Correcting the bias of empirical frequency parameter estimators in codon models.
Markov models of codon substitution are powerful inferential tools for studying biological processes such as natural selection and preferences in amino acid substitution. The equilibrium character distributions of these models are almost always estimated using nucleotide frequencies observed in a sequence alignment, primarily as a matter of historical convention. In this note, we demonstrate that a popular class of such estimators are biased, and that this bias has an adverse effect on goodness of fit and estimates of substitution rates. We propose a "corrected" empirical estimator that begins with observed nucleotide counts, but accounts for the nucleotide composition of stop codons. We show via simulation that the corrected estimates outperform the de facto standard estimates not just by providing better estimates of the frequencies themselves, but also by leading to improved estimation of other parameters in the evolutionary models. On a curated collection of sequence alignments, our estimators show a significant improvement in goodness of fit compared to the approach. Maximum likelihood estimation of the frequency parameters appears to be warranted in many cases, albeit at a greater computational cost. Our results demonstrate that there is little justification, either statistical or computational, for continued use of the -style estimators.


TTC7B emerges as a novel risk factor for ischemic stroke through the convergence of several genome-wide approaches.
We hereby propose a novel approach to the identification of ischemic stroke (IS) susceptibility genes that involves converging data from several unbiased genetic and genomic tools. We tested the association between IS and genes differentially expressed between cases and controls, then determined which data mapped to previously reported linkage peaks and were nominally associated with stroke in published genome-wide association studies. We first performed gene expression profiling in peripheral blood mononuclear cells of 20 IS cases and 20 controls. Sixteen differentially expressed genes mapped to reported whole-genome linkage peaks, including the TTC7B gene, which has been associated with major cardiovascular disease. At the TTC7B locus, 46 tagging polymorphisms were tested for association in 565 Portuguese IS cases and 520 controls. Markers nominally associated in at least one test and defining associated haplotypes were then examined in 570 IS Spanish cases and 390 controls. Several polymorphisms and haplotypes in the intron 5-intron 6 region of TTC7B were also associated with IS risk in the Spanish and combined data sets. Multiple independent lines of evidence therefore support the role of TTC7B in stroke susceptibility, but further work is warranted to identify the exact risk variant and its pathogenic potential.


Apoptosis in the cochlear nucleus and inferior colliculus upon repeated noise exposure.
The time course of apoptosis and the corresponding neuronal loss was previously shown in central auditory pathway of mice after a single noise exposure. However, repeated acoustic exposure is a major risk factor for noise-induced hearing loss. The present study investigated apoptosis by terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (TUNEL) assay after a second noise trauma in the ventral and dorsal cochlear nucleus and central nucleus of the inferior colliculus. Mice [Naval Medical Research Institute (NMRI) strain] were noise exposed [115 dB sound pressure level, 5-20 kHz, 3 h) at day 0. A double group received the identical noise exposure a second time at day 7 post-exposure and apoptosis was either analyzed immediately (7-day group-double) or 1 week later (14-day group-double). Corresponding single exposure groups were chosen as controls. No differences in TUNEL were seen between 7-day or 14-day single and double-trauma groups. Interestingly, independent of the second noise exposure, apoptosis increased significantly in the 14-day groups compared to the 7-day groups in all investigated areas. It seems that the first noise trauma has a long-lasting effect on apoptotic mechanisms in the central auditory pathway that were not largely influenced by a second trauma. Homeostatic mechanisms induced by the first trauma might protect the central auditory pathway from further damage during a specific time slot. These results might help to understand the underlying mechanisms of different psychoacoustic phenomena in noise-induced hearing loss.


Survey of women's experiences of care in a new freestanding midwifery unit in an inner city area of London, England: 2. Specific aspects of care.
to describe and compare women's experiences of specific aspects of maternity care before and after the opening of the Barkantine Birth Centre, a new freestanding midwifery unit in an inner city area. telephone surveys undertaken in late pregnancy and about six weeks after birth. Two separate waves of interviews were conducted, Phase 1 before the birth centre opened and Phase 2 after it had opened. Tower Hamlets, a deprived inner city borough in east London, 2007-2010. 620 women who were resident in Tower Hamlets and who satisfied the Barts and the London Trust's eligibility criteria for using the birth centre. Of these, 259 women were recruited to Phase 1 and 361 to Phase 2. the replies women gave show marked differences between the model of care in the birth centre and that at the obstetric unit at the Royal London Hospital with respect to experiences of care and specific practices. Women who initially booked for birth centre care were more likely to attend antenatal classes and find them useful and were less likely to be induced. Women who started labour care at the birth centre in spontaneous labour were more likely to use non-pharmacological methods of pain relief, most notably water and less likely to use pethidine than women who started care at the hospital. They were more likely to be able to move around in labour and less likely to have their membranes ruptured or have continuous CTG. They were more likely to be told to push spontaneously when they needed to rather than under directed pushing and more likely to report that they had been able to choose their position for birth and deliver in places other than the bed, in contrast to the situation at the hospital. The majority of women who had a spontaneous onset of labour delivered vaginally, with 28.6 per cent of women at the birth centre but no one at the hospital delivering in water. Primiparous women who delivered at the birth centre were less likely to have an episiotomy. Most women who delivered at the birth centre reported that they had chosen whether or not to have a physiological third stage, whereas a worrying proportion at the hospital reported that they had not had a choice. A higher proportion of women at the birth centre reported skin to skin contact with their baby in the first two hours after birth. significant differences were reported between the hospital and the birth centre in practices and information given to the women, with lower rates of intervention, more choice and significant differences in women's experiences. This case study of a single inner-city freestanding midwifery unit, linked to the Birthplace in England Research Programme, indicates that this model of care also leads to greater choice and a better experience for women who opted for it.


Learning weighted metrics to minimize nearest-neighbor classification error.
In order to optimize the accuracy of the Nearest-Neighbor classification rule, a weighted distance is proposed, along with algorithms to automatically learn the corresponding weights. These weights may be specific for each class and feature, for each individual prototype, or for both. The learning algorithms are derived by (approximately) minimizing the Leaving-One-Out classification error of the given training set. The proposed approach is assessed through a series of experiments with UCI/STATLOG corpora, as well as with a more specific task of text classification which entails very sparse data representation and huge dimensionality. In all these experiments, the proposed approach shows a uniformly good behavior, with results comparable to or better than state-of-the-art results published with the same data so far.


