The role of motivational and volitional factors for self-regulated running training: associations on the between- and within- person level.
Most studies examine associations between social-cognitive variables and self-regulated behavioural change across two or three occasions only. This study adopts an innovative perspective by analysing associations across 11 occasions, which allows examining patterns of associations both on the between- and within-person levels. Thirty initially untrained participants of a running training programme completed 11 monthly questionnaires. All questionnaires assessed motivational and volitional variables and self-reported running. Additionally, net running time of marathon, or half-marathon distance at the end of programme, was available. Self-efficacy turned out to be associated with intentions on the between- and within-person levels. Individual differences in change patterns and within-person fluctuations in volitional variables, intentions, and self-efficacy turned out to be consistently associated with change patterns and within-person fluctuations in self-regulated running training over time and with successfully running marathon or half-marathon distance. In contrast to examining only one facet of change, this study is the first to differentiate two components of change in health behaviour self-regulation: a systematic trend component, and a component representing within-person unsystematic fluctuations. Thus, results of the present study provide a comprehensive picture of the dynamic relations between motivational, volitional, and behavioural characteristics which occur between and within persons.


Does place of residence affect risk of suicide? a spatial epidemiologic investigation in Kentucky from 1999 to 2008.
Approximately 32,000 people take their own lives every year in the United States. In Kentucky, suicide mortality rates have been steadily increasing since 1999. Few studies in the United States have assessed spatial clustering of suicides. The purpose of this study was to identify high-risk clusters of suicide at the county level in Kentucky and assess the characteristics of those suicide cases within the clusters. A spatial epidemiological study was undertaken using suicide data for the period January 1, 1999 to December 31, 2008, obtained from the Kentucky Office of Vital Statistics. Descriptive analyses using Pearson's chi-square test and t-test were performed to determine whether differences existed in age, marital status, year, season, and suicide method between males and females, and between cases inside and outside high-risk spatial clusters. Annual age-adjusted cumulative incidence rates were also calculated. Suicide incidence rates were spatially smoothed using the Spatial Empirical Bayesian technique. Kulldorff's spatial scan statistic was applied on all suicide cases at the county level to identify counties with the highest risks of suicide. Temporal cluster analysis was also performed. There were a total of 5,551 suicide cases in Kentucky from 1999 to 2008, of which 5,237 (94%) were included in our analyses. The majority of suicide cases were males (82%). The average age of suicide victims was 45.4 years. Two statistically significant (p < 0.05) high-risk spatial clusters, involving 15 counties, were detected. The county level cumulative incidence rate in the most likely high-risk cluster ranged from 12.4 to 21.6 suicides per 100,000 persons. The counties inside both high-risk clusters had relative risks ranging from 1.24 to 1.38. Statistically significant high-risk spatial clusters of suicide were detected at the county level. This study may be useful for guiding future research and intervention efforts. Future studies will need to focus on these high-risk clusters to investigate reasons for these occurrences.


Wnt/β-Catenin Signaling Axis Is Required for TFEB-Mediated Gastric Cancer Metastasis and Epithelial-Mesenchymal Transition.
Gastric cancer remains the third leading cause of cancer-related death, and tumor metastasis is the main risk factor for poor prognosis of patients with gastric cancer. Transcription factor EB (TFEB) is a MiT family member and has been found to drive tumorigenesis in a number of tissues, whereas few studies were focused on investigating its prometastasis role and mechanism in gastric cancer. Here, we found TFEB was upregulated in gastric cancer tissues compared with adjacent normal gastric epithelial tissues. IHC analysis from gastric cancer tissue microarray revealed that TFEB in gastric cancer was correlated with depth of tumor invasion, lymph node or distant metastasis, tumor tumor-node-metastasis stage, and overall survival. Gastric cancer cells with TFEB overexpression presented an increased cell migration or invasion, and epithelial-mesenchymal transition (EMT). Furthermore, gene correlation analysis and gene set enrichment analysis enriched Wnt/β-catenin signaling pathway members in TFEB high-expression group, and the TOP/FOPflash assay verified the effect of TFEB on β-catenin transcription activity. Besides, we found that TFEB could trigger the aggregation of β-catenin in nucleus and activate its transcription, as well as facilitate the expression of Wnt/β-catenin target genes and EMT-related markers, which could be reversed by the Wnt/β-catenin inhibitor XAV-939. Collectively, TFEB enhances gastric cancer metastatic potential by activating Wnt/β-catenin signaling pathway and may become a promising therapeutic target for gastric cancer metastasis. IMPLICATIONS: Overexpressed TFEB predicts a higher rate of metastasis and worse survival in patients with gastric cancer. Mechanistically, TFEB activates Wnt/β-catenin signaling to fuel migratory and invasive activities of gastric cancer cells, as well as EMT.


The impact of graphic cigarette warning labels and smoke-free law on health awareness and thoughts of quitting in Taiwan.
The present study evaluated the impact of Taiwan's graphic cigarette warning labels and smoke-free law on awareness of the health hazards of smoking and thoughts of quitting smoking. National representative samples of 1074 and 1094 people, respectively, were conducted successfully by telephone in July 2008 (pre-law) and March 2009 (post-law). Results reveal that the prevalence of thinking about the health hazards of smoking among smokers increased from 50.6% pre-law to 79.6% post-law, while the prevalence among non-smokers increased from 68.8 to 94.1% during the same period. The prevalence rates of smokers who reported thinking of quitting rose from 30.2% pre-law to 51.7% post-law. Multivariate analyses results indicated that the implementation of graphic warning labels and the smoke-free law significantly increased the odds of awareness about the health hazards of smoking [odds ratio (OR) = 6.39, 95% confidence interval (CI) = 4.84-8.44] and thoughts of quitting smoking (OR = 2.39, 95% CI = 1.48-3.87). In conclusion, the implementation of a smoke-free law in combination with graphic cigarette warning labels has been effective in increasing thoughts about the health hazards of smoking and quitting smoking.


The Impact of Coronavirus (COVID-19) Related Public-Health Measures on Training Behaviours of Individuals Previously Participating in Resistance Training: A Cross-Sectional Survey Study.
Understanding the impact of lockdown upon resistance training (RT), and how people adapted their RT behaviours, has implications for strategies to maintain engagement in similar positive health behaviours. Further, doing so will provide a baseline for investigation of the long-term effects of these public health measures upon behaviours and perceptions, and facilitate future follow-up study. To determine how the onset of coronavirus (COVID-19), and associated 'lockdown', affected RT behaviours, in addition to motivation, perceived effectiveness, enjoyment, and intent to continue, in those who regularly performed RT prior to the pandemic. We conducted an observational, cross-sectional study using online surveys in multiple languages (English, Danish, French, German, Italian, Portuguese, Slovakian, Swedish, and Japanese) distributed across social media platforms and through authors' professional and personal networks. Adults (n = 5389; median age = 31 years [interquartile range (IQR) = 25, 38]), previously engaged in RT prior to lockdown (median prior RT experience = 7 years [IQR = 4, 12]) participated. Outcomes were self-reported RT behaviours including: continuation of RT during lockdown, location of RT, purchase of specific equipment for RT, method of training, full-body or split routine, types of training, repetition ranges, exercise number, set volumes (per exercise and muscle group), weekly frequency of training, perception of effort, whether training was planned/recorded, time of day, and training goals. Secondary outcomes included motivation, perceived effectiveness, enjoyment, and intent to continue RT. A majority of individuals (82.8%) maintained participation in RT during-lockdown. Marginal probabilities from generalised linear models and generalised estimating equations for RT behaviours were largely similar from pre- to during-lockdown. There was reduced probability of training in privately owned gyms (~ 59% to ~ 7%) and increased probability of training at home (~ 18% to ~ 89%); greater probability of training using a full-body routine (~ 38% to ~ 51%); reduced probability of resistance machines (~ 66% to ~ 13%) and free weight use (~ 96% to ~ 81%), and increased probability of bodyweight training (~ 62% to ~ 82%); reduced probability of moderate repetition ranges (~ 62-82% to ~ 55-66%) and greater probability of higher repetition ranges (~ 27% to ~ 49%); and moderate reduction in the perception of effort experienced during-training (r = 0.31). Further, individuals were slightly less likely to plan or record training during lockdown and many changed their training goals. Additionally, perceived effectiveness, enjoyment, and likelihood of continuing current training were all lower during-lockdown. Those engaged in RT prior to lockdown these behaviours with only slight adaptations in both location and types of training performed. However, people employed less effort, had lower motivation, and perceived training as less effective and enjoyable, reporting their likelihood of continuing current training was similar or lower than pre-lockdown. These results have implications for strategies to maintain engagement in positive health behaviours such as RT during-restrictive pandemic-related public health measures. PRE-REGISTRATION: https://osf.io/qcmpf . The preprint version of this work is available on SportRχiv: https://osf.io/preprints/sportrxiv/b8s7e/ .


Modeling guidance and recognition in categorical search: bridging human and computer object detection.
Search is commonly described as a repeating cycle of guidance to target-like objects, followed by the recognition of these objects as targets or distractors. Are these indeed separate processes using different visual features? We addressed this question by comparing observer behavior to that of support vector machine (SVM) models trained on guidance and recognition tasks. Observers searched for a categorically defined teddy bear target in four-object arrays. Target-absent trials consisted of random category distractors rated in their visual similarity to teddy bears. Guidance, quantified as first-fixated objects during search, was strongest for targets, followed by target-similar, medium-similarity, and target-dissimilar distractors. False positive errors to first-fixated distractors also decreased with increasing dissimilarity to the target category. To model guidance, nine teddy bear detectors, using features ranging in biological plausibility, were trained on unblurred bears then tested on blurred versions of the same objects appearing in each search display. Guidance estimates were based on target probabilities obtained from these detectors. To model recognition, nine bear/nonbear classifiers, trained and tested on unblurred objects, were used to classify the object that would be fixated first (based on the detector estimates) as a teddy bear or a distractor. Patterns of categorical guidance and recognition accuracy were modeled almost perfectly by an HMAX model in combination with a color histogram feature. We conclude that guidance and recognition in the context of search are not separate processes mediated by different features, and that what the literature knows as guidance is really recognition performed on blurred objects viewed in the visual periphery.


