HIV-1 reverse transcriptase (RT) genotype and susceptibility to RT inhibitors during abacavir monotherapy and combination therapy.
To examine changes in HIV-1 susceptibility (genotype and phenotype) during an initial abacavir monotherapy phase followed by the addition of zidovudine and lamivudine. Sixty HIV-1 infected, antiretroviral therapy-naive subjects were randomized to receive 100, 300 or 600 mg abacavir twice daily. Subjects completing 24 weeks of randomized therapy or meeting a protocol defined switch criterion could switch to open label abacavir/zidovudine/lamivudine. Plasma HIV-1 reverse transcriptase was genotyped at baseline, week 12, and at the last time point on ABC monotherapy. Drug susceptibility was analysed at baseline and on subsequent samples with sufficient HIV-1 RNA levels using the recombinant virus assay. Virological responses (week 24) were correlated to week 24 genotypes. Mutant viruses were not detected before week 12 with the exception of one subject. At the latest time point on abacavir monotherapy (range, weeks 6-48), 21 out of 43 subjects harboured virus with resistance conferring mutations including single, double and triple combinations of K65R, L74V, Y115F and M184V. The most common mutational pattern was L74V + M184V (11/21 cases). Twenty of the 21 subjects with isolates containing abacavir-associated mutations reached week 48, and upon addition of lamivudine/zidovudiine, 16 out of 20 (80%) had week 48 plasma HIV-1 -RNA below 400 copies/ml. At week 48, 16 out of 46 genotypes were obtained; one of these was wild-type; 15 contained M184V either alone, in combination with K65R and/or L74V and/or Y115F or with thymidine analogue-associated mutations. Week 48 viral load levels for these 15 subjects was low (median 3.43 log10 copies/ml or -1.99 log10 copies reduction from baseline). Genotype correlated well with phenotypic resistance to ABC; four samples with three abacavir-associated mutations had high level abacavir resistance (> 8-fold) and six samples with two or three mutations showed intermediate (4-8-fold) resistance. All samples with single mutations retained full ABC susceptibility. Resistance conferring mutations to abacavir were relatively slow to develop during the monotherapy phase, and did not preclude durable efficacy of abacavir/lamivudine/zidovudine up to 48 weeks.


IPF, comorbidities and management implications: Patient case 2.
PATIENT PRESENTATION AND DIAGNOSIS: The patient is a 50-year-old woman who was referred to a tertiary centre with an HRCT showing definite UIP and a 6-minute walking distance of 145 metres. She was severely ill at presentation with a diffusion capacity of just 20%.The patient had a history of peripheral arterial disease and had undergone both aortofemoral and femoro-femoral bypass due to arteriosclerosis and gluteal ischaemia. She also was suffering from renal impairment and had recently quit smoking.


Genomic and functional analysis of Romboutsia ilealis CRIBT reveals adaptation to the small intestine.
The microbiota in the small intestine relies on their capacity to rapidly import and ferment available carbohydrates to survive in a complex and highly competitive ecosystem. Understanding how these communities function requires elucidating the role of its key players, the interactions among them and with their environment/host. The genome of the gut bacterium Romboutsia ilealis CRIBT was sequenced with multiple technologies (Illumina paired-end, mate-pair and PacBio). The transcriptome was sequenced (Illumina HiSeq) after growth on three different carbohydrate sources, and short chain fatty acids were measured via HPLC. We present the complete genome of Romboutsia ilealis CRIBT, a natural inhabitant and key player of the small intestine of rats. R. ilealis CRIBT possesses a circular chromosome of 2,581,778 bp and a plasmid of 6,145 bp, carrying 2,351 and eight predicted protein coding sequences, respectively. Analysis of the genome revealed limited capacity to synthesize amino acids and vitamins, whereas multiple and partially redundant pathways for the utilization of different relatively simple carbohydrates are present. Transcriptome analysis allowed identification of the key components in the degradation of glucose, L-fucose and fructo-oligosaccharides. This revealed that R. ilealis CRIBT is adapted to a nutrient-rich environment where carbohydrates, amino acids and vitamins are abundantly available.


Integrative taxonomy of Leptonetela spiders (Araneae, Leptonetidae), with descriptions of 46 new species.
Extreme environments, such as subterranean habitats, are suspected to be responsible for morphologically inseparable cryptic or sibling species and can bias biodiversity assessment. A DNA barcode is a short, standardized DNA sequence used for taxonomic purposes and has the potential to lessen the challenges presented by a biotic inventory. Here, we investigate the diversity of the genus Leptonetela Kratochvíl, 1978 that is endemic to karst systems in Eurasia using DNA barcoding. We analyzed 624 specimens using one mitochondrial gene fragment (COI). The results show that DNA barcoding is an efficient and rapid species identification method in this genus. DNA barcoding gap and automatic barcode gap discovery (ABGD) analyses indicated the existence of 90 species, a result consistent with previous taxonomic hypotheses, and supported the existence of extreme male pedipalpal tibial spine and median apophysis polymorphism in Leptonetela species, with direct implications for the taxonomy of the group and its diversity. Based on the molecular and morphological evidence, we delimit and diagnose 90 Leptonetela species, including the type species Leptonetela kanellisi (Deeleman-Reinhold, 1971). Forty-six of them are previously undescribed. The female of Leptonetela zhai Wang & Li, 2011 is reported for the first time. Leptonetela tianxinensis (Tong & Li, 2008) comb. nov. is transferred from the genus Leptoneta Simon, 1872; the genus Guineta Lin & Li, 2010 syn. nov. is a junior synonym of Leptonetela; Leptonetela gigachela (Lin & Li, 2010) comb. nov. is transferred from Guineta. The genus Sinoneta Lin & Li, 2010 syn. nov. is a junior synonym of Leptonetela; Leptonetela notabilis (Lin & Li, 2010) comb. nov. and Leptonetela sexdigiti (Lin & Li, 2010) comb. nov. are transferred from Sinoneta; Leptonetela sanchahe Wang & Li nom. nov. is proposed as a replacement name for Sinoneta palmata (Chen et al., 2010) because Leptonetela palmata is preoccupied.


Maintenance treatment of bipolar disorders.
Conventional antipsychotic drugs, although efficacious in the treatment of mania, have not demonstrated a significant usefulness in the maintenance treatment of bipolar disorder. This has primarily been due to a tendency to induce depressive symptoms and depressive recurrences in this group of patients in the course of long-term administration. However, the picture has changed following the introduction of second-generation antipsychotics. These drugs have pro-depressant properties (if any) that are much weaker than conventional antipsychotics. Furthermore, their tolerability, especially in long-term treatment, is more favorable compared to classical antipsychotics. Clinical observations of the action profile of second-generation antipsychotic drugs in the treatment of schizophrenia have pointed to a possibility of these agents possessing mood-stabilizing properties. The first such suggestion was made by Zarate (1995) in connection with clozapine. The prevention of manic and depressive recurrences in bipolar disorder is a hallmark of the definition of mood-stabilizers.


Dendrodendritic inhibition through reversal of dopamine transport.
Synapses in the central nervous system are usually defined by presynaptic exocytotic release sites and postsynaptic differentiations. We report here a demonstration of dendrodendritic inhibition that does not engage a conventional synapse. Using amperometric and patch-clamp recordings in rat brain slices of the substantia nigra, we found that blockade of the dopamine transporter abolished the dendritic release of dopamine and the resulting self-inhibition. These findings demonstrate that dendrodendritic autoinhibition entails the carrier-mediated release of dopamine rather than conventional exocytosis. This suggests that some widely used antidepressants that inhibit the dopamine transporter may benefit patients in the early stages of Parkinson's disease.


A panel of cancer-testis genes exhibiting broad-spectrum expression in haematological malignancies.
Cancer-testis (CT) antigens/genes show restricted expression in normal tissues but widespread expression in many tumour types. This, coupled with their ability to induce cytotoxic T-lymphocyte responses, makes them attractive vaccine candidates. Following our identification of PASD1, we have used RT-PCR to analyse the mRNA expression profile of a large panel of CT genes in cell lines derived from haematological malignancies, and have studied Sp17 protein expression in the same cell lines and diffuse large B-cell lymphoma (DLBCL) biopsies. Our extensive analysis revealed multiple CT transcripts exhibiting widespread expression across cell lines derived from 21 B- and 4 T-cell malignancies. The broadest mRNA expression profiles were observed for the following eight CT genes: Sp17 (25/25), PRAME (25/25), CSAGE (24/25), PASD1 (22/25), CAGE/DDX53 (19/25), CTAGE1 (19/25), HAGE/DDX43 (16/25) and PLU-1/JARID1B (15/25). Cell lines derived from more aggressive lymphoma subtypes generally expressed CT transcripts at higher frequency. Sp17 protein was detected in a number of cell lines and in six of eleven (54.5%) DLBCL biopsies. Analysis of Sp17 protein expression, by immunohistochemistry and Western blotting, broadens the scope of this CT antigen as a potentially relevant clinical target in haematological malignancies. Further studies of protein expression are now needed to validate these antigens as vaccine candidates.


High incidence of Dieulafoy's lesions in upper gastrointestinal bleeding associated with polyarteritis--clinical examination of patients of polyarteritis nodosa with rapidly progressive glomerulonephritis.
Polyarteritis nodosa (PN) has been classified into polyarteritis (PA) and microscopic polyarteritis (MA) histologically. To clarify of the characteristics of upper gastrointestinal bleeding lesions in PN, we investigated the patients of PN with rapidly progressive glomerulonephritis (RPGN) presenting with upper gastrointestinal bleeding. The subjects of this study were 21 patients of PN with RPGN (PA: 11, MA: 10) who presented with upper gastrointestinal bleeding. The bleeding lesions and their locations were examined endoscopically in the study subjects, and the relationship of the bleeding to the severity of renal failure, the necessity of hemodialysis (HD), presence/ absence of H. pylori infection and the gender of the patients were analyzed. The bleeding lesions were endoscopically identified as esophageal ulcers in 2 cases, gastric ulcers in 15 cases and duodenal ulcers in 4 cases, respectively. In 10 of the 15 cases with gastric ulcers, the ulcer assumed the form of Dieulafoy's lesions affecting the gastric body, and the underlying disease was PA in all the 10 cases. In the remaining 5 cases of gastric ulcers and 2 cases of esophageal ulcer with underlying MA or 4 cases of duodenal ulcers, in whom assumed the bleeding form of oozing from the marginal zone of ulcers. In all of the 4 cases of duodenal ulcers, and the 1 case with underlying PA and the other cases with MA, no correlation was found between the onset of the upper gastrointestinal bleeding and the severity of renal failure or the necessity for HD, presence of H. pylori infection, or the gender of the patients. Dieulafoy's lesions are the most frequent sources of upper gastrointestinal bleeding in cases of PA.


