Acute tryptophan depletion and sweet food consumption by overweight adults.
Serotonergic involvement has been implicated in preferential consumption of treat foods. We tested the effect of acute tryptophan depletion (ATD) on food consumption by overweight and lean adults with and without a history of recurrent major depressive disorder (MDD). ATD and taste-matched placebo challenges were administered double-blind in counter-balanced order. Participants were classified as lean (n=36) or overweight (n=19) on the basis of body mass index (BMI). Total calorie, carbohydrate, protein, and sweet food consumption were assessed via a test meal 8-h following ATD. Four food items of comparable palatability were offered as a part of the test: two sweet (one carbohydrate-rich, and one protein-rich) and two non-sweet (one carbohydrate-rich, and one protein-rich). As compared to the placebo challenge, ATD significantly increased sweet calorie intake among overweight participants and increased their propensity to consume sweet food first before any other type of food. Lean participants' sweet calorie intake and food preference were unaffected by ATD. Findings suggest serotonergic involvement in the sweet food consumption by overweight individuals.


A longitudinal, microgenetic study of the emergence of false belief understanding and inhibition skills.
Two theories that attempt to explain the relationship between false belief understanding and inhibition skills were investigated: (1) theory of mind development improves self-control, and (2) executive control is necessary for developing a theory of mind. A microgenetic approach was adopted, with a group of 21 children completing a battery of inhibition and false belief understanding tasks every four weeks for six phases of testing. The results showed that the majority of children were able to perform well on a test of executive inhibition before having a good understanding of false beliefs, thus supporting theory (2). The results also illustrated that while the children's inhibition skills developed relatively gradually, their understanding of false beliefs progressed from a consistent lack of understanding through a period of unstable performance, during which some children failed tests that they had previously passed.


Gene-environment interaction study for BMI reveals interactions between genetic factors and physical activity, alcohol consumption and socioeconomic status.
Previous genome-wide association studies (GWAS) have identified hundreds of genetic loci to be associated with body mass index (BMI) and risk of obesity. Genetic effects can differ between individuals depending on lifestyle or environmental factors due to gene-environment interactions. In this study, we examine gene-environment interactions in 362,496 unrelated participants with Caucasian ancestry from the UK Biobank resource. A total of 94 BMI-associated SNPs, selected from a previous GWAS on BMI, were used to construct weighted genetic scores for BMI (GSBMI). Linear regression modeling was used to estimate the effect of gene-environment interactions on BMI for 131 lifestyle factors related to: dietary habits, smoking and alcohol consumption, physical activity, socioeconomic status, mental health, sleeping patterns, as well as female-specific factors such as menopause and childbirth. In total, 15 lifestyle factors were observed to interact with GSBMI, of which alcohol intake frequency, usual walking pace, and Townsend deprivation index, a measure of socioeconomic status, were all highly significant (p = 1.45*10-29, p = 3.83*10-26, p = 4.66*10-11, respectively). Interestingly, the frequency of alcohol consumption, rather than the total weekly amount resulted in a significant interaction. The FTO locus was the strongest single locus interacting with any of the lifestyle factors. However, 13 significant interactions were also observed after omitting the FTO locus from the genetic score. Our analyses indicate that many lifestyle factors modify the genetic effects on BMI with some groups of individuals having more than double the effect of the genetic score. However, the underlying causal mechanisms of gene-environmental interactions are difficult to deduce from cross-sectional data alone and controlled experiments are required to fully characterise the causal factors.


Complete density calculations of q-state Potts and clock models: Reentrance of interface densities under symmetry breaking.
All local bond-state densities are calculated for q-state Potts and clock models in three spatial dimensions, d=3. The calculations are done by an exact renormalization group on a hierarchical lattice, including the density recursion relations, and simultaneously are the Migdal-Kadanoff approximation for the cubic lattice. Reentrant behavior is found in the interface densities under symmetry breaking, in the sense that upon lowering the temperature, the value of the density first increases and then decreases to its zero value at zero temperature. For this behavior, a physical mechanism is proposed. A contrast between the phase transition of the two models is found and explained by alignment and entropy, as the number of states q goes to infinity. For the clock models, the renormalization-group flows of up to 20 energies are used.


No place for /h/: an ERP investigation of English fricative place features.
The representational format of speech units in long-term memory is a topic of debate. We present novel event-related brain potential evidence from the Mismatch Negativity (MMN) paradigm that is compatible with abstract, non-redundant feature-based models like the Featurally Underspecified Lexicon (FUL). First, we show that the fricatives /s/ and /f/ display an asymmetric pattern of MMN responses, which is predicted if /f/ has a fully specified place of articulation ([Labial]) but /s/ does not ([Coronal], which is lexically underspecified). Second, we show that when /s/ and /h/ are contrasted, no such asymmetric MMN pattern occurs. The lack of asymmetry suggests both that (i) oral and laryngeal articulators are represented distinctly and that (ii) /h/ has no oral place of articulation in long-term memory. The lack of asymmetry between /s/ and /h/ is also in-line with traditional feature-geometric models of lexical representations.


Use of Cardiac Magnetic Resonance Imaging in Assessing Mitral Regurgitation: Current Evidence.
Accurate quantification of regurgitant volume is a central component to the management of mitral regurgitation. Cardiac magnetic resonance imaging (CMR) accurately quantifies mitral regurgitation as the difference between left ventricular stroke volume and forward stroke volume using steady state free precession and phase contrast imaging. The CMR measurement of mitral regurgitant volume is reproducible and can quantify mitral regurgitation in patients without regard to regurgitant jet morphology, such as patients with multiple and eccentric jets. It can be used to quantify regurgitant volume in patients with multiple valve lesions and concomitant intracardiac shunts without the use of intravenous contrast. Studies have highlighted the accuracy and reproducibility of CMR in quantifying mitral regurgitation and have begun to link CMR to clinical outcomes.


Reasons for non-uptake of measles, mumps, and rubella catch up immunisation in a measles epidemic and side effects of the vaccine.
To investigate the reasons for poor uptake of immunisation (non-immunisation) and the possible side effects of measles, mumps, and rubella vaccine in a catch up immunisation campaign during a community outbreak of measles. Descriptive study of reasons for non-immunisation and retrospective cohort study of side effects of the vaccine. Secondary schools in South Glamorgan. Random cluster sample of the parents of 500 children targeted but not immunised and a randomised sample of 2866 of the children targeted. Reasons for non-immunisation; symptoms among immunised and non-immunised children. Immunisation coverage of the campaign was only 43.4% (7633/17,595). The practical problems experienced included non-return of consent forms (6698/17,595), refusal of immunisation (2061/10,897 forms returned), and absence from school on day of immunisation (1203/8836 children with consent for immunisation). The most common reasons cited for non-immunisation were previous measles infection (145/232), previous immunisation against measles (78/232), and concern about side effects (55/232). Symptoms were equally common among immunised and non-immunised subjects. However, significantly more immunised boys than non-immunised boys reported fever (relative risk 2.31 (95% confidence interval 1.36 to 3.93)), rash (2.00 (1.10 to 3.64), joint symptoms (1.58; 1.05 to 2.38), and headache (1.31 (1.04 to 1.65)). Many of the objections raised by parents could be overcome by emphasising that primary immunisation does not necessarily confer immunity and that diagnosis of measles is unreliable. Measles, mumps, and rubella vaccine is safe in children aged 11-15.


Effect of bee venom or proplis on molecular and parasitological aspects of Schistosoma mansoni infected mice.
The present study was performed to elucidate the efficacy of Apis mellifera L bee venom (BV) or proplis (200 mg/kg orally for three consecutive days) on Schistosoma mansoni infected mice. The results recorded reduction in the total worm burden, numbers of immature eggs and the ova count in hepatic tissue in BV (sting or injection) or proplis treated groups as compared to the infected group. Histological examination illustrated a significant increase (P ≤ 0.05) in the diameter of hepatic granuloma in BV treated groups (272.78 and 266.9, respectively) and a significant decrease in proplis treated mice (229.35) compared with the infected group (260.67). Electrophoretic pattern of RNA showed a decrease in mean of maximal optical density in liver and intestine of S. mansoni infected mice treated with bee venom (sting or injection) as compared with infected group. Flow cytometry analyses of RNA or apoptotic percentage of worms recovered from BV sting (19 and 49 % respectively); BV injected (20.5 and 51.17 %, respectively) and proplis (35 and 23.93 %, respectively) groups were compared with S. mansoni infected group (37.87 and 39.21 %, respectively). It can be concluded that administration of bee venom or proplis are effective in case of S. mansoni infection. Although bee venom cause increase of granuloma diameter and this might be due to venom concentration and further studies are required to avoid such harmful effect.


Molecular cloning of Snyder-Theilen feline leukemia and sarcoma viruses: comparative studies of feline sarcoma virus with its natural helper virus and with Moloney murine sarcoma virus.
Extrachromosomal DNA obtained from mink cells acutely infected with the Snyder-Theilen (ST) strain of feline sarcoma virus (feline leukemia virus) [FeSV(FeLV)] was fractionated electrophoretically, and samples enriched for FeLV and FeSV linear intermediates were digested with EcoRI and cloned in lambda phage. Hybrid phages were isolated containing either FeSV or FeLV DNA "inserts" and were characterized by restriction enzyme analysis, R-looping with purified 26 to 32S viral RNA, and heteroduplex formation. The recombinant phages (designated lambda FeSV and lambda FeLV) contain all of the genetic information represented in FeSV and FeLV RNA genomes but lack one extended terminally redundant sequence of 750 bases which appears once at each end of parental linear DNA intermediates. Restriction enzyme and heteroduplex analyses confirmed that sequences unique to FeSV (src sequences) are located at the center of the FeSV genome and are approximately 1.5 kilobase pairs in length. With respect to the 5'-3' orientation of genes in viral RNA, the order of genes in the FeSV genome is 5'-gag-src-env-c region-3'; only 0.9 kilobase pairs of gag and 0.6 kilobase pairs of env-derived FeLV sequences are represented in ST FeSV. Heteroduplex analyses between lambda FeSV or lambda FeLV DNA and Moloney murine sarcoma virus DNA (strain m1) were performed under conditions of reduced stringency to demonstrate limited regions of base pair homology. Two such regions were identified: the first occurs at the extreme 5' end of the leukemia and both sarcoma viral genomes, whereas the second corresponds to a 5' segment of leukemia virus "env" sequences conserved in both sarcoma viruses. The latter sequences are localized at the 3' end of FeSV src and at the 5' end of murine sarcoma virus src and could possibly correspond to regions of helper virus genomes that are required for retroviral transforming functions.