Warm-hot baryons comprise 5-10 per cent of filaments in the cosmic web.
Observations of the cosmic microwave background indicate that baryons account for 5 per cent of the Universe's total energy content. In the local Universe, the census of all observed baryons falls short of this estimate by a factor of two. Cosmological simulations indicate that the missing baryons have not condensed into virialized haloes, but reside throughout the filaments of the cosmic web (where matter density is larger than average) as a low-density plasma at temperatures of 10(5)-10(7) kelvin, known as the warm-hot intergalactic medium. There have been previous claims of the detection of warm-hot baryons along the line of sight to distant blazars and of hot gas between interacting clusters. These observations were, however, unable to trace the large-scale filamentary structure, or to estimate the total amount of warm-hot baryons in a representative volume of the Universe. Here we report X-ray observations of filamentary structures of gas at 10(7) kelvin associated with the galaxy cluster Abell 2744. Previous observations of this cluster were unable to resolve and remove coincidental X-ray point sources. After subtracting these, we find hot gas structures that are coherent over scales of 8 megaparsecs. The filaments coincide with over-densities of galaxies and dark matter, with 5-10 per cent of their mass in baryonic gas. This gas has been heated up by the cluster's gravitational pull and is now feeding its core. Our findings strengthen evidence for a picture of the Universe in which a large fraction of the missing baryons reside in the filaments of the cosmic web.


Radiographic abnormalities and mortality in subjects with exposure to crocidolite.
Plain chest radiographs from a one in six random sample of the workforce of the asbestos industry at Wittenoom, Western Australia between 1943 and 1966 have been classified for degree of profusion and pleural thickening by two independent observers according to the 1980 UICC-ILO Classification of Radiographs for the pneumoconioses to clarify the effect of degree of radiological abnormality on survival. A total of 1106 subjects were selected. Each subject's age, cumulative exposure to crocidolite, and time since first exposure were determined from employment records, the results of a survey of airborne concentrations of fibres > 5 mu in length conducted in 1966, and an exposure rating by an industrial hygienist and an ex-manager of the mine and mill at Wittenoom. By the end of 1986 193 subjects had died. Conditional logistic regression was used to model the relative risk of death in five separate case-control analyses in which the outcomes were deaths from: (1) all causes, (2) malignant mesothelioma, (3) lung cancer, (4) asbestosis, and (5) other causes excluding cancer and asbestosis. Up to 20 controls per case were randomly chosen from all men of the same age who were not known to have died before the date of death of the index case. After adjustment for exposure and time since first exposure, there were significant and independent effects of radiographic profusion and pleural thickening on all cause mortality. The effect of profusion was largely a result of the effect on mortality from malignant mesothelioma and asbestosis but not lung cancer. The effect of pleural thickening was greatest on mortality from other causes, mainly ischaemic heart disease. This study has shown that degree of radiographic abnormality has an independent effect on mortality from malignant mesothelioma, asbestosis, and all causes even after allowing for the effects of age, degree of exposure, and time since first exposure.


Differential regulation of blood flow-induced neovascularization and mural cell recruitment by vascular endothelial growth factor and angiopoietin signalling.
Combining nitric oxide (NO)-mediated increased blood flow with angiopoietin-1-Tie2 receptor signalling induces arteriolargenesis - the formation of arterioles from capillaries - in a model of physiological angiogenesis. This NO-Tie-mediated arteriolargenesis requires endogenous vascular endothelial growth factor (VEGF) signalling. Inhibition of VEGF signalling increases pericyte coverage in microvessels. Together these findings indicate that generation of functional neovasculature requires close titration of NO-Tie2 signalling and localized VEGF induction, suggesting that the use of exogenous VEGF expression as a therapeutic for neovascularization may not be successful. Signalling through vascular endothelial growth factor (VEGF) receptors and the tyrosine kinase with IgG and EGF domains-2 (Tie2) receptor by angiopoietins is required in combination with blood flow for the formation of a functional vascular network. We tested the hypothesis that VEGF and angiopoietin-1 (Ang1) contribute differentially to neovascularization induced by nitric oxide (NO)-mediated vasodilatation, by comparing the phenotype of new microvessels in the mesentery during induction of vascular remodelling by over-expression of endothelial nitric oxide synthase in the fat pad of the adult rat mesentery during inhibition of angiopoietin signalling with soluble Tie2 (sTie2) and VEGF signalling with soluble Fms-like tyrosine kinase receptor-1 (sFlt1). We found that NO-mediated angiogenesis was blocked by inhibition of VEGF with sFlt1 (from 881 ± 98% increase in functional vessel area to 279 ± 72%) and by inhibition of angiopoietin with sTie2 (to 337 ± 67%). Exogenous angiopoietin-1 was required to induce arteriolargenesis (8.6 ± 1.3% of vessels with recruitment of vascular smooth muscle cells; VSMCs) in the presence of enhanced flow. sTie2 and sFlt1 both inhibited VSMC recruitment (both 0%), and VEGF inhibition increased pericyte recruitment to newly formed vessels (from 27 ± 2 to 54 ± 3% pericyte ensheathment). We demonstrate that a fine balance of VEGF and angiopoietin signalling is required for the formation of a functional vascular network. Endogenous VEGF signalling prevents excess neovessel pericyte coverage, and is required for VSMC recruitment during increased nitric oxide-mediated vasodilatation and angiopoietin signalling (NO-Tie-mediated arteriogenesis). Therapeutic vascular remodelling paradigms may therefore require treatments that modulate blood flow to utilize endogenous VEGF, in combination with exogenous Ang1, for effective neovascularization.


Hepatic expression profiling identifies steatosis-independent and steatosis-driven advanced fibrosis genes.
Chronic liver disease (CLD) is associated with tissue-destructive fibrosis. Considering that common mechanisms drive fibrosis across etiologies, and that steatosis is an important cofactor for pathology, we performed RNA sequencing on liver biopsies of patients with different fibrosis stages, resulting from infection with hepatitis C virus (HCV) (with or without steatosis) or fatty liver disease. In combination with enhanced liver fibrosis score correlation analysis, we reveal a common set of genes associated with advanced fibrosis, as exemplified by those encoding the transcription factor ETS-homologous factor (EHF) and the extracellular matrix protein versican (VCAN). We identified 17 fibrosis-associated genes as candidate EHF targets and demonstrated that EHF regulates multiple fibrosis-associated genes, including VCAN, in hepatic stellate cells. Serum VCAN levels were also elevated in advanced fibrosis patients. Comparing biopsies from patients with HCV with or without steatosis, we identified a steatosis-enriched gene set associated with advanced fibrosis, validating follistatin-like protein 1 (FSTL1) as an exemplar of this profile. In patients with advanced fibrosis, serum FSTL1 levels were elevated in those with steatosis (versus those without). Liver Fstl1 mRNA levels were also elevated in murine CLD models. We thus reveal a common gene signature for CLD-associated liver fibrosis and potential biomarkers and/or targets for steatosis-associated liver fibrosis.


The efficacy and safety of statin in combination with ezetimibe compared with double-dose statin in patients with high cardiovascular risk: A meta-analysis.
Currently, statins are the first-line therapies for dyslipidemia and atherosclerotic cardiovascular disease, however, their hypolipidemic effects have not been satisfactory. We performed a meta-analysis to compare lipid-lowering efficacy and safety of ezetimibe and statin combination therapy with double-dose statin monotherapy in patients with high cardiovascular risk. Fourteen studies involving 3105 participants were included in the final analysis; 1558 (50.18%) participants received ezetimibe and statin combination therapy and 1547 (49.82%) received double-dose statin monotherapy. Eight studies reported the percentages of changes in several lipid parameters from baseline to endpoint in both groups. Lipid parameters changed more significantly in patients coadministered with ezetimibe and statin (low-density lipoprotein cholesterol [LDL-C]: MD = -9.39, 95% CI -13.36 to -5.42; non-high-density lipoprotein cholesterol [non-HDL-C]: MD = -10.36, 95% CI -14.23 to -6.50; total cholesterol [TC]: MD = -8.11, 95% CI -10.95 to -5.26; and triglyceride [TG]: MD = -5.96, 95% CI -9.12 to -2.80), with moderate to high heterogeneity among the studies. Two out of fourteen studies investigated several different statins. Our subgroup analysis showed that, compared with double-dose atorvastatin monotherapy, ezetimibe and atorvastatin combination therapy significantly decreased LDL-C, non-HDL-C, TC, and TG levels by 14.16%, 14.01%, 11.06%, and 5.96%, respectively (p < 0.001). No significant difference was found in the incidence of laboratory-related adverse events (AEs) between statin combination therapy and monotherapy. Overall, ezetimibe and statin combination therapy significantly decreased LDL-C, non-HDL-C, and TC levels in patients with high cardiovascular risk, among which ezetimibe combined with atorvastatin had the best therapeutic effect. Compared with ezetimibe and statin combination therapy, double-dose statin monotherapy did not increase the risk of AEs.


Going native? Flower use by bumblebees in English urban gardens.
Although urban gardens provide opportunities for pollinators in an otherwise inhospitable environment, most garden plants are not native to the recipient biogeographical region and their value to local pollinators is disputed. This study tested the hypothesis that bumblebees foraging in English urban gardens preferentially visited sympatric Palaearctic-range plants over species originating outside their native range. Twenty-seven surveys of flower availability and bumblebee visitation (Bombus spp.) were conducted over a 3-month summer period. Plants were categorized according to whether they were native British, Palaearctic or non-Palaearctic in origin. A phylogeny of the 119 plant species recorded was constructed and the relationship between floral abundance and the frequency of pollinator visits investigated by means of phylogenetically independent contrasts. Differentiation in utilization of plant species by the five bumblebee species encountered was investigated using niche overlap analyses. There was conflicting evidence for preferential use of native-range Palaearctic plant species by bumblebees depending on which plants were included in the analysis. Evidence was also found for niche partitioning between species based on respective preferences for native and non-native biogeographical range plants. Two bumblebees (Bombus terrestris and B. pratorum) concentrated their foraging activity on non-Palaearctic plants, while two others (B. hortorum and B. pascourum) preferred Palaearctic species. The long-running debate about the value of native and non-native garden plants to pollinators probably stems from a failure to properly consider biogeographical overlap between plant and pollinator ranges. Gardeners can encourage pollinators without consideration of plant origin or bias towards 'local' biogeographical species. However, dietary specialist bumblebees seem to prefer plants sympatric with their own biogeographical range and, in addition to the cultivation of these species in gardens, provision of native non-horticultural ('weed') species may also be important for pollinator conservation.


