined for 47 control volunteers, although displaced in magnitude. This suggests that an endogenous chromophore(s), the same as or similar to that/those responsible for human sunburn, may be responsible for initiation of the abnormal reaction to irradiation in CAD, and that the putative antigen associated with the CAD reaction may be derived from that/those or associated molecules.


Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation.
Opioid use for pain management has dramatically increased, with little assessment of potential pathophysiological consequences for the primary pain condition. Here, a short course of morphine, starting 10 d after injury in male rats, paradoxically and remarkably doubled the duration of chronic constriction injury (CCI)-allodynia, months after morphine ceased. No such effect of opioids on neuropathic pain has previously been reported. Using pharmacologic and genetic approaches, we discovered that the initiation and maintenance of this multimonth prolongation of neuropathic pain was mediated by a previously unidentified mechanism for spinal cord and pain-namely, morphine-induced spinal NOD-like receptor protein 3 (NLRP3) inflammasomes and associated release of interleukin-1β (IL-1β). As spinal dorsal horn microglia expressed this signaling platform, these cells were selectively inhibited in vivo after transfection with a novel Designer Receptor Exclusively Activated by Designer Drugs (DREADD). Multiday treatment with the DREADD-specific ligand clozapine-N-oxide prevented and enduringly reversed morphine-induced persistent sensitization for weeks to months after cessation of clozapine-N-oxide. These data demonstrate both the critical importance of microglia and that maintenance of chronic pain created by early exposure to opioids can be disrupted, resetting pain to normal. These data also provide strong support for the recent "two-hit hypothesis" of microglial priming, leading to exaggerated reactivity after the second challenge, documented here in the context of nerve injury followed by morphine. This study predicts that prolonged pain is an unrealized and clinically concerning consequence of the abundant use of opioids in chronic pain.


Biological activities of Bellis perennis volatiles and extracts.
Different parts of Bellis perennis were subjected to hydrodistillation and the products were subsequently analyzed by GC and GC/MS. Aqueous and methanol extracts were prepared from the aerial parts. Antioxidant [1,1-diphenyl-2-picryl-hydrazyl (DPPH) radical scavenging, reducing activity, total antioxidant] and antimicrobial activity of the plant materials were studied. The aqueous extracts showed higher DPPH scavenging activity (85.8% at 102.5 microg/mL) than the methanol extract. Reducing power was also observed for both tested extracts, where the formation of linoleic acid peroxides was more for the aqueous extract than the methanol extract. Antimicrobial activities of all plant materials were evaluated at varying concentrations against a panel of pathogens, but without pronounced inhibitory effect.


Computational Consequences of a Bias toward Short Connections.
A fundamental observation in the neurosciences is that the brain is a modular system in which different regions perform different tasks. Recent evidence, however, raises questions about the accuracy of this characterization with respect to neo-nates. One possible interpretation of this evidence is that certain aspects of the modular organization of the adult brain arise developmentally. To explore this hypothesis we wish to characterize the computational principles that underlie the development of modular systems. In previous work we have considered computational schemes that allow a learning system to discover the modular structure that is present in the environment (Jacobs, Jordan, & Barto, 1991). In the current paper we present a complementary approach in which the development of modularity is due to an architectural bias in the learner. In particular, we examine the computational consequences of a simple architectural bias toward short-range connections. We present simulations that show that systems that learn under the influence of such a bias have a number of desirable properties, including a tendency to decompose tasks into subtasks, to decouple the dynamics of recurrent subsystems, and to develop location-sensitive internal representations. Furthermore, the system's units develop local receptive and projective fields, and the system develops characteristics that are typically associated with topographic maps.


Recent advances in understanding cell types during human gastrulation.
Gastrulation is a fundamental process during embryonic development, conserved across all multicellular animals [1]. In the majority of metazoans, gastrulation is characterised by large scale morphogenetic remodeling, leading to the conversion of an early pluripotent embryonic cell layer into the three primary 'germ layers': an outer ectoderm, inner endoderm and intervening mesoderm layer. The morphogenesis of these three layers of cells is closely coordinated with cellular diversification, laying the foundation for the generation of the hundreds of distinct specialized cell types in the animal body. The process of gastrulation has for a long time attracted tremendous attention in a broad range of experimental systems ranging from sponges to mice. In humans the process of gastrulation starts approximately 14 days after fertilization and continues for slightly over a week. However our understanding of this important process, as it pertains to human, is limited. Donations of human fetal material at these early stages are exceptionally rare, making it nearly impossible to study human gastrulation directly. Therefore, our understanding of human gastrulation is predominantly derived from animal models such as the mouse [2,3] and from studies of limited collections of fixed whole samples and histological sections of human gastrulae [4-7], some of which date back to over a century ago. More recently we have been gaining valuable molecular insights into human gastrulation using in vitro models of hESCs [8-12] and increasingly, in vitro cultured human and non-human primate embryos [13-16]. However, while methods have been developed to culture human embryos into this stage (and probably beyond), current ethical standards prohibit the culture of human embryos past 14 days again limiting our ability to experimentally probe human gastrulation. This review discusses recent molecular insights from the study of a rare CS 7 human gastrula obtained as a live sample and raises several questions arising from this recent study that it will be interesting to address in the future using emerging models of human gastrulation.