Prevalence of risk factors for non-communicable diseases in rural & urban Tamil Nadu.
Surveillance of risk factors is important to plan suitable control measures for non-communicable diseases (NCDs). The objective of this study was to assess the behavioural, physical and biochemical risk factors for NCDs in Vellore Corporation and Kaniyambadi, a rural block in Vellore district, Tamil Nadu, India. This cross-sectional study was carried out among 6196 adults aged 30-64 yr, with 3799 participants from rural and 2397 from urban areas. The World Health Organization-STEPS method was used to record behavioural risk factors, anthropometry, blood pressure, fasting blood glucose and lipid profile. Multiple logistic regression was used to assess associations between risk factors. The proportion of tobacco users (current smoking or daily use of smokeless tobacco) was 23 per cent in the rural sample and 18 per cent in the urban, with rates of smoking being similar. Ever consumption of alcohol was 62 per cent among rural men and 42 per cent among urban men. Low physical activity was seen among 63 per cent of the urban and 43 per cent of the rural sample. Consumption of fruits and vegetables was equally poor in both. In the urban sample, 54 per cent were overweight, 29 per cent had hypertension and 24 per cent diabetes as compared to 31, 17 and 11 per cent, respectively, in the rural sample. Physical inactivity was associated with hypertension, body mass index (BMI) ≥25 kg/m[2], central obesity and dyslipidaemia after adjusting for other factors. Increasing age, male sex, BMI ≥25 kg/m[2] and central obesity were independently associated with both hypertension and diabetes. Diabetes, hypertension, dyslipidaemia, physical inactivity and overweight were higher in the urban area as compared to the rural area which had higher rates of smokeless tobacco use and alcohol consumption. Smoking and inadequate consumption of fruits and vegetables were equally prevalent in both the urban and rural samples. There is an urgent need to address behavioural risk factors such as smoking, alcohol consumption, physical inactivity and inadequate intake of fruits and vegetables through primary prevention.


Nonmedical Uses of Antibiotics: Time to Restrict Their Use?
The global crisis of antibiotic resistance has reached a point where, if action is not taken, human medicine will enter a postantibiotic world and simple injuries could once again be life threatening. New antibiotics are needed urgently, but better use of existing agents is just as important. More appropriate use of antibiotics in medicine is vital, but the extensive use of antibiotics outside medical settings is often overlooked. Antibiotics are commonly used in animal husbandry, bee-keeping, fish farming and other forms of aquaculture, ethanol production, horticulture, antifouling paints, food preservation, and domestically. This provides multiple opportunities for the selection and spread of antibiotic-resistant bacteria. Given the current crisis, it is vital that the nonmedical use of antibiotics is critically examined and that any nonessential use halted.


Theorising transient mood after ingestion.
Ingesting foods or drugs can alter rated mood. Moods have been theorised as reinforcers that cause ingestion. This assumption may be incompatible with the current two-system models of affect, where 'moods' are less intense yet more protracted than emotions, and affective states are caused by primary rapid affect processing and secondary cognitive appraisal. In ingestion research, moods may be transient rather than protracted and significant changes on mood rating scales are found without reportable changes in mood. Transient mood is caused cognitively and the temporal dynamics of mood are important. Consequently, when ingestion directly causes changes in affect these may be brief emotions rather than moods. In the absence of emotion, ingestion may provide input to the cognitive processes that cause transient mood, but physiological change cannot easily be inferred backwards from mood ratings. There are a number of unresolved questions about the relationship between rapid affect processing, cognitive appraisal and learning.


Do specific types of sleep disturbances represent risk factors for poorer health-related quality of life in inflammatory bowel disease? A longitudinal cohort study.
Poor global sleep quality is commonly reported in people with inflammatory bowel disease (IBD) and is linked to poorer health-related quality of life (HRQoL). However, understanding is currently limited by a lack of: (1) longitudinal research and (2) research investigating the impact of specific types of problems sleeping on IBD-related outcomes, particularly on HRQoL. Observational longitudinal cohort study. N = 276 participants with IBD completed measures at baseline (T1) and 4 weeks later at T2. Four specific sleep disturbances associated with IBD including sleep apnoea, insomnia, restless legs, and nightmares were measured alongside depression, anxiety and stress, and HRQoL. After controlling for participant demographics and clinical characteristics, T1 depression, anxiety, stress, and T1 HRQoL, more severe symptom severity of sleep apnoea (B = -0.30, p < .05) and insomnia symptoms (B = -0.23, p < .05) at T1 significantly predicted poorer HRQoL at T2. However, the experience of restless legs (B = -0.03, p > .87) and nightmares (B = -0.14, p > .11) at T1 did not predict HRQoL. Symptoms synonymous with sleep apnoea and insomnia might represent modifiable risk factors that provide independent contributions to HRQoL over time in those with IBD. These findings suggest that interventions designed to improve sleep apnoea and insomnia could confer benefits to HRQoL in those with IBD. However, more longitudinal research is needed to understand the contribution of sleep disturbances over the longer term, as well as more randomized controlled trials testing the effect of improving sleep on IBD-related outcomes.


Effective photodarkening suppression in Yb-doped fiber lasers by visible light injection.
Al-silicate fibers have excellent manufacturing quality. Unfortunately, high-Yb doping concentration may be limited by severe losses induced by photodarkening phenomenon. In this paper we demonstrate for the first time that Al-silicate Yb-doped fibers with high-inversion and doping concentration above 1 wt% can be successfully used by implementing a simple optical bleaching scheme. A co-injection into the active fiber of a few mW of light at around 550 nm wavelength successfully eliminates almost all photodarkening induced losses. We demonstrate operation at above 90% of the pristine output power level in several lasers with up to 30% Yb ions in the excited state. These results may allow using Yb-doped Al-silicate fibers with doping level increased by one order of magnitude. Finally, we provide a comprehensive picture of main parameters affecting photobleaching performance and, to the best of our knowledge, we report the first quantitative measurement of the Ytterbium excited state absorption cross-section in the visible range.


A study on utilization of oral contraceptives in the City of Zagreb (2008-2010).
Main aim of this study is to quantify and analyze the utilization and utilization trends of oral hormonal contraceptives in the City of Zagreb, 2008-2010, and to propose potential interventions, if necessary. Data gathered from Zagreb pharmacies were assessed by Anatomical Therapeutic Chemical Classification of drugs and Daily Defined Dose methodology. An alarming decrease in total utilization of hormonal contraceptives by 76% from 2008-2009 was found as the main result of this study. A major decrease by 95.5% in utilization of G03AB04 subgroup, sequential combined oral contraceptives, was noted in the year 2009. The subgroup G03AC0, progesterone-only pill group, showed a stable trend, and it became the most utilized subgroup in 2010, due to the decrease in utilization of both fixed and sequential combined oral contraceptives. Utilization of oral contraceptives in Croatia is not regulated adequately, since such dynamics in utilization can occur unnoticed. Measures need to take place in order to improve this situation. Proposed measures include organized farmacovigilance, prescription based on guidelines, and strict screening for risk factors in women seeking oral contraception. More research is required in Croatia to understand the pattern of utilization of hormonal contraceptives and to find the true cause of decrease in utilization of oral contraceptives.