Stressful life events, hopelessness, and suicidal intent in patients admitted with attempted suicide in a tertiary care general hospital.
Suicide is a psychiatric emergency. Stressors in life and social variables (like marital status, family, and social support) are among the determinants of suicide. Hopelessness and suicidal intent are among the psychological variables that have shown promise in the prediction of suicide. To assess stressful life events, hopelessness, suicidal intent, and sociodemographic variables in patients of attempted suicide. Fifty consecutive patients admitted with attempted suicide were interviewed. Presumptive Stressful Life Event Scale, Beck Hopelessness Scale, and Beck Suicidal Intent Scale were used along with a semistructured pro forma for interview. Data were analyzed with statistical tests. Sixty-six percent of the participants were females, 72% were less than 30 years of age. Sixty-six percent of the patients had stressful life event score between 101 and 200 with the mean score of 127. The stressful life event score in those who considered they are in need of psychiatric help was significantly high. Most of the patients had mild (34%) and moderate (40%) degrees of hopelessness, and the mean score was 9.64. The mean suicidal intent in the participants was 25.14, when correlated with hopelessness score significant positive correlation was found. Lethality of the attempt increases with the increase in hopelessness.


Rapid divergence of mussel populations despite incomplete barriers to dispersal.
Striking genetic structure among marine populations at small spatial scales is becoming evident with extensive molecular studies. Such observations suggest isolation at small scales may play an important role in forming patterns of genetic diversity within species. Isolation-by-distance, isolation-by-environment and historical priority effects are umbrella terms for a suite of processes that underlie genetic structure, but their relative importance at different spatial and temporal scales remains elusive. Here, we use marine lakes in Indonesia to assess genetic structure and assess the relative roles of the processes in shaping genetic differentiation in populations of a bivalve mussel (Brachidontes sp.). Marine lakes are landlocked waterbodies of similar age (6,000-10,000 years), but with heterogeneous environments and varying degrees of connection to the sea. Using a population genomic approach (double-digest restriction-site-associated DNA sequencing), we show strong genetic structuring across populations (range FST : 0.07-0.24) and find limited gene flow through admixture plots. At large spatial scales (>1,400 km), a clear isolation-by-distance pattern was detected. At smaller spatial scales (<200 km), this pattern is maintained, but accompanied by an association of genetic divergence with degree of connection. We hypothesize that (incomplete) dispersal barriers can cause initial isolation, allowing priority effects to give the numerical advantage necessary to initiate strong genetic structure. Priority effects may be strengthened by local adaptation, which the data may corroborate by showing a high correlation between mussel genotypes and temperature. Our study indicates an often-neglected role of (evolution-mediated) priority effects in shaping population divergence.


Forensic psychiatry and the internet: practical perspectives on sexual predators and obsessional harassers in cyberspace.
The growth of the Internet has revolutionized how society conducts business in many areas. Not to be left behind, the sexual predator and the obsessional harasser have found cyberspace to be a vehicle capable of meeting their needs: obtaining information, monitoring and contacting victims, developing fantasy, overcoming inhibitions, avoiding apprehension, and communicating with other offenders. Although clearly disparate offender categories, these two groups are included in this article because of the likelihood of their using the Internet in pursuit of their goals. Forensic psychiatrists should become familiar with computers and the Internet so that they can conduct relevant psychiatric evaluations of such individuals and can advise attorneys, victims, and law enforcement personnel competently, when retained in that capacity. This article discusses the Internet and its use by the sexual predator and the obsessional harasser, highlighting information of interest to the forensic psychiatrist, including the poorly understood field of digital evidence. Aspects of the Internet, such as on-line dating and cybersex also are covered, because they relate to sexual predation and stalking.


COHORT PROFILE: The Complications of Long-Term Antiretroviral Therapy study in Uganda (CoLTART), a prospective clinical cohort.
Antiretroviral therapy (ART) improves the survival and quality of life of HIV-positive individuals, but the effects of long-term ART use do eventually manifest. The Complications of Long-Term Antiretroviral Therapy cohort study in Uganda (CoLTART) was established to investigate the metabolic and renal complications of long-term ART use among Ugandan adults. We describe the CoLTART study set-up, aims, objectives, study methods, and also report some preliminary cross-sectional study enrolment metabolic and renal complications data analysis results. HIV-positive ART naïve and experienced adults (18 years and above) in Uganda were enrolled. Data on demographic, dietary, medical, social economic and behaviour was obtained; and biophysical measurements and a clinical examination were undertaken. We measured: fasting glucose and lipid profiles, renal and liver function tests, full blood counts, immunology, virology and HIV drug resistance testing. Plasma samples were stored for future studies. Between July 2013 and October 2014, we enrolled 1095 individuals, of whom 964 (88.0%) were ART experienced (6 months or more), with a median of 9.4 years (IQR 7.0-9.9) on ART. Overall, 968 (88.4%) were aged 35 years and above, 711 (64.9%) were females, 608 (59.6%) were or had ever been on a Tenofovir ART regimen and 236 (23.1%) on a Protease Inhibitor (PI) regimen. There were no differences in renal dysfunction between patients on Tenofovir and Non-Tenofovir containing ART regimens. Patients on PI regimens had higher total cholesterol, lower high density lipoprotein, higher low density lipoprotein, higher triglycerides, and a high atherogenic index for plasma than the non-PI regimen, p = 0.001 or < 0.001. Patients on Non-PI regimens had higher mean diastolic hypertension than patients on PI regimens, p < 0.001. Our finding of no differences in renal dysfunction between patients on Tenofovir and those on Non-Tenofovir containing ART regimens means that Tenofovir based first line ART can safely be initiated even in settings without routine renal function monitoring. However, integration of cardiovascular risk assessment, preventive and curative measures against cardiovascular disease are required. The CoLTART cohort is a good platform to investigate the complications of long-term ART use in Uganda.


Large-loop excision of the transformation zone: effect on the pathologic interpretation of resection margins.
To determine the effect of large-loop excision of the transformation zone (LLETZ) on the ability to interpret adequately the pathologic specimen and surgical margins. Fifty consecutive LLETZ specimens were used for repeat histopathologic assessment with emphasis on the interpretability of the surgical specimen and margin. All reevaluations were performed by a single pathologist. Complete lesion evaluability was defined as satisfactory accuracy of the histologic diagnosis and the ability to evaluate thoroughly all surgical margins. Medical records of the patients from whom the specimens were obtained were reviewed and analyzed for possible correlates to the status of specimen interpretability. Histologic accuracy was sufficient in 46 cases (92%). Extensive heat distortion precluded full assessment of the ectocervical margins in ten (20%) and the endocervical margins in 22 (44%) of the cases. There was no difference in complete lesion evaluability whether LLETZ was performed solely for treatment in cases suitable for ablative procedures or for both diagnosis and treatment in patients who traditionally would have undergone a cone biopsy. If the latter group (N = 25) was analyzed separately, extensive heat distortion made histopathologic diagnosis impossible in four cases (16%) and precluded full assessment of the ectocervical margin in eight (32%) and the endocervical margin in 12 (48%). The high rate of surgical-margin thermal destruction, with related limitation of interpretability, may represent a serious diagnostic and therapeutic limitation of the LLETZ procedure when considered as an alternative to cold knife conization.


Use of complementary and alternative medicine by patients presenting to a Paediatric Emergency Department.
Although the popularity of complementary and alternative medicine (CAM) has risen in the last decade, information about its use by paediatric patients presenting to an Emergency Department is still sparse. We report here the results of a cross-sectional survey of paediatric patients presenting to an urban, tertiary paediatric Emergency Department between October 2006 and March 2007. In total, 1143 questionnaires (68% of those distributed) were completed and available for analysis. Of these, 58% (n = 665) of all respondents admitted that their child had received some form of CAM therapy, while 25% (n = 291) admitted that their child was receiving CAM for the present illness. In 31% of the respondents (n = 354), CAM had been prescribed by a physician, while 50% (n = 575) used CAM as self-medication. Patients presented to the Emergency Department mostly because of an infection (42% of total; 29% of these used CAM) or a trauma (38% of total; 19% of these used CAM). Parents of CAM-users were significantly older, more often born in Switzerland and had significantly higher school education than those of the non-users. Nearly two-thirds of the administered CAM therapies were not prescribed by a physician, and 50% of the families using CAM did not discuss this with their general practitioner. Parental requirements implied that medical professionals on a paediatric Emergency Department should know the effects and side-effects of CAM therapies and even be able to recommend them. The study population, even trauma patients, frequently used CAM. The use of CAM is characterised by a high rate of self-medication and the exclusion of the physicians from the decision-making process. The parents of paediatric patients frequently demand that CAM be considered as a possible treatment option and wish to have an open discussion with the medical professionals on this topic.


The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn's and Colitis Organization: when to start, when to stop, which drug to choose, and how to predict response?
The advent of biological therapy has revolutionized inflammatory bowel disease (IBD) care. Nonetheless, not all patients require biological therapy. Selection of patients depends on clinical characteristics, previous response to other medical therapy, and comorbid conditions. Availability, reimbursement guidelines, and patient preferences guide the choice of first-line biological therapy for luminal Crohn's disease (CD). Infliximab (IFX) has the most extensive clinical trial data, but other biological agents (adalimumab (ADA), certolizumab pegol (CZP), and natalizumab (NAT)) appear to have similar benefits in CD. Steroid-refractory, steroid-dependent, or complex fistulizing CD are indications for starting biological therapy, after surgical drainage of any sepsis. For fistulizing CD, the efficacy of IFX for inducing fistula closure is best documented. Unique risks of NAT account for its labeling as a second-line biological agent in some countries. Patients who respond to induction therapy benefit from systematic re-treatment. The combination of IFX with azathioprine is better than monotherapy for induction of remission and mucosal healing up to 1 year in patients who are naïve to both agents. Whether this applies to other agents remains unknown. IFX is also effective for treatment-refractory, moderate, or severely active ulcerative colitis. Patients who have a diminished or loss of response to anti-tumor necrosis factor (TNF) therapy may respond to dose adjustment of the same agent or switching to another agent. Careful consideration should be given to the reasons for loss of response. There are insufficient data to make recommendations on when to stop anti-TNF therapy. Preliminary evidence suggests that a substantial proportion of patients in clinical remission for >1 year, without signs of active inflammation can remain in remission after stopping treatment.