Can rheumatologists diagnose and manage Giant Cell Arteritis better than non-rheumatologists? The Maltese Experience.
Giant Cell Arteritis (GCA) remains a challenge both in terms of diagnosis and management as patients may present to several different specialists. The objectives were to determine incidence of biopsy-proven GCA in Malta and to compare the management between rheumatologists and non-rheumatologists. This was a retrospective observational population study of patients with suspected GCA who underwent a temporal artery biopsy (TAB) between 2012 and 2015. Data collected consisted of demographics, presenting symptoms, TAB histology reports, treatment and outcome. The British Society for Rheumatology (BSR) 2010 guidelines were used as standard of care. 136 patients underwent a TAB for suspected GCA of which 26 were positive. The incidence of biopsy-proven GCA in Malta was 3.82 per 100,000 patient years in the over 50 population. There were 63 patients who were treated as GCA. Only 43.3% of confirmed cases had rheumatology input. TABs requested by rheumatologists were twice more likely to be positive compared to requests by non-rheumatologists (30.5% vs. 14.1%).The majority of patients were started on a Prednisolone dose between 40-60mg. Rheumatologists maintained patients on high doses for at least 1 month in 54% of cases as opposed to 20% under non-rheumatologists. Monitoring was more regular for cases followed up by rheumatologists (40% vs. 21%). Malta has a low incidence of biopsy proven GCA. Although rheumatologists are more likely to adhere to the recommended guidelines, improvement is needed. Rheumatologists should take the lead to minimise variation and optimise management of GCA.


Integration of Genomic and Other Epidemiologic Data to Investigate and Control a Cross-Institutional Outbreak of Streptococcus pyogenes.
Single-strain outbreaks of Streptococcus pyogenes infections are common and often go undetected. In 2013, two clusters of invasive group A Streptococcus (iGAS) infection were identified in independent but closely located care homes in Oxfordshire, United Kingdom. Investigation included visits to each home, chart review, staff survey, microbiologic sampling, and genome sequencing. S. pyogenes emm type 1.0, the most common circulating type nationally, was identified from all cases yielding GAS isolates. A tailored whole-genome reference population comprising epidemiologically relevant contemporaneous isolates and published isolates was assembled. Data were analyzed independently using whole-genome multilocus sequencing and single-nucleotide polymorphism analyses. Six isolates from staff and residents of the homes formed a single cluster that was separated from the reference population by both analytical approaches. No further cases occurred after mass chemoprophylaxis and enhanced infection control. Our findings demonstrate the ability of 2 independent analytical approaches to enable robust conclusions from nonstandardized whole-genome analysis to support public health practice.


Prevention of Atherosclerosis by Berries: The Case of Blueberries.
Berry consumption has been associated with cardiovascular disease prevention in recent years. Atherosclerosis is one of the major causes of cardiovascular diseases. However, research on the prevention of atherosclerosis through consuming individual whole berries, specifically direct evidence, remains scarce. Therefore, further elucidating the role that berries play in the prevention of atherosclerosis is warranted. In this perspective, blueberries were selected to articulate research strategies for studying atheroprotective effects of berries. Studies from human subjects and various animal models are summarized. The mechanisms by which blueberries may act, through reducing oxidative stress, decreasing inflammation, improving endothelial dysfunction, regulating cholesterol accumulation and trafficking, along with potentially influencing gut microbiota, are also discussed. Blueberries contain high levels of polyphenolic compounds, which were widely indicated as major bioactive compounds. Nonetheless, the metabolites/catabolites after blueberry consumption, such as simple phenolic acids, rather than original compounds in berries, may be the actual in vivo bioactive compounds. Future research should focus on obtaining more direct evidence, preferably in humans, understanding of the mechanisms of action at the molecular level, and identifying bioactive compounds as well as which compounds act synergistically to convey health benefits. The research strategy discussed here may also be applied to the studies of other fruits and berries.