The absence of the Pseudomonas aeruginosa OprF protein leads to increased biofilm formation through variation in c-di-GMP level.
OprF is the major outer membrane porin in bacteria belonging to the Pseudomonas genus. In previous studies, we have shown that OprF is required for full virulence expression of the opportunistic pathogen Pseudomonas aeruginosa. Here, we describe molecular insights on the nature of this relationship and report that the absence of OprF leads to increased biofilm formation and production of the Pel exopolysaccharide. Accordingly, the level of c-di-GMP, a key second messenger in biofilm control, is elevated in an oprF mutant. By decreasing c-di-GMP levels in this mutant, both biofilm formation and pel gene expression phenotypes were restored to wild-type levels. We further investigated the impact on two small RNAs, which are associated with the biofilm lifestyle, and found that expression of rsmZ but not of rsmY was increased in the oprF mutant and this occurs in a c-di-GMP-dependent manner. Finally, the extracytoplasmic function (ECF) sigma factors AlgU and SigX displayed higher activity levels in the oprF mutant. Two genes of the SigX regulon involved in c-di-GMP metabolism, PA1181 and adcA (PA4843), were up-regulated in the oprF mutant, partly explaining the increased c-di-GMP level. We hypothesized that the absence of OprF leads to a cell envelope stress that activates SigX and results in a c-di-GMP elevated level due to higher expression of adcA and PA1181. The c-di-GMP level can in turn stimulate Pel synthesis via increased rsmZ sRNA levels and pel mRNA, thus affecting Pel-dependent phenotypes such as cell aggregation and biofilm formation. This work highlights the connection between OprF and c-di-GMP regulatory networks, likely via SigX (ECF), on the regulation of biofilm phenotypes.


Synergistic tumoricidal effect of combined hMUC1 vaccination and hNIS radioiodine gene therapy.
We examined the merits of combinatorial hMUC1 vaccination and hNIS radioiodine gene therapy and evaluated its tumoricidal effects in an animal tumor model. CMNF (CT26 expressing hMUC1, hNIS, and firefly luciferase) cells were transplanted into 28 mice, and 4 and 11 days after tumor challenge, tumor-bearing mice were immunized i.m. with pcDNA3.1 or pcDNA-hMUC1 vaccine and subsequently administered PBS or (131)I i.p. [four groups (7 mice per group): pcDNA3.1 + PBS, phMUC1 + PBS, pcDNA3.1 + (131)I, and phMUC1 + (131)I groups]. Thirty-two days after tumor challenge, we rechallenged mice in the pcDNA3.1 + (131)I and phMUC1 + (131)I groups with CMNF cells. Tumor progression and tumor-free mice (%) were monitored by bioluminescence. We investigated hMUC1-associated immune response generated by combination therapy. Marked tumor growth inhibition was observed in the phMUC1 + (131)I group by bioluminescence at 32 days after tumor challenge. Mice in phMUC1 + (131)I group showed complete hMUC1-expressing tumor suppression after tumor rechallenge, whereas mice in the pcDNA3.1 + (131)I group did not. The tumor-free mice (%) were much higher in the phMUC1 + (131)I group than in the other three groups. Levels of hMUC1-associated CD8(+)IFN-gamma(+) T cells were higher in the phMUC1 + (131)I group than in the other three groups. hMUC1-loaded CD11(+) cells in the phMUC1 + (131)I group were found to be most effective at generating hMUC1-associated CD8(+)IFN-gamma(+) T cells. The activities of hMUC1-associated cytotoxic T cells in the phMUC1 + (131)I group were higher than in the other three groups. Our data suggest that phMUC1 + (131)I combination therapy synergistically generates marked tumoricidal effects against established hMUC1-expressing cancers.


Interpersonal violence among immigrants in Portugal.
To assess prevalence of interpersonal violence among a mixed gender sample of immigrants in Portugal, describing the type of violence and associated factors. A cross-sectional study was conducted between October 2008 and May 2009, evaluating a sample of 702 immigrants residing in the Lisbon region. Information was obtained by trained interviewers using a structured questionnaire. Overall, 15.1 % (15.5 % females and 14.7 % males; p = 0.844) of the immigrants reported to be victims of at least one episode of violence during the last year, regardless of which type of violence was involved. The prevalence of intimate-partner violence was 4.1 %, and it was significantly higher among women than men (7.1 % vs. 0.9 %, respectively, p < 0.001). Women who reported being victims of violence during the previous year stated that the episodes occurred more often at home (54.4 %) with the partner as the perpetrator (43.9 %). On the other hand, male victims stated that the violent episodes occurred mostly in public spaces (40.8 %); men indicated that the perpetrator was frequently a stranger (28.6 %) or a co-worker (18.4 %). Violence is a frequent problem among both female and male immigrants living in Portugal, with different gender patterns regarding the perpetrators and settings of abuse.


Validation and cultural adaptation of the Arabic versions of the Mini-Mental Status Examination - 2 and Mini-Cog test.
The elderly population is increasing around the world, and the prevalence of dementia increases with age. Hence, it is expected that the number of people with dementia will increase significantly in the coming years. The Mini-Mental Status Examination - 2 (MMSE-2) and Mini-Cog are widely used tests to screen for dementia. These scales have good reliability and validity and are easy to administer in clinical and research settings. The purpose of this study was to validate the Arabic versions of MMSE-2 and Mini-Cog. These scales were assessed against the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria for dementia, as the gold standard. The standard versions of the MMSE-2 and Mini-Cog were translated to Arabic following the back-translation method. Then, a trained rater administered these tests to 134 Arab elderly aged >60 years. A physician, blind to the results of these two tests, assessed the participants for vascular dementia or probable Alzheimer's disease, based on the DSM-IV-TR criteria. The sample included 67.2% Qataris. The mean age was 74.86 years (standard deviation =7.71), and 61.9% did not attend school. The mean of the adjusted scores of MMSE-2 based on age and education level was 19.60 (standard deviation =6.58). According to DSM-IV-TR, 17.2% of the participants had dementia. Sensitivity and specificity of the MMSE-2 and the Mini-Cog together were 71.4% and 61.6%, respectively, which were better than those of each test alone. Together, the Arabic versions of MMSE-2 and Mini-Cog are good screening tools for cognitive impairment in Arabs.


In vivo trafficking and targeted delivery of magnetically labeled stem cells.
Targeted delivery of intravenously administered genetically altered cells or stem cells is still in an early stage of investigation. We developed a method of delivering iron oxide (ferumoxide)-labeled mesenchymal stem cells (MSCs) to a targeted area in an animal model by applying an external magnet. Rats with or without an external magnet placed over the liver were injected intravenously with ferumoxide-labeled MSCs and magnetic resonance imaging (MRI) signal intensity (SI) changes, iron concentration, and concentration of MSCs in the liver were monitored at different time points. SI decreased in the liver after injection of MSCs and returned gradually to that of control rat livers at approximately day 29. SI decreases were greater in rats with external magnets. Higher iron concentration and increased labeled cell numbers were detected in rat livers with external magnets. The external magnets influenced the movement of labeled MSCs such that the cells were retained in the region of interest. These results potentially open a new area of investigation for delivering stem cells or genetically altered cells.


Heterogeneity in breast cancer.
Breast cancer is a heterogeneous disease. There is a high degree of diversity between and within tumors as well as among cancer-bearing individuals, and all of these factors together determine the risk of disease progression and therapeutic resistance. Advances in technologies such as whole-genome sequencing and functional viability screens now allow us to analyze tumors at unprecedented depths. However, translating this increasing knowledge into clinical practice remains a challenge in part due to tumor evolution driven by the diversity of cancer cell populations and their microenvironment. The articles in this Review series discuss recent advances in our understanding of breast tumor heterogeneity, therapies tailored based on this knowledge, and future ways of assessing and treating heterogeneous tumors.