Intramolecular energy transfer within butadiyne-linked chlorophyll and porphyrin dimer-faced, self-assembled prisms.
The synthesis and photophysical properties of butadiyne-linked chlorophyll and porphyrin dimers in toluene solution and in several self-assembled prismatic structures are described. The butadiyne linkage between the 20-positions of the macrocycles results in new electronic transitions polarized along the long axes of the dimers. These transitions greatly increase the ability of these dimers to absorb the solar spectrum over a broad wavelength range. Femtosecond transient absorption spectroscopy reveals the relative rate of rotation of the macrocycles around the butadiyne bond joining them. Following addition of 3-fold symmetric, metal-coordinating ligands, both macrocyclic dimers self-assemble into prismatic structures in which the dimers comprise the faces of the prisms. These structures were confirmed by small-angle X-ray scattering experiments in solution using a synchrotron source. Photoexcitation of the prismatic assemblies reveals that efficient, through-space energy transfer occurs between the macrocyclic dimers within the prisms. The distance dependence of energy transfer between the faces of the prisms was observed by varying the size of the prismatic assemblies through the use of 3-fold symmetric ligands having arms with different lengths. These results show that self-assembly of discrete macrocyclic prisms provides a useful new strategy for controlling singlet exciton flow in antenna systems for artificial photosynthesis and solar cell applications.


Liver X receptors interfere with the deleterious effect of diethylstilbestrol on testicular physiology.
Liver X receptors LXRα (NR1H3) and LXRβ (NR1H2) are transcription factors belonging to the nuclear receptor superfamily, activated by specific oxysterols, oxidized derivatives of cholesterol. These receptors are involved in the regulation of testis physiology. Lxr-deficient mice pointed to the physiological roles of these nuclear receptors in steroid synthesis, lipid homeostasis and germ cell apoptosis and proliferation. Diethylstilbestrol (DES) is a synthetic estrogen considered as an endocrine disruptor that affects the functions of the testis. Various lines of evidences have made a clear link between estrogens, their nuclear receptors ERα (NR3A1) and ERβ (NR3A2), and Lxrα/β. As LXR activity could also be regulated by the nuclear receptor small heterodimer partner (SHP, NR0A2) and DES could act through SHP, we wondered whether LXR could be targeted by estrogen-like endocrine disruptors such as DES. For that purpose, wild-type and Lxr-deficient mice were daily treated with 0.75 μg DES from days 1 to 5 after birth. The effects of DES were investigated at 10 or 45 days of age. We demonstrated that DES induced a decrease of the body mass at 10 days only in the Lxr-deficient mice suggesting a protective effect of Lxr. We defined three categories of DES-target genes in testis: those whose accumulation is independent of Lxr; those whose accumulation is enhanced by the lack of both Lxrα/β; those whose accumulation is repressed by the absence of Lxrα/β. Lipid accumulation is also modified by neonatal DES injection. Lxr-deficient mice present different lipid profiles, demonstrating that DES could have its effects in part due to Lxrα/β. Altogether, our study shows that both nuclear receptors Lxrα and Lxrβ are not only basally important for testicular physiology but could also have a preventive effect against estrogen-like endocrine disruptors.


Tumour characteristics and survival in patients with invasive interval breast cancer classified according to mammographic findings at the latest screening: a comparison of true interval and missed interval cancers.
The aim of this study was to investigate whether different mammographic categories of interval cancer classified according to findings at the latest screening are associated with different distributions of prognostic factors or with different survival rates. The series consisted of all patients with invasive interval cancer detected from May 1978 to August 1995 (n = 544). The tumours were evaluated with regard to age, radiological category, interval between the latest screen and diagnosis and tumour characteristics at the time of diagnosis. We investigated possible relationships between the survival rate of patients with interval cancer and the interval between the latest screen and diagnosis, tumour characteristics and radiological category of the interval tumours. The study focused on comparison of patients with true interval and missed interval cancer. Women with mammographically occult tumours were younger than those in the other radiological categories. Comparisons of true interval cancers with overlooked or misinterpreted tumours showed equal distributions of age, tumour size, TNM stage and lymph node status. The overlooked or misinterpreted tumours showed significantly higher proportions of grade-I tumours (22 vs 11 %), tumours with low S-phase fraction (SPF; 44 vs 24 %) and oestrogen receptor (ER) positive tumours (72 vs 57 %). However, analyses of survival rates disclosed no clear differences between the two radiological categories. Radiological category and interval between the latest screen and diagnosis were not genuine predictors of the prognosis in patients with invasive interval breast cancer. No certain prognostic difference existed between true interval cancers and overlooked or misinterpreted interval breast cancers, despite higher proportions of grade-I tumours, ER positive tumours and tumours with low SPF in the latter group.


Tumor microRNAs Identified by Small RNA Sequencing as Potential Response Predictors in Locally Advanced Rectal Cancer Patients Treated With Neoadjuvant Chemoradiotherapy.
Rectal cancer accounts for approximately one-third of all colorectal cancers. Currently, the standard treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy (CRT) with capecitabine or 5-fluorouracil followed by curative surgery. Unfortunately, only 20% of patients with LARC present complete pathological response after CRT, whereas in 20-40% cases the response is poor or absent. The aim of our study was to evaluate whether microRNAs (miRNAs) in tumor biopsy specimen have the potential to predict therapeutic response in LARC patients. In total 87 LARC patients treated by CRT were enrolled in our prospective study. To identify predictive miRNAs, we used small RNA sequencing in 40 tumor biopsy samples of LARC patients (20 responders, 20 non-responders) and qPCR validation of selected miRNA candidates. In the discovery phase of the study, we identified 69 miRNAs to have significantly different expression between the group of responders (TRG 1,2) and a group of non-responders (TRG 4,5) to neoadjuvant CRT. Among these miRNAs, 48 showed a lower expression and 21 showed higher expression in tumor tissues from poorly responding LARC patients. Five miRNAs were selected for validation, but only miR-487a-3p was confirmed to have a significantly higher expression in the tumor biopsy specimens of non-responders to neoadjuvant CRT (p<0.0006, AUC=0.766). Gene Ontology (GO) clustering and pathway enrichment analysis of the miR-487a-3p mRNA targets, revealed potential mechanisms behind miR-487a-3p roles in chemoradioresistance (e.g. TGF-beta signaling pathway, protein kinase activity, double-stranded DNA binding, or microRNAs in cancer). By combination of miRNA expression profiling and integrative computational biology we identified miR-487a-3p as a potential predictive biomarker of CRT response in LARC patients.


Assessing the Genetic Landscape of Animal Behavior.
Although most animal behaviors are associated with some form of heritable genetic variation, we do not yet understand how genes sculpt behavior across evolution, either directly or indirectly. To address this, I here compile a data set comprised of over 1000 genomic loci representing a spectrum of behavioral variation across animal taxa. Comparative analyses reveal that courtship and feeding behaviors are associated with genomic regions of significantly greater effect than other traits, on average threefold greater than other behaviors. Investigations of whole-genome sequencing and phenotypic data for 87 behavioral traits from the Drosophila Genetics Reference Panel indicate that courtship and feeding behaviors have significantly greater genetic contributions and that, in general, behavioral traits overlap little in individual base pairs but increasingly interact at the levels of genes and traits. These results provide evidence that different types of behavior are associated with variable genetic bases and suggest that, across animal evolution, the genetic landscape of behavior is more rugged, yet predictable, than previously thought.


Evidence that chronic alcohol exposure promotes intestinal oxidative stress, intestinal hyperpermeability and endotoxemia prior to development of alcoholic steatohepatitis in rats.
Not all alcoholics develop liver disease (ALD). Thus, excessive ethanol consumption is necessary, but not sufficient, to induce alcoholic steatohepatitis (ASH) and ALD. Since endotoxemia is present in patients with ALD, it has been proposed that gut-derived, circulating endotoxin is the necessary co-factor for ASH. But, it is not known whether endotoxemia is the consequence or the trigger for ALD. Accordingly, the aim of the current study was to determine whether endotoxemia occurs prior to development of ASH and whether gut leakiness is the primary cause of the endotoxemia in an animal model of ASH. Time courses for development of gut hyperpermeability, nitric oxide production, oxidative injury to the gut, endotoxemia, and liver injury were assessed in rats during 10 weeks of daily alcohol gavage. Liver fat and serum transaminase increased after 2 weeks, but evidence of liver cell injury and inflammation (ASH) occurred after 8 weeks. Gut leakiness, intestinal oxidative injury, and endotoxemia occurred in weeks 2-4 and progressed thereafter. That alcohol-induced gut leakiness and endotoxemia preceded steatohepatitis indicates they are not the consequence of ALD. Our data support the hypothesis that gut leakiness resulting in endotoxemia is a key co-factor (trigger) for ASH.


The cell cycle and sorting behaviour in Dictyostelium discoideum.
Synchronized cells of the cellular slime mould Dictyostelium discoideum were prepared by mitotic wash-off. Cell counts and DNA synthesis measurements indicated a high degree of synchrony. Cells from each phase of the cell cycle were fluorescently labelled and mixed with unlabelled asynchronous cells. Cells that were in S-phase and very early G2 at the onset of starvation demonstrated a strong tendency to sort to the tip of the subsequent slugs. With reference to these results and published evidence, we discuss the possible role of cell-cycle-related adhesion differences in cell sorting.


Trade and Geography in the Spread of Islam.
In this study we explore the historical determinants of contemporary Muslim representation. Motivated by a plethora of case studies and historical accounts among Islamicists stressing the role of trade for the adoption of Islam, we construct detailed data on pre-Islamic trade routes, harbors, and ports to determine the empirical regularity of this argument. Our analysis - conducted across countries and across ethnic groups within countries - establishes that proximity to the pre-600 CE trade network is a robust predictor of today's Muslim adherence in the Old World. We also show that Islam spread successfully in regions that are ecologically similar to the birthplace of the religion, the Arabian Peninsula. Namely, territories characterized by a large share of arid and semiarid regions dotted with few pockets of fertile land are more likely to host Muslim communities. We discuss the various mechanisms that may give rise to the observed pattern.