Photic Entrainment of the Circadian System.
Circadian rhythms are essential for the survival of all organisms, enabling them to predict daily changes in the environment and time their behaviour appropriately. The molecular basis of such rhythms is the circadian clock, a self-sustaining molecular oscillator comprising a transcriptional-translational feedback loop. This must be continually readjusted to remain in alignment with the external world through a process termed entrainment, in which the phase of the master circadian clock in the suprachiasmatic nuclei (SCN) is adjusted in response to external time cues. In mammals, the primary time cue, or "zeitgeber", is light, which inputs directly to the SCN where it is integrated with additional non-photic zeitgebers. The molecular mechanisms underlying photic entrainment are complex, comprising a number of regulatory factors. This review will outline the photoreception pathways mediating photic entrainment, and our current understanding of the molecular pathways that drive it in the SCN.


Asthma in inner-city children at 5-11 years of age and prenatal exposure to phthalates: the Columbia Center for Children's Environmental Health Cohort.
Studies suggest that phthalate exposures may adversely affect child respiratory health. We evaluated associations between asthma diagnosed in children between 5 and 11 years of age and prenatal exposures to butylbenzyl phthalate (BBzP), di-n-butyl phthalate (DnBP), di(2-ethylhexyl) phthalate (DEHP), and diethyl phthalate (DEP). Phthalate metabolites were measured in spot urine collected from 300 pregnant inner-city women. Children were examined by an allergist or pulmonologist based on the first parental report of wheeze, other respiratory symptoms, and/or use of asthma rescue/controller medication in the preceding 12 months on repeat follow-up questionnaires. Standardized diagnostic criteria were used to classify these children as either having or not having current asthma at the time of the physician examination. Children without any report of wheeze or the other asthma-like symptoms were classified as nonasthmatics at the time of the last negative questionnaire. Modified Poisson regression analyses were used to estimate relative risks (RR) controlling for specific gravity and potential confounders. Of 300 children, 154 (51%) were examined by a physician because of reports of wheeze, other asthma-like symptoms, and/or medication use; 94 were diagnosed with current asthma and 60 without current asthma. The remaining 146 children were classified as nonasthmatic. Compared with levels in nonasthmatics, prenatal metabolites of BBzP and DnBP were associated with a history of asthma-like symptoms (p < 0.05) and with the diagnosis of current asthma: RR = 1.17 (95% CI: 1.01, 1.35) and RR = 1.25 (95% CI: 1.04, 1.51) per natural log-unit increase, respectively. Risk of current asthma was > 70% higher among children with maternal prenatal BBzP and DnBP metabolite concentrations in the third versus the first tertile. Prenatal exposure to BBzP and DnBP may increase the risk of asthma among inner-city children. However, because this is the first such finding, results require replication.


Socioeconomic Factors, Perioperative Complications, and 30-Day Readmission Rates Associated With Delayed Cranial Vault Reconstruction for Craniosynostosis.
Premature fusion of the cranial sutures can lead to significant neurocognitive, developmental, and esthetic consequences, especially if not corrected within the first year of life. This study aimed to identify the drivers of delayed cranial vault reconstruction (CVR) and its impact on complication and 30-day readmission rates among craniosynostosis patients. The medical records of all children who underwent CVR for craniosynostosis between 2005 and 2017 at an academic institution were retrospectively reviewed. A delay in operation was defined by surgery performed >12 months of age. Patient demographics, comorbidities, perioperative complication rates, and 30-day readmission rates were collected. A total of 96 patients underwent primary CVR, with 79 (82.3%) patients undergoing nondelayed surgery and 17 (17.7%) patients undergoing surgery >12 months of age. Children undergoing delayed surgery were significantly more likely to be non-White (P < 0.0001), have Medicaid insurance (P = 0.023), and have a non-English primary language (P < 0.005). There was increased incidence of developmental disability identified at first consult (no-delay: 3.9% vs delay: 41.2%, P < 0.0001) and increased intracranial pressure (no-delay: 6.3% vs delay: 29.4%, P < 0.005) among children undergoing delayed surgery. The delayed cohort had a significantly higher unplanned 30-day readmission rate (no-delay: 0.0% vs delay: 5.9%, P = 0.03). Our study suggests that craniosynostosis patients who are non-White, have a non-English primary language, and have Medicaid insurance are at risk for delayed primary surgery, which may lead to increased 30-day readmission. Interventions are necessary to reduce craniosynostosis patients' barriers to care to minimize the sequelae associated with delayed surgery.


Evidence from population mixing in British New Towns 1946-85 of an infective basis for childhood leukaemia.
Mortality from leukaemia under age 25 was studied in British New Towns to test the hypothesis that leukaemia represents a rare response to a much commoner (but unrecognised) infection, the transmission of which is facilitated when large numbers of people come together. The density of children was higher in the rural, but lower in the overspill, New Towns than in the areas from which their incomers originated. Residents of the rural New Towns had greater diversity of origin than those of the overspill towns of London and Glasgow. These two factors would encourage a greater rise in the postulated underlying infection in the rural towns, and in these a significant excess of leukaemia at ages 0-4 was found in 1946-65. In both sets of towns there was a significant deficit in other age groups consistent with immunising effects of the relevant infection. There are parallels with feline leukaemia virus infection, in which contrasting leukaemogenic and immunising effects occur in different social settings owing mainly to differences in intensity of viral exposure.


Voxel-based adaptive spatio-temporal modelling of perfusion cardiovascular MRI.
Contrast enhanced myocardial perfusion magnetic resonance imaging (MRI) is a promising technique, providing insight into how reduced coronary flow affects the myocardial tissue. Stenosis in a coronary vessel leads to reduced myocardial blood flow, but collaterals may secure the blood supply of the myocardium, with altered tracer kinetics. Due to a low signal-to-noise ratio, quantitative analysis of the signal is typically difficult to achieve at the voxel level. Hence, analysis is often performed on measurements that are aggregated in predefined myocardial segments, that ignore the variability in blood flow in each segment. The approach presented in this paper uses local spatial information that enables one to perform a robust analysis at the voxel level. The spatial dependencies between local response curves are modelled via a hierarchical Bayesian model. In the proposed framework, all local systems are analyzed simultaneously along with their dependencies, producing a more robust context-driven estimation of local kinetics. Detailed validation on both simulated and patient data is provided.


Two critical periods of Sonic Hedgehog signaling required for the specification of motor neuron identity.
Antibodies that block Sonic Hedgehog (SHH) signaling have been used to show that SHH activity is required for the induction of floor plate differentiation by the notochord and independently for the induction of motor neurons by both the notochord and midline neural cells. Motor neuron generation depends on two critical periods of SHH signaling: an early period during which naive neural plate cells are converted into ventralized progenitors and a late period that extends well into S phase of the final progenitor cell division, during which SHH drives the differentiation of ventralized progenitors into motor neurons. The ambient SHH concentration during the late period determines whether ventralized progenitors differentiate into motor neurons or interneurons, thus defining the pattern of neuronal cell types generated in the neural tube.


[Comparison between resection and primary anastomosis and staged resection in obstructing adenocarcinoma of the left colon].
The surgical option to deal with obstruction of the left side of the large bowel is still controversial. To report the experience of our group in the treatment of malignant left-sided colonic obstruction focusing on the immediate results using either one-stage resection and primary anastomoses or staged resection. Twenty-three patients (median age = 52 (39-84) years; 10 males and 13 females) with potentially resectable obstructed adenocarcinomas of the left colon entered the study. The patients were submitted to different surgical procedure: 14 (60,9%) underwent one stage colonic resection (intra-operative lavage of colon (n = 10) or subtotal colectomy (n = 4); resection and primary anastomoses group) and 9 patients (39,1%) underwent staged resection (Hartmann's operation (n = 4) or loop colostomy (n = 5); staged resection group). Two patients (8,7%) died. All were from the staged resection group. Four patients (44,4%) of staged resection group did not complete the treatment with the closing of the colostomy. The incidence of complications was 28,6% in resection and primary anastomoses group (4/14) and 66,7% in staged resection group (6/9). Hospital stay was 15 (9-45) in staged resection patients and 8 (6-20) in resection and primary anastomoses group. There was one case (7,1%) of anastomotic dehiscence in resection and primary anastomoses group and two cases (22,2%) in staged resection group. The treatment of obstruction of left colon in one stage is safe and may be indicated for the management of the majority of cases.


Towards harmonization of microscopy methods for malaria clinical research studies.
Microscopy performed on stained films of peripheral blood for detection, identification and quantification of malaria parasites is an essential reference standard for clinical trials of drugs, vaccines and diagnostic tests for malaria. The value of data from such research is greatly enhanced if this reference standard is consistent across time and geography. Adherence to common standards and practices is a prerequisite to achieve this. The rationale for proposed research standards and procedures for the preparation, staining and microscopic examination of blood films for malaria parasites is presented here with the aim of improving the consistency and reliability of malaria microscopy performed in such studies. These standards constitute the core of a quality management system for clinical research studies employing microscopy as a reference standard. They can be used as the basis for the design of training and proficiency testing programmes as well as for procedures and quality assurance of malaria microscopy in clinical research.