The utility of the zebrafish model in conditioned place preference to assess the rewarding effects of drugs.
Substance abuse is a significant public health concern both domestically and worldwide. The persistent use of substances regardless of aversive consequences forces the user to give higher priority to the drug than to normal activities and obligations. The harmful and hazardous use of psychoactive substances can lead to a dependence syndrome. In this regard, the genetic and neurobiological underpinnings of reward-seeking behavior need to be fully understood in order to develop effective pharmacotherapies and other methods of treatment. Animal models are often implemented in preclinical screening for testing the efficacy of novel treatments. Several paradigms exist that model various facets of addiction including sensitization, tolerance, withdrawal, drug seeking, extinction, and relapse. Self-administration and, most notably, conditioned place preference (CPP) are relatively simple tests that serve as indicators of the aforementioned aspects of addiction by means of behavioral quantification. CPP is a commonly used technique to evaluate the motivational effects of compounds and experiences that have been associated with a positive or negative reward, which capitalizes on the basic principles of Pavlovian conditioning. During training, the unconditioned stimulus is consistently paired with a neutral set of environmental stimuli, which obtain, during conditioning, secondary motivational properties that elicit approach behavior in the absence of the unconditioned stimulus. For over 50 years, rodents have been the primary test subjects. However, the zebrafish (Danio rerio) is gaining favor as a valuable model organism in the fields of biology, genetics, and behavioral neuroscience. This paper presents a discussion on the merits, advantages, and limitations of the zebrafish model and its utility in relation to CPP.


Non-covalent interactions: complexes of guanidinium with DNA and RNA nucleobases.
Considering that guanidine-based derivatives are good DNA minor groove binders, we have theoretically studied, using the Polarizable Continuum model mimicking water solvation, the complexes formed by the biologically relevant guanidinium cation and the DNA and RNA nucleobases (adenine, guanine, cytosine, thymine, and uracil). The interactions established within these complexes both by hydrogen bonds and by cation-π interactions have been analyzed by means of the Atoms in Molecules and Natural Bond Orbital approaches. Moreover, maps of electron density difference have been produced to understand the cation-π complexes. Finally, the NICS and three-dimensional NICS maps of the cation-π complexes have been studied to understand the effect of the guanidinium cation on the aromaticity of the nucleobases.


Dietary Variation and Evolution of Gene Copy Number among Dog Breeds.
Prolonged human interactions and artificial selection have influenced the genotypic and phenotypic diversity among dog breeds. Because humans and dogs occupy diverse habitats, ecological contexts have likely contributed to breed-specific positive selection. Prior to the advent of modern dog-feeding practices, there was likely substantial variation in dietary landscapes among disparate dog breeds. As such, we investigated one type of genetic variant, copy number variation, in three metabolic genes: glucokinase regulatory protein (GCKR), phytanol-CoA 2-hydroxylase (PHYH), and pancreatic α-amylase 2B (AMY2B). These genes code for proteins that are responsible for metabolizing dietary products that originate from distinctly different food types: sugar, meat, and starch, respectively. After surveying copy number variation among dogs with diverse dietary histories, we found no correlation between diet and positive selection in either GCKR or PHYH. Although it has been previously demonstrated that dogs experienced a copy number increase in AMY2B relative to wolves during or after the dog domestication process, we demonstrate that positive selection continued to act on amylase copy number in dog breeds that consumed starch-rich diets in time periods after domestication. Furthermore, we found that introgression with wolves is not responsible for deterioration of positive selection on AMY2B among diverse dog breeds. Together, this supports the hypothesis that the amylase copy number expansion is found universally in dogs.


Small splenic B cells that bind to antigen-specific T helper (Th) cells and face the site of cytokine production in the Th cells selectively proliferate: immunofluorescence microscopic studies of Th-B antigen-presenting cell interactions.
Antigen (Ag)-specific T helper (Th) cells regulate the proliferation and differentiation of Ag-specific B cells by secreting cytokines and by expressing activating receptors like gp39. In vitro, the cytokines and the activating receptors function in an Ag-nonspecific manner. It is unclear, therefore, how Ag specificity is imposed on B cell responses in physiological Th-B cell interactions. Here we studied, at the single cell level, the interactions between cloned Th cells and small splenic B cells, which served as Ag-specific antigen-presenting cells (APCs) to the Th cells. Digital confocal immunofluorescence microscopy of Th-B cell conjugates revealed significant variability in the molecular and cellular properties of these interactions, in spite of the fact that all the interactions in this system were expected to be Ag specific. After 30 h of incubation B cells began to divide, and this process was entirely dependent on the presence of both Th cells and Ag. Immunofluorescence microscopic studies showed that essentially all the mitotic B cells were bound to Th cells and faced the microtubule organizing center (MTOC) in the Th cells where interleukin 4 was highly concentrated. Other B cells that were bound to the same Th cells but were not close to the Th-MTOC remained in interphase. These results provide the first direct structural and functional evidence that the site of interaction of B cells with Th cells affects their immune response. We propose that, during Ag-induced Th-B cell interactions, B cells that are bound facing the Th-MTOC proliferate preferentially because they are the recipients of locally secreted cytokines. In addition, these B cells may interact with newly expressed receptors, which may also be locally inserted into the Th membrane. The polarized delivery of activating molecules towards the Th-bound APCs may impose functional specificity on effector molecules that otherwise are not Ag specific.