Environmental limits to growth: physiological niche boundaries of corals along turbidity-light gradients.
The physiological responses of organisms to resources and environmental conditions are important determinants of niche boundaries. In previous work, functional relationships between organism energetics and environment have been limited to energy intakes. However, energetic costs of maintenance may also depend on the supply of resources. In many mixotrophic organisms, two such resource types are light and particle concentration (turbidity). Using two coral species with contrasting abundances along light and turbidity gradients (Acropora valida and Turbinaria mesenterina), we incorporate the dual resource-stressor roles of these variables by calibrating functional responses of energy costs (respiration and loss of organic carbon) as well as energy intake (photosynthesis and particle feeding). This allows us to characterize physiological niche boundaries along light and turbidity gradients, identify species-specific differences in these boundaries, and assess the sensitivity of these differences to interspecific differences in particular functional response parameters. The turbidity-light niche of T. mesenterina was substantially larger than that of A. valida, consistent with its broader ecological distribution. As expected, the responses of photosynthesis, heterotrophic capacity, respiration, and organic carbon loss to light and turbidity varied between species. Niche boundaries were highly sensitive to the functional responses of energy costs to light and turbidity. Moreover, the study species' niche differences were almost entirely attributable to species-specific differences in one functional response: that of respiration to turbidity. These results demonstrate that functional responses of energy-loss processes are important determinants of species-specific physiological limits to growth, and thereby of niche differences in reef corals. Given that many resources can stress organisms when supply rates are high, we propose that the functional responses of energy losses will prove to be important determinants of niche differences in other systems as well.


Caring electronically for young outpatients who have epilepsy.
The purpose of this study was to review electronic tools that might improve the delivery of epilepsy care, reduce medical care costs, and empower families to improve self-management capability. We reviewed the epilepsy-specific literature about self-management, electronic patient-reported or provider-reported outcomes, on-going remote surveillance, and alerting/warning systems. The improved care delivery system that we envision includes self-management, electronic patient (or provider)-reported outcomes, on-going remote surveillance, and alerting/warning systems. This system and variants have the potential to reduce seizure burden through improved management, keep children out of the emergency department and hospital, and even reduce the number of outpatient visits.


Blockade of clearance of immune complexes by an anti-Fc gamma receptor monoclonal antibody.
Clearance of immune complexes by the mononuclear phagocyte system is important for maintaining normal host defenses against bacterial and viral assault (1), but also contributes to the pathogenesis of a variety of immune- mediated diseases . For example, removal from the circulation of IgG-coated erythrocytes and platelets by the MPS is the sine qua non of immune-mediated cytopenias (2, 3). On the other hand, abnormally decreased removal by the MPS of smaller, soluble immune complexes may play a role in the pathogenesis of immune complex-mediated tissue damage found in such autoimmune diseases as SLE (4). Although the physicochemical nature and the size of immune complexes can influence rates of clearance and sites of deposition (reviewed in 5), interactions between immune complexes and the MPS in vivo are poorly understood. The inability to directly measure binding or internalization of immune complexes by cells in the liver and spleen has made the analysis of the molecular basis of immune complex clearance very difficult . Receptors for the Fc portion of IgG (FcgammaR) and for complement (CR) undoubtedly play a role in the removal of immune complexes, but the relative importance of these receptors is not known.


An Improved Drugs Screening System Reveals that Baicalein Ameliorates the Aβ/AMPA/NMDA-Induced Depolarization of Neurons.
The presence of amyloid-β (Aβ) plaque and tau protein hyperphosphorylation in brain tissue is the pathological hallmark of Alzheimer's disease (AD). At least some Aβ neurotoxicity is caused by the presence of excess glutamate that has been induced by Aβ accumulation. Memantine is currently the only NMDA receptor inhibitor approved for treating moderate-to-severe AD patients. We utilized primary cortical neurons and DiBAC4(3), a slow-response voltage sensitive fluorescence dye, to create a novel system for screening herbal medicines that allows the identification of pure compounds able to ameliorate Aβ-induced abnormal depolarization. The intensity of DiBAC4(3) fluorescence was increased when primary neurons were stimulated by Aβ; furthermore, pre-treatment with memantine abolished this change. Using this system, we identified six crude extracts made from herbal medicines that effectively alleviated this Aβ-induced abnormal depolarization. Among these herbal medicines, one pure compound, baicalein, which was known to be present in Scutellaria baricalensis and is known to improve memory using an AD mouse model, was identified by our assay. However, the compound's molecular mechanism remained unknown. We found that baicalein, in addition to inhibiting Aβ-induced depolarization, possibly functions as an antagonist of AMPA and NMDA receptors. Taken together, we have established a system/platform to identify herbal medicines that ameliorate Aβ-induced depolarization of neurons. Equally important, baicalein is a candidate drug with great potential for the treatment of AD patients.


Genome-wide associations for birth weight and correlations with adult disease.
Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10-8). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (Rg = -0.22, P = 5.5 × 10-13), T2D (Rg = -0.27, P = 1.1 × 10-6) and coronary artery disease (Rg = -0.30, P = 6.5 × 10-9). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10-4). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.


Tissue-specific plantar fascia-stretching exercise enhances outcomes in patients with chronic heel pain. A prospective, randomized study.
Approximately 10% of patients with plantar fasciitis have development of persistent and often disabling symptoms. A poor response to treatment may be due, in part, to inappropriate and nonspecific stretching techniques. We hypothesized that patients with chronic plantar fasciitis who are managed with the structure-specific plantar fascia-stretching program for eight weeks have a better functional outcome than do patients managed with a standard Achilles tendon-stretching protocol. One hundred and one patients who had chronic proximal plantar fasciitis for a duration of at least ten months were randomized into one of two treatment groups. The mean age was forty-six years. All patients received prefabricated soft insoles and a three-week course of celecoxib, and they also viewed an educational video on plantar fasciitis. The patients received instructions for either a plantar fascia tissue-stretching program (Group A) or an Achilles tendon-stretching program (Group B). All patients completed the pain subscale of the Foot Function Index and a subject-relevant outcome survey that incorporated generic and condition-specific outcome measures related to pain, function, and satisfaction with treatment outcome. The patients were reevaluated after eight weeks. Eighty-two patients returned for follow-up evaluation. With the exception of the duration of symptoms (p < 0.01), covariates for baseline measures revealed no significant differences between the groups. The pain subscale scores of the Foot Function Index showed significantly better results for the patients managed with the plantar fascia-stretching program with respect to item 1 (worst pain; p = 0.02) and item 2 (first steps in the morning; p = 0.006). Analysis of the response rates to the outcome measures also revealed significant differences with respect to pain, activity limitations, and patient satisfaction, with greater improvement seen in the group managed with the plantar fascia-stretching program. A program of non-weight-bearing stretching exercises specific to the plantar fascia is superior to the standard program of weight-bearing Achilles tendon-stretching exercises for the treatment of symptoms of proximal plantar fasciitis. These findings provide an alternative option to the present standard of care in the nonoperative treatment of patients with chronic, disabling plantar heel pain.