Therapeutic vaccine targeting Epstein-Barr virus latent protein, LMP1, suppresses LMP1-expressing tumor growth and metastasis in vivo.
In endemic area, nasopharyngeal carcinoma (NPC) tumor cells harbor EBV latent infection and expresses viral antigens such as EBNA1, LMP1 and LMP2. In this study, we established a NPC-mimicry animal model and assessed the therapeutic potential of LMP1 vaccine. Animal models were established by injection of LMP1-expressing TC-1 cells in C57BL6/J mice subcutaneously or through tail veins. pcDNA3.1 empty vector or LMP1/pcDNA3.1 vaccine was delivered by a helium-driven gene gun. Effectiveness of vaccine was evaluated by measuring the tumor size and numbers of metastatic lung nodules. Circulating cytokines were evaluated by ELISArray. Populations of activated cytotoxic T lymphocytes (CTLs) and LMP1-specific T lymphocytes were evaluated by flow cytometry with CD8/CD107a double staining and interferon-γ ELISPOT assay, respectively. LMP1 vaccine significantly suppressed tumor growth (n = 3) and metastasis (n = 4) in vivo. When vaccinated before tumor challenge, all mice in vaccine group were tumor-free, whereas all mice in the control group developed tumors within 2 weeks after tumor challenge (n = 10). Cytokine ELISArray revealed elevation of a panel of proinflammatory cytokines in mice receiving LMP1 vaccine. Flow cytometry and interferon-γ ELISPOT assay revealed that LMP1 vaccine induced larger populations of activated CTLs and LMP1-specific T lymphocytes. This pre-clinical study provides a promising result that LMP1 vaccine suppresses LMP1-expressing tumor growth and metastasis in vivo.


Accuracy of the ABC/2 Score for Intracerebral Hemorrhage: Systematic Review and Analysis of MISTIE, CLEAR-IVH, and CLEAR III.
The ABC/2 score estimates intracerebral hemorrhage (ICH) volume, yet validations have been limited by small samples and inappropriate outcome measures. We determined accuracy of the ABC/2 score calculated at a specialized reading center (RC-ABC) or local site (site-ABC) versus the reference-standard computed tomography-based planimetry (CTP). In Minimally Invasive Surgery Plus Recombinant Tissue-Type Plasminogen Activator for Intracerebral Hemorrhage Evacuation-II (MISTIE-II), Clot Lysis Evaluation of Accelerated Resolution of Intraventricular Hemorrhage (CLEAR-IVH) and CLEAR-III trials. ICH volume was prospectively calculated by CTP, RC-ABC, and site-ABC. Agreement between CTP and ABC/2 was defined as an absolute difference up to 5 mL and relative difference within 20%. Determinants of ABC/2 accuracy were assessed by logistic regression. In 4369 scans from 507 patients, CTP was more strongly correlated with RC-ABC (r(2)=0.93) than with site-ABC (r(2)=0.87). Although RC-ABC overestimated CTP-based volume on average (RC-ABC, 15.2 cm(3); CTP, 12.7 cm3), agreement was reasonable when categorized into mild, moderate, and severe ICH (κ=0.75; P<0.001). This was consistent with overestimation of ICH volume in 6 of 8 previous studies. Agreement with CTP was greater for RC-ABC (84% within 5 mL; 48% of scans within 20%) than for site-ABC (81% within 5 mL; 41% within 20%). RC-ABC had moderate accuracy for detecting ≥5 mL change in CTP volume between consecutive scans (sensitivity, 0.76; specificity, 0.86) and was more accurate with smaller ICH, thalamic hemorrhage, and homogeneous clots. ABC/2 scores at local or central sites are sufficiently accurate to categorize ICH volume and assess eligibility for the CLEAR-III and MISTIE III studies and moderately accurate for change in ICH volume. However, accuracy decreases with large, irregular, or lobar clots. URL: http://www.clinicaltrials.gov. Unique identifier: MISTIE-II NCT00224770; CLEAR-III NCT00784134.


Synergistic antitumor activity of cisplatin and interleukin 1 in sensitive and resistant solid tumors.
The antitumor activity of cis-diamminedichloroplatinum(II) (cP) and human recombinant interleukin-1 alpha (IL-1 alpha) was studied in RIF-1 and SC VII solid tumor models and in a cP-resistant subline of RIF-1 designated RIF-R1cP. In RIF-1 tumors, clonogenic cell survival after cP plus IL-1 alpha combinations was highly schedule and IL-1 alpha dose dependent. More than additive clonogenic cell kill was seen when cP was given 6 h before, but not 8 h before or at 2-6 h after IL-1 alpha. Time course studies indicated that maximal clonogenic cell killing was achieved within 4-6 h after the cP plus IL-1 alpha combination, with little or no recovery for up to 24 h. In vivo dose-response studies indicated that cP plus IL-1 alpha combinations induced more clonogenic cell kill than cP alone in all three tumor models, and analysis by the median effect principle indicated highly synergistic antitumor activity. Dexamethasone but not indomethacin inhibited the synergistic interaction. IL-1 alpha had no effect on the cytotoxicity of cP in SCC VII cells in vitro, and neither in vitro hypoxia nor in vivo ischemia, induced by clamping tumor blood supply, significantly affected cP clonogenic cell killing. Increased clonogenic cell killing was seen, however, after removal of the clamp, implicating reperfusion events, such as oxyradical stress, as a potential mechanism for increased cP cytotoxicity in SCC VII solid tumors. The data from our model systems provide a rationale for additional work to define the mechanisms of the synergistic antitumor activity of the cP plus IL-1 alpha combination and indicate that IL-1 alpha might be a useful adjunct to increase the clinical efficacy of cP-containing strategies for both sensitive and cP-resistant cancers.


The confluence of structure and dynamics in lanthanide(III) chelates: how dynamics help define structure in solution.
Coordination exchange processes tend to dominate the solution state behaviour of lanthanide chelates and generally prohibit the study of small conformational changes. In this article we take advantage of coordinatively rigid Eu(3+) chelates to examine the small conformational changes that occur in these chelates as water dissociatively exchanges in and out of the inner coordination sphere. The results show that the time-averaged conformation of the chelate alters as the water exchange rate increases. This conformational change reflects a change in the hydration state (q/r(LnH)(6)) of the chelate. The hydration state has recently come to be expressed as two separate parameters q and r(LnH). However, these two parameters simultaneously describe the same structural considerations which in solution are indistinguishable and intrinsically related to, and dependent upon, the dissociative water exchange rate. This realization leads to the broader understanding that a solution state structure can only be appreciated with reference to the dynamics of the system.


Anticipatory postural adjustments contribute to age-related changes in compensatory steps associated with unilateral perturbations.
Compensatory steps are essential for preventing falls following perturbations. This study aimed to explore age-related changes in compensatory steps to unilateral perturbations, specifically in terms of whether anticipatory postural adjustments (APAs) play a role in stabilizing lateral balance. Five young and five elderly male adults participated. The split-belt treadmill was used to provide bi- and unilateral perturbations, as forward or backward transitions, applied 10 times in random order. Backward steps evoked by unilateral forward perturbations were evaluated. We measured temporal characteristics, mediolateral (ML) center of mass (COM) motion, and ML step length of compensatory steps. Compensatory steps to unexpected perturbations showed delayed onset of foot-off (FO) and expanded lateral swing length in elderly compared to young subjects. Differences in COM motions and step width arose related to APAs. Elderly subjects showing APAs exhibited no significant differences in ML COM, ML COM velocity, or ML swing length compared to young subjects. However, elderly subjects without APAs showed significant changes toward instability in these parameters. The fact that APAs play a notable role, particularly in the elderly, in stability offers a new insight into preventing falls. However, APAs occurred in 29% of the steps of young and 35% of the steps of elderly subjects. If the occurrence of APAs in elderly people in response to compensatory steps was more frequent, fall risk would be reduced. Further studies, particularly into APA frequency, might contribute to improved intervention to prevent falls.


Chikungunya virus mobilizes the apoptotic machinery to invade host cell defenses.
Chikungunya virus (CHIKV) surprised medical workers by a massive outbreak in the Indian Ocean region, reaching Europe in 2007, with exceptional pathologies in infants and elderly patients. Although CHIKV was recently shown to persist in myoblasts, monocytes, and macrophages, we argued that robust antiviral mechanisms, including apoptosis, are essential to ward off the virus. Herein, we tested the capacity of CHIKV to mobilize the apoptotic machinery in HeLa cells as well as primary fibroblasts, making use of several inhibitors of caspases, cell blebbing, and engulfment of the apoptotic blebs by neighboring cells. CHIKV triggered apoptosis through intrinsic and extrinsic pathways. Bystander apoptosis was also evidenced in neighboring cells in a caspase-8-dependent manner. Remarkably, by hiding in apoptotic blebs, CHIKV was able to infect neighboring cells. In HeLa cells, these events were inhibited specifically by zVAD-fmk and DEVD-cho (caspase inhibitors), blebbistatin, Y-27632 (ROCK inhibitor), and genistein, annexin V, and cytochalasin B (inhibitors of blebbing and engulfment). These CHIKV-apoptotic blebs were also capable of infecting macrophages (primary cultures, MM6- and THP1-PMA differentiated cells) otherwise refractory to infection by CHIKV alone. Remarkably, viral replication in macrophages did not yield a proinflammatory response. We describe a novel infectious mechanism by which CHIKV invades host cells and escapes the host response.


A Canadian survey on the management of corticosteroid induced osteoporosis by rheumatologists.
To survey the practice pattern of Canadian rheumatologists (CR) on their management of corticosteroid induced osteoporosis in their premenopausal (PrM) and postmenopausal (PoM) female patients. The practice pattern was surveyed using a 17 item questionnaire probing the diagnosis, prevention, treatment, and monitoring of osteoporosis in PrM and PoM women receiving longterm oral systemic corticosteroid therapy. Most CR investigated and treated osteoporosis themselves, 13% referred to other specialists for investigation, and 22% referred for treatment. Eighty-two percent of CR used dual energy x-ray absorptiometry (DEXA) to confirm a diagnosis of osteoporosis. Most CR initiated investigation for osteoporosis at the start or within the first year of starting longterm systemic corticosteroid therapy: PrM 87% and PoM 93%. The most frequently used initial strategy for the prevention of osteoporosis was as follows. PrM: calcium and vitamin D3 (53%); PoM: hormone replacement therapy (HRT) and calcium (29%). The most common initial choice for treatment of established osteoporosis was as follows: PrM: etidronate (53%); PoM: bisphosphonates +/- HRT (53%). Ninety-six percent of CR used only bone mineral density (BMD) measurement to monitor therapy for corticosteroid induced osteoporosis. Most CR monitored BMD every 12 to 24 months for PrM (81%) and PoM (84%). The BMD parameter(s) (T and Z scores as measured by DEXA) used to initiate therapy for corticosteroid induced osteoporosis was variable. It appears that, while certain trends are evident, there is still considerable variability in the management of corticosteroid induced osteoporosis.