Caveolin-1 single-nucleotide polymorphism and arterial stiffness in non-dialysis chronic kidney disease.
Arteriosclerosis is an independent predictor of increased cardiovascular mortality in chronic kidney disease (CKD). Histologically it is characterized by hypertrophy and fibrosis of the arterial media wall leading to increased arterial stiffness and end-organ damage. Caveolin-1 acts as an intracellular signalling pathway chaperone in human fibrotic and vascular diseases. The purpose of this study was to assess the association between caveolin-1 (CAV1) single-nucleotide polymorphism (SNP) rs4730751 and arterial stiffness as measured by arterial pulse wave velocity (PWV) in an early-stage CKD cohort and in a cohort with more severe CKD. Two prospectively maintained patient cohorts with non-dialysis CKD were studied: 144 patients in the Chronic Renal Impairment in Birmingham (CRIB) cohort and 147 patients in the Renal Impairment in Secondary Care (RIISC) cohort, with matched exclusion criteria and DNA sampling availability. At entry to each cohort database, each patient's initial arterial PWV was measured, as well as their anthropomorphic and biochemical data. CAV1 rs4730751 SNP genotyping was performed using Taqman technology. The CAV1 rs4730751 SNP CC genotype was associated with lower arterial PWV in both CRIB early stage CKD patients [8.1 versus 8.6 m/s; coefficient -0.780 (-1.412, -0.149); P = 0.016] and RIISC more advanced stage CKD patients [8.7 versus 9.4 m/s; coefficient -0.695 (-1.288, -0.102); P = 0.022]; these relationships held following adjustment for other important confounders. This replicated study suggests potential utility of the studied CAV1 SNP as a genetic biomarker in CKD and a role for CAV1 in the development of arteriosclerosis in this setting. Further studies are warranted to further explore the basic science driving these clinical observations.


Graphlet-based edge clustering reveals pathogen-interacting proteins.
Prediction of protein function from protein interaction networks has received attention in the post-genomic era. A popular strategy has been to cluster the network into functionally coherent groups of proteins and assign the entire cluster with a function based on functions of its annotated members. Traditionally, network research has focused on clustering of nodes. However, clustering of edges may be preferred: nodes belong to multiple functional groups, but clustering of nodes typically cannot capture the group overlap, while clustering of edges can. Clustering of adjacent edges that share many neighbors was proposed recently, outperforming different node clustering methods. However, since some biological processes can have characteristic 'signatures' throughout the network, not just locally, it may be of interest to consider edges that are not necessarily adjacent. We design a sensitive measure of the 'topological similarity' of edges that can deal with edges that are not necessarily adjacent. We cluster edges that are similar according to our measure in different baker's yeast protein interaction networks, outperforming existing node and edge clustering approaches. We apply our approach to the human network to predict new pathogen-interacting proteins. This is important, since these proteins represent drug target candidates. Software executables are freely available upon request. email@example.com Supplementary data are available at Bioinformatics online.


Shared decision making and the concept of equipoise: the competences of involving patients in healthcare choices.
Involving patients in healthcare decisions makes a potentially significant and enduring difference to healthcare outcomes. One difficulty (among many) is that the 'involvement' of patients in decisions has been left undefined. It is usually conceptualised as 'patient centredness', which is a broad and variably interpreted concept that is difficult to assess using current tools. This paper attempts to gauge general practitioners' (GPs') attitudes to patient involvement in decision making and their views about the contextual factors, competences, and stages required to achieve shared decisions within consultations. To explore and understand what constitutes the appropriate involvement of patients in decision making within consultations, to consider previous theory in this field, and to propose a set of competences (skills) and steps that would enable clinical practitioners (generalists) to undertake 'shared decision making' in their clinical environment. Qualitative study using focus group interviews of key informants. Experienced GPs with educational roles have positive attitudes to the involvement of patients in decisions, provided the process matches the role individuals wish to play. They perceive some clinical problems as being more suited to a cooperative approach to decision making and conceptualised the existence of professional equipoise towards the existence of legitimate treatment options as an important facilitative factor. A sequence of skills was proposed as follows: 1) implicit or explicit involvement of patients in the decision-making process; 2) explore ideas, fears, and expectations of the problem and possible treatments; 3) portrayal of equipoise and options; 4) identify preferred data format and provide tailor-made information; 5) checking process: understanding of information and reactions (e.g. ideas, fears, and expectations of possible options); 6) acceptance of process and decision making role preference; 7) make, discuss or defer decisions; 8) arrange follow-up. These clinicians viewed involvement as an implicit ethos that should permeate medical practice, provided that clinicians respect and remain alert to patients' individual preferred roles in decision making. The interpersonal skills and the information requirements needed to successfully share decisions are major challenges to the clinical consultation process in medical practice. The benefits of patient involvement and the skills required to achieve this approach need to be given much higher priority at all levels: at policy, education, and within further professional development strategies.


Cell rearrangement and segmentation in Xenopus: direct observation of cultured explants.
We make use of a novel system of explant culture and high resolution video-film recording to analyse for the first time the cell behaviour underlying convergent extension and segmentation in the somitic mesoderm of Xenopus. We find that a sequence of activities sweeps through the somitic mesoderm from anterior to posterior during gastrulation and neurulation, beginning with radial cell intercalation or thinning, continuing with mediolateral intercalation and cell elongation, and culminating in segmentation and somite rotation. Radial intercalation at the posterior tip lengthens the tissue, while mediolateral intercalation farther anterior converges it toward the midline. This extension of the somitic mesoderm helps to elongate the dorsal side of intact neurulae. By separating tissues, we demonstrate that cell rearrangement is independent of the notochord, but radial intercalation - and thus the bulk of extension - requires the presence of an epithelium, either endodermal or ectodermal. Segmentation, on the other hand, can proceed in somitic mesoderm isolated at the end of gastrulation. Finally, we discuss the relationship between cell rearrangement and segmentation.


Optical-fiber-attenuation investigation using stimulated Brillouin scattering between a pulse and a continuous wave.
A new technique for measuring optical-fiber-attenuation characteristics is described. The technique uses stimulated Brillouin scattering in the fiber between a counterpropagating pulsed pump wave and a cw Stokes probe wave. Fiber attenuation is estimated nondestructively from amplification of the probe wave through stimulated Brillouin scattering. Experiments with a 5.2-km-long single-mode fiber reveal that the output signal is approximately 100 times that of the Rayleigh backscattered signal observed in conventional optical time-domain reflectometry. The signal fluctuation due to polarization-dependent Brillouin gain is successfully removed by polarization averaging.


Anticipated Notification of Sexual Partners following STD Diagnosis among Men Who Have Sex with Men and Transgender Women in Lima, Peru: A Mixed Methods Analysis.
New strategies to support partner notification (PN) are critical for STD control and require detailed understanding of how specific individual and partnership characteristics guide notification decisions. From 2011 to 2012, 397 MSM and TW recently diagnosed with HIV, syphilis, or another STD completed a survey on anticipated notification of recent sexual partners and associated factors. Qualitative interviews were conducted with a subset of participants to provide further depth to quantitative findings. Prevalence ratios and generalized estimating equation (GEE) models were used to analyze participant- and partner-level factors associated with anticipated PN. Among all partners reported, 52.5% were described as "Very Likely" or "Somewhat Likely" to be notified. Anticipated notification was more likely for main partners than casual (adjusted Prevalence Ratio [aPR], 95% CI: 0.63, 0.54-0.75) or commercial (aPR, 95% CI: 0.44, 0.31-0.62) partners. Other factors associated with likely notification included perception of the partner as an STD source (aPR, 95% CI: 1.27, 1.10-1.48) and anticipated future sexual contact with the partner (aPR, 95% CI: 1.30, 1.11-1.52). An HIV diagnosis was associated with a lower likelihood of notification than non-HIV STDs (aPR: 0.68, 0.55-0.86). Qualitative discussion of the barriers and incentives to PN reflected a similar differentiation of anticipated notification according to partnership type and type of HIV/STD diagnosis. Detailed attention to how partnership characteristics guide notification outcomes is essential to the development of new PN strategies. By accurately and thoroughly assessing the diversity of partnership interactions among individuals with HIV/STD, new notification techniques can be tailored to partner-specific circumstances.


Large-scale transcriptome analysis in chickpea (Cicer arietinum L.), an orphan legume crop of the semi-arid tropics of Asia and Africa.
Chickpea (Cicer arietinum L.) is an important legume crop in the semi-arid regions of Asia and Africa. Gains in crop productivity have been low however, particularly because of biotic and abiotic stresses. To help enhance crop productivity using molecular breeding techniques, next generation sequencing technologies such as Roche/454 and Illumina/Solexa were used to determine the sequence of most gene transcripts and to identify drought-responsive genes and gene-based molecular markers. A total of 103,215 tentative unique sequences (TUSs) have been produced from 435,018 Roche/454 reads and 21,491 Sanger expressed sequence tags (ESTs). Putative functions were determined for 49,437 (47.8%) of the TUSs, and gene ontology assignments were determined for 20,634 (41.7%) of the TUSs. Comparison of the chickpea TUSs with the Medicago truncatula genome assembly (Mt 3.5.1 build) resulted in 42,141 aligned TUSs with putative gene structures (including 39,281 predicted intron/splice junctions). Alignment of ∼37 million Illumina/Solexa tags generated from drought-challenged root tissues of two chickpea genotypes against the TUSs identified 44,639 differentially expressed TUSs. The TUSs were also used to identify a diverse set of markers, including 728 simple sequence repeats (SSRs), 495 single nucleotide polymorphisms (SNPs), 387 conserved orthologous sequence (COS) markers, and 2088 intron-spanning region (ISR) markers. This resource will be useful for basic and applied research for genome analysis and crop improvement in chickpea.