Root-Lesion Nematodes Suppress Cabbage Aphid Population Development by Reducing Aphid Daily Reproduction.
Empirical studies have shown that belowground feeding herbivores can affect the performance of aboveground herbivores in different ways. Often the critical life-history parameters underlying the observed performance effects remain unexplored. In order to better understand the cause for the observed effects on aboveground herbivores, these ecological mechanisms must be better understood. In this study we combined empirical experiments with a modeling approach to analyze the effect of two root feeding endoparasitic nematodes with different feeding strategies on the population growth of the aboveground feeding specialist aphid Brevicoryne brassicae on Brassica nigra. The aim was to test whether emerging differences in life history characteristics (days until reproduction, daily reproduction) would be sufficient to explain observed differences in aphid population development on plants with and without two species of nematodes. Aphid numbers were lower on plants with Pratylenchus penetrans in comparison to aphid numbers on plants with Meloidogyne spp. A dedicated experiment showed that aphid daily reproduction was lower on plants with P. penetrans (3.08 offspring female(-1) day(-1)) in comparison to both uninfested plants and plants with Meloidogyne spp. (3.50 offspring female(-1) day(-1)). The species-specific reduction of aphid reproduction appeared independent of changes in amino acids, soluble sugars or the glucosinolate sinigrin in the phloem. An individual-based model revealed that relatively small differences in reproduction rate per female were sufficient to yield a similar difference in aphid populations as was found in the empirical experiments.


Role of the parasympathetic nervous system in airway hyperresponsiveness after ozone inhalation.
Airway hyperresponsiveness develops in dogs after ozone inhalation. This study examined the role of the parasympathetic nervous system in ozone-induced airway hyperresponsiveness in dogs. Dose-response curves to acetylcholine (n = 8) and histamine (n = 4) were measured before and after exposure to ozone (3 ppm for 30 min). The provocative concentration of each agonist was measured on two randomly assigned days separated by at least 1 wk. On one day a control experiment was performed, and on the other day the dogs were pretreated with the ganglionic blocker hexamethonium bromide in doses that block ganglionic transmission. The acetylcholine provocative concentration decreased on the control day from 5.5 mg/ml (%SE 1.8) before ozone to 0.5 mg/ml (%SE 2.0) after ozone (P less than 0.0001). After pretreatment with hexamethonium the acetylcholine provocative concentration decreased from 9.0 mg/ml (%SE 1.8) before ozone to 1.0 mg/ml (%SE 2.0) after ozone (P = 0.002). The results were similar when histamine was used as the agonist. Therefore, ganglionic blockade does not prevent airway hyperresponsiveness after ozone inhalation, and a parasympathetic reflex mechanism is not responsible for airway hyperresponsiveness after ozone inhalation in dogs.


Tunneling conductivity in anisotropic nanofiber composites: a percolation-based model.
The critical path approximation ('CPA') is integrated with a lattice-based approach to percolation to provide a model for conductivity in nanofiber-based composites. Our treatment incorporates a recent estimate for the anisotropy in tunneling-based conductance as a function of the relative angle between the axes of elongated nanoparticles. The conductivity is examined as a function of the volume fraction, degree of clustering, and of the mean value and standard deviation of the orientational order parameter. Results from our calculations suggest that the conductivity can depend strongly upon the standard deviation in the orientational order parameter even when all the other variables (including the mean value of the order parameter 〈S〉) are held invariant.


Repeated and targeted transfer of angiogenic plasmids into the infarcted rat heart via ultrasound targeted microbubble destruction enhances cardiac repair.
Ultrasound-targeted microbubble destruction (UTMD) uses ultrasound energy to selectively deliver genes into the myocardium using plasmids conjugated to microbubbles. We hypothesized that repeated delivery of stem cell-mobilizing genes could boost the ability of this therapy to enhance cardiac repair and ventricular function after a myocardial infarction. Beginning 7 days after coronary artery ligation, stem cell factor (SCF) and stromal cell-derived factor (SDF)-1α genes were administered to adult rats using 1, 3, or 6 UTMD treatments (repeat 1, 3, and 6 groups) at 2-day intervals (control=6 treatments with empty plasmid). Cardiac function (echocardiography) and myocardial perfusion (myocardial contrast echocardiography) were assessed on Days -7, 0, and 24 relative to the first treatment. Histological and biochemical assessments were performed on Day 24. Multiple UTMD treatments were associated with an increased presence of myocardial SCF and SDF-1α proteins and their receptors (vs. control and Repeat 1). All UTMD recipients exhibited increased vascular densities and smaller infarct regions (vs. control), with the highest ventricular densities in response to multiple treatments. Myocardial perfusion and ventricular function at Day 24 also improved progressively (vs. control) with the number of UTMD treatments. Targeted ultrasound delivery of SCF and SDF-1α genes to the infarcted myocardium recruited progenitor cells and increased vascular density. Multiple UTMD treatments enhanced tissue repair, perfusion, and cardiac function. Repeated UTMD therapy may be applied to tailor the number of interventions required to optimize cardiac regeneration after an infarction.


Inverse axial mounting stiffness design for lithographic projection lenses.
In order to balance axial mounting stiffness of lithographic projection lenses and the image quality under dynamic working conditions, an easy inverse axial mounting stiffness design method is developed in this article. Imaging quality deterioration at the wafer under different axial vibration levels is analyzed. The desired image quality can be determined according to practical requirements, and axial vibrational tolerance of each lens is solved with the damped least-squares method. Based on adaptive interval adjustment, a binary search algorithm, and the finite element method, the axial mounting stiffness of each lens can be traveled in a large interval, and converges to a moderate numerical solution which makes the axial vibrational amplitude of the lens converge to its axial vibrational tolerance. Model simulation is carried out to validate the effectiveness of the method.


Dual role for the RNA-binding domain of Xenopus laevis SLBP1 in histone pre-mRNA processing.
The replication-dependent histone mRNAs end in a conserved 26-nt sequence that forms a stem-loop structure. This sequence is required for histone pre-mRNA processing and plays a role in multiple aspects of histone mRNA metabolism. Two proteins that bind the 3' end of histone mRNA are found in Xenopus oocytes. xSLBP1 is found in the nucleus, where it functions in histone pre-mRNA processing, and in the cytoplasm, where it may control histone mRNA translation and stability. xSLBP2 is a cytoplasmic protein, inactive in histone pre-mRNA processing, whose expression is restricted to oogenesis and early development. These proteins are similar only in their RNA-binding domains (RBD). A chimeric protein (1-2-1) in which the RBD of xSLBP1 has been replaced with the RBD of xSLBP2 binds the stem-loop with an affinity similar to the original protein. The 1-2-1 protein efficiently localizes to the nucleus of the frog oocyte, but is not active in processing of histone pre-mRNA in vivo. This protein does not support processing in a nuclear extract, but inhibits processing by competing with the active SLBP by binding to the substrate. The 1-2-1 protein also inhibits processing of synthetic histone pre-mRNA injected into frog oocytes, but has no effect on processing of histone pre-mRNA transcribed from an injected histone gene. This result suggests that sequences in the RBD of xSLBP1 give it preferential access to histone pre-mRNA transcribed in vivo.


Aggregation dynamics, structure, and mechanical properties of bigels.
Recently we have introduced bigels, inter-penetrating gels made of two different colloidal species. Even if particles with simple short-range isotropic potential are employed, the selective interactions enable the tunability of the self-assembly, leading to the formation of complex structures. In the present paper, we explore the non-equilibrium dynamics and the phenomenology underlying the kinetic arrest under quench and the formation of bigels. We demonstrate that the peculiar bigel kinetics can be described through an arrested spinodal decomposition driven by demixing of the colloidal species. The role played by the presence of a second colloidal species on the phase diagram, as expanded to account for the increased number of parameters, is clarified both via extensive numerical simulations and experiments. We provide details on the realisation of bigels, by means of DNA-coated colloids (DNACCs), and the consequent imaging techniques. Moreover we evidence, by comparison with the usual one-component gel formation, the emergence of controllable timescales in the aggregation of the bigels, whose final stages are also experimentally studied to provide morphological details. Finally, we use numerical models to simulate the bigel response to mechanical strain, highlighting how such a new material can bear significantly higher stress compared to the usual one-component gel. We conclude by discussing possible technological uses and by providing insights on the viable research steps to undertake for more complex and yet tuneable multi-component colloidal systems.


Differential Regulation of Genes Involved in Root Morphogenesis and Cell Wall Modification is Associated with Salinity Tolerance in Chickpea.
Salinity is a major constraint for intrinsically salt sensitive grain legume chickpea. Chickpea exhibits large genetic variation amongst cultivars, which show better yields in saline conditions but still need to be improved further for sustainable crop production. Based on previous multi-location physiological screening, JG 11 (salt tolerant) and ICCV 2 (salt sensitive) were subjected to salt stress to evaluate their physiological and transcriptional responses. A total of ~480 million RNA-Seq reads were sequenced from root tissues which resulted in identification of 3,053 differentially expressed genes (DEGs) in response to salt stress. Reproductive stage shows high number of DEGs suggesting major transcriptional reorganization in response to salt to enable tolerance. Importantly, cationic peroxidase, Aspartic ase, NRT1/PTR, phosphatidylinositol phosphate kinase, DREB1E and ERF genes were significantly up-regulated in tolerant genotype. In addition, we identified a suite of important genes involved in cell wall modification and root morphogenesis such as dirigent proteins, expansin and casparian strip membrane proteins that could potentially confer salt tolerance. Further, phytohormonal cross-talk between ERF and PIN-FORMED genes which modulate the root growth was observed. The gene set enrichment analysis and functional annotation of these genes suggests they may be utilised as potential candidates for improving chickpea salt tolerance.