Human DNA polymerase iota promotes replication through a ring-closed minor-groove adduct that adopts a syn conformation in DNA.
Acrolein, an alpha,beta-unsaturated aldehyde, is generated in vivo as the end product of lipid peroxidation and from oxidation of polyamines. The reaction of acrolein with the N2 group of guanine in DNA leads to the formation of a cyclic adduct, gamma-hydroxy-1,N2-propano-2'-deoxyguanosine (gamma-HOPdG). Previously, we have shown that proficient replication through the gamma-HOPdG adduct can be mediated by the sequential action of human DNA polymerases (Pols) iota and kappa, in which Poliota incorporates either pyrimidine opposite gamma-HOPdG, but Polkappa extends only from the cytosine. Since gamma-HOPdG can adopt either a ring-closed cyclic form or a ring-opened form in DNA, to better understand the mechanisms that Pols iota and kappa employ to promote replication through this lesion, we have examined the ability of these polymerases to replicate through the structural analogs of gamma-HOPdG that are permanently either ring closed or ring opened. Our studies with these model adducts show that whereas the ring-opened form of gamma-HOPdG is not inhibitory to synthesis by human Pols eta, iota, or kappa, only Poliota is able to incorporate nucleotides opposite the ring-closed form, which is known to adopt a syn conformation in DNA. From these studies, we infer that (i) Pols eta, iota, and kappa have the ability to proficiently replicate through minor-groove DNA lesions that do not perturb the Watson-Crick hydrogen bonding of the template base with the incoming nucleotide, and (ii) Poliota can accommodate a minor-groove-adducted template purine which adopts a syn conformation in DNA and forms a Hoogsteen base pair with the incoming nucleotide.


An evaluation of the 'Designated Research Team' approach to building research capacity in primary care.
This paper describes an evaluation of an initiative to increase the research capability of clinical groups in primary and community care settings in a region of the United Kingdom. The 'designated research team' (DRT) approach was evaluated using indicators derived from a framework of six principles for research capacity building (RCB) which include: building skills and confidence, relevance to practice, dissemination, linkages and collaborations, sustainability and infrastructure development. Information was collated on the context, activities, experiences, outputs and impacts of six clinical research teams supported by Trent Research Development Support Unit (RDSU) as DRTs. Process and outcome data from each of the teams was used to evaluate the extent to which the DRT approach was effective in building research capacity in each of the six principles (as evidenced by twenty possible indicators of research capacity development). The DRT approach was found to be well aligned to the principles of RCB and generally effective in developing research capabilities. It proved particularly effective in developing linkages, collaborations and skills. Where research capacity was slow to develop, this was reflected in poor alignment between the principles of RCB and the characteristics of the team, their activities or environment. One team was unable to develop a research project and the funding was withdrawn at an early stage. For at least one individual in each of the remaining five teams, research activity was sustained beyond the funding period through research partnerships and funding successes. An enabling infrastructure, including being freed from clinical duties to undertake research, and support from senior management were found to be important determinants of successful DRT development. Research questions of DRTs were derived from practice issues and several projects generated outputs with potential to change daily practice, including the use of research evidence in practice and in planning service changes. The DRT approach was effective at RCB in teams situated in a supportive organisation and in particular, where team members could be freed from clinical duties and management backing was strong. The developmental stage of the team and the research experience of constituent members also appeared to influence success. The six principles of RCB were shown to be useful as a framework for both developing and evaluating RCB initiatives.


High-value, cost-conscious health care: concepts for clinicians to evaluate the benefits, harms, and costs of medical interventions.
Health care costs in the United States are increasing unsustainably, and further efforts to control costs are inevitable and essential. Efforts to control expenditures should focus on the value, in addition to the costs, of health care interventions. Whether an intervention provides high value depends on assessing whether its health benefits justify its costs. High-cost interventions may provide good value because they are highly beneficial; conversely, low-cost interventions may have little or no value if they provide little benefit. Thus, the challenge becomes determining how to slow the rate of increase in costs while preserving high-value, high-quality care. A first step is to decrease or eliminate care that provides no benefit and may even be harmful. A second step is to provide medical interventions that provide good value: medical benefits that are commensurate with their costs. This article discusses 3 key concepts for understanding how to assess the value of health care interventions. First, assessing the benefits, harms, and costs of an intervention is essential to understand whether it provides good value. Second, assessing the cost of an intervention should include not only the cost of the intervention itself but also any downstream costs that occur because the intervention was performed. Third, the incremental cost-effectiveness ratio estimates the additional cost required to obtain additional health benefits and provides a key measure of the value of a health care intervention.


FusionSense: Emotion Classification Using Feature Fusion of Multimodal Data and Deep Learning in a Brain-Inspired Spiking Neural Network.
Using multimodal signals to solve the problem of emotion recognition is one of the emerging trends in affective computing. Several studies have utilized state of the art deep learning methods and combined physiological signals, such as the electrocardiogram (EEG), electroencephalogram (ECG), skin temperature, along with facial expressions, voice, posture to name a few, in order to classify emotions. Spiking neural networks (SNNs) represent the third generation of neural networks and employ biologically plausible models of neurons. SNNs have been shown to handle Spatio-temporal data, which is essentially the nature of the data encountered in emotion recognition problem, in an efficient manner. In this work, for the first time, we propose the application of SNNs in order to solve the emotion recognition problem with the multimodal dataset. Specifically, we use the NeuCube framework, which employs an evolving SNN architecture to classify emotional valence and evaluate the performance of our approach on the MAHNOB-HCI dataset. The multimodal data used in our work consists of facial expressions along with physiological signals such as ECG, skin temperature, skin conductance, respiration signal, mouth length, and pupil size. We perform classification under the Leave-One-Subject-Out (LOSO) cross-validation mode. Our results show that the proposed approach achieves an accuracy of 73.15% for classifying binary valence when applying feature-level fusion, which is comparable to other deep learning methods. We achieve this accuracy even without using EEG, which other deep learning methods have relied on to achieve this level of accuracy. In conclusion, we have demonstrated that the SNN can be successfully used for solving the emotion recognition problem with multimodal data and also provide directions for future research utilizing SNN for Affective computing. In addition to the good accuracy, the SNN recognition system is requires incrementally trainable on new data in an adaptive way. It only one pass training, which makes it suitable for practical and on-line applications. These features are not manifested in other methods for this problem.


Tissue localization and solubilities of αA-crystallin and its numerous C-terminal truncation products in pre- and postcataractous ICR/f rat lenses.
To investigate the tissue distribution and solubilities of various αA-crystallin truncation products in the cataractous ICR/f rat model. Rat lenses from precataractous (21-day) and postcataractous (100-day) ICR/f rats were sectioned and applied to a matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF) target plate. Mass spectrometry images were collected to obtain a macromolecular profile of the abundant lens proteins. Separately, age-matched lenses were extracted into water-soluble (WS) and water-insoluble/urea-soluble (WI-US) fractions and subjected to MALDI-TOF mass spectrometry to correlate the protein solubilities with the imaging data. Protein identities were assigned by using a top-down proteomics approach on a high-resolution mass spectrometer. Ten novel αA-crystallin truncation products were identified, along with six previously known αA-crystallin truncation products. Nearly all truncations exhibited nuclear localization, with larger truncated products displaying a ringlike localization that progressed outward toward the extranuclear, cortical region. The distributions were similar in both ages with the only significant difference being the amount of tissue area encompassed by a particular species with increasing age. Almost all nuclear products fractionated into the WI-US fraction, whereas the five largest extranuclear species exhibited mixed solubility. A successful methodology for the sectioning and imaging of pre- and postcataractous ICR/f rat lenses has been established. Data collected from these analyses indicate that there are multiple αA-crystallin truncation products present in both pre- and postcataractous rats. Furthermore, these species have defined lenticular localizations and unique solubilities that may be a consequence of lens development and protein function within the lens environment.


Allocating external financing for health: a discrete choice experiment of stakeholder preferences.
Most donors of external financing for health use allocation policies to determine which countries are eligible to receive financial support and how much support each should receive. Currently, most of these policies place a great deal of weight on income per capita as a determinant of aid allocation but there is increasing interest in putting more weight on other country characteristics in the design of such policies. It is unclear, however, how much weight should be placed on other country characteristics. Using an online discrete choice experiment designed to elicit preferences over country characteristics to guide decisions about the allocation of external financing for health, we find that stakeholders assign a great deal of importance to health inequalities and the burden of disease but put very little weight on income per capita. We also find considerable variation in preferences across stakeholders, with people from low- and middle-income countries putting more weight on the burden of disease and people from high-income countries putting more weight on health inequalities. These findings suggest that stakeholders put more weight on burden of disease and health inequalities than on income per capita in evaluating which countries should received external financing for health and that that people living in aid recipient may have different preferences than people living in donor countries. Donors may wish to take these differences in preferences in mind if they are reconsidering their aid allocation policies.


VIRUS PARTICLES IN THE THYMUS OF CONVENTIONAL AND GERM-FREE MICE.
Electron microscope study of thymuses of both conventional and germ-free mice has revealed the presence of typical virus particles associated with the thymic lymphocytes or with the thymic epithelial cells. The particles resemble those associated with several murine leukemias and their viral nature seems convincingly substantiated by morphological observation. Germ-free mice are therefore not virus-free. The biological significance of these particles is still unknown and we can only speculate as to the possible relationship of these particles to the incidence of "spontaneous" leukemia, to the lymphocytosis stimulating factor of Metcalf, and to the numerous latent viral infections of laboratory mice.