Diabetes prevalence and determinants in Indigenous Australian populations: A systematic review.
To perform a systematic review of the prevalence of diabetes and impaired glucose tolerance (IGT) in Indigenous Australians in order to clarify overall patterns, by determinants such as age, gender, region, ethnicity and remoteness. The OVID interface to Medline and the Australian Indigenous HealthInfoNet databases were systematically searched from years 1997 to 2010. Studies reporting diabetes prevalence were included if they used population-based samples of Indigenous Australians. Diagnosis of diabetes was based on self-report or standard diagnostic criteria. Twenty-four studies were included. The diabetes prevalence ranged from 3.5 to 33.1%; IGT estimates ranged from 4.7 to 21.1%. Prevalence was greater among Indigenous Australian women compared to men, the Northern Territory's Top End compared to Central Australia, Torres Strait Islanders compared to Aboriginals, older (≥35 years) compared to younger (<35 years) age groups, and remote compared to urban settings. Patterns of IGT prevalence were similar to those observed for diabetes. Although the prevalence of diabetes and IGT is high, there appears to be considerable variation in prevalence between different segments of the Australian Indigenous population. Data on diabetes prevalence in the urban Australian Indigenous population is lacking, despite accounting for almost three quarters of the total population.


Genomic reconnaissance of clinical isolates of emerging human pathogen Mycobacterium abscessus reveals high evolutionary potential.
Mycobacterium abscessus (Ma) is an emerging human pathogen that causes both soft tissue infections and systemic disease. We present the first comparative whole-genome study of Ma strains isolated from patients of wide geographical origin. We found a high proportion of accessory strain-specific genes indicating an open, non-conservative pan-genome structure, and clear evidence of rapid phage-mediated evolution. Although we found fewer virulence factors in Ma compared to M. tuberculosis, our data indicated that Ma evolves rapidly and therefore should be monitored closely for the acquisition of more pathogenic traits. This comparative study provides a better understanding of Ma and forms the basis for future functional work on this important pathogen.


Genetic analysis of the proximal region of chromosome 2 of Drosophila melanogaster. I. Detachment products of compound autosomes.
To examine the genetic composition of proximal heterochromatin in chromosome 2, the detachment of compound second autosomes, for generating proximal deficiencies, appeared a promising method. Compound seconds were detached by gamma radiation. A fraction of the detachment products were recessive lethals owing to proximal deficiencies. Analysis by inter se complementation, pseudo-dominance tests with proximal mutations and allelism tests with known deficiencies provided evidence for at least two loci between the centromere and the light locus in 2L and one locus in 2R between the rolled locus and the centromere. The data further demonstrate that rolled, and probably light, are located within the proximal heterochromatin. Thus, functional genetic loci are found in heterochromatin, albeit at low density.


Distributional reaction time properties in the Eriksen task: marked differences or hidden similarities with the Simon task?
In conflict tasks, the irrelevant stimulus attribute needs to be suppressed for the correct response to be produced. In the Simon task, earlier researchers have proposed that this suppression is the reason that, after an initial increase, the interference effect decreases for longer RTs, as reflected by late, negative-going delta plots. This view has been challenged by observations of positive-going delta plots, even for long RTs, in other conflict tasks, despite a similar necessity for suppression. For late negative-going delta plots to be interpreted as reflecting suppression, a necessary, although maybe not sufficient, condition is that similar patterns should be observed for other conflict tasks. We reasoned that a similar suppression could be present, but hidden, in the Eriksen flanker task. By recording and analyzing electromyograms of the muscles involved in response execution, we could compute delta plots separately for trials that elicited a subthreshold incorrect response activation (partial error). Late negative-going delta plots were observable on partial-error trials, although they were weaker than for the Simon task, reducing the impact of this inversion on the overall distribution. We further showed that this pattern is modulated by time pressure. Those results indicate that mechanisms leading to negative-going delta plots, similar to those observed in the Simon task, are also at play in the Eriksen task. The link between negative-going delta plots and executive online control is discussed.


Inhibition of striatonigral autophagy as a link between cannabinoid intoxication and impairment of motor coordination.
The use of cannabis is rapidly expanding worldwide. Thus, innovative studies aimed to identify, understand and potentially reduce cannabis-evoked harms are warranted. Here, we found that Δ9-tetrahydrocannabinol, the psychoactive ingredient of cannabis, disrupts autophagy selectively in the striatum, a brain area that controls motor behavior, both in vitro and in vivo. Boosting autophagy, either pharmacologically (with temsirolimus) or by dietary intervention (with trehalose), rescued the Δ9-tetrahydrocannabinol-induced impairment of motor coordination in mice. The combination of conditional knockout mouse models and viral vector-mediated autophagy-modulating strategies in vivo showed that cannabinoid CB1 receptors located on neurons belonging to the direct (striatonigral) pathway are required for the motor-impairing activity of Δ9-tetrahydrocannabinol by inhibiting local autophagy. Taken together, these findings identify inhibition of autophagy as an unprecedented mechanistic link between cannabinoids and motor performance, and suggest that activators of autophagy might be considered as potential therapeutic tools to treat specific cannabinoid-evoked behavioral alterations.


Foxp3+ regulatory T cells participate in repair of ischemic acute kidney injury.
T lymphocytes modulate early ischemia-reperfusion injury in the kidney; however, their role during repair is unknown. We studied the role of TCRbeta(+)CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs), known to blunt immune responses, in repair after ischemia-reperfusion injury to the kidney. Using a murine model of ischemic acute kidney injury we found that there was a significant trafficking of Tregs into the kidneys after 3 and 10 days. Post-ischemic kidneys had increased numbers of TCRbeta(+)CD4(+) and TCRbeta(+)CD8(+) T cells with enhanced pro-inflammatory cytokine production. Treg depletion starting 1 day after ischemic injury using anti-CD25 antibodies increased renal tubular damage, reduced tubular proliferation at both time points, enhanced infiltrating T lymphocyte cytokine production at 3 days and TNF-alpha generation by TCRbeta(+)CD4(+) T cells at 10 days. In separate mice, infusion of CD4(+)CD25(+) Tregs 1 day after initial injury reduced INF-gamma production by TCRbeta(+)CD4(+) T cells at 3 days, improved repair and reduced cytokine generation at 10 days. Treg manipulation had minimal effect on neutrophil and macrophage infiltration; Treg depletion worsened mortality and serum creatinine, while Treg infusion had a late beneficial effect on serum creatinine in bilateral ischemia. Our study demonstrates that Tregs infiltrate ischemic-reperfused kidneys during the healing process promoting repair, likely through modulation of pro-inflammatory cytokine production of other T cell subsets. Treg targeting could be a novel therapeutic approach to enhance recovery from ischemic acute kidney injury.