Detecting female precise natal philopatry in green turtles using assignment methods.
It is well established that sea turtles return to natal rookeries to mate and lay their eggs, and that individual females are faithful to particular nesting sites within the rookery. Less certain is whether females are precisely returning to their natal beach. Attempts to demonstrate such precise natal philopatry with genetic data have had mixed success. Here we focused on the green turtles of three nesting sites in the Ascension Island rookery, separated by 5-15 km. Our approach differed from previous work in two key areas. First, we used male microsatellite data (five loci) reconstructed from samples collected from their offspring (N = 17) in addition to data for samples taken directly from females (N = 139). Second, we employed assignment methods in addition to the more traditional F-statistics. No significant genetic structure could be demonstrated with F(ST). However, when average assignment probabilities of females were examined, those for nesting populations in which they were sampled were indeed significantly higher than their probabilities for other populations (Mann-Whitney U-test: P < 0.001). Further evidence was provided by a significant result for the mAI(C) test (P < 0.001), supporting greater natal philopatry for females compared with males. The results suggest that female natal site fidelity was not sufficient for significant genetic differentiation among the nesting populations within the rookery, but detectable with assignment tests.


Functional interactions between sphingolipids and sterols in biological membranes regulating cell physiology.
Sterols and sphingolipids are limited to eukaryotic cells, and their interaction has been proposed to favor formation of lipid microdomains. Although there is abundant biophysical evidence demonstrating their interaction in simple systems, convincing evidence is lacking to show that they function together in cells. Using lipid analysis by mass spectrometry and a genetic approach on mutants in sterol metabolism, we show that cells adjust their membrane composition in response to mutant sterol structures preferentially by changing their sphingolipid composition. Systematic combination of mutations in sterol biosynthesis with mutants in sphingolipid hydroxylation and head group turnover give a large number of synthetic and suppression phenotypes. Our unbiased approach provides compelling evidence that sterols and sphingolipids function together in cells. We were not able to correlate any cellular phenotype we measured with plasma membrane fluidity as measured using fluorescence anisotropy. This questions whether the increase in liquid order phases that can be induced by sterol-sphingolipid interactions plays an important role in cells. Our data revealing that cells have a mechanism to sense the quality of their membrane sterol composition has led us to suggest that proteins might recognize sterol-sphingolipid complexes and to hypothesize the coevolution of sterols and sphingolipids.


In vitro synthesis of transfer RNA. II. Identification of required enzymatic activities.
We have shown that the synthesis of active su+III tRNATyr from a phi80psu+III DNA template requires the action of four distinct enzymatic activities. The first of these, DNA-dependent RNA polymerase, catalyzes the formation of a large molecular weight transcript, initiating synthesis at a specific site 41 nucleotides proximal to the 5' end of the su+III tRNATyr structural gene and continuing at least 100 nucleotides beyond the 3' terminus of the su+III tRNATyr sequence. The second required component, designated Fraction V, allows purified DNA-DEPENDENT RNA polymerase to function in tRNA synthesis. We have shown that this fraction contains an endonuclease that together with DNA-dependent RNA polymerase is responsible for the synthesis of su+III tRNATyr "precursor". Thus, su+III tRNATyr precursor is not itself the primary transcription product of the su+III tRNATyr gene, but rather, it arises as a result of post-transcriptional cleavage of a much larger transcript by the action of the nuclease present in Fraction V. The third enzymatic activity required for synthesis of active su+III tRNATyr is a ribonuclease (RNase P III) that specifically catalyzes the removal of the 3' extra nucleotides from the su+III tRNATyr precursor. The fourth activity required for synthesis of tRNA is a previously identified endonuclease, RNase P, that specifically catalyzes the removal of the 5' extra nucleotides from tRNA precursors. The properties of RNase P purified according to the procedure developed in this laboratory have been compared with those of the enzyme purified from ribosomes according to the procedure described by Robertson et al. (Robertson, H.D., Altman, S., and Smith, F.D. (1972) J.Biol. Chem. 247, 5243-5251.).


Non-medical use of methylphenidate among medical students of the University of the Free State.
Faced with demanding training programmes, medical students may be more prone to use methylphenidate for non-medical purposes in order to improve concentration, alertness and academic performance. The study aimed to investigate the prevalence of the non-medical use of methylphenidate and knowledge of this drug among undergraduate medical students of the University of the Free State. This was a cross-sectional study. A self-administered, anonymous questionnaire was distributed during lectures to all students in the five year groups of the undergraduate medical programme. Of the 643 undergraduate medical students, 541 completed the questionnaire (response rate: 84.1%). Approximately 11.0% of surveyed students were using methylphenidate at the time of the study, of which the majority (67.9%) used it for academic purposes and 70.6% received it from a medical health professional. Less than a third of users had been diagnosed with Attention-Deficit/Hyperactivity Disorder. Methylphenidate users' median knowledge was greater than non-users, and methylphenidate knowledge increased from first-year and second-year students to third-year to fifth-year students. Median knowledge scores per year group ranged from 52.0% to 60.0%. Methylphenidate is mainly used for non-medical purposes by medical students. Students generally have a low level of knowledge on methylphenidate. Specific information on methylphenidate should be included in lectures on stress management and study methods during the course of the medical curriculum.


Exercise and diabetes-related cardiovascular disease: systematic review of published evidence from observational studies and clinical trials.
The cost of treating cardiovascular disease (CVD) and diabetes is enormous and is set to rise in the coming years. Physical inactivity and sedentary behaviors are major risk factors for these diseases and are estimated to account for several million global deaths annually. Lifestyle interventions, particularly those aimed at enhancing physical activity levels, have a substantial favorable impact on diabetes progression in people at high risk of the disease. Although observational studies and small intervention studies suggest that physical activity might also prevent CVD in people with diabetes, this is not supported by the results of larger randomized controlled trials of lifestyle intervention. The purpose of this review is to provide an overview of the published studies focused on the role of physical activity in CVD prevention in persons with diabetes, and to discuss the implications of these studies' findings. Our review identified almost 100 studies published in the past decade relevant to this topic.


Ischemic stroke outcome: racial differences in the trial of danaparoid in acute stroke (TOAST).
To determine racial differences in baseline stroke risk factors and other measures in the Trial of ORG 10172 in Acute Stroke Therapy (TOAST). Differences in these factors could influence response to acute stroke therapy and overall stroke outcome. The authors compared baseline demographic, medical, stroke, physical examination, CT, laboratory, and neurologic factors among 292 African-American and 801 white patients who enrolled in the TOAST study. TOAST compared danaparoid (ORG 10172) with placebo among acute ischemic stroke patients who were treated within 24 hours of stroke onset. African-Americans were younger and more frequently had hypertension, diabetes mellitus, congestive heart failure, and prior strokes. In addition, African-Americans had higher mean diastolic blood pressure, more lacunar strokes, and more severe prestroke disability. There were no significant differences between African-Americans and white patients in outcomes at 7 days, overall number of adverse experiences, or occurrence of serious bleeds or hemorrhagic transformations. However, there was a trend toward a higher rate of favorable outcomes in white patients at 7 days. There was no significant difference in very favorable outcome at 3 months between African-American and white patients, but significantly more white patients had favorable outcome at 3 months. Although African-Americans possess a number of factors that should predict higher rates of poor stroke outcome after acute therapy, they have the capacity to respond similarly to white patients after acute stroke therapy. Perhaps younger age and presence of lacunar infarction are stronger predictors of good outcomes than was appreciated previously.


Quantum correlated light beams from non-degenerate four-wave mixing in an atomic vapor: the D1 and D2 lines of 85Rb and 87Rb.
We present experimental results showing that quantum correlated light can be produced using non-degenerate, off-resonant, four-wave mixing (4WM) on both the D1 (795 nm) and D2 (780 nm) lines of (85)Rb and (87)Rb, extending earlier work on the D1 line of (85)Rb. Using this 4WM process in a hot vapor cell to produce bright twin beams, we characterize the degree of intensity-difference noise reduction below the standard quantum limit for each of the four systems. Although each system approximates a double-lambda configuration, differences in details of the actual level structure lead to varying degrees of noise reduction. The observation of quantum correlations on light produced using all four of these systems, regardless of their substructure, suggests that it should be possible to use other systems with similar level structures in order to produce narrow frequency, non-classical beams at a particular wavelength.


Manipulating affective state using extended picture presentations.
Separate, extended series of positive, negative, and neutral pictures were presented to 24 (12 men, 12 women) undergraduates. Each series was presented on a different day, with full counterbalancing of presentation orders. Affective state was measured using (a) orbicularis oculi activity in response to acoustic startle probes during picture presentation, (b) corrugator supercilii activity between and during picture presentation, and (c) changes in self-reports of positive and negative affect. Participants exhibited larger eyeblink reflex magnitudes when viewing negative than when viewing positive pictures. Corrugator activity was also greater during the negative than during the positive picture set, during both picture presentation and the period between pictures. Self-reports of negative affect increased in response to the negative picture set, and self-reports of positive affect were greatest following the positive picture set. These findings suggest that extended picture presentation is an effective method of manipulating affective state and further highlight the utility of startle probe and facial electromyographic measures in providing on-line readouts of affective state.


The cure of cancer: a European perspective.
Cancer survival analyses based on cancer registry data do not provide direct information on the main aim of cancer treatment, the cure of the patient. In fact, classic survival indicators do not distinguish between patients who are cured, and patients who will die of their disease and in whom prolongation of survival is the main objective of treatment. In this study, we applied parametric cure models to the cancer incidence and follow-up data provided by 49 EUROCARE-4 (European Cancer Registry-based study, fourth edition) cancer registries, with the aims of providing additional insights into the survival of European cancer patients diagnosed from 1988 to 1999, and of investigating between-population differences. Between-country estimates the proportion of cured patients varied from about 4-13% for lung cancer, from 9% to 30% for stomach cancer, from 25% to 49% for colon and rectum cancer, and from 55% to 73% for breast cancer. For all cancers combined, estimates varied between 21% and 47% in men, and 38% and 59% in women and were influenced by the distribution of cases by cancer site. Countries with high proportions of cured and long fatal case survival times for all cancers combined were characterised by generally favourable case mix. For the European pool of cases both the proportion of cured and the survival time of fatal cases were associated with age, and increased from the early to the latest diagnosis period. The increases over time in the proportions of Europeans estimated cured of lung, stomach and colon and rectum cancers are noteworthy and suggest genuine progress in cancer control. The proportion of cured of all cancers combined is a useful general indicator of cancer control as it reflects progress in diagnosis and treatment, as well as success in the prevention of rapidly fatal cancers.