Probiotics prevent hepatic encephalopathy in patients with cirrhosis: a randomized controlled trial.
Hepatic encephalopathy (HE) is associated with a poor prognosis in patients with advanced liver disease. Probiotics alter the intestinal microbiota with non-urease-producing organisms that reduce production of ammonia. We investigated the efficacy of probiotics for the primary prophylaxis of HE. We conducted a prospective trial at a tertiary care referral institute in New Delhi, India, from January 2012 through March 2013, of patients with cirrhosis without overt HE (age, 48.6 ± 11.1 y; 96 men and 64 women); 25 were Child-Turcotte-Pugh (CTP) class A, 51 were CTP class B, and 84 were CTP class C. Subjects were assigned randomly to groups given probiotics (1 × 10(8) colony-forming units, 3 times daily; n = 86, 42 with minimal HE) or no test article (control, n = 74; 33 with minimal HE). All subjects underwent psychometric analyses, critical flicker fusion (CFF) threshold assessments, glucose hydrogen breath tests to identify small intestinal bacterial overgrowth (SIBO), and lactulose hydrogen breath tests to measure orocecal transit time (OCTT). The primary end point was the development of overt HE. At baseline, subjects in each group had comparable CTP score, model for end-stage liver disease scores, CFF assessments, psychometric hepatic encephalopathy scores, and OCTT. After a mean follow-up period of 38.6 ± 8.80 weeks for patients given probiotics and 40.3 ± 9.8 weeks for controls, 6 patients given probiotics and 7 controls died (P = .81). Three months of probiotic administration significantly reduced levels of arterial ammonia, SIBO, and OCTT; increased psychometric hepatic encephalopathy scores; and increased CFF thresholds, compared with baseline. Seven subjects in the probiotic group and 14 controls developed overt HE (P < .05; hazard ratio for controls vs probiotic group, 2.1; 95% confidence interval, 1.31-6.53). Psychometric hepatic encephalopathy scores, CTP scores, and SIBO correlated with the development of overt HE. In a prospective, randomized controlled trial, probiotics were found to be effective in preventing HE in patients with cirrhosis. Trial registration No: CTRI/2012/07/002807.


Puzzling role of genetic risk factors in human longevity: "risk alleles" as pro-longevity variants.
Complex diseases are major contributors to human mortality in old age. Paradoxically, many genetic variants that have been associated with increased risks of such diseases are found in genomes of long-lived people, and do not seem to compromise longevity. Here we argue that trade-off-like and conditional effects of genes can play central role in this phenomenon and in determining longevity. Such effects may occur as result of: (i) antagonistic influence of gene on the development of different health disorders; (ii) change in the effect of gene on vulnerability to death with age (especially, from "bad" to "good"); (iii) gene-gene interaction; and (iv) gene-environment interaction, among other factors. A review of current knowledge provides many examples of genetic factors that may increase the risk of one disease but reduce chances of developing another serious health condition, or improve survival from it. Factors that may increase risk of a major disease but attenuate manifestation of physical senescence are also discussed. Overall, available evidence suggests that the influence of a genetic variant on longevity may be negative, neutral or positive, depending on a delicate balance of the detrimental and beneficial effects of such variant on multiple health and aging related traits. This balance may change with age, internal and external environments, and depend on genetic surrounding. We conclude that trade-off-like and conditional genetic effects are very common and may result in situations when a disease "risk allele" can also be a pro-longevity variant, depending on context. We emphasize importance of considering such effects in both aging research and disease prevention.


A BEME systematic review of the effects of interprofessional education: BEME Guide No. 39.
Interprofessional education (IPE) aims to bring together different professionals to learn with, from, and about one another in order to collaborate more effectively in the delivery of safe, high-quality care for patients/clients. Given its potential for improving collaboration and care delivery, there have been repeated calls for the wider-scale implementation of IPE across education and clinical settings. Increasingly, a range of IPE initiatives are being implemented and evaluated which are adding to the growth of evidence for this form of education. The overall aim of this review is to update a previous BEME review published in 2007. In doing so, this update sought to synthesize the evolving nature of the IPE evidence. Medline, CINAHL, BEI, and ASSIA were searched from May 2005 to June 2014. Also, journal hand searches were undertaken. All potential abstracts and papers were screened by pairs of reviewers to determine inclusion. All included papers were assessed for methodological quality and those deemed as "high quality" were included. The presage-process-product (3P) model and a modified Kirkpatrick model were employed to analyze and synthesize the included studies. Twenty-five new IPE studies were included in this update. These studies were added to the 21 studies from the previous review to form a complete data set of 46 high-quality IPE studies. In relation to the 3P model, overall the updated review found that most of the presage and process factors identified from the previous review were further supported in the newer studies. In regard to the products (outcomes) reported, the results from this review continue to show far more positive than neutral or mixed outcomes reported in the included studies. Based on the modified Kirkpatrick model, the included studies suggest that learners respond well to IPE, their attitudes and perceptions of one another improve, and they report increases in collaborative knowledge and skills. There is more limited, but growing, evidence related to changes in behavior, organizational practice, and benefits to patients/clients. This updated review found that key context (presage) and process factors reported in the previous review continue to have resonance on the delivery of IPE. In addition, the newer studies have provided further evidence for the effects on IPE related to a number of different outcomes. Based on these conclusions, a series of key implications for the development of IPE are offered.


Occupational Exposure to Multi-Walled Carbon Nanotubes During Commercial Production Synthesis and Handling.
The world-wide production of carbon nanotubes (CNTs) has increased substantially in the last decade, leading to occupational exposures. There is a paucity of exposure data of workers involved in the commercial production of CNTs. The goals of this study were to assess personal exposure to multi-walled carbon nanotubes (MWCNTs) during the synthesis and handling of MWCNTs in a commercial production facility and to link these exposure levels to specific activities. Personal full-shift filter-based samples were collected, during commercial production and handling of MWCNTs, R&D activities, and office work. The concentrations of MWCNT were evaluated on the basis of EC concentrations. Associations were studied between observed MWCNT exposure levels and location and activities. SEM analyses showed MWCNTs, present as agglomerates ranging between 200 nm and 100 µm. Exposure levels of MWCNTs observed in the production area during the full scale synthesis of MWCNTs (N = 23) were comparable to levels observed during further handling of MWCNTs (N = 19): (GM (95% lower confidence limit-95% upper confidence limit)) 41 μg m(-3) (20-88) versus 43 μg m(-3) (22-86), respectively. In the R&D area (N = 11) and the office (N = 5), exposure levels of MWCNTs were significantly (P < 0.05) lower: 5 μg m(-3) (2-11) and 7 μg m(-3) (2-28), respectively. Bagging, maintenance of the reactor, and powder conditioning were associated with higher exposure levels in the production area, whereas increased exposure levels in the R&D area were related to handling of MWCNTs powder.


Estrogen receptor alpha mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen.
Estrogen is an important vasoprotective molecule that causes the rapid dilation of blood vessels by activating endothelial nitric oxide synthase (eNOS) through an unknown mechanism. In studies of intact ovine endothelial cells, 17beta-estradiol (E2) caused acute (five-minute) activation of eNOS that was unaffected by actinomycin D but was fully inhibited by concomitant acute treatment with specific estrogen receptor (ER) antagonists. Overexpression of the known transcription factor ERalpha led to marked enhancement of the acute response to E2, and this was blocked by ER antagonists, was specific to E2, and required the ERalpha hormone-binding domain. In addition, the acute response of eNOS to E2 was reconstituted in COS-7 cells cotransfected with wild-type ERalpha and eNOS, but not by transfection with eNOS alone. Furthermore, the inhibition of tyrosine kinases or mitogen-activated protein (MAP) kinase kinase prevented the activation of eNOS by E2, and E2 caused rapid ER-dependent activation of MAP kinase. These findings demonstrate that the short-term effects of estrogen central to cardiovascular physiology are mediated by ERalpha functioning in a novel, nongenomic manner to activate eNOS via MAP kinase-dependent mechanisms.


Clinical effectiveness of pneumococcal vaccination against acute myocardial infarction and stroke in people over 60 years: the CAPAMIS study, one-year follow-up.
Conflicting results have been recently reported evaluating the relationship between pneumococcal vaccination and the risk of thrombotic vascular events. This study assessed the clinical effectiveness of the 23-valent polysaccharide pneumococcal vaccine (PPV23) against acute myocardial infarction and ischaemic stroke in older adults. Population-based prospective cohort study conducted from December 1, 2008 until November 30, 2009, including all individuals ≥ 60 years-old assigned to nine Primary Care Centres in Tarragona, Spain (N = 27,204 individuals). Primary outcomes were hospitalisation for acute myocardial infarction and/or ischaemic stroke. All cases were validated by checking clinical records. The association between pneumococcal vaccination and the risk of each outcome was evaluated by Multivariable Cox proportional-hazard models (adjusted by age, sex, influenza vaccine status, presence of comorbidities and cardiovascular risk factors). Cohort members were followed for a total of 26,444 person-years, of which 34% were for vaccinated subjects. Overall incidence rates (per 1000 person-years) were 4.9 for myocardial infarction and 4.6 for ischaemic stroke. In the multivariable analysis, vaccination was associated with a marginally significant 35% lower risk of stroke (hazard ratio [HR]: 0.65; 95% confidence interval [CI]: 0.42-0.99; p = 0.046). We found no evidence for an association between pneumococcal vaccination and reduced risk of myocardial infarction (HR: 0.83; 95% CI: 0.56-1.22; p = 0.347). Our data supports a benefit of PPV23 against ischaemic stroke among the general population over 60 years, suggesting a possible protective role of pneumococcal vaccination against some acute thrombotic events.


Seeing grating-textured surface begins at the border.
Two experiments were conducted to reveal that the human visual system represents grating texture surface using a border-to-interior strategy. This strategy dictates that the visual system first registers the surface boundary contour and then sequentially spreads texture from the border to the interior of the image. Our experiments measured the perceived grating texture surface at various stimulus durations after the onset of a grating texture image. We found that the grating texture is initially seen near the boundary contours, with eventual spreading inward to the center of the image. To quantify the observation, the extent of the texture spreading from the boundary contour is measured as a function of the stimulus duration (30-500 ms). This allows us to analyze the texture spreading in retinal and cortical distances, based on human fMRI studies of the cortical magnification factor in cortical areas V1-V4, and to derive the spreading speed. We found that the spreading speed is constant when scaled according to the cortical distance. Similar findings are obtained no matter whether the grating texture image is presented monocularly or dichoptically, suggesting the generality of the border-to-interior strategy for representing surfaces.