Long-term influence of bone marrow-derived mesenchymal stem cells on liver ischemia-reperfusion injury in a rat model.
The aim of this study was to evaluate the long-term usefulness of intraportal injection of the bone marrow-derived mesenchymal stem cells (BM-MSCs) in limitation of experimentally induced ischemia-reperfusion injury (IRI) in a rat model. Twenty Wistar rats were divided into 3 groups: donor group (n=5), study group (n=10), and control group (n=5). IRI was performed using a modified hanging-weight system after left portal triad occlusion in study group animals. Isolated autologous BM-MSCs were labeled with fluorochrome PKH-26 then intraportally injected into the rats in the study group. Control group animals were intraportally injected with 1 ml of PBS. Follow-up was 3 months, after which animals were sacrificed for histopathological examination. Migration of BM-MSCs into different organs was examined. H&E staining of liver tissue sections from "time zero" biopsies did not show many irregularities in structural or histological construction compared to liver sections from the control group. However, a small amount of centrilobular hepatocyte necrosis and coagulative necrosis with neutrophil infiltration areas was observed in liver sections of the study group. The migration assay of BM-MSCs labeled with PKH-26 showed the highest positive BM-MSCs staining (6%) in the spleen, while few positively stained cells were found (2%) in liver sections. No BM-MSCs were detected in brain, kidney, or lung tissues. These results suggest that intraportal bone marrow-derived mesenchymal stem cell injection is safe and cells do not migrate chaotically to other organs after targeted implementation.


Molecular characterisation of Cryptosporidium (Apicomplexa) in children and cattle in Romania.
To investigate the transmission of species of Cryptosporidium Tyzzer, 1907 in Timis County, Romania, 48 isolates of Cryptosporidium coccidia from 11 children, 29 calves and eight pigs were characterised by molecular analysis of two loci (SSU rRNA and 60-kDa glycoprotein gene). Overall, 22 isolates were amplified and sequence analyses revealed that all isolates were Cryptosporidium parvum Tyzzer, 1912. Two subtype families were identified, IIa and IId. Subtype IIdA22G1 (n = 4) was the single C. parvum subtype found in children. Subtypes found in calves included IIdA27G1 (n = 8), a novel subtype, IIdA25G1 (n = 5), IIdA22G1 (n = 2), IIdA21G1a (n = 1), and IIaA16G1R1 (n = 1). Subtype IIdA26G1 was found in a pig. These results were significantly different from previous Romanian reports, as the five subtypes of family IId identified in this study were never identified previously in this country. Thus, cattle may be a source of Cryptosporidium infections for humans and the transmission dynamics of C. parvum in Romania is more complex than previously believed.


Analysis of local and wide-field movements in the superior temporal visual areas of the macaque monkey.
The middle temporal (MT) and medial superior temporal (MST) areas of the macaque cortex have many cells that respond to straight movements in the frontoparallel plane with directional selectivity (D cells). We examined their responses to movements of a bar, of a wide dot pattern, and to combined movements of the two in anesthetized and immobilized animals. D cells in MT showed a wide variety in the strength of the inhibitory field surrounding the excitatory center field. Responses of SI+-type cells to a bar moving across the excitatory field were suppressed when a wide dot pattern moved over the surround field in the same direction and at the same speed as the bar. Inhibition was selective to the direction and speed of the surround movement, and the effective area for inhibition occupied a wide area, which expanded in all radial directions. Responses of SI- -type cells to a center bar movement were changed little by a conjoint movement over the surround field. Consequently, SI- -type cells responded to wide-field movement as well as to stimuli confined within the excitatory field. Although D cells in MST commonly had large excitatory fields, a proportion of them (Figure type) responded to bar movement much more strongly than to wide-field movement. Their responses to a bar movement were suppressed direction-selectively by a conjoint movement of a wide dot-pattern background. The effective area for inhibition coexisted with the excitatory field in these cells. MST cells of the Nonselective type responded comparably well to the two stimuli, and those of the Field type responded much more strongly to wide-field movement than to bar movement. It is thus suggested that MT cells of the SI+ type and MST cells of the Figure type can detect a difference between movements of an object and its wide background, whereas MST cells of the Field type can detect a conjoint movement of a wide field, neglecting the movements of a single object.


Health promoting lifestyle behaviour in medical students: a multicentre study from Turkey.
The aim of this study was to determine the predictors of health promoting lifestyle behaviour among medical students attending seven of the medical schools in Turkey. This cross- sectional descriptive study was performed during the second semester of the first and last (sixth) years of study from March to May 2011. A questionnaire with two sections was specifically designed. The first section contained questions on demographic characteristics; the second consisted of the Health Promoting Lifestyle Profile II (HPLP) Scale. From a total of 2,309 medical students, 2,118 (response rate 91.7%) completed the questionnaire. Data were analyzed using descriptive statistics, t, Anova, Tukey test and binary logistic regression analysis. The research was approved by the Ethics Committee of Erciyes University. The mean age was 20.7±2.9 years and it was found that 55.1% were men, 62.3% were in the first year. The overall prevalence of smoking was 19.1%, and for drinking alcohol was 19.4%. HPLP point averages of the first year students were 129.2±17.7, and for last year 125.5±19.0. The overall mean score for the HPLP II was 2.5±0.4. They scored highest on the spiritual growth subscale (2.9±0.5), interpersonal relations (2.8±0.5), health responsibility subscale (2.3±0.5), nutrition subscale (2.3±0.5), stress management subscale (2.3±0.4), and the lowest subscale physical activity (2.0±0.5). It is established that student's grade, educational level of parents, economic status of family, marital status, smoking and general health perception of the students resulted in a significant difference in HPLP Scale total score average and the mean score of majority of subscales.There was no statistically significant difference between the total HPLP when evaluated for gender, chronic disease, alcohol drinking status and BMI. Based on these results, particularly in the curriculum of medical students in order to increase positive health behaviours including physical activity, health promotion issues, and giving more space to aim at behaviour change in these matters is recommended.


Variables to Predict Nephrological Disease in General, and Glomerulonephritis in Particular, in Patients With Microhematuria.
Microhematuria (MH) is a symptom frequently leading to uncertainty as to when a nephrology referral is appropriate. Because MH may be indicative of severe kidney disorders, prompt diagnosis and potential treatment initiation can be important. We aimed to identify further variables that point at a nephrological cause, in particular of glomerulonephritis (GN), when MH is diagnosed. A retrospective analysis of data acquired from patients attending a nephrology office due to MH was performed. Demographic information and diagnostic tests were evaluated in order to identify factors that were associated with a nephrological cause. Patients with MH (n = 805) as indicated by a urine stick analysis were included. Of these, MH was confirmed by urine sediment analysis in 543 patients (67.5%). Of those, 48.3% had a nephrological cause, including 12.4% with GN and 2.9% with rapid progressive GN (RPGN). A urine dipstick finding of ≥ 250 erythrocytes per microliter, microalbuminuria and elevated leukocytes increased the probability of having a GN to 62.4%. Furthermore, the presence of microalbuminuria, GFR < 60 mL/min, history of hypertension and diabetes mellitus increased the probability for all nephrological causes to 95.4%. There are a number of factors available that help to assess the need for a nephrology referral in patients with microhematuria.