A brief history of the global effort to develop a preventive HIV vaccine.
Soon after HIV was discovered as the cause of AIDS in 1983-1984, there was an expectation that a preventive vaccine would be rapidly developed. In trying to achieve that goal, three successive scientific paradigms have been explored: induction of neutralizing antibodies, induction of cell mediated immunity, and exploration of combination approaches and novel concepts. Although major progress has been made in understanding the scientific basis for HIV vaccine development, efficacy trials have been critical in moving the field forward. In 2009, the field was reinvigorated with the modest results obtained from the RV144 trial conducted in Thailand. Here, we review those vaccine development efforts, with an emphasis on events that occurred during the earlier years. The goal is to provide younger generations of scientists with information and inspiration to continue the search for an HIV vaccine.


Terminal care at home: perspective from general practice.
A survey of general practitioners in north west London was undertaken by questionnaire to elicit information about problems that they had had in looking after patients at home who were terminally ill and about their perceived needs for both training and support services. The response rate was 73% (196 of 268 doctors). Thirty two per cent of respondents frequently or always had problems in controlling pain in such patients, and 45% frequently or always had difficulties in coping with the emotional distress of patients or relatives, or both. Between 20 and 30% of respondents often had problems with inadequate support services, poor communication with support services and hospital specialists, and difficulty in admitting patients who were terminally ill. Roughly half of the respondents thought that more training in managing pain and other symptoms that are associated with terminal illness would be of great help, and a similar response was noted for bereavement counselling. About 40% of respondents indicated that training in communicating with dying patients would be a great help in improving care and three quarters that more home nursing support was necessary.


Neuropsychological profile of executive function in girls with attention-deficit/hyperactivity disorder.
The majority of research on neurobehavioral functioning among children with Attention-Deficit/Hyperactivity Disorder (ADHD) is based on samples comprised primarily (or exclusively) of boys. Although functional impairment is well established, available research has yet to specify a neuropsychological profile distinct to girls with ADHD. The purpose of this study was to examine performance within four components of executive function (EF) in contemporaneously recruited samples of girls and boys with ADHD. Fifty-six children with ADHD (26 girls) and 90 controls (42 girls), ages 8-13, were administered neuropsychological tests emphasizing response inhibition, response preparation, working memory, and planning/shifting. There were no significant differences in age or SES between boys or girls with ADHD or their sex-matched controls; ADHD subtype distribution did not differ by sex. Compared with controls, children with ADHD showed significant deficits on all four EF components. Girls and boys with ADHD showed similar patterns of deficit on tasks involving response preparation and working memory; however, they manifested different patterns of executive dysfunction on tasks related to response inhibition and planning. Girls with ADHD showed elevated motor overflow, while boys with ADHD showed greater impairment during conscious, effortful response inhibition. Girls, but not boys with ADHD, showed impairment in planning. There were no differences between ADHD subtypes on any EF component. These findings highlight the importance of studying boys and girls separately (as well as together) when considering manifestations of executive dysfunction in ADHD.


Wavefront control in adaptive microscopy using Shack-Hartmann sensors with arbitrarily shaped pupils.
In adaptive optical microscopy of thick biological tissue, strong scattering and aberrations can change the effective pupil shape by rendering some Shack-Hartmann spots unusable. The change of pupil shape leads to a change of wavefront reconstruction or control matrix that should be updated accordingly. Modified slope and modal wavefront control methods based on measurements of a Shack-Hartmann wavefront sensor are proposed to accommodate an arbitrarily shaped pupil. Furthermore, we present partial wavefront control methods that remove specific aberration modes like tip, tilt and defocus from the control loop. The proposed control methods were investigated and compared by simulation using experimentally obtained aberration data. The performance was then tested experimentally through closed-loop aberration corrections using an obscured pupil.


HMO family physicians: men and women differ in their work.
The goal was to identify differences in the type of work and amount of work performed by male and female family HMO physicians. Data were collected by self-administered physician surveys, retrospective analysis of encounter forms, ambulatory care group (ACG) analysis of physicians' patient panels, and participant observation. A large HMO-based clinical facility. PARTICIPANTS. Family practitioners (n = 21) at one HMO clinic. Measures included patient encounters/day, self-assessed and encounter-form-based workload, ambulatory care group panel evaluation and qualitative observation of practice patterns and team functioning. These data show that the kind of work male and female physicians did at this site differed, when compared on the basis of encounter-form-based diagnoses, ambulatory care group panel assessments and participant observation. However, the amount of work performed by each gender did not appear to different when evaluated by age-sex-adjusted panel size, patient encounters per unit time, a subjective magnitude estimation workload questionnaire and an encounter-form-based workload assessment. In this study, multiple measures for evaluating physician workload revealed distinct differences in the kind of clinical work performed by male and female HMO family physicians. These findings have implications for clinicians, managers, planners, researchers and educators.


The ubiquitin-specific protease USP8 is critical for the development and homeostasis of T cells.
The modification of proteins by ubiquitin has a major role in cells of the immune system and is counteracted by various deubiquitinating enzymes (DUBs) with poorly defined functions. Here we identified the ubiquitin-specific protease USP8 as a regulatory component of the T cell antigen receptor (TCR) signalosome that interacted with the adaptor Gads and the regulatory molecule 14-3-3β. Caspase-dependent processing of USP8 occurred after stimulation of the TCR. T cell-specific deletion of USP8 in mice revealed that USP8 was essential for thymocyte maturation and upregulation of the gene encoding the cytokine receptor IL-7Rα mediated by the transcription factor Foxo1. Mice with T cell-specific USP8 deficiency developed colitis that was promoted by disturbed T cell homeostasis, a predominance of CD8(+) γδ T cells in the intestine and impaired regulatory T cell function. Collectively, our data reveal an unexpected role for USP8 as an immunomodulatory DUB in T cells.


Ultrafast energy transfer in oligofluorene-aluminum bis(8-hydroxyquinoline)acetylacetone coordination polymers.
Understanding the excited-state dynamics in conjugated systems can lead to their better utilization in optical sensors, organic photovoltaics (OPVs), and organic light-emitting diodes (OLEDs). We present the synthesis of self-assembled coordination polymers comprising two types of fluorescent moieties: discrete fluorene oligomers of a well-defined length (n = 1-9) connected via aluminum(III) bis(8-quinolinolate)acetylacetone joints. Due to their well-defined structure, these materials allowed for a detailed study of energy migration processes within the materials. Thus, femtosecond transient spectroscopy was used to study the ultrafast energy transfer from the oligofluorene to the quinolinolate moieties, which was found to proceed at a rate of 10(11) s(-1). The experimental results were found to be in agreement with the behavior predicted according to the Beljonne's improved Forster model of energy transfer. In addition, the solid-state and semiconductor properties of these coordination polymers allowed for the fabrication of OLEDs. Preliminary experiments with simple two- and three-layer devices fabricated by spin-coating yield bright yellow electroluminescence with maximum brightness of 6000 cd/m(2), with a turn-on voltage of approximately 6 V and a maximum external quantum efficiency of up to 1.2%, suggesting their potential for use in PLED applications.


Statistical resolution of ambiguous HLA typing data.
High-resolution HLA typing plays a central role in many areas of immunology, such as in identifying immunogenetic risk factors for disease, in studying how the genomes of pathogens evolve in response to immune selection pressures, and also in vaccine design, where identification of HLA-restricted epitopes may be used to guide the selection of vaccine immunogens. Perhaps one of the most immediate applications is in direct medical decisions concerning the matching of stem cell transplant donors to unrelated recipients. However, high-resolution HLA typing is frequently unavailable due to its high cost or the inability to re-type historical data. In this paper, we introduce and evaluate a method for statistical, in silico refinement of ambiguous and/or low-resolution HLA data. Our method, which requires an independent, high-resolution training data set drawn from the same population as the data to be refined, uses linkage disequilibrium in HLA haplotypes as well as four-digit allele frequency data to probabilistically refine HLA typings. Central to our approach is the use of haplotype inference. We introduce new methodology to this area, improving upon the Expectation-Maximization (EM)-based approaches currently used within the HLA community. Our improvements are achieved by using a parsimonious parameterization for haplotype distributions and by smoothing the maximum likelihood (ML) solution. These improvements make it possible to scale the refinement to a larger number of alleles and loci in a more computationally efficient and stable manner. We also show how to augment our method in order to incorporate ethnicity information (as HLA allele distributions vary widely according to race/ethnicity as well as geographic area), and demonstrate the potential utility of this experimentally. A tool based on our approach is freely available for research purposes at http://microsoft.com/science.


More Severe Insomnia Complaints in People with Stronger Long-Range Temporal Correlations in Wake Resting-State EEG.
The complaints of people suffering from Insomnia Disorder (ID) concern both sleep and daytime functioning. However, little is known about wake brain temporal dynamics in people with ID. We therefore assessed possible alterations in Long-Range Temporal Correlations (LRTC) in the amplitude fluctuations of band-filtered oscillations in electroencephalography (EEG) recordings. We investigated whether LRTC differ between cases with ID and matched controls. Within both groups, we moreover investigated whether individual differences in subjective insomnia complaints are associated with LRTC. Resting-state high-density EEG (256-channel) was recorded in 52 participants with ID and 43 age- and sex-matched controls, during Eyes Open (EO) and Eyes Closed (EC). Detrended fluctuation analysis was applied to the amplitude envelope of band-filtered EEG oscillations (theta, alpha, sigma, beta-1, beta-2) to obtain the Hurst exponents (H), as measures of LRTC. Participants rated their subjective insomnia complaints using the Insomnia Severity Index (ISI). Through general linear models, we evaluated whether H, aggregated across electrodes and frequencies, differed between cases and controls, or showed within-group associations with individual differences in ISI. Additionally, we characterized the spatio-spectral profiles of group differences and associations using non-parametric statistics. H did not differ between cases with ID and controls in any of the frequency bands, neither during EO nor EC. During EO, however, within-group associations between H and ISI indicated that individuals who experienced worse sleep quality had stronger LRTC. Spatio-spectral profiles indicated that the associations held most prominently for the amplitude fluctuations of parietal theta oscillations within the ID group, and of centro-frontal beta-1 oscillations in controls. While people suffering from insomnia experience substantially worse sleep quality than controls, their brain dynamics express similar strength of LRTC. In each group, however, individuals experiencing worse sleep quality tend to have stronger LRTC during eyes open wakefulness, in a spatio-spectral range specific for each group. Taken together, the findings indicate that subjective insomnia complaints involve distinct dynamical processes in people with ID and controls. The findings are in agreement with recent reports on decreasing LRTC with sleep depth, and with the hypothesis that sleep balances brain excitability.