The BEL information extraction workflow (BELIEF): evaluation in the BioCreative V BEL and IAT track.
Network-based approaches have become extremely important in systems biology to achieve a better understanding of biological mechanisms. For network representation, the Biological Expression Language (BEL) is well designed to collate findings from the scientific literature into biological network models. To facilitate encoding and biocuration of such findings in BEL, a BEL Information Extraction Workflow (BELIEF) was developed. BELIEF provides a web-based curation interface, the BELIEF Dashboard, that incorporates text mining techniques to support the biocurator in the generation of BEL networks. The underlying UIMA-based text mining pipeline (BELIEF Pipeline) uses several named entity recognition processes and relationship extraction methods to detect concepts and BEL relationships in literature. The BELIEF Dashboard allows easy curation of the automatically generated BEL statements and their context annotations. Resulting BEL statements and their context annotations can be syntactically and semantically verified to ensure consistency in the BEL network. In summary, the workflow supports experts in different stages of systems biology network building. Based on the BioCreative V BEL track evaluation, we show that the BELIEF Pipeline automatically extracts relationships with an F-score of 36.4% and fully correct statements can be obtained with an F-score of 30.8%. Participation in the BioCreative V Interactive task (IAT) track with BELIEF revealed a systems usability scale (SUS) of 67. Considering the complexity of the task for new users-learning BEL, working with a completely new interface, and performing complex curation-a score so close to the overall SUS average highlights the usability of BELIEF.Database URL: BELIEF is available at http://www.scaiview.com/belief/.


Karyotype instability in Cryptococcus neoformans infection.
The electrophoretic karyotypes of 32 clinical and 3 environmental Cryptococcus neoformans isolates from New York City were studied by contour clamped homogeneous electrophoresis. There was extensive variation among the electrophoretic karyotypes of isolates from different patients. Sequential C. neoformans isolates from patients with chronic or relapsing infection had very similar karyotypes. However, minor differences in electrophoretic karyotypes were detected among sequential isolates from 50% of the patients studied, suggesting the occurrence of chromosomal rearrangements or deletions in vivo. This hypothesis was tested by infecting mice, recovering isolates from mouse organs, and comparing the electrophoretic karyotypes before and after passage. Three clinical and three environmental strains were studied before and after passage in mice. Karyotype differences were detected after mouse passage for one clinical and two environmental strains. Our results indicate (i) extensive karyotype variation among isolates from a small geographic regions, (ii) a high frequency of electrophoretic karyotype differences among sequential isolates from individual patients, and (iii) the occurrence of electrophoretic karyotype changes during experimental infection of mice. The implications of these observations are discussed.


Uptake and effectiveness of the Children's Fitness Tax Credit in Canada: the rich get richer.
The Government of Canada implemented a Children's Fitness Tax Credit (CFTC) in 2007 which allows a non-refundable tax credit of up to $500 to register a child in an eligible physical activity (PA) program. The purposes of this study were to assess whether the awareness, uptake, and perceived effectiveness of this tax credit varied by household income among Canadian parents. An internet-based panel survey was conducted in March 2009 with a representative sample of 2135 Canadians. Of those, parents with children aged 2 to 18 years of age (n = 1004) were asked if their child was involved in organized PA programs (including dance and sports), the associated costs to register their child in these programs, awareness of the CFTC, if they had claimed the CFTC for the tax year 2007, and whether they planned to claim it in the upcoming year. Parents were also asked if they believed the CFTC has lead to their child being more involved in PA programs. Among parents, 54.4% stated their child was in organized PA and 55.5% were aware of the CFTC. Parents in the lowest income quartile were significantly less aware and less likely to claim the CFTC than other income groups. Among parents who had claimed the CFTC, few (15.6%) believed it had increased their child's participation in PA programs. More than half of Canadian parents with children have claimed the CFTC. However, the tax credit appears to benefit the wealthier families in Canada.


Microdissection TESE is superior to conventional TESE in patients with nonobstructive azoospermia caused by Y chromosome microdeletions.
Nonobstructive azoospermia is caused in up to 10% by microdeletions of the Y chromosome in the azoospermia factor (AZF) region, which is divided into three nonoverlapping areas (AZFa, AZFb and AZFc). In 25 male patients with AZF microdeletions, the results of two different techniques for surgical sperm retrieval (SR), conventional multilocular TESE and microdissection TESE, were studied retrospectively over a period of 19 years. Conventional multilocular TESE was carried out in 11 patients and microdissection TESE in 14 patients. Successful SR was possible only in patients with isolated AZFc microdeletions, so only the 20 patients with AZFc microdeletions alone were taken into account for the comparison of the both operative techniques. The sperm detection rate for conventional multilocular TESE was 25%, the sperm detection for microdissection TESE was significantly higher with 67%. In all patients, a histological examination of the testicular tissue was carried out, which showed a mixed picture, but Sertoli-cell-only syndrome in most cases. FSH was no prognostic marker for successful SR. In two of six couples performing an intracytoplasmic sperm injection until now, a pregnancy occurred.


Strengthening Integrated Care Through Population-Focused Primary Care Services: International Experiences Outside the United States.
Many high- and middle-income countries (HMICs) are experiencing a burden of comorbidity and chronic diseases. Together with increasing patient expectations, this burden is raising demand for population health-oriented innovation in health care. Using desk review and country case studies, we examine strategies applied in HMICs outside the United States to address these challenges, with a focus on and use of a new framework for analyzing primary care (PC). The article outlines how a population health approach has been supported by focusing assessment on and clustering services around social groups and multimorbidity, with support for community roles. It presents ways in which early first contact and continuity of PC, PC coordination of referral, multidisciplinary team approaches, investment in PC competencies, and specific payment and incentive models have all supported comprehensive approaches. These experiences locate PC as a site of innovation, where information technology and peer-to-peer learning networks support learning from practice.


Olanzapine alone or in combination for acute mania.
Olanzapine, an atypical antipsychotic, is used in the treatment of mania both as monotherapy and combined with other medicines. To review the efficacy and tolerability of olanzapine in the treatment of mania The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR), The Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, MEDLINE, CINAHL and PsycINFO were searched. Randomised trials comparing olanzapine with placebo or other drug in acute manic or mixed episodes. Two reviewers independently extracted data from trial reports Six trials (1422 participants) were included in the review. There was a high rate of failure to complete treatment on all treatments which may have biased the estimates of relative efficacy. Olanzapine was superior to placebo at reducing manic symptoms as monotherapy (Young Mania Rating Scale (YMRS) - weighted mean difference (WMD): -5.94, 95% CI -9.09 to -2.80) and in combination with lithium/valproate (YMRS) (WMD -4.01, 95% confidence interval -6.06 to -1.96). Olanzapine monotherapy was superior at reducing psychotic symptoms (PANSS positive symptoms subscale WMD: -3.54, 95% CI -5.28 to -1.80). Olanzapine was superior to divalproex at reducing manic symptoms (standardised mean difference (SMD): -0.29, 95% CI -0.50 to -0.08). Olanzapine did not lead to a statistically higher rate of clinical response than haloperidol (RR: 1.03, 95% CI 0.77 to 1.38). Fewer patients discontinued treatment on olanzapine than placebo (RR: 0.62, 95% CI 0.48 to 0.80). Olanzapine caused greater weight gain than placebo (WMD 1.91Kg, 95% CI 1.29 to 2.53) and somnolence (RR: 2.13 95% CI 1.62 to 2.79) but not more depressive symptoms (RR: 0.95, 95% CI 0.65 to 1.40) or movement disorder (WMD: -0.33, 95% CI -0.74 to 0.09). Olanzapine caused more prolactin elevation than placebo (RR: 4.35 95%CI 1.77 to 10.70). Olanzapine caused greater weight gain (WMD: 1.54, 95% CI 1.02 to 2.05); somnolence (RR: 1.80 95% CI 1.32 to 2.46) and movement disorders (SAS - WMD: 0.72 95% CI 0.11 to 1.33) than divalproex but less nausea ( RR: 0.36 95% CI 0.20 to 0.65). Olanzapine caused more weight gain than haloperidol (RR: 3.59, 95% CI 1.49 to 8.64) but less movement disorder (EPS RR: 0.10, 95% CI 0.04 to 0.24). Olanzapine is an effective treatment for mania and may be more efficacious than divalproex, though leads to more weight gain. Clinicians should consider both the relative efficacy and the different incidence of specific adverse effects of available drugs.


Trichodesmium genome maintains abundant, widespread noncoding DNA in situ, despite oligotrophic lifestyle.
Understanding the evolution of the free-living, cyanobacterial, diazotroph Trichodesmium is of great importance because of its critical role in oceanic biogeochemistry and primary production. Unlike the other >150 available genomes of free-living cyanobacteria, only 63.8% of the Trichodesmium erythraeum (strain IMS101) genome is predicted to encode protein, which is 20-25% less than the average for other cyanobacteria and nonpathogenic, free-living bacteria. We use distinctive isolates and metagenomic data to show that low coding density observed in IMS101 is a common feature of the Trichodesmium genus, both in culture and in situ. Transcriptome analysis indicates that 86% of the noncoding space is expressed, although the function of these transcripts is unclear. The density of noncoding, possible regulatory elements predicted in Trichodesmium, when normalized per intergenic kilobase, was comparable and twofold higher than that found in the gene-dense genomes of the sympatric cyanobacterial genera Synechococcus and Prochlorococcus, respectively. Conserved Trichodesmium noncoding RNA secondary structures were predicted between most culture and metagenomic sequences, lending support to the structural conservation. Conservation of these intergenic regions in spatiotemporally separated Trichodesmium populations suggests possible genus-wide selection for their maintenance. These large intergenic spacers may have developed during intervals of strong genetic drift caused by periodic blooms of a subset of genotypes, which may have reduced effective population size. Our data suggest that transposition of selfish DNA, low effective population size, and high-fidelity replication allowed the unusual "inflation" of noncoding sequence observed in Trichodesmium despite its oligotrophic lifestyle.


CRIMALDDI: a co-ordinated, rational, and integrated effort to set logical priorities in anti-malarial drug discovery initiatives.
Despite increasing efforts and support for anti-malarial drug R&D, globally anti-malarial drug discovery and development remains largely uncoordinated and fragmented. The current window of opportunity for large scale funding of R&D into malaria is likely to narrow in the coming decade due to a contraction in available resources caused by the current economic difficulties and new priorities (e.g. climate change). It is, therefore, essential that stakeholders are given well-articulated action plans and priorities to guide judgments on where resources can be best targeted.The CRIMALDDI Consortium (a European Union funded initiative) has been set up to develop, through a process of stakeholder and expert consultations, such priorities and recommendations to address them. It is hoped that the recommendations will help to guide the priorities of the European anti-malarial research as well as the wider global discovery agenda in the coming decade.