Recurrent GNAS mutations define an unexpected pathway for pancreatic cyst development.
More than 2% of the adult U.S. population harbors a pancreatic cyst. These often pose a difficult management problem because conventional criteria cannot always distinguish cysts with malignant potential from those that are innocuous. One of the most common cystic neoplasms of the pancreas, and a bona fide precursor to invasive adenocarcinoma, is called intraductal papillary mucinous neoplasm (IPMN). To help reveal the pathogenesis of these lesions, we purified the DNA from IPMN cyst fluids from 19 patients and searched for mutations in 169 genes commonly altered in human cancers. In addition to the expected KRAS mutations, we identified recurrent mutations at codon 201 of GNAS. A larger number (113) of additional IPMNs were then analyzed to determine the prevalence of KRAS and GNAS mutations. In total, we found that GNAS mutations were present in 66% of IPMNs and that either KRAS or GNAS mutations could be identified in 96%. In eight cases, we could investigate invasive adenocarcinomas that developed in association with IPMNs containing GNAS mutations. In seven of these eight cases, the GNAS mutations present in the IPMNs were also found in the invasive lesion. GNAS mutations were not found in other types of cystic neoplasms of the pancreas or in invasive adenocarcinomas not associated with IPMNs. In addition to defining a new pathway for pancreatic neoplasia, these data suggest that GNAS mutations can inform the diagnosis and management of patients with cystic pancreatic lesions.


pH-Potentiometric Investigation towards Chelating Tendencies of p-Hydroquinone and Phenol Iminodiacetate Copper(II) Complexes.
Copper ions in the active sites of several proteins/enzymes interact with phenols and quinones, and this interaction is associated to the reactivity of the enzymes. In this study the speciation of the Cu(2+) with iminodiacetic phenolate/hydroquinonate ligands has been examined by pH-potentiometry. The results reveal that the iminodiacetic phenol ligand forms mononuclear complexes with Cu(2+) at acidic and alkaline pHs, and a binuclear O(phenolate)-bridged complex at pH range from 7 to 8.5. The binucleating hydroquinone ligand forms only 2 : 1 metal to ligand complexes in solution. The pK values of the protonation of the phenolate oxygen of the two ligands are reduced about 2 units after complexation with the metal ion and are close to the pK values for the copper-interacting tyrosine phenol oxygen in copper enzymes.


Kinetic investigation into the chemoselective hydrogenation of α,β-unsaturated carbonyl compounds catalyzed by Ni(0) nanoparticles.
A series of Ni(0) nanocatalysts was prepared from a Ni(COD)2 complex in the presence of different stabilizers (hexadecylamine, polyvinylpyrrolidone (PVP), PVP/triphenylphosphine, octanoic acid and stearic acid) for their evaluation in the selective hydrogenation reaction of α,β-unsaturated carbonyl compounds by H2 under mild reaction conditions, i.e., low H2 pressure, temperature and catalyst loading. All nanocatalysts were active in reducing only the C[double bond, length as m-dash]C bond and this chemoselectivity was attributed to the reduced nature of the Ni-NPs surface. Moreover, the hydrogenation reaction rate appeared to be sensitive to ligand type, with the carboxylic acid-stabilized systems showing the best performances. A full kinetic investigation into the t-chalcone chemoselective reduction of the C[double bond, length as m-dash]C bond, with the best catalyst (Ni-octanoic acid) revealed that the rate-determining step is the hydrogenation of the adsorbed substrate on the NPs surface, following a Horiuti-Polanyi type of mechanism. Regarding sustainable chemistry concerns, the best catalyst could be reused up to 10 times without significant loss of activity.


Neonatal candidemia and end-organ damage: a critical appraisal of the literature using meta-analytic techniques.
Neonatal candidemia is an increasing cause of infant morbidity and mortality. We evaluated the current medical literature in an effort to critique the literature and to document the reported prevalences of end-organ damage after neonatal candidemia. We analyzed all peer-reviewed articles of neonatal candidemia published in the English language; inclusion criteria included a cohort limited to all neonatal intensive care unit admissions or all episodes of candidemia in neonates. Articles that also incorporated older patients, did not define a numerator and a denominator for at least 1 form of end-organ damage, included patients from other reports, or did not include all episodes of candidemia in the source population were excluded from the analysis. Thirty-four articles reported episodes of candidemia and mortality; 21 articles reported prevalence for at least 1 form of end-organ damage. Only 4 (19%) of 21 articles reported prevalence for >4 forms of end-organ damage from the following list: endophthalmitis, meningitis, brain parenchyma invasion, endocarditis, renal abscesses, positive cultures from other normally sterile body fluids, or hepatosplenic abscesses. The median reported prevalence of endophthalmitis was 3% (interquartile range [IQR]: 0%-17%), of meningitis was 15% (IQR: 3%-23%), of brain abscess or ventriculitis was 4% (IQR: 3%-21%), of endocarditis was 5% (IQR: 0%-13%), of positive renal ultrasound was 5% (IQR: 0%-14%), and of positive urine culture was 61% (IQR: 40%-76%). The medical literature concerning end-organ evaluation after episodes of neonatal candidemia is heterogeneous and consists largely of single-center retrospective studies. Year that the data were collected and prevalence of neonates infected with Candida albicans were associated with observed heterogeneity. Given the heterogeneity of the medical literature, precise estimates of the frequencies of end-organ damage are not possible and a prospective multicenter trial is warranted, but the data from the published literature suggest that the prevalence of neonates with end-organ damage not only is greater than 0 but also is high enough that until such a prospective trial is completed, end-organ studies should be considered before the conclusion of antifungal therapy.


Upper limb function in Duchenne muscular dystrophy: 24 month longitudinal data.
The aim of the study was to establish 24 month changes in upper limb function using a revised version of the performance of upper limb test (PUL 2.0) in a large cohort of ambulant and non-ambulant boys with Duchenne muscular dystrophy and to identify possible trajectories of progression. Of the 187 patients studied, 87 were ambulant (age range: 7-15.8 years), and 90 non-ambulant (age range: 9.08-24.78). The total scores changed significantly over time (p<0.001). Non-ambulant patients had lower total scores at baseline (mean 19.7) when compared to the ambulant ones (mean 38.4). They also had also a bigger decrease in total scores over 24 months compared to the ambulant boys (4.36 vs 2.07 points). Multivariate model analysis showed that the Performance of Upper Limb changes reflected the entry level and ambulation status, that were independently associated to the slope of Performance of Upper Limb changes. This information will be of help both in clinical practice and at the time of designing clinical trials.


Resistance associated metabolite profiling of Aspergillus leaf spot in cotton through non-targeted metabolomics.
Aspergillus tubingensis is an important pathogen of economically important crops. Different biotic stresses strongly influence the balance of metabolites in plants. The aim of this study was to understand the function and response of resistance associated metabolites which, in turn are involved in many secondary metabolomics pathways to influence defense mechanism of cotton plant. Analysis of non-targeted metabolomics using ultra high performance liquid chromatography-mass spectrometry (UPLC-MS) revealed abundant accumulation of key metabolites including flavonoids, phenylpropanoids, terpenoids, fatty acids and carbohydrates, in response to leaf spot of cotton. The principal component analysis (PCA), orthogonal partial least squares discriminant analysis (OPLS-DA) and partial least squares discriminant analysis (PLS-DA) score plots illustrated the evidences of variation between two varieties of cotton under mock and pathogen inoculated treatments. Primary metabolism was affected by the up regulation of pyruvate and malate and by the accumulation of carbohydrates like cellobiose and inulobiose. Among 241 resistance related (RR) metabolites, 18 were identified as resistance related constitutive (RRC) and 223 as resistance related induced (RRI) metabolites. Several RRI metabolites, identified in the present study were the precursors for many secondary metabolic pathways. These included phenylpropanoids (stilbenes and furanocoumarin), flavonoids (phlorizin and kaempferol), alkaloids (indolizine and acetylcorynoline) and terpenoids (azelaic acid and oleanolic acid). Our results demonstrated that secondary metabolism, primary metabolism and energy metabolism were more active in resistant cultivar, as compared to sensitive cultivar. Differential protein and fatty acid metabolism was also depicted in both cultivars. Accumulation of these defense related metabolites in resistant cotton cultivar and their suppression in susceptible cotton cultivar revealed the reason of their respective tolerance and susceptibility against A. tubingensis.


School environment and mental health in early adolescence - a longitudinal study in Sweden (KUPOL).
Longitudinal studies indicate strong associations between school proficiency and indicators of mental health throughout adulthood, but the mechanisms of such associations are not fully elucidated. The Kupol study is a prospective cohort study in Sweden set up in order to: (i) describe the association of school pedagogic and social environment and its specific dimensions with the risk of mental ill-health and psychiatric disorders in adolescence; (ii) evaluate the direct effects of school pedagogic and social environment on mental health and the effects mediated by the individual's academic achievements; and (iii) assess if school pedagogic and social environment are associated with mental ill-health through epigenetic mechanisms, in particular those involving genes regulating the response to stress. The Kupol cohort at baseline consists of 3959 children attending the 7th grade of compulsory school (13-14 years old) in 8 regions of central Sweden in the school years 2013-2014 or 2014-2015. Three follow-up surveys in subsequent years are planned. Teachers' and students' perceptions of the culture, climate and ethos of their schools, and students' mental ill-health are assessed at the whole school level by annual questionnaire surveys. In order to conduct epigenetic analyses saliva specimens are collected from a nested sample of students at inception and two years later. Further, class-, family- and child-level information is collected at baseline and during each year of follow-up. Self-reported information is being complemented with register data via record-linkages to national and regional health and administrative registers. The topic being investigated is new, and the sample constitutes the largest adolescent cohort in Sweden involved in an ad hoc study. Epigenetic analyses centered on environmental cues to stress response are a thoroughly new approach. Finally a notable feature is the multi-informant and multi-method data collection, with surveys at the school, class, family, and student level. Collaboration and data access: interested investigators should contact the coordinating centre. Additional information is available on the study's website, http://kupolstudien.se/ .