Effects of long-term treatment with resveratrol and subcutaneous and oral estradiol administration on the pituitary-thyroid-axis.
The lack of estrogen during menopause is associated with various symptoms including osteoporosis, cardiovascular diseases, and menopausal symptoms. For many years, conventional hormone replacement therapy has been successfully used to treat these conditions. However, in light of recent studies that draw attention to potential hazards of conventional HRT, various attempts were undertaken to search for alternatives of classical HRT. Phytoestrogens are supposed to ameliorate various discomforts associated with menopause. Resveratrol (RES) is present in red wine, grapes and peanuts and has been implicated in cardioprotection and prevention of adverse side effects observed after regular HRT. As the pituitary-thyroid axis is a target of estrogen action, we first assessed the effects of E2 administration on thyroid hormone stimulating hormone releasing hormone (TRH)-induced thyroid stimulating hormone (TSH) secretion from pituitary cell cultures in vitro. Our data reveal that E2 treatment augments the TRH-induced TSH secretion. We furthermore designed a long-term study of three months to assess the effects of subcutaneous and oral administration of 17beta-estradiol (E2), as well as the actions of RES on the pituitary-thyroid axis in ovariectomized (OVX) female rats. Our results demonstrate that serum levels of 1.0 and 8.1 microM RES lead to a significant increase in total serum triiodthyronine (T3) levels. OVX induces TSHbeta mRNA in the adenohypohysis and E2 treatment attenuates this effect. Treatment of rats with subcutaneous implants of E2 does not affect the pituitary-thyroid axis, whereas orally applied E2 benzoate (E2B) increases plasma TSH and total thyroxine (T4) in OVX rats. In all animals, we could not detect changes in thyroid morphology as assessed by hematoxylin-eosin (HE) and Perjod-Acid Schiff's (PAS) staining.


Food insecure families: description of access and barriers to food from one pediatric primary care center.
Despite evidence that food insecurity negatively impacts child health, health care providers play little role in addressing the issue. To inform potential primary care interventions, we sought to assess a range of challenges faced by food insecure (FI) families coming to an urban, pediatric primary care setting. A cross-sectional study was performed at a hospital-based, urban, academic pediatric primary care clinic that serves as a medical home for approximately 15,000 patients with 35,000 annual visits. Subjects included a convenience sample of caregivers of children presenting for either well child or ill care over a 4 months period in 2012. A self-administered survey assessed household food security status, shopping habits, transportation access, budgeting priorities, and perceptions about nutrition access in one's community. Bivariate analyses between food security status and these characteristics were performed using Chi square statistics or Fisher's exact test. The survey was completed by 199 caregivers. Approximately 33% of families were FI; 93% received food-related governmental assistance. FI families were more likely to obtain food from a corner/convenience store, utilize food banks, require transportation other than a household car, and prioritize paying bills before purchasing food. FI families perceived less access to healthy, affordable foods within their community. Thus, FI families may face unique barriers to accessing food. Knowledge of these barriers could allow clinicians to tailor in-clinic screening and create family-centered interventions.


The combination of intravitreal triamcinolone and phacoemulsification surgery in patients with diabeticfoveal oedema and cataract.
The management of diabetic patients with refractory macular oedema or patients with no adequate pre-operative view to administer laser treatment provide a challenge to the ophthalmologist. We wished to assess the use, safety and effect of intravitreal triamcinolone injection at the time of cataract surgery in patients with diabetic foveal oedema and sight limiting lens opacities. This was a longitudinal non-randomised prospective pilot study in 18 eyes (12 patients). All patients had visually significant lens opacities and either persistent diabetic foveal oedema unresponsive to laser treatment-group A, or foveal oedema with no adequate pre-operative view for laser treatment- group B. The cataract surgery was carried out under full aseptic technique using a self-sealing temporal incision and a foldable acrylic lens. Intravitreal triamcinolone was given infratemporally pars plana at the completion of the cataract surgery. The patients were reviewed at day 5, 2 weeks, 2 months and then every 3 months as required. The Wilcoxin matched-pairs test was used to assess the significance of the improvement in visual acuity at 2 months. Twelve patients with a total of 18 eyes were included in the study. There were 10 patients (15 eyes) in group A and 3 patients (3 eyes) in group B. Preoperatively 16 of the 18 eyes had a visual acuity of 6/24 or worse. Postoperatively 83% of patients had completely dry foveae at 2 weeks. Best-corrected visual acuities at two months review ranged from 6/6 to CF with 9 eyes (50%) achieving 6/12 or better (7 eyes (47%) in group A and 2 eyes (67%) in group B). Three eyes had no recorded improvement in visual acuity, but no eyes had deterioration in acuity. The improvement in visual acuity was significant at p = 0.001. There were no significant sight threatening complications. Intravitreal triamcinolone has been shown to lead to an improvement in macular oedema and visual improvement in diabetic patients not undergoing cataract surgery but has not, to our knowledge, been previously used in a study like this one.We suggest that intravitreal injection at the time of cataract surgery could be carried out safely with encouraging visual outcomes in patients with diabetic foveal oedema and cataract.


Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis.
We present a genome-wide association study of ileal Crohn disease and two independent replication studies that identify several new regions of association to Crohn disease. Specifically, in addition to the previously established CARD15 and IL23R associations, we identified strong and significantly replicated associations (combined P < 10(-10)) with an intergenic region on 10q21.1 and a coding variant in ATG16L1, the latter of which was also recently reported by another group. We also report strong associations with independent replication to variation in the genomic regions encoding PHOX2B, NCF4 and a predicted gene on 16q24.1 (FAM92B). Finally, we demonstrate that ATG16L1 is expressed in intestinal epithelial cell lines and that functional knockdown of this gene abrogates autophagy of Salmonella typhimurium. Together, these findings suggest that autophagy and host cell responses to intracellular microbes are involved in the pathogenesis of Crohn disease.


Measurement of the [Formula: see text] dijet cross section in pp collisions at [Formula: see text] TeV with the ATLAS detector.
The dijet production cross section for jets containing a b-hadron (b-jets) has been measured in proton-proton collisions with a centre-of-mass energy of [Formula: see text] TeV, using the ATLAS detector at the LHC. The data used correspond to an integrated luminosity of [Formula: see text]. The cross section is measured for events with two identified b-jets with a transverse momentum [Formula: see text] GeV and a minimum separation in the [Formula: see text]-[Formula: see text] plane of [Formula: see text]. At least one of the jets in the event is required to have [Formula: see text] GeV. The cross section is measured differentially as a function of dijet invariant mass, dijet transverse momentum, boost of the dijet system, and the rapidity difference, azimuthal angle and angular distance between the b-jets. The results are compared to different predictions of leading order and next-to-leading order perturbative quantum chromodynamics matrix elements supplemented with models for parton-showers and hadronization.


Psychological Functioning Among Latino Victims of Teen Dating Violence: The Role of Relational and Collective Resources.
This study examined whether the relationship between teen dating violence (DV) and psychological functioning (depression, anxiety, and hostility) varied as a function of relational and collective resources (social support, familism, and school connectedness) among Latino teen victims of DV. Data came from a subset of youth who experienced DV (n = 95) from the Dating Violence Among Latinos Adolescents Study, a national survey of Latino teens aged 12-18 years old. Multivariate regression models showed that school connectedness was associated with lower depression and anxiety for DV victims. Additionally, five interactions were significant across depression, anxiety, and hostility: Three following a pattern of protective-enhancing (DV × School connectedness for depression and anxiety; DV × Social support for anxiety) and two following a pattern of vulnerability-reactive (DV × Familism for anxiety and hostility). School connectedness is an important protective factor for Latino teen victims of DV and one that can inform intervention efforts. Latino victims of DV benefit from high levels of school connectedness and social support, especially when DV is high. At high levels of DV familism is associated with a worsening of mental health. It is important to understand the nuances of how these resources work at varying levels of DV for intervention and prevention purposes.


Clinical and preclinical treatment of urologic diseases with phosphodiesterase isoenzymes 5 inhibitors: an update.
Phosphodiesterase isoenzymes 5 inhibitors (PDE5-Is) are the first-line therapy for erectile dysfunction (ED). The constant discoveries of nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) cell-signaling pathway for smooth muscle (SM) control in other urogenital tracts (UGTs) make PDE5-Is promising pharmacologic agents against other benign urological diseases. This article reviews the literature and contains some previously unpublished data about characterizations and activities of PDE5 and its inhibitors in treating urological disorders. Scientific discoveries have improved our understanding of cell-signaling pathway in NO/cGMP-mediated SM relaxation in UGTs. Moreover, the clinical applications of PDE5-Is have been widely recognized. On-demand PDE5-Is are efficacious for most cases of ED, while daily-dosing and combination with testosterone are recommended for refractory cases. Soluble guanylate cyclase (sGC) stimulators also have promising role in the management of severe ED conditions. PDE5-Is are also the first rehabilitation strategy for postoperation or postradiotherapy ED for prostate cancer patients. PDE5-Is, especially combined with α-adrenoceptor antagonists, are very effective for benign prostatic hyperplasia (BPH) except on maximum urinary flow rate (Q max ) with tadalafil recently proved for BPH with/without ED. Furthermore, PDE5-Is are currently under various phases of clinical or preclinical researches with promising potential for other urinary and genital illnesses, such as priapism, premature ejaculation, urinary tract calculi, overactive bladder, Peyronie's disease, and female sexual dysfunction. Inhibition of PDE5 is expected to be an effective strategy in treating benign urological diseases. However, further clinical studies and basic researches investigating mechanisms of PDE5-Is in disorders of UGTs are required.