The sequence of structural, functional and cognitive changes in multiple sclerosis.
As disease progression remains poorly understood in multiple sclerosis (MS), we aim to investigate the sequence in which different disease milestones occur using a novel data-driven approach. We analysed a cohort of 295 relapse-onset MS patients and 96 healthy controls, and considered 28 features, capturing information on T2-lesion load, regional brain and spinal cord volumes, resting-state functional centrality ("hubness"), microstructural tissue integrity of major white matter (WM) tracts and performance on multiple cognitive tests. We used a discriminative event-based model to estimate the sequence of biomarker abnormality in MS progression in general, as well as specific models for worsening physical disability and cognitive impairment. We demonstrated that grey matter (GM) atrophy of the cerebellum, thalamus, and changes in corticospinal tracts are early events in MS pathology, whereas other WM tracts as well as the cognitive domains of working memory, attention, and executive function are consistently late events. The models for disability and cognition show early functional changes of the default-mode network and earlier changes in spinal cord volume compared to the general MS population. Overall, GM atrophy seems crucial due to its early involvement in the disease course, whereas WM tract integrity appears to be affected relatively late despite the early onset of WM lesions. Data-driven modelling revealed the relative occurrence of both imaging and non-imaging events as MS progresses, providing insights into disease propagation mechanisms, and allowing fine-grained staging of patients for monitoring purposes.


Novel chemical kinetics for a single enzyme reaction: relationship between substrate concentration and the second moment of enzyme reaction time.
We report a robust quadratic relation between the inverse substrate concentration and the second moment, <t(2)>, of the catalytic turnover time distribution for enzyme reactions. The results hold irrespective of the mechanism and dynamics of the enzyme reaction and suggest a novel single molecule experimental analysis that provides information about reaction processes of the enzyme-substrate complex and ergodicity of the enzyme reaction system, which is beyond the reach of the conventional analysis for the mean reaction time, <t>. It turns out that <t(2)> - 2<t>(2) is linear in inverse substrate concentration for an ergodic homogeneous enzyme system given that the enzyme substrate encounter is a simple rate process, and its value at the high substrate concentration limit provides direct information about if any non-Poisson reaction process of the enzyme-substrate complex. For a nonergodic heterogeneous reaction system, the corresponding quantity becomes a quadratic function of the inverse substrate concentration. This leads us to suggest an ergodicity measure for single enzyme reaction systems. We obtain a simple analytic expression of the randomness parameter for the single catalytic turnover time, which could provide a quantitative explanation about the previously reported randomness data of the beta-galactosidase enzyme. In obtaining the results, we introduce novel chemical kinetics applicable to a non-Poisson reaction network with arbitrary connectivity, as a generalization of the conventional chemical kinetics.


HIV infection, antiretroviral therapy initiation and longitudinal changes in biomarkers of organ function.
HIV is associated with end-organ diseases of aging via unclear mechanisms. Longitudinally assessing how HIV infection and ART initiation affect biomarkers of end organ function/disease could clarify these mechanisms. We investigated longitudinal changes in clinical biomarkers following 1) HIV infection and 2) ART initiation with evidence of viral suppression. Veterans Aging COHORT Study Virtual COHORT (VACS VC). VACS VC is a longitudinal cohort of HIV infected (HIV+) and race-ethnicity, sex, age, and clinical site-matched uninfected Veterans enrolled in the same calendar year. a negative and successively positive (>six months) HIV antibody test. We used Wilcoxon signedrank tests to analyze 1) the effect of HIV infection on lipids, renal, hepatic and hematologic/cardiovascular biomarkers and 2)whether ART initiation with HIV-1 RNA<500 cpm reverts any changes back to pre-HIV levels. 422 Veterans had at least 1 biomarker measurement available prior to HIV infection and prior to ART initiation. 297 had at least 1 biomarker measurement available prior to HIV infection and after ART initiation with evidence of viral suppression. Mean age prior to HIV infection was 43 years. HIV infection was associated with reduction in total cholesterol, HDL cholesterol, LDL cholesterol, serum albumin, ALT, platelet count, hemoglobin and elevation of FIB-4 score and triglycerides. These changes occurred without significant changes in BMI. ART initiation (with HIV-1 RNA<500cpm) did not reverse alteration in triglycerides, LDL cholesterol, hemoglobin, or FIB-4 to pre-HIV infection levels. HIV infection is associated with longitudinal changes in serum levels of several biomarkers of end-organ function/disease and mortality. Multiple biomarkers (triglycerides, LDL cholesterol, hemoglobin, and FIB-4 ) remain altered from levels prior to HIV infection levels even following inititiation of ART and evidence of viral suppression. These results give insights into underlying mechanisms of increased risk for aging-related chronic diseases in the context of HIV infection.


Acute atrial arrhythmogenicity and altered Ca(2+) homeostasis in murine RyR2-P2328S hearts.
The experiments explored for atrial arrhythmogenesis and its possible physiological background in recently developed hetero-(RyR2(+/S)) and homozygotic (RyR2(S/S)) RyR2-P2328S murine models for catecholaminergic polymorphic ventricular tachycardia (VT) for the first time. They complement previous clinical and experimental reports describing increased ventricular arrhythmic tendencies associated with physical activity, stress, or catecholamine infusion, potentially leading to VT and ventricular fibrillation. Atrial arrhythmogenic properties were compared at the whole animal, Langendorff-perfused heart, and single, isolated atrial myocyte levels using electrophysiological and confocal fluorescence microscopy methods. This demonstrated that: (i) electrocardiographic parameters in intact anaesthetized wild-type (WT), RyR2(+/S) and RyR2(S/S) mice were statistically indistinguishable both before and after addition of isoproterenol apart from increases in heart rates. (ii) Bipolar electrogram and monophasic action potential recordings showed significantly higher incidences of arrhythmogenesis in isolated perfused RyR2(S/S), but not RyR2(+/S), relative to WT hearts during either regular pacing or programmed electrical stimulation. The addition of isoproterenol increased such incidences in all three groups. (iii) However, there were no accompanying differences in cardiac anatomy or action potential durations at 90% repolarization and refractory periods. (iv) In contrast, episodes of diastolic Ca(2+) release were observed under confocal microscopy in isolated fluo-3-loaded RyR2(S/S), but not RyR2(+/S) or WT, atrial myocytes. The introduction of isoproterenol resulted in significant diastolic Ca(2+) release in all three groups. These findings establish acute atrial arrhythmogenic properties in RyR2-P2328S hearts and correlate these with altered Ca(2+) homeostasis in an absence of repolarization abnormalities for the first time.


Public health model identifies recruitment barriers among older adults with delirium and dementia.
Recruiting older adults and their family caregivers into research studies presents challenges. Although the literature notes some general recruitment challenges, no studies specifically address the unique challenges of recruiting older adults who have Alzheimer's Disease (AD) and their family caregivers in studies about delirium or suggest using a framework to identify barriers to recruiting this population. In conducting a pilot study about preparing family caregivers to detect delirium symptoms in older adults with (AD) the researchers used the Public Health Model for identifying barriers to recruitment. The goals of this methodological article are to: (1) briefly describe the methodology of the pilot study to illustrate how the Public Health Model was applied in the context of the present study and (2) discuss the benefits of the Public Health Model for identifying the barriers to recruitment in a study that prepared family caregivers to detect delirium symptoms in older adults with AD. The Public Health Model helped us to identify four specific barriers to recruitment (lack of knowledge about delirium, desire to maintain normalcy, protective caregiving behaviors, and older adult's fears) and ways to overcome them. The Public Health Model might also help other researchers address similar issues.


Prevalence of hypertension and associated cardiovascular risk factors in Central India.
To study the difference in the prevalence of hypertension and associated risk factors in urban and rural populations and the association of hypertension with various determinants. A community-based cross-sectional study was conducted in 48 villages and 15 urban wards of Jabalpur District of Central India. Nine hundred and thirty-nine individuals aged 20 years and above (624 from rural areas and 315 from urban areas) were included in the study. The prevalence of hypertension and associated cardiovascular risk factors was assessed in the urban and rural populations. A pretested questionnaire was used to collect data on socio-demographic, behavioral, and dietary factors. Anthropometric measurements of weight, height, waist and hip circumference, and blood pressure measurements were taken using the standard methodology. The glucose oxidase-peroxidase and cholesterol oxidase-cholesterol peroxidase methods were used to measure plasma glucose and serum cholesterol, respectively. Bivariate analysis was followed by multivariate analysis to detect the odds of getting hypertension with various risk factors for the urban and rural populations separately. Hypertension was defined as per Joint National Committee (JNC) - VII criteria. The response rate was 97%. Overall prevalence of hypertension was 17%, with 21.4% in the urban population and 14.8% in the rural population. Significantly higher mean values of weight, height, body mass index (BMI), hip circumference (HC), waist circumference (WC), waist hip ratio (WHR), systolic blood pressure (SBP), fasting blood sugar (FBS), and serum cholesterol levels were mapped in the urban population in comparison with the rural population. Multivariate logistic regression analysis identified increasing age, parental history of hypertension, tobacco smoking, tobacco chewing, physical inactivity, high estimated per capita salt consumption, and BMI ≥27.5 kg/m(2) as independent predictors for hypertension in the urban population, while in the rural population, increasing age, physical inactivity, central obesity, tobacco chewing and tobacco smoking were independent predictors for hypertension. The prevalence of hypertension and other cardiovascular risk factors was high in both urban and rural communities. Therefore, there is a need for comprehensive health promotion programs to encourage lifestyle modification.