Tocotrienols: Vitamin E beyond tocopherols.
In nature, eight substances have been found to have vitamin E activity: alpha-, beta-, gamma- and delta-tocopherol; and alpha-, beta-, gamma- and delta-tocotrienol. Yet, of all papers on vitamin E listed in PubMed less than 1% relate to tocotrienols. The abundance of alpha-tocopherol in the human body and the comparable efficiency of all vitamin E molecules as antioxidants, led biologists to neglect the non-tocopherol vitamin E molecules as topics for basic and clinical research. Recent developments warrant a serious reconsideration of this conventional wisdom. Tocotrienols possess powerful neuroprotective, anti-cancer and cholesterol lowering properties that are often not exhibited by tocopherols. Current developments in vitamin E research clearly indicate that members of the vitamin E family are not redundant with respect to their biological functions. alpha-Tocotrienol, gamma-tocopherol, and delta-tocotrienol have emerged as vitamin E molecules with functions in health and disease that are clearly distinct from that of alpha-tocopherol. At nanomolar concentration, alpha-tocotrienol, not alpha-tocopherol, prevents neurodegeneration. On a concentration basis, this finding represents the most potent of all biological functions exhibited by any natural vitamin E molecule. An expanding body of evidence support that members of the vitamin E family are functionally unique. In recognition of this fact, title claims in manuscripts should be limited to the specific form of vitamin E studied. For example, evidence for toxicity of a specific form of tocopherol in excess may not be used to conclude that high-dosage "vitamin E" supplementation may increase all-cause mortality. Such conclusion incorrectly implies that tocotrienols are toxic as well under conditions where tocotrienols were not even considered. The current state of knowledge warrants strategic investment into the lesser known forms of vitamin E. This will enable prudent selection of the appropriate vitamin E molecule for studies addressing a specific need.


High Prevalence of Back Pain and Axial Spondyloarthropathy in Patients with Hidradenitis Suppurativa.
Hidradenitis suppurativa (HS) is a chronic inflammatory disease, causing fistulating sinuses in the intertriginous skin of axillary, genitofemoral and perianal sites. As other chronic inflammatory diseases, e.g. psoriasis, are frequently associated with spondyloarthropathies (SpA), the goal of this study was to quantify the prevalence of back pain and SpA in HS patients. A prospective questionnaire survey in 100 HS patients and a retrospective evaluation of pelvic magnetic resonance imaging (MRI) scans in 46 HS patients were conducted. 71% of HS patients were suffering from back pain. There was no difference between age at onset of HS, disease duration, body mass index (BMI), or disease severity between HS patients with and without back pain. Evaluating pelvic MRI scans, 32.6% of HS patients showed signs of chronic SpA and 39.1% signs of active SpA. Again, no significant differences between patients with/without SpA were found regarding age at time of MRI, age at onset of HS, disease duration, smoking habits, and BMI. Furthermore, there was no correlation between these parameters and the degree of SpA. Only patients with moderate/severe HS (Hurley stage II and III) in genitofemoral/perianal sites were analysed via MRI scans. Back pain and SpA are very common among patients with moderate/severe HS. Neither medical history nor clinical parameters provide hints for the presence of SpA.