Effects of subchronic exposure to a 1439 MHz electromagnetic field on the microcirculatory parameters in rat brain.
THE AIM of this study was to investigate whether repeated exposure to radio frequency electromagnetic field (RF-EMF) of 1439 MHz affects the cerebral microcirculation, including blood-brain barrier function, in a rat brain. The head of the rat was exposed for four weeks (60 min/day, 5 days/week) to RF-EMF at 2.4 W/kg of brain averaged specific absorption rate (BASAR). Three microcirculatory parameters: blood-brain barrier permeability, leukocyte behavior and plasma velocity were measured before and after RF-EMF exposure using a closed cranial window method. No extravasation of intravenously injected dyes from pial venules was found at any BASAR level. No significant changes in the number of endothelial-adhering leukocytes after exposure were found. The plasma velocity remained constant within the physiological range through each exposure. These findings suggest that there were no effects on the cerebral microcirculation under the given RF-EMF exposure conditions.


Golgi cell dendrites are restricted by Purkinje cell stripe boundaries in the adult mouse cerebellar cortex.
Despite the general uniformity in cellular composition of the adult cerebellar cortex, there is a complex underlying pattern of parasagittal stripes of Purkinje cells with characteristic molecular phenotypes and patterns of connectivity. It is not known whether interneuron processes are restricted at stripe boundaries. To begin to address the issue, three strategies were used to explore how cerebellar Golgi cell dendrites are organized with respect to parasagittal stripes: first, double immunofluorescence staining combining anti-neurogranin to identify Golgi cell dendrites with the Purkinje cell compartmentation antigens zebrin II/aldolase C, HNK-1, and phospholipase Cbeta4; second, zebrin II immunohistochemistry combined with a rapid Golgi-Cox impregnation procedure to reveal Golgi cell dendritic arbors; third, stripe antigen expression was used on sections of a GlyT2-EGFP transgenic mouse in which reporter expression is prominent in Golgi cell dendrites. In each case, the dendritic projections of Golgi cells were studied in the vicinity of Purkinje cell stripe boundaries. The data presented here show that the dendrites of a cerebellar interneuron, the Golgi cell, respect the fundamental cerebellar stripe cytoarchitecture.


Comparative analysis of methods for detection of anti-laminin 5 autoantibodies in patients with anti-epiligrin cicatricial pemphigoid.
Anti-epiligrin cicatricial pemphigoid (AECP) is a subepidermal blistering disease characterized by circulating anti-basement membrane autoantibodies to laminin 5. To evaluate the relative sensitivity of immunoblotting and immunoprecipitation techniques for the detection of anti-laminin 5 antibodies, comparative studies using reference laminin 5 antiserum as well as sera from patients with AECP, other immunobullous diseases, and normal volunteers were performed. Equivalent amounts of protein from five different substrates were studied by immunoblotting; immunoprecipitation experiments examined biosynthetically radiolabeled human keratinocyte (HK) extracts. Results HK extracellular matrix (ECM) was the most sensitive substrate for detection of antibodies to laminin 5; extracts of HKs, A-431 cells and HaCat cells represented alternative test substrates (though the later required higher amounts of protein input). Sera from patients with AECP immunoblotted laminin 5 in HK ECM at end titers exceeding those identified in indirect immunofluorescence microscopy studies of 1 M NaCl split skin. Immunoprecipitation studies found that a 10,000-fold dilution of reference laminin 5 antiserum retained the ability to identify laminin 5. Maximal dilutions of sera from AECP patients retaining the ability to immunoprecipitate laminin 5 ranged from 500 to 5,000. Immunoprecipitation was the most sensitive technique for detection of anti-laminin 5 antibodies, while immunoblotting of HK ECM or HK extracts represented practical alternatives.


Efficacy of an orally administered combination of hyaluronic acid, chondroitin sulfate, curcumin and quercetin for the prevention of recurrent urinary tract infections in postmenopausal women.
To assess whether the orally administered combination of hyaluronic acid (HA), chondroitin sulfate (CS), curcumin and quercetin could be effective in preventing recurrent cystitis in postmenopausal women and whether its efficacy was conditioned by the concurrent use of local estrogen therapy. This was a prospective evaluation of 145 postmenopausal women consecutively recruited from the database of three different investigators. All women should have mild-to-moderate urogenital atrophy and a history of recurrent urinary tract infections (≥2 episodes within 6 months or ≥3 episodes within 12 months documented by positive urine cultures) during the last year. Patients were assigned to three different therapeutic regimens: the first group was treated only with vaginal estrogens, the second group only with HA, CS, curcumin and quercetin per os, and the third group was treated with HA, CS, curcumin and quercetin associated with local estrogens. We evaluated the number of patients with <2 infective episodes in the 6-month follow-up and <3 episodes in the 12-month follow-up (main aim definition) and the reduction of related symptoms through a Visual Analog Scale (VAS) and the Pelvic Pain and Urgency/Frequency (PUF) patient symptom scale. Student's t-test and chi-squared test were used for data analysis as appropriate. At 6-month follow up, the main aim rate was 8%, 11.1% and 25% in the three groups, respectively (p<0.05 compared to baseline only in group 3). Although the reduction in the number of recurrent episodes became significant in all groups at 1 year follow-up, the main aim rate was almost double in women receiving both local estrogens and oral therapy (group 3) compared to those receiving single treatments. The improvement of related symptoms was significant in all groups at 12-month follow-up. In postmenopausal women, the combination of HA, CS, curcumin and quercetin per os was effective in preventing recurrent urinary tract infections, especially if administered with vaginal estrogen therapy.


Comparing neural response telemetry amplitude growth functions with loudness growth functions: preliminary results.
Comparisons of the subjective loudness growth function and the objective evoked compound action potential (ECAP) amplitude growth function indicate that both functions are exponential in nature. This implies that a more accurate estimate of the ECAP threshold would be obtained using exponential regression of the amplitude growth function instead of the currently used linear regression. The perceptual threshold and the ECAP threshold seem to approach each other when the stimulation rate is lowered to reduce temporal summation effects. The effect of the stimulation rate on the perceptual threshold will have to be taken into account when trying to use the ECAP threshold for predicting the perceptual threshold.


CpGcluster: a distance-based algorithm for CpG-island detection.
Despite their involvement in the regulation of gene expression and their importance as genomic markers for promoter prediction, no objective standard exists for defining CpG islands (CGIs), since all current approaches rely on a large parameter space formed by the thresholds of length, CpG fraction and G+C content. Given the higher frequency of CpG dinucleotides at CGIs, as compared to bulk DNA, the distance distributions between neighboring CpGs should differ for bulk and island CpGs. A new algorithm (CpGcluster) is presented, based on the physical distance between neighboring CpGs on the chromosome and able to predict directly clusters of CpGs, while not depending on the subjective criteria mentioned above. By assigning a p-value to each of these clusters, the most statistically significant ones can be predicted as CGIs. CpGcluster was benchmarked against five other CGI finders by using a test sequence set assembled from an experimental CGI library. CpGcluster reached the highest overall accuracy values, while showing the lowest rate of false-positive predictions. Since a minimum-length threshold is not required, CpGcluster can find short but fully functional CGIs usually missed by other algorithms. The CGIs predicted by CpGcluster present the lowest degree of overlap with Alu retrotransposons and, simultaneously, the highest overlap with vertebrate Phylogenetic Conserved Elements (PhastCons). CpGcluster's CGIs overlapping with the Transcription Start Site (TSS) show the highest statistical significance, as compared to the islands in other genome locations, thus qualifying CpGcluster as a valuable tool in discriminating functional CGIs from the remaining islands in the bulk genome. CpGcluster uses only integer arithmetic, thus being a fast and computationally efficient algorithm able to predict statistically significant clusters of CpG dinucleotides. Another outstanding feature is that all predicted CGIs start and end with a CpG dinucleotide, which should be appropriate for a genomic feature whose functionality is based precisely on CpG dinucleotides. The only search parameter in CpGcluster is the distance between two consecutive CpGs, in contrast to previous algorithms. Therefore, none of the main statistical properties of CpG islands (neither G+C content, CpG fraction nor length threshold) are needed as search parameters, which may lead to the high specificity and low overlap with spurious Alu elements observed for CpGcluster predictions.


Therapeutic effect of N-acetylcysteine on chemotherapy-induced liver injury.
N-acetylcysteine (NAC) may be useful in the management of chemotherapy-induced liver injury. The present study evaluates the possible therapeutic effects of NAC on chemotherapy-induced hepatotoxicity. A total of 102 patients' files who were diagnosed with cancer between 2015 and 2019 were evaluated retrospectively. Two patient groups with and without NAC were selected. NAC was administered in a 3-μg/kg IV dose in a 24-h infusion to 70 patients when any alanine aminotransferase (ALT) or gamma-glutamyl transferase (GGT) values reached three times the normal levels. The other group consisted of 32 patients who were not treated with NAC. Alanine aminotransferase and GGT values were recorded at pretreatment, and on the 1st, 3rd, 5th, and 7th days in both the NAC and non-NAC groups from files. In the NAC group, ALT and GGT values on day 1, 3, 5, and 7 differed from each other, decreasing from day 1 to day 7. A statistically significant difference was noted between the values in the NAC group (p < 0.001). In the non-NAC group, the ALT values on day 7 were lower than the ALT values on day 1. A comparison of the ALT and GGT values in the NAC and non-NAC groups found that the values in the NAC group decreased earlier than in the non-NAC group. This study shows that NAC has a therapeutic effect on hepatotoxicity in children being treated with chemotherapeutic agents due to underlying malign diseases. The early reduction in the results of liver function tests is important for the continuation of chemotherapy.


Using postal questionnaires to evaluate physical activity and diet behaviour change: case study exploring implications of valid responder characteristics in interpreting intervention outcomes.
Patient reported outcome measures (PROMs) are used to evaluate lifestyle interventions but little is known about differences between patients returning valid and invalid responses, or of potential for bias in evaluations. We aimed to examine the characteristics of patients who returned valid responses to lifestyle questionnaires compared to those whose responses were invalid for evaluating lifestyle change. We conducted a secondary data analysis from the SPHERE Study, a trial of an intervention to improve outcomes for patients with coronary heart disease in primary care. Postal questionnaires were used to assess physical activity (Godin) and diet (DINE) among study participants at baseline and 18 month follow-up. Three binary response variables were generated for analysis: (1) valid Godin score; (2) valid DINE Fibre score; and (3) valid DINE Total Fat score. Multivariate analysis comprised generalised estimating equation regression to examine the association of patients' characteristics with their return of valid responses at both timepoints. Overall, 92.1% of participants (832/903) returned questionnaires at both baseline and 18 months. Relatively fewer valid Godin scores were returned by those who left school aged <15 years (36.5%) than aged 18 and over (50.5%), manual workers (39.5%) than non-manual (49.5%) and those with an elevated cholesterol (>5 mmol) (34.7%) than those with a lower cholesterol (44.4%) but multivariate analysis identified that only school leaving age (p = 0.047) was of statistical significance.Relatively fewer valid DINE scores were returned by manual than non-manual workers (fibre: 80.8% v 86.8%; fat: 71.2% v 80.0%), smokers (fibre: 72.6% v 84.7%; fat: 67.5% v 76.9%), patients with diabetes (fibre: 75.9% v 82.9%; fat: 66.9% v 75.8%) and those with cholesterol >5 mmol (fat: 68.2% v 76.2%) but multivariate analysis showed statistical significance only for smoking (fibre: p = 0.013; fat: p = 0.045), diabetes (fibre: p = 0.039; fat: p = 0.047), and cholesterol (fat: p = 0.039). Our findings illustrate the importance of detailed reporting of research methods, with clear information about response rates, respondents and valid outcome data. Outcome measures which are relevant to a study population should be chosen carefully. The impact of methods of outcome measurement and valid response rates in evaluating healthcare requires further study.


The validity of diagnosing chronic obstructive pulmonary disease from a large administrative database.
Health authorities create and maintain administrative databases. Despite the potential advantages of these databases, the validity of the information they include must be considered. To examine the validity of diagnosing chronic obstructive pulmonary disease (COPD) from a large administrative database. Physician services and prescription claims data related to COPD and asthma were extracted from the Quebec universal medical insurance register (Régie de l'assurance-maladie du Québec; RAMQ) from the period of April 1, 1994 to March 31, 1999. Before obtaining the data, criteria for the validity of the COPD diagnosis in the database were formulated based on the epidemiology of COPD in the province. The extent to which the database satisfied these criteria are described within the present paper. For patients aged 65 years or older, COPD was two times more prevalent in the RAMQ database than in the 1994/1995 National Population Health Survey. One in three patients with a RAMQ-diagnosis of COPD also had a RAMQ-diagnosis of asthma, and 47% of patients aged 65 years or older with a RAMQ-diagnosis of COPD did not fill any prescription for beta-2-agonists. In addition, 42% of patients with a RAMQ-diagnosis of COPD who never had a RAMQ-diagnosis of asthma appeared only once with that diagnosis in the database. Of all patients aged 65 years or older with a RAMQ-diagnosis of COPD, 37% and 23% met the operational definitions of 'possible COPD' and 'probable COPD', respectively. Most RAMQ-diagnoses of COPD lack validity; therefore, the validity of database diagnoses should be routinely ascertained before using administrative databases in clinical and health services research.


Medical treatment of gastrointestinal stromal tumors: state of the art and future perspectives.
Gastrointestinal Stromal Tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract, and it is characterized by the occurrence, in > 90 % of cases, of a gain of function mutation in the c-kit proto-oncogene. STI-571 (imatinib mesylate), a selective KIT tyrosine kinase inhibitor, has changed the natural history of this disease, since it has shown high effectiveness in metastatic GIST, and it is currently under investigation also in the adjuvant and neoadjuvant setting. Mechanisms of resistance to imatinib mesylate include both de novo, and, more frequently, acquired resistance, which may occur after several months of drug administration and possibly depends, in most cases, upon an acquired second mutation. In order to overcome imatinib mesylate resistance, the addition of other drugs may be considered in patients who have less than an optimal response to imatinib mesylate monotherapy. Investigational agents that are being studied in this setting include the mammalian target of rapamycin (mTOR) inhibitor RAD 001 and the protein kinase C inhibitor PKC412. In addition, other KIT tyrosine kinase inhibitors with anti-VEGF receptor inhibitory activity, such as SU11248, PTK787/ZK787 and AMG 706, are currently being explored as second line monotherapy for imatinib mesylate-resistant GIST. Finally, another new drug, ecteinascidin (ET-743), that blocks cell cycle progression in G2/M phase through a p53-independent apoptotic mechanism, has shown important preclinical and clinical activity against a number of human solid tumors, including GIST.


Detection of antineutrophil cytoplasmic antibodies (ANCAs): a multicentre European Vasculitis Study Group (EUVAS) evaluation of the value of indirect immunofluorescence (IIF) versus antigen-specific immunoassays.
This multicentre study was performed to evaluate the diagnostic accuracy of a wide spectrum of novel technologies nowadays available for detection of myeloperoxidase (MPO) and proteinase 3 (PR3)-antineutrophil cytoplasmic antibodies (ANCAs). Sera (obtained at the time of diagnosis) from 251 patients with ANCA-associated vasculitis (AAV), including granulomatosis with polyangiitis and microscopic polyangiitis, and from 924 disease controls were tested for the presence of cytoplasmic pattern/perinuclear pattern and atypical ANCA (A-ANCA) by indirect immunofluorescence (IIF) (at two sites) and for the presence of PR3-ANCA and MPO-ANCA by eight different immunoassays. The area under the curve (AUC) of the receiver operating characteristic curve to discriminate AAV from controls was 0.923 (95% CI 0.902 to 0.944) and 0.843 (95% CI 0.814 to 0.871) for the two IIF methods. For the antigen-specific immunoassays, the AUC varied between 0.936 (95% CI 0.912 to 0.960) and 0.959 (95% CI 0.941 to 0.976), except for one immunoassay for which the AUC was 0.919 (95% CI 0.892 to 0.945). Our comparison of various ANCA detection methods showed (i) large variability between the two IIF methods tested and (ii) a high diagnostic performance of PR3-ANCA and MPO-ANCA by immunoassay to discriminate AAV from disease controls. Consequently, dual IIF/antigen-specific immunoassay testing of each sample is not necessary for maximal diagnostic accuracy. These results indicate that the current international consensus on ANCA testing for AAV needs revision.


Gravimetric and analytical evaluation of welding fume in an automobile part manufacturing factory.
Welding is one of the most exercised industrial processes which welders are exposed to chemical and physical Hazardous agents. This study was conducted to evaluate occupational and environmental exposures to aerosols generated by welding processes in a factory. A total of 28 samples of aerosols were collected at 4 different locations including indoor, outdoor, source of welding and the stacks using a high volume pump with a volumetric flow rate of 112 lit/min calibrated with a dry gas meter. The samples were collected on round 110 mm fiber glass filters, measured gravimetrically, extracted using nitric acid and analyzed with atomic absorption spectroscopy method for heavy metals including Fe, Mn, Ni, Cr3+, Cr+6, Co, and Zn. Gravimetric measuring has shown the mean values of indoor air: 1.33 mg/m3, breathing zone of the welders using coated electrodes and CO2: 7.25 mg/m3 and 6.45 mg/m3 respectively and in ventilation exhausts: 95.07 mg/m3. The mean values of Fe, Mn, and Ni were 0.8, 0.041, and 0.00 mg/m3 in indoor air, 2.7, 0.18, and 0.15 mg/m3 in breathing zone of welders used coated electrodes, and 1.75, 0.08, and 0.22 mg/m3 in breathing zone of welders used CO2 welding respectively. The concentrations of Cr3+, Cr+6, Co, and Zn were too low to be detected. The welders were exposed to high concentration of metallic fumes, which raise the risk of pulmonary dysfunction and other health disorders. Using suitable respiratory masks and Appling the effective local ventilation system may improve the working condition.


Ulcerative colitis-associated colorectal cancer arises in a field of short telomeres, senescence, and inflammation.
Inflammation plays a role in the progression to cancer and it is linked to the presence of senescent cells. Ulcerative colitis (UC) is a chronic inflammatory disease that predisposes to colorectal cancer. Tumorigenesis in this setting is associated with telomere shortening that can be observed in the nondysplastic epithelium of UC patients with high-grade dysplasia (HGD) or cancer (UC progressors). We hypothesized that a preneoplastic field of inflammation, telomere shortening, and senescence underlies tumor progression in UC progressors. Multiple biopsies of varying histologic grade were collected along the colon of nine UC progressors and analyzed for telomere length, DNA damage, senescence, p53, p16, and chronic and acute inflammation. Twenty biopsies from four UC nonprogressors and twenty-one biopsies from control individuals without UC were also analyzed. Short telomeres and increased DNA damage, senescence, and infiltrating leukocytes were observed in biopsies located less than 10 cm from HGD or cancer. Low-grade dysplasia (LGD) had the shortest telomeres along with the highest levels of senescence and infiltrating leukocytes, whereas HGD biopsies showed the opposite pattern. The expression of p16 and p53 was low in nondysplastic biopsies but progressively increased in LGD and HGD. In addition, high levels of infiltrating leukocytes were associated with telomere shortening, senescence, and reduced p53 expression. These results suggest that dysplasia arises in a preneoplastic field of chronic inflammation, which leads to telomere shortening, DNA damage, and senescence. Our findings argue that senescence acts as a tumor suppressor mechanism that is abrogated during the transition from LGD to HGD in UC.


The Fungal Cell Wall: Candida, Cryptococcus, and Aspergillus Species.
The fungal cell wall is located outside the plasma membrane and is the cell compartment that mediates all the relationships of the cell with the environment. It protects the contents of the cell, gives rigidity and defines the cellular structure. The cell wall is a skeleton with high plasticity that protects the cell from different stresses, among which osmotic changes stand out. The cell wall allows interaction with the external environment since some of its proteins are adhesins and receptors. Since, some components have a high immunogenic capacity, certain wall components can drive the host's immune response to promote fungus growth and dissemination. The cell wall is a characteristic structure of fungi and is composed mainly of glucans, chitin and glycoproteins. As the components of the fungal cell wall are not present in humans, this structure is an excellent target for antifungal therapy. In this article, we review recent data on the composition and synthesis, influence of the components of the cell wall in fungi-host interaction and the role as a target for the next generation of antifungal drugs in yeasts (Candida and Cryptococcus) and filamentous fungi (Aspergillus).