Prevalence of Pragmatically Defined High CV Risk and its Correlates in LMIC: A Report From 10 LMIC Areas in Africa, Asia, and South America.
Currently available tools for assessing high cardiovascular risk (HCR) often require measurements not available in resource-limited settings in low- and middle-income countries (LMIC). There is a need to assess HCR using a pragmatic evidence-based approach. This study sought to report the prevalence of HCR in 10 LMIC areas in Africa, Asia, and South America and to investigate the profiles and correlates of HCR. Cross-sectional analysis using data from the National Heart, Lung, and Blood Institute-UnitedHealth Group Centers of Excellence. HCR was defined as history of heart disease/heart attack, history of stroke, older age (≥50 years for men and ≥60 for women) with history of diabetes, or older age with systolic blood pressure ≥160 mm Hg. Prevalence estimates were standardized to the World Health Organization's World Standard Population. A total of 37,067 subjects ages ≥35 years were included; 53.7% were women and mean age was 53.5 ± 12.1 years. The overall age-standardized prevalence of HCR was 15.4% (95% confidence interval: 15.0% to 15.7%), ranging from 8.3% (India, Bangalore) to 23.4% (Bangladesh). Among men, the prevalence was 1.7% for the younger age group (35 to 49 years) and 29.1% for the older group (≥50); among women, 3.8% for the younger group (35 to 59 years) and 40.7% for the older group (≥60). Among the older group, measured systolic blood pressure ≥160 mm Hg (with or without other conditions) was the most common criterion for having HCR, followed by diabetes. The proportion of having met more than 1 criterion was nearly 20%. Age, education, and body mass index were significantly associated with HCR. Cross-site differences existed and were attenuated after adjusting for age, sex, education, smoking, and body mass index. The prevalence of HCR in 10 LMIC areas was generally high. This study provides a starting point to define targeted populations that may benefit from interventions combining both primary and secondary prevention strategies.


Geographic assignment of seabirds to their origin: combining morphologic, genetic, and biogeochemical analyses.
Longline fisheries, oil spills, and offshore wind farms are some of the major threats increasing seabird mortality at sea, but the impact of these threats on specific populations has been difficult to determine so far. We tested the use of molecular markers, morphometric measures, and stable isotope (delta15N and delta13C) and trace element concentrations in the first primary feather (grown at the end of the breeding period) to assign the geographic origin of Calonectris shearwaters. Overall, we sampled birds from three taxa: 13 Mediterranean Cory's Shearwater (Calonectris diomedea diomedea) breeding sites, 10 Atlantic Cory's Shearwater (Calonectris diomedea borealis) breeding sites, and one Cape Verde Shearwater (C. edwardsii) breeding site. Assignment rates were investigated at three spatial scales: breeding colony, breeding archipelago, and taxa levels. Genetic analyses based on the mitochondrial control region (198 birds from 21 breeding colonies) correctly assigned 100% of birds to the three main taxa but failed in detecting geographic structuring at lower scales. Discriminant analyses based on trace elements composition achieved the best rate of correct assignment to colony (77.5%). Body measurements or stable isotopes mainly succeeded in assigning individuals among taxa (87.9% and 89.9%, respectively) but failed at the colony level (27.1% and 38.0%, respectively). Combining all three approaches (morphometrics, isotopes, and trace elements on 186 birds from 15 breeding colonies) substantially improved correct classifications (86.0%, 90.7%, and 100% among colonies, archipelagos, and taxa, respectively). Validations using two independent data sets and jackknife cross-validation confirmed the robustness of the combined approach in the colony assignment (62.5%, 58.8%, and 69.8% for each validation test, respectively). A preliminary application of the discriminant model based on stable isotope delta15N and delta13C values and trace elements (219 birds from 17 breeding sites) showed that 41 Cory's Shearwaters caught by western Mediterranean long-liners came mainly from breeding colonies in Menorca (48.8%), Ibiza (14.6%), and Crete (31.7%). Our findings show that combining analyses of trace elements and stable isotopes on feathers can achieve high rates of correct geographic assignment of birds in the marine environment, opening new prospects for the study of seabird mortality at sea.


Integrating an internet-mediated walking program into family medicine clinical practice: a pilot feasibility study.
Regular participation in physical activity can prevent many chronic health conditions. Computerized self-management programs are effective clinical tools to support patient participation in physical activity. This pilot study sought to develop and evaluate an online interface for primary care providers to refer patients to an Internet-mediated walking program called Stepping Up to Health (SUH) and to monitor participant progress in the program. In Phase I of the study, we recruited six pairs of physicians and medical assistants from two family practice clinics to assist with the design of a clinical interface. During Phase II, providers used the developed interface to refer patients to a six-week pilot intervention. Provider perspectives were assessed regarding the feasibility of integrating the program into routine care. Assessment tools included quantitative and qualitative data gathered from semi-structured interviews, surveys, and online usage logs. In Phase I, 13 providers used SUH and participated in two interviews. Providers emphasized the need for alerts flagging patients who were not doing well and the ability to review participant progress. Additionally, providers asked for summary views of data across all enrolled clinic patients as well as advertising materials for intervention recruitment. In response to this input, an interface was developed containing three pages: 1) a recruitment page, 2) a summary page, and 3) a detailed patient page. In Phase II, providers used the interface to refer 139 patients to SUH and 37 (27%) enrolled in the intervention. Providers rarely used the interface to monitor enrolled patients. Barriers to regular use of the intervention included lack of integration with the medical record system, competing priorities, patient disinterest, and physician unease with exercise referrals. Intention-to-treat analyses showed that patients increased walking by an average of 1493 steps/day from pre- to post-intervention (t = (36) = 4.13, p < 0.01). Providers successfully referred patients using the SUH provider interface, but were less willing to monitor patient compliance in the program. Patients who completed the program significantly increased their step counts. Future research is needed to test the effectiveness of integrating SUH with clinical information systems over a longer evaluation period.


Thermodynamic properties of selenoether-functionalized ionic liquids and their use for the synthesis of zinc selenide nanoparticles.
Three selenoether-functionalized ionic liquids (ILs) of N-[(phenylseleno)methylene]pyridinium (1), N-(methyl)- (2) and N-(butyl)-N'-[(phenylseleno)methylene]imidazolium (3) with bis(trifluoromethanesulfonyl)imide anions ([NTf2]) were prepared from pyridine, N-methylimidazole and N-butylimidazole with in situ obtained phenylselenomethyl chloride, followed by ion exchange to give the desired compounds. The crystal structures of the bromide and tetraphenylborate salts of the above cations (1-Br, 2-BPh4 and 3-BPh4) confirm the formation of the desired cations and indicate a multitude of different supramolecular interactions besides the dominating Coulomb interactions between the cations and anions. The vaporization enthalpies of the synthesized [NTf2]-containing ILs were determined by means of a quartz-crystal microbalance method (QCM) and their densities were measured with an oscillating U-tube. These thermodynamic data have been used to develop a method for assessment of miscibility of conventional solvents in the selenium-containing ILs by using Hildebrandt solubility parameters, as well as for modeling with the electrolyte perturbed-chain statistical associating fluid theory (ePC-SAFT) method. Furthermore, structure-property relations between selenoether-functionalized and similarly shaped corresponding aryl-substituted imidazolium- and pyridinium-based ILs were analyzed and showed that the contribution of the selenium moiety to the enthalpy of vaporization of an IL is equal to the contribution of a methylene (CH2) group. An incremental approach to predict vaporization enthalpies of ILs by a group contribution method has been developed. The reaction of these ILs with zinc acetate dihydrate under microwave irradiation led to ZnSe nanoparticles of an average diameter between 4 and 10 nm, depending on the reaction conditions.