The Seminal fluid proteome of the polyandrous Red junglefowl offers insights into the molecular basis of fertility, reproductive ageing and domestication.
Seminal fluid proteins (SFPs) are emerging as fundamental contributors to sexual selection given their role in post-mating reproductive events, particularly in polyandrous species where the ejaculates of different males compete for fertilisation. SFP identification however remains taxonomically limited and little is known about avian SFPs, despite extensive work on sexual selection in birds. We characterize the SF proteome of the polyandrous Red junglefowl, Gallus gallus, the wild species that gave rise to the domestic chicken. We identify 1,141 SFPs, including proteins involved in immunity and antimicrobial defences, sperm maturation, and fertilisation, revealing a functionally complex SF proteome. This includes a predominant contribution of blood plasma proteins that is conserved with human SF. By comparing the proteome of young and old males with fast or slow sperm velocity in a balanced design, we identify proteins associated with ageing and sperm velocity, and show that old males that retain high sperm velocity have distinct proteome characteristics. SFP comparisons with domestic chickens revealed both qualitative and quantitative differences likely associated with domestication and artificial selection. Collectively, these results shed light onto the functional complexity of avian SF, and provide a platform for molecular studies of fertility, reproductive ageing, and domestication.


Movement Initiation Signals in Mouse Whisker Motor Cortex.
Frontal cortex plays a central role in the control of voluntary movements, which are typically guided by sensory input. Here, we investigate the function of mouse whisker primary motor cortex (wM1), a frontal region defined by dense innervation from whisker primary somatosensory cortex (wS1). Optogenetic stimulation of wM1 evokes rhythmic whisker protraction (whisking), whereas optogenetic inactivation of wM1 suppresses initiation of whisking. Whole-cell membrane potential recordings and silicon probe recordings of action potentials reveal layer-specific neuronal activity in wM1 at movement initiation, and encoding of fast and slow parameters of movements during whisking. Interestingly, optogenetic inactivation of wS1 caused hyperpolarization and reduced firing in wM1, together with reduced whisking. Optogenetic stimulation of wS1 drove activity in wM1 with complex dynamics, as well as evoking long-latency, wM1-dependent whisking. Our results advance understanding of a well-defined frontal region and point to an important role for sensory input in controlling motor cortex.


Impaired cardiac and vascular motion in patients with Takayasu's arteritis: A velocity vector imaging-based study.
Takayasu's arteritis (TAK) is a chronic inflammatory vasculitis of the aorta and its major branches. In the present study, we aimed to evaluate the motion of the vascular wall and myocardial contractility by using a novel strain imaging method, velocity vector imaging (VVI), in patients with TAK. We also aimed to compare them with another inflammatory autoimmune disorder, systemic lupus erythematosus (SLE). We studied 33 patients with TAK, 18 patients with SLE, and 20 age- and sex-matched controls. All participants were subjected to carotid artery Doppler ultrasonography and transthoracic echocardiographic evaluation. VVI analysis was also performed to assess subclinical left ventricular (LV) systolic dysfunction and to determine tissue motion of the common carotid arteries (CCAs). Aortic strain and distensibility were significantly impaired in patients with TAK, while the aortic stiffness and carotid artery stiffness indexes were increased. Aortic distensibility was the only parameter that was decreased among SLE patients. The values of CCA peak longitudinal strain, strain rate, and total longitudinal displacement (TLD) were also impaired in patients with TAK. Peak radial velocity was decreased while time-to-peak radial velocity was increased. In the SLE group, peak longitudinal strain, strain rate, TLD, and peak radial velocity were impaired. LV longitudinal peak systolic strain and strain rate were reduced in patients with TAK. Similarly, we revealed impaired subclinical LV systolic function in patients with SLE. VVI is a novel strain imaging technique with additional value to determine early impairment in vascular and myocardial wall motion in patients with TAK.


Cognitive behavioral therapy for depression changes medial prefrontal and ventral anterior cingulate cortex activity associated with self-referential processing.
Cognitive behavioral therapy (CBT), an effective treatment for depression, targets self-referential processing of emotional stimuli. We examined the effects of CBT on brain functioning during self-referential processing in depressive patients using functional magnetic resonance imaging (fMRI). Depressive patients (n = 23) and healthy participants (n = 15) underwent fMRI scans during a self-referential task using emotional trait words. The depressive patients had fMRI scans before and after completing a total of 12 weekly sessions of group CBT for depression, whereas the healthy participants underwent fMRI scans 12 weeks apart with no intervention. Before undergoing CBT, the depressive patients showed hyperactivity in the medial prefrontal cortex (MPFC) during self-referential processing of negative words. Following CBT, MPFC and ventral anterior cingulate cortex (vACC) activity during self-referential processing among depressive patients was increased for positive stimuli, whereas it was decreased for negative stimuli. Improvements in depressive symptoms were negatively correlated with vACC activity during self-referential processing of negative stimuli. These results suggest that CBT-related improvements in depressive symptoms are associated with changes in MPFC and vACC activation during self-referential processing of emotional stimuli.