Adalimumab for nail psoriasis: Efficacy and safety from the first 26 weeks of a phase 3, randomized, placebo-controlled trial.
Previous clinical trials have not evaluated improvement in nail psoriasis as a primary end point. This phase 3 trial evaluated the safety and efficacy of adalimumab in patients with moderate-to-severe fingernail psoriasis and moderate-to-severe plaque psoriasis. Patients were randomized 1:1 to 40 mg adalimumab every other week or placebo. The primary efficacy end point was at least 75% improvement in total-fingernail modified Nail Psoriasis Severity Index (NAPSI75) response rate at week 26. Ranked secondary end point scores evaluated at week 26 were total-fingernail NAPSI and modified NAPSI, nail pain, Nail Psoriasis Physical Functioning Severity, Brigham Scalp Nail Inverse Palmo-Plantar Psoriasis Index, and Physician's Global Assessment (fingernail psoriasis). Of the 217 randomized patients (108 received placebo and 109 received adalimumab), 188 (86.6%) completed 26 weeks of treatment (period A) or escaped early to the open-label period. The study met the primary end point (response rate of 3.4% with placebo vs 46.6% with adalimumab [P < .001]) and all ranked secondary end points. The serious adverse event rates (placebo vs adalimumab) in period A were 4.6% versus 7.3%; the serious infections rates were 1.9% versus 3.7%. Patients with less than 5% BSA involvement were not eligible for enrollment. After 26 weeks of adalimumab treatment, significant improvements were seen in the primary and all ranked secondary end points and in signs and symptoms of moderate-to-severe nail psoriasis versus with placebo and no new safety risks were identified.


Minimum Clinically Important Difference in 30-s Sit-to-Stand Test After Pulmonary Rehabilitation in Subjects With COPD.
The sit-to-stand (STS) test is a feasible tool for measuring peripheral muscle strength of the lower limbs. There is evidence of increasing use of STS tests in patients with COPD. We sought to evaluate in subjects with COPD the minimum clinically important difference in 30-s STS test after pulmonary rehabilitation. Stable COPD subjects undergoing a 30-s STS test and a 6-min walk test (6MWT) before and after pulmonary rehabilitation were included. Responsiveness to pulmonary rehabilitation was determined by the change in 30-s STS test results (Δ 30-s STS) before and after pulmonary rehabilitation. The minimum clinically important difference was evaluated using an anchor-based method. 96 subjects with moderate-to-severe COPD were included. At baseline, 30-s STS test results were significantly related to distance covered in a 6MWT (6MWD) (r = 0.65, P < .001), FVC (r = 0.46, P < .001), PaCO2 (r = -0.42, P < .001), FEV1 (r = 0.39, P < .001), and age (r = -0.31, P = .002). After pulmonary rehabilitation, a significant improvement in 30-s STS test results was observed (mean difference +2 repetitions, P < .001). The Δ30-s STS was positively related to Δ6MWD (r = 0.62, P < .001), transitional dyspnea index (r = 0.67, P < .001), and baseline residual volume (r = 0.27, P = .007). The receiver operating characteristic curves method identified a Δ 30-s STS cut-off of 2 repetitions as the best discriminating value (area under the curve: 0.892, P < .001) to identify the minimum clinically important difference for Δ6MWD (30 m). In a multivariate logistic regression model, baseline 30-s STS (odds ratio 2.63; 95% CI 1.09-6.35, P = .031) and diffusing capacity of the lung for carbon monoxide (< 53% predicted) (odds ratio 2.49, 95% CI 1.04-5.98, P = .041) predict the risk to have a Δ 30-s STS ≥ 2 repetitions. Our study indicates that in stable subjects with moderate-to-severe COPD, the 30-s STS test was a sensitive tool to assess the efficacy of pulmonary rehabilitation. A Δ 30-s STS of ≥ 2 repetitions represented the minimum clinically important difference, which may be predicted by the baseline ability in the 30-s STS test and lung function in terms of diffusing lung capacity (ClinicalTrials.gov registration NCT03627624).


Achieving transparency in implementing abortion laws.
National and international courts and tribunals are increasingly ruling that although states may aim to deter unlawful abortion by criminal penalties, they bear a parallel duty to inform physicians and patients of when abortion is lawful. The fear is that women are unjustly denied safe medical procedures to which they are legally entitled, because without such information physicians are deterred from involvement. With particular attention to the European Court of Human Rights, the UN Human Rights Committee, the Constitutional Court of Colombia, the Northern Ireland Court of Appeal, and the US Supreme Court, decisions are explained that show the responsibility of states to make rights to legal abortion transparent. Litigants are persuading judges to apply rights to reproductive health and human rights to require states' explanations of when abortion is lawful, and governments are increasingly inspired to publicize regulations or guidelines on when abortion will attract neither police nor prosecutors' scrutiny.


Epigenetics and the transition from acute to chronic pain.
The objective of this study was to review the epigenetic modifications involved in the transition from acute to chronic pain and to identify potential targets for the development of novel, individualized pain therapeutics. Epigenetics is the study of heritable modifications in gene expression and phenotype that do not require a change in genetic sequence to manifest their effects. Environmental toxins, medications, diet, and psychological stresses can alter epigenetic processes such as DNA methylation, histone acetylation, and RNA interference. As epigenetic modifications potentially play an important role in inflammatory cytokine metabolism, steroid responsiveness, and opioid sensitivity, they are likely key factors in the development of chronic pain. Although our knowledge of the human genetic code and disease-associated polymorphisms has grown significantly in the past decade, we have not yet been able to elucidate the mechanisms that lead to the development of persistent pain after nerve injury or surgery. This is a focused literature review of epigenetic science and its relationship to chronic pain. Significant laboratory and clinical data support the notion that epigenetic modifications are affected by the environment and lead to differential gene expression. Similar to mechanisms involved in the development of cancer, neurodegenerative disease, and inflammatory disorders, the literature endorses an important potential role for epigenetics in chronic pain. Epigenetic analysis may identify mechanisms critical to the development of chronic pain after injury, and may provide new pathways and target mechanisms for future drug development and individualized medicine.


Porphyromonas gingivalis invasion of gingival epithelial cells.
Porphyromonas gingivalis, a periodontal pathogen, can invade primary cultures of gingival epithelial cells. Optimal invasion occurred at a relatively low multiplicity of infection (i.e., 100) and demonstrated saturation at a higher multiplicity of infection. Following the lag phase, during which bacteria invaded poorly, invasion was independent of growth phase. P. gingivalis was capable of replicating within the epithelial cells. Invasion was an active process requiring both bacterial and epithelial cell energy production. Invasion was sensitive to inhibitors of microfilaments and microtubules, demonstrating that epithelial cell cytoskeletal rearrangements are involved in bacterial entry. P. gingivalis, but not epithelial cell, protein synthesis was necessary for invasion. Invasion within the epithelial cells was not blocked by inhibitors of protein kinase activity. Invasion was inhibited by protease inhibitors, suggesting that P. gingivalis proteases may be involved in the invasion process. Low-passage clinical isolates of P. gingivalis invaded with higher efficiency than the type strain. Serum inhibited invasion of the type strain but had no effect on the invasion of a clinical isolate. Invasion of gingival epithelial cells by P. gingivalis may contribute to the pathology of periodontal diseases.


Cocoa beans improve mitochondrial biogenesis via PPARγ/PGC1α dependent signalling pathway in MPP+ intoxicated human neuroblastoma cells (SH-SY5Y).
Polyphenols are shown to protect from or delay the progression of chronic neurodegenerative diseases. Mitochondrial dysfunction plays a key role in the pathogenesis of Parkinson's disease (PD). This study was aims to gain insight into the role of ahydroalcoholic extract of cocoa (standardised for epicatechin content) on mitochondrial biogenesis in MPP+ intoxicated human neuroblastoma cells (SHSY5Y). The effects of cocoa on PPARγ, PGC1α, Nrf2 and TFAM protein expression and mitochondrial membrane potential were evaluated. A pre-exposure to cocoa extract decreased reactive oxygen species formation and restored mitochondrial membrane potential. The cocoa extract was found to up-regulate the expression of PPARγ and the downstream signalling proteins PGC1α, Nrf2 and TFAM. It increased the expression of the anti-apoptotic protein BCl2 and increased superoxide dismutase activity. Further, the cocoa extract down-regulated the expression of mitochondria fission 1 (Fis1) and up-regulated the expression of mitochondria fusion 2 (Mfn2) proteins, suggesting an improvement in mitochondrial functions in MPP+ intoxicated cells upon treatment with cocoa. Interestingly, cocoa up-regulates the expression of tyrosine hydroxylase, the rate limiting enzyme in dopamine synthesis. No change in the expression of PPARγ on treatment with cocoa extract was observed when the cells were pre-treated with PPARγ antagonist GW9662. This data suggests that cocoa mediates mitochondrial biogenesis via a PPARγ/PGC1α dependent signalling pathway and also has the ability to improve dopaminergic functions by increasing tyrosine hydroxylase expression. Based on our data, we propose that a cocoa bean extract and products thereof could be used as potential nutritional supplements for neuroprotection in PD.


Genome-wide meta-analysis of joint tests for genetic and gene-environment interaction effects.
There is growing interest in the study of gene-environment interactions in the context of genome-wide association studies (GWASs). These studies will likely require meta-analytic approaches to have sufficient power. We describe an approach for meta-analysis of a joint test for genetic main effects and gene-environment interaction effects. Using simulation studies based on a meta-analysis of five studies (total n = 10,161), we compare the power of this test to the meta-analysis of marginal test of genetic association and the meta-analysis of standard 1 d.f. interaction tests across a broad range of genetic main effects and gene-environment interaction effects. We show that the joint meta-analysis is valid and can be more powerful than classical meta-analytic approaches, with a potential gain of power over 50% compared to the marginal test. The standard interaction test had less than 1% power in almost all the situations we considered. We also show that regardless of the test used, sample sizes far exceeding those of a typical individual GWAS will be needed to reliably detect genes with subtle gene-environment interaction patterns. The joint meta-analysis is an attractive approach to discover markers which may have been missed by initial GWASs focusing on marginal marker-trait associations.


Feedforward ankle strategy of balance during quiet stance in adults.
1. We studied quiet stance investigating strategies for maintaining balance. Normal subjects stood with natural stance and with feet together, with eyes open or closed. Kinematic, kinetic and EMG data were evaluated and cross-correlated. 2. Cross-correlation analysis revealed a high, positive, zero-phased correlation between anteroposterior motions of the centre of gravity (COG) and centre of pressure (COP), head and COG, and between linear motions of the shoulder and knee in both sagittal and frontal planes. There was a moderate, negative, zero-phased correlation between the anteroposterior motion of COP and ankle angular motion. 3. Narrow stance width increased ankle angular motion, hip angular motion, mediolateral sway of the COG, and the correlation between linear motions of the shoulder and knee in the frontal plane. Correlations between COG and COP and linear motions of the shoulder and knee in the sagittal plane were decreased. The correlation between the hip angular sway in the sagittal and frontal planes was dependent on interaction between support and vision. 4. Low, significant positive correlations with time lags of the maximum of cross-correlation of 250-300 ms were found between the EMG activity of the lateral gastrocnemius muscle and anteroposterior motions of the COG and COP during normal stance. Narrow stance width decreased both correlations whereas absence of vision increased the correlation with COP. 5. Ankle mechanisms dominate during normal stance especially in the sagittal plane. Narrow stance width decreased the role of the ankle and increased the role of hip mechanisms in the sagittal plane, while in the frontal plane both increased. 6. The modulation pattern of the lateral gastrocnemius muscle suggests a central program of control of the ankle joint stiffness working to predict the loading pattern.


The impact of Staphylococcus aureus genomic variation on clinical phenotype of children with acute hematogenous osteomyelitis.
Children with acute hematogenous osteomyelitis (AHO) have a broad spectrum of illness ranging from mild to severe. The purpose of this study is to evaluate the impact of genomic variation of Staphylococcus aureus on clinical phenotype of affected children and determine which virulence genes correlate with severity of illness. De novo whole genome sequencing was conducted for a strain of Community Acquired Methicillin Resistant Staphylococcus aureus (CA-MRSA), using PacBio Hierarchical Genome Assembly Process (HGAP) from 6 Single Molecule Real Time (SMRT) Cells, as a reference for DNA library assembly of 71 Staphylococcus aureus isolates from children with AHO. Virulence gene annotation was based on exhaustive literature review and genomic data in NCBI for Staphylococcus aureus. Clinical phenotype was assessed using a validated severity score. Kruskal-Wallis rank sum test determined association between clinical severity and virulence gene presence using False Discovery Rate (FDR), significance <0.01. PacBio produced an assembled genome of 2,898,306 bp and 2054 Open Reading Frames (ORFs). Annotation confirmed 201 virulence genes. Statistical analysis of gene presence by clinical severity found 40 genes significantly associated with severity of illness (FDR ≤0.009). MRSA isolates encoded a significantly greater number of virulence genes than did MSSA (p < 0.0001). Phylogenetic analysis by maximum likelihood (PAML) demonstrated the relatedness of genomic distance to clinical phenotype. The Staphylococcus aureus genome contains virulence genes which are significantly associated with severity of illness in children with osteomyelitis. This study introduces a novel reference strain and detailed annotation of Staphylococcus aureus virulence genes. While this study does not address bacterial gene expression, a platform is created for future transcriptome investigations to elucidate the complex mechanisms involved in childhood osteomyelitis.


Determining the dimensions of essential medical coverage required by military body armour plates utilising Computed Tomography.
Military body armour is designed to prevent the penetration of ballistic projectiles into the most vulnerable structures within the thorax and abdomen. Currently the OSPREY and VIRTUS body armour systems issued to United Kingdom (UK) Armed Forces personnel are provided with a single size front and rear ceramic plate regardless of the individual's body dimensions. Currently limited information exists to determine whether these plates overprotect some members of the military population, and no method exists to accurately size plates to an individual. Computed Tomography (CT) scans of 120 male Caucasian UK Armed Forces personnel were analysed to measure the dimensions of internal thoraco-abdominal anatomical structures that had been defined as requiring essential medical coverage. The boundaries of these structures were related to three potential anthropometric landmarks on the skin surface and statistical analysis was undertaken to validate the results. The range of heights of each individual used in this study was comparable to previous anthropometric surveys, confirming that a representative sample had been used. The vertical dimension of essential medical coverage demonstrated good correlation to torso height (suprasternal notch to iliac crest) but not to stature (r(2)=0.53 versus 0.04). Horizontal coverage did not correlate to either measure of height. Surface landmarks utilised in this study were proven to be reliable surrogate markers for the boundaries of the underlying anatomical structures potentially requiring essential protection by a plate. Providing a range of plate sizes, particularly multiple heights, should optimise the medical coverage and thus effectiveness of body armour for UK Armed Forces personnel. The results of this work provide evidence that a single width of plate if chosen correctly will provide the essential medical coverage for the entire military population, whilst recognising that it still could overprotect the smallest individuals. With regards to anthropometric measurements; it is recommended, based on this work, that torso height is used instead of stature for sizing body armour. Coverage assessments should now be undertaken for side protection as well as for other non-Caucasian populations and females, with anthropometric surveys utilising the three landmarks recommended in this study.


An SNP-based second-generation genetic map of Daphnia magna and its application to QTL analysis of phenotypic traits.
Although Daphnia is increasingly recognized as a model for ecological genomics and biomedical research, there is, as of yet, no high-resolution genetic map for the genus. Such a map would provide an important tool for mapping phenotypes and assembling the genome. Here we estimate the genome size of Daphnia magna and describe the construction of an SNP array based linkage map. We then test the suitability of the map for life history and behavioural trait mapping. The two parent genotypes used to produce the map derived from D. magna populations with and without fish predation, respectively and are therefore expected to show divergent behaviour and life-histories. Using flow cytometry we estimated the genome size of D. magna to be about 238 mb. We developed an SNP array tailored to type SNPs in a D. magna F2 panel and used it to construct a D. magna linkage map, which included 1,324 informative markers. The map produced ten linkage groups ranging from 108.9 to 203.6 cM, with an average distance between markers of 1.13 cM and a total map length of 1,483.6 cM (Kosambi corrected). The physical length per cM is estimated to be 160 kb. Mapping infertility genes, life history traits and behavioural traits on this map revealed several significant QTL peaks and showed a complex pattern of underlying genetics, with different traits showing strongly different genetic architectures. The new linkage map of D. magna constructed here allowed us to characterize genetic differences among parent genotypes from populations with ecological differences. The QTL effect plots are partially consistent with our expectation of local adaptation under contrasting predation regimes. Furthermore, the new genetic map will be an important tool for the Daphnia research community and will contribute to the physical map of the D. magna genome project and the further mapping of phenotypic traits. The clones used to produce the linkage map are maintained in a stock collection and can be used for mapping QTLs of traits that show variance among the F2 clones.


Clustering-based denoising with locally learned dictionaries.
In this paper, we propose K-LLD: a patch-based, locally adaptive denoising method based on clustering the given noisy image into regions of similar geometric structure. In order to effectively perform such clustering, we employ as features the local weight functions derived from our earlier work on steering kernel regression . These weights are exceedingly informative and robust in conveying reliable local structural information about the image even in the presence of significant amounts of noise. Next, we model each region (or cluster)-which may not be spatially contiguous-by "learning" a best basis describing the patches within that cluster using principal components analysis. This learned basis (or "dictionary") is then employed to optimally estimate the underlying pixel values using a kernel regression framework. An iterated version of the proposed algorithm is also presented which leads to further performance enhancements. We also introduce a novel mechanism for optimally choosing the local patch size for each cluster using Stein's unbiased risk estimator (SURE). We illustrate the overall algorithm's capabilities with several examples. These indicate that the proposed method appears to be competitive with some of the most recently published state of the art denoising methods.


Large-scale probabilistic functional modes from resting state fMRI.
It is well established that it is possible to observe spontaneous, highly structured, fluctuations in human brain activity from functional magnetic resonance imaging (fMRI) when the subject is 'at rest'. However, characterising this activity in an interpretable manner is still a very open problem. In this paper, we introduce a method for identifying modes of coherent activity from resting state fMRI (rfMRI) data. Our model characterises a mode as the outer product of a spatial map and a time course, constrained by the nature of both the between-subject variation and the effect of the haemodynamic response function. This is presented as a probabilistic generative model within a variational framework that allows Bayesian inference, even on voxelwise rfMRI data. Furthermore, using this approach it becomes possible to infer distinct extended modes that are correlated with each other in space and time, a property which we believe is neuroscientifically desirable. We assess the performance of our model on both simulated data and high quality rfMRI data from the Human Connectome Project, and contrast its properties with those of both spatial and temporal independent component analysis (ICA). We show that our method is able to stably infer sets of modes with complex spatio-temporal interactions and spatial differences between subjects.


Chemokine receptors in epithelial ovarian cancer.
Ovarian carcinoma is the deadliest gynecologic malignancy with very poor rate of survival, and it is characterized by the presence of vast incurable peritoneal metastasis. Studies of the role of chemokine receptors, a family of proteins belonging to the group of G protein-coupled receptors, in ovarian carcinoma strongly placed this family of membrane receptors as major regulators of progression of this malignancy. In this review, we will discuss the roles that chemokine-receptor interactions play to support angiogenesis, cell proliferation, migration, adhesion, invasion, metastasis, and immune evasion in progression of ovarian carcinoma. Data regarding the role that the chemokine receptors play in the disease progression accumulated insofar strongly suggest that this family of proteins could be good therapeutic targets against ovarian carcinoma.