Pregnancy and mental health among women veterans returning from Iraq and Afghanistan.
Veterans of Operations Enduring Freedom and Iraqi Freedom (OEF/OIF) may experience significant stress during military service that can have lingering effects. Little is known about mental health problems or treatment among pregnant OEF/OIF women veterans. The aim of this study was to determine the prevalence of mental health problems among veterans who received pregnancy-related care in the Veterans Health Administration (VHA) system. Data from the Defense Manpower Data Center (DMDC) deployment roster of military discharges from October 1, 2001, through April 30, 2008, were used to assemble an administrative cohort of female OEF/OIF veterans enrolled in care at the VHA (n = 43,078). Pregnancy and mental health conditions were quantified according to ICD-9-CM codes and specifications. Mental healthcare use and prenatal care were assessed by analyzing VHA stop codes. During the study period, 2966 (7%) women received at least one episode of pregnancy-related care, and 32% of veterans with a pregnancy and 21% without a pregnancy received one or more mental health diagnoses (p < 0.0001). Veterans with a pregnancy were twice as likely to have a diagnosis of depression, anxiety, posttraumatic stress disorder (PTSD), bipolar disorder, or schizophrenia as those without a pregnancy. Women OEF/OIF veterans commonly experience mental health problems after military service. The burden of mental health conditions is higher among women with an identified instance of pregnancy than among those without. Because women do not receive pregnancy care at the VHA, however, little is known about ongoing concomitant prenatal and mental healthcare or about pregnancy outcomes among these women veterans.


Inverted-wedge silica resonators for controlled and stable coupling.
Silica microresonators with an inverted-wedge shape were fabricated using conventional semiconductor fabrication methods. The measured quality factors of the resonators were greater than 10(6) in 1550 nm band. Controllable coupling from undercoupling to the overcoupling regime through the critical coupling point was demonstrated by horizontally moving a fiber taper while in touch with the top surface of the resonator. The thin outer ring of the resonator provided a support for the fiber taper leading to robust stable coupling.


Deaths of HIV-positive men in the context of assisted reproduction: five case studies from a single center.
Provision of reproductive services to individuals infected with HIV-1 is gaining popular acceptance and is generally endorsed by specialists in reproductive medicine. In the situation in which the male is HIV positive and the female partner is not infected, a large body of evidence has demonstrated that the use of assisted reproductive technology is effective for achieving pregnancy, while eliminating the risk of viral transmission to the mother and fetus. No reports have documented the well-being of the HIV-infected partners subsequent to seeking fertility services. In the current report, we document the cases of five HIV-positive men who died secondary to complications of HIV infection shortly after participating in the assisted reproduction program for HIV-1-serodiscordant couples at Columbia University. Three of these couples successfully achieved pregnancy and live birth, including one set of triplets, and one case of posthumous conception; the fourth case resulted in the cryopreservation of all embryos after the sudden death of the male before the time of embryo transfer; the fifth couple failed to conceive. None of the deaths, which occurred within a few months to 2 years from initial consultation, were related to infertility treatment. The demographic and social statuses of these patients were not different from the general population of men seeking assisted reproduction in our clinic. Regarding the HIV infection status of these cases, three patients had a longer duration of infection compared to the general population of men in our cohort, and one had a significantly lower CD4 cell count. All five men had stable HIV viral loads, and were determined by their primary care providers to be clinically healthy at the time of entry into the program for assisted reproduction. The untimely deaths of these patients underscores the importance of the thoughtful consideration of the complex issues involved in family planning for these individuals, including advanced directives for the use of cryopreserved gametes and embryos, and the social, emotional, and practical issues for the children and surviving partners subsequent to the death of the HIV-positive parent.


Dietary behaviors, physical activity and sedentary lifestyle associated with overweight and obesity, and their socio-demographic correlates, among Pakistani primary school children.
There is no data on diet- and activity-related behaviors associated with overweight and obesity among Pakistani school-aged children. The study aimed to explore dietary behaviors, physical activity and sedentary lifestyle associated with overweight and obesity, and their socio-demographic correlates, among Pakistani primary school children. A population-based cross-sectional study was conducted with a representative multistage random cluster sample of 1860 children aged five to twelve years in Lahore, Pakistan. Overweight (>+1 SD) and obesity (>+2 SD) were defined using the World Health Organization reference 2007. Chi-square test was used as the test of trend. Linear regression was used to examine the predictive power of independent variables in relation to body mass index (BMI). Logistic regression was used to quantify the independent predictors and adjusted odds ratios (aOR) with 95% confidence intervals (CI) were obtained. Statistical significance was considered at P<0.05. Children skipping breakfast (8%), eating fast food and snacks≥once a week (43%) and being involved in sedentary lifestyle>one hour a day (49%) were significantly more likely to be overweight and obese while those participating in physical activity>twice a week (53%) were significantly less likely to be overweight and obese (all P<0.01). Skipping breakfast (P<0.001), eating fast food and snacks (P=0.001) and sedentary lifestyle (P<0.001) showed an independent positive association with BMI while physical activity showed an independent inverse association (P=0.001). Skipping breakfast (aOR 1.82, 95% CI 1.22-2.71), eating fast food and snacks≥once a week (OR 1.41, 95% CI 1.07-1.86), physical activity>twice a week (aOR 0.49, 95% CI 0.34-0.70) and sedentary lifestyle>one hour a day (aOR 1.56, 95% CI 1.19-2.03) were independent predictors of being overweight. Skipping breakfast had independent inverse association with physical activity (aOR 0.63, 95% CI 0.45-0.89) and eating fast food and snacks had independent positive association with sedentary lifestyle (aOR 1.79, 95% CI 1.49-2.16). Female gender was independently associated with skipping breakfast (aOR 1.50, 95% CI 1.04-2.16). Male gender (aOR 1.64, 95% CI 1.33-2.02), urban area with high SES (aOR 5.09, 95% CI 3.02-8.60) and higher parental education (aOR 1.74, 95% CI 1.12-2.68) were significant independent predictors of eating fast food and snacks≥once a week. Living in the rural area was independently associated (aOR 2.51, 95% CI 1.71-3.68) with physical activity>twice a week. Male gender (aOR 1.60, 95% CI 1.31-1.95), urban area with low SES (aOR 1.46, 95% CI 1.02-2.09), high-income neighborhoods (aOR 1.52, 95% CI 1.02-2.25), higher parental education (aOR 1.55, 95% CI 1.03-2.34) and fewer siblings (aOR 1.38, 95% CI 1.10-1.73) were independent predictors of sedentary lifestyle>one hour a day. Dietary behaviors, physical activity and sedentary lifestyle are independent predictors of overweight and higher BMI among Pakistani primary school children, and are significantly affected by the child's socio-demographic characteristics. These findings support the urgent need to develop a National strategy for diet and physical activity and to implement culturally relevant behavioral interventions in the resource-poor developing country settings.


A biallelic variant in CLRN2 causes non-syndromic hearing loss in humans.
Deafness, the most frequent sensory deficit in humans, is extremely heterogeneous with hundreds of genes involved. Clinical and genetic analyses of an extended consanguineous family with pre-lingual, moderate-to-profound autosomal recessive sensorineural hearing loss, allowed us to identify CLRN2, encoding a tetraspan protein, as a new deafness gene. Homozygosity mapping followed by exome sequencing identified a 14.96 Mb locus on chromosome 4p15.32p15.1 containing a likely pathogenic missense variant in CLRN2 (c.494C > A, NM_001079827.2) segregating with the disease. Using in vitro RNA splicing analysis, we show that the CLRN2 c.494C > A variant leads to two events: (1) the substitution of a highly conserved threonine (uncharged amino acid) to lysine (charged amino acid) at position 165, p.(Thr165Lys), and (2) aberrant splicing, with the retention of intron 2 resulting in a stop codon after 26 additional amino acids, p.(Gly146Lysfs*26). Expression studies and phenotyping of newly produced zebrafish and mouse models deficient for clarin 2 further confirm that clarin 2, expressed in the inner ear hair cells, is essential for normal organization and maintenance of the auditory hair bundles, and for hearing function. Together, our findings identify CLRN2 as a new deafness gene, which will impact future diagnosis and treatment for deaf patients.


Molecular identification and characterization of the Arabidopsis AtADF1, AtADFS and AtADF6 genes.
Actin depolymerizing factor (ADF) is a key regulator of the organization of the actin cytoskeleton during various cellular activities. We found that ADF genes in Arabidopsis form a large family consisting of at least nine members, four of which were cloned and sequenced in this study. Comparison of genomic and cDNA sequences showed that the AtADF1, AtADF5, and AtADF6 genes all contain two introns at conserved positions. Analysis of transgenic Arabidopsis plants carrying promoter-GUS fusion constructs revealed that AtADF1 and AtADF6 are expressed in the vascular tissues of all organs, whereas expression of AtADF5 is restricted to the root tip meristem. GFP-AtADFI, GFP-AtADF5, and GFP-AtADF6 fusion proteins were found to bind to actin filaments in vivo, and to reorganize the actin cytoskeleton when transiently expressed in plant cells.


Transvenous embolization for carotid-cavernous fistula in a patient with vascular type of Ehlers-Danlos syndrome--direct superior ophthalmic vein approach: case report.
The vascular type of Ehlers-Danlos syndrome (vEDS) is an autosomal dominant hereditary disease characterized by connective tissue fragility throughout the body, including the arteries, viscera, and gastrointestinal tract. We report a case in which we performed transvenous embolization (TVE) via direct superior ophthalmic vein (SOV) approach to treat a direct carotid-cavernous fistula (CCF) in a patient with Ehlers-Danlos syndrome (EDS). The patient was a 37-year-old woman who developed tinnitus in her left ear and a headache during examination in the outpatient clinic of another hospital in order to make a definitive diagnosis of vEDS, and she was referred to our hospital and examined. Based on the results of all of the studies she was diagnosed with a CCF. Conservative treatment was attempted, but was not very effective. Because of progressing aphasia, TVE was performed via the SOV direct cut. There were no intraoperative or postoperative complications. It has been reported that cerebral angiography is generally contraindicated in vEDS and that the morbimortality associated with endovascular treatment is very high. When performing treatment it is necessary to be sufficiently aware of the risks it entails.