Multicentre prospective study of perinatal depression in Japan: incidence and correlates of antenatal and postnatal depression.
A multicentre study on the epidemiology of perinatal depression was conducted among Japanese women expecting the first baby (N = 290). The incidence rate of the onset of the DSM-III-R Major Depressive Episode during pregnancy (antenatal depression) and within 3 months after delivery (postnatal depression) were 5.6% and 5.0%, respectively. Women with antenatal depression were characterised by young age and negative attitude towards the current pregnancy, whereas women with postnatal depression were characterised by poor accommodation, dissatisfaction with sex of the newborn baby and with the emotional undermining. Antenatal depression was a major risk factor for postnatal depression.


Fish-protection devices at unscreened water diversions can reduce entrainment: evidence from behavioural laboratory investigations.
Diversion (i.e. extraction) of water from rivers and estuaries can potentially affect native wildlife populations if operation is not carefully managed. For example, open, unmodified water diversions can act as a source of injury or mortality to resident or migratory fishes from entrainment and impingement, and can cause habitat degradation and fragmentation. Fish-protection devices, such as exclusion screens, louvres or sensory deterrents, can physically or behaviourally deter fish from approaching or being entrained into water diversions. However, empirical assessment of their efficacy is often lacking or is investigated only for particular economically or culturally important fishes, such as salmonids. The Southern population of anadromous green sturgeon (Acipenser medirostris) is listed as threatened in California, and there is a high density of water diversions located within their native range (the Sacramento-San Joaquin watershed). Coupled with their unique physiology and behaviour compared with many other fishes native to California, the green sturgeon is susceptible to entrainment into diversions and is an ideal species with which to study the efficacy of mitigation techniques. Therefore, we investigated juvenile green sturgeon (188-202 days post-hatch) in the presence of several fish-protection devices to assess behaviour and entrainment risk. Using a large experimental flume (∼500 kl), we found that compared with an open diversion pipe (control), the addition of a trash-rack box, louvre box, or perforated cylinder on the pipe inlet all significantly reduced the proportion of fish that were entrained through the pipe (P = 0.03, P = 0.028, and P = 0.028, respectively). Likewise, these devices decreased entrainment risk during a single movement past the pipe by between 60 and 96%. These fish-protection devices should decrease the risk of fish entrainment during water-diversion activities.


Evaluation of hydrotherapy, using passive tests and power tests, for recovery across a cyclic week of competitive rugby union.
In team sports, a cycle of training, competition, and recovery occurs weekly during the competitive season. In this research, we evaluated hydrotherapy for recovery from a simulated game of rugby union tracked over a week of training. Twenty-four experienced male rugby union players (mean ± SD age 19.46 ± 0.82 years, weight 82.38 ± 11.12 kg, height 178.54 ± 5.75 cm) were randomly divided into 3 groups: cold water immersion (n = 8), contrast bath therapy (n = 8), and a control group (n = 8). The 2 forms of hydrotherapy were administered immediately after a simulated rugby game. Testing was conducted 1 hour before the game and at 5 intervals postgame: 1, 48, 72, 96, and 144 hours. Dependent variables included countermovement jump, 10- and 40-m sprints, sessional rating of perceived exertion (RPE), flexibility, thigh circumference, and self-reported delayed onset muscle soreness (DOMS). Significant differences in DOMS were found between the cold water immersion and contrast bath groups at 48 hours post intervention (p = 0.02), and between the control and contrast bath groups at 72 (p = 0.03) and 96 (p = 0.04) hours post intervention. Cold water immersion and contrast bath groups reported significantly different RPE at 72 hours (p = ?) and 96 hours post (p = 0.05) intervention. Athletes' perceptions of muscle soreness and sessional RPE scores for training were greater in the contrast bath group (20%) after the simulated game and throughout the training week. Although results from passive and power tests were inconclusive in determining whether cold water immersion or passive recovery was more effective in attenuating fatigue, results indicated contrast baths had little benefit in enhancing recovery during a cyclic week of rugby union.


Immunomodulatory Effect of Gymnema sylvestre (R.Br.) Leaf Extract: An In Vitro Study in Rat Model.
Gymnema sylvestre Wild R.Br (family: Asclepidaceae) is a valuable medicinal plant used in folk medicine to treat diabetes, obesity, asthma etc. in India for antiquity. Diabetes mellitus is a syndrome characterized immunologically by lymphocyte apoptosis and reduced cell-mediated and humoral immunity. Modulation of immune responses to alleviate diseases has been of interest, and traditional herbal medicines may play an important role in this regard. In this study, we aim to evaluate the immunomodulatory potential of methanolic extract of G. sylvestre leaf using rat model. HPLC analysis of leaf extract was carried out for gymnemic acid. The method involves the initial hydrolysis of gymnemic acids, the active ingredients, to a common aglycone followed by the quantitative estimation of gymnemagenin, using gymnemagenin as reference standard. Gymnemic acid content was 2.40% (w/w) in G. sylvestre leaf extract. In vitro immunomodulatory activity of the methanolic extract of G. sylvestre leaf (1-200μg/ml) was evaluated by gauging its effects on nitroblue tetrazolium reduction and nitrite release in rat peritoneal macrophages and on mitogen (ConA, PHA and LPS) induced splenic lymphocyte proliferation. G. sylvestre leaf extract showed significant (<0.05) enhancement in NO and ROS generation in macrophages and in proliferation of lymphocytes in dose dependent manner. EC50 value was 3.10, 3.75 and 2.68 μg/ml for NBT reduction, nitrite release and lymphoproliferation, respectively. Potential effect was observed at 100 μg/ml in NO and ROS generation in macrophages and 20 μg/ml in lymphocyte proliferation. G. sylvestre leaf extract stimulates macrophage reactivity, increasing the level of activity even higher when combined with PMA or LPS. These findings suggest the presence of active compounds, gymnemic acid, in methanolic extract of G. sylvestre leaf that stimulates both myeloid and lymphoid components of immune system, and therefore can restore the innate immune function. Through this study, the traditional knowledge of anti-diabetic property of G. sylvestre is scientifically supplemented with its immunomodulatory properties.


A Systematic Review of Completeness of Reporting in Randomized Controlled Trials in Dermatologic Surgery: Adherence to CONSORT 2010 Recommendations.
Randomized controlled trials are the gold standard for comparing safety and effectiveness of surgical interventions. Reporting guidelines are available for conveying the results of