The utility of uterine artery Doppler velocimetry in prediction of preeclampsia in a low-risk population.
The underlying pathophysiology of preeclampsia is thought to be abnormal trophoblast invasion of the spiral arteries leading to maldevelopment of uteroplacental perfusion. We estimated whether uterine artery Doppler measurements made in the early second trimester would predict the subsequent development of preeclampsia. Uterine artery Doppler measurements before 21 weeks of gestation (median 16.6 weeks) were correlated with subsequent development of preeclampsia in a cohort of 2,188 low-risk nulliparous women in a randomized control trial of antioxidant supplementation for prevention of preeclampsia. Preeclampsia developed in 165 (7.5%) women. Development of preeclampsia overall was associated with increased resistance index, pulsatility index, a pulsatility index or resistance index multiple of the median at or above the 75th percentile but not the presence of a notch or a bilateral notch before 21 weeks of gestation. The sensitivity was 43% (95% confidence interval [CI] 35-51) and specificity 67% (95% CI 65-69) for prediction of preeclampsia overall. The presence of a notch or bilateral notch, resistance index, and pulsatility index multiple of the median was significantly associated with early onset (before 34 weeks of gestation) compared with late onset or no preeclampsia (odds ratio [OR] 6.9, 95% CI 2.3-20.9; sensitivity 78%, 95% CI 52-94; specificity 66%, 95% CI 64-68). The presence of a notch or resistance index multiple of the median at or above the 75th percentile increased the odds of developing severe compared with mild or no preeclampsia (OR 2.2, 95% CI 1.4-3.7; sensitivity 53%, 95% CI 40-65; specificity 66%, 95% CI 64-68). Our data show poor sensitivity of second-trimester Doppler ultrasound measurements for prediction of preeclampsia overall in a well-characterized, low-risk, nulliparous population. The technique has utility in identifying poor trophoblast invasion of spiral arteries of a magnitude that severely compromises uteroplacental blood flow and gives early-onset disease. II.


Collaboration of allogeneic T and B lymphocytes in the primary antibody response to sheep erythrocytes in vitro.
This study provides a direct quantitative comparison of the helper effects of allogeneic and syngeneic rat T cells in the production of direct SRBC plaque-forming cell (PFC) responses by B cells in culture. In syngeneic T-B combinations, log-log plots of the number of PFC generated after 5.5 days in culture vs. the number of T cells employed as helpers showed a linear response between 10(4) and 2.5 times 10(5) T cells added. Allogeneic T-B combinations, in which the T cells possess the capacity for reactivity to major alloantigens of the B-cell donor, showed a different dose/response relationship in which PFC responses were decreased at high T/B ratios and augmented at low T/B rations. In this system responses were detected with as few as 10(3) allogeneic T cells. Use of negatively selected allogeneic T populations, specifically depleted of mixed lymphocyte interaction (MLI) and graft-vs-host reactivity for B-cell alloantigens, as helpers gave dose/response curves quantitatively identical to responses with syngeneic T-B combinations and also with F1 T-cell parental B-cell combinations. These data indicate that rat T and B cells need not share a major histocompatibility complex haplotype in order to collaborate effectively in a primary direct PFC response to SRBC in culture. In addition, the PFC response required the combinaed presence of T and B cells as well as antigen in the cultures, a finding consistent with the two signal model of B-cell activation. Finally, the dose/response data obtained suggest the possibility that although SRBC antigen is required in the cultures helper activity with low numbers of normal allogeneic T cells may not depend on T cells having specificity for this antigen.


Sequence variation in S-antigen genes of Plasmodium falciparum.
S-antigens are soluble heat-stable antigens released into the circulation at the time of schizogony of Plasmodium falciparum. Many serologically distinct S-antigens exist and we have shown that this diversity results from repetitive sequences that vary in repeat number, length, sequence and/or reading frame among different S-antigens. We present here the complete sequence of the S-antigen of a Vietnamese isolate V1. The major repeat of 33 base-pairs can be considered to be derived by a deletion event from a 45 base-pair sequence that is located at the 3' repeat boundary and is related in sequence to all S-antigen repeats known so far. We also show that the non-repetitive coding region of the S-antigen gene of V1 is identical to that of K1 and only two amino acids different to that of NF7. In contrast, the sequences are considerably different to those of the FC27 and Wellcome isolates. We conclude that S-antigen genes are highly polymorphic in the repetitive regions but show more restricted diversity in non-repetitive regions.


g-B3N3C: a novel two-dimensional graphite-like material.
: A novel crystalline structure of hybrid monolayer hexagonal boron nitride (BN) and graphene is predicted by means of the first-principles calculations. This material can be derived via boron or nitrogen atoms which are substituted by carbon atoms evenly in the graphitic BN with vacancies. The corresponding structure is constructed from a BN hexagonal ring linking an additional carbon atom. The unit cell is composed of seven atoms, three of which are boron atoms, three are nitrogen atoms, and one is a carbon atom. It shows a similar space structure as graphene, which is thus coined as g-B3N3C. Two stable topological types associated with the carbon bond formation, i.e., C-N or C-B bonds, are identified. Interestingly, distinct ground states of each type, depending on C-N or C-B bonds, and electronic bandgap as well as magnetic properties within this material have been studied systematically. Our work demonstrates a practical and efficient access to electronic properties of two-dimensional nanostructures, providing an approach to tackling open fundamental questions in bandgap-engineered devices and spintronics.


Function of activation loop tyrosine phosphorylation in the mechanism of c-Kit auto-activation and its implication in sunitinib resistance.
The activation of receptor tyrosine kinases (RTKs) is tightly regulated through a variety of mechanisms. Kinetic studies show that activation of c-Kit RTK occurs through an inter-molecular autophosphorylation. Phosphopeptide mapping of c-Kit reveals that 14-22 phosphates are added to each mol of wild-type (WT) c-Kit during the activation. Phosphorylation sites are found on the JM, kinase insert (KID), c-terminal domains and the activation loop (A-loop), but only the sites on the JM domain contribute to the kinase activation. The A-loop tyrosine (Y(823)) is not phosphorylated until very late in the activation (>90% completion), indicating that the A-loop phosphorylation is not required for c-Kit activation. A sunitinib-resistant mutant D816H that accelerates auto-activation by 184-fold shows no phosphorylation on the A-loop tyrosine after full activation. A loss-of-phosphorylation mutation Y823F remains fully competent in auto-activation. Similar to WT and D816H, the unactivated Y823F mutant binds sunitinib and imatinib with high affinity (K(D) = 5.9 nM). But unlike the WT and D816H where the activated enzymes lose the ability to bind the two drugs, activated Y823F binds the two inhibitors effectively. These observations suggest that the A-loop of activated Y823F remains flexible and can readily adopt unactivated conformations to accommodate DFG-out binders.


The role of social support in weight loss maintenance: results from the MedWeight study.
The role of social support in weight management is not fully understood, as more support has been linked to both favorable and unfavorable outcomes. We examined social support in relation to weight loss maintenance, comparing between maintainers and regainers of weight loss. The MedWeight study is a Greek registry of people who have intentionally lost ≥10 % of their weight and are either maintaining this loss for over a year (maintainers), or have regained weight (regainers). Demographics and lifestyle habits questionnaires are completed online. Dietary assessment is carried out by two telephone 24 h recalls. Perceived social support was assessed by validated scales examining support from family and friends regarding healthy eating and exercise. 289 maintainers and 122 regainers participated. Regainers received more support compared to maintainers. However, maintainers reported receiving compliments and active participation, whereas regainers receiving verbal instructions and encouragements. Maintainers who received diet support displayed improved dietary intakes, such as lower energy intake; regainers' diet was unaffected by support. Positive, rather than instructive, support appears beneficial in weight loss maintenance.


Supplementation with the antioxidant lycopene significantly decreases oxidative stress parameters and the bone resorption marker N-telopeptide of type I collagen in postmenopausal women.
To date, no intervention studies have been published demonstrating the effect of the antioxidant lycopene on bone. Postmenopausal women supplemented with lycopene had significantly increased antioxidant capacity and decreased oxidative stress and the bone resorption marker N-telopeptide (NTx). Lycopene decreases bone resorption markers and may reduce the risk of osteoporosis. We have previously shown in vitro and in vivo that lycopene from tomato is associated with a protective effect on bone, but lycopene intervention studies have not been reported. Our aim was to carry out a randomized controlled intervention study to determine whether lycopene would act as an antioxidant to decrease oxidative stress parameters, resulting in decreased bone turnover markers, thus reducing the risk of osteoporosis in postmenopausal women. Sixty postmenopausal women, 50-60 years old, were recruited. Following a 1-month washout without lycopene consumption, participants consumed either (N = 15/group): (1) regular tomato juice, (2) lycopene-rich tomato juice, (3) tomato Lyc-O-Mato lycopene capsules, or (4) placebo capsules, twice daily for total lycopene intakes of 30, 70, 30, and 0 mg/day respectively for 4 months. Serum collected after the washout, 2 and 4 months of supplementation, was assayed for cross-linked aminoterminal N-telopeptide, carotenoid content, total antioxidant capacity (TAC), lipid, and protein oxidation. Participants who consumed juice or lycopene capsules were analyzed in one group designated "LYCOPENE-supplemented". Repeated measures ANOVA showed that LYCOPENE-supplementation for 4 months significantly increased serum lycopene compared to placebo (p < 0.001). LYCOPENE-supplementation for 4 months resulted in significantly increased TAC (p < 0.05) and decreased lipid peroxidation (p < 0.001), protein oxidation (p < 0.001), and NTx (p < 0.001). These decreases in lipid peroxidation, protein oxidation, and NTx were significantly different from the corresponding changes resulting from placebo supplementation (p < 0.05, p < 0.005, and p < 0.02, respectively). Our findings suggest that the antioxidant lycopene is beneficial in reducing oxidative stress parameters and the bone resorption marker NTx.


Application of logic models in a large scientific research program.
It is the purpose of this article to discuss the development and application of a logic model in the context of a large scientific research program within the Commonwealth Scientific and Industrial Research Organisation (CSIRO). CSIRO is Australia's national science agency and is a publicly funded part of Australia's innovation system. It conducts mission-driven scientific research focussed on delivering results with relevance and impact for Australia, where impact is defined and measured in economic, environmental and social terms at the national level. The Australian Government has recently signalled an increasing emphasis on performance assessment and evaluation, which in the CSIRO context implies an increasing emphasis on ensuring and demonstrating the impact of its research programs. CSIRO continues to develop and improve its approaches to impact planning and evaluation, including conducting a trial of a program logic approach in the CSIRO Preventative Health National Research Flagship. During the trial, improvements were observed in clarity of the research goals and path to impact, as well as in alignment of science and support function activities with national challenge goals. Further benefits were observed in terms of communication of the goals and expected impact of CSIRO's research programs both within CSIRO and externally. The key lesson learned was that significant value was achieved through the process itself, as well as the outcome. Recommendations based on the CSIRO trial may be of interest to managers of scientific research considering developing similar logic models for their research projects. The CSIRO experience has shown that there are significant benefits to be gained, especially if the project participants have a major role in the process of developing the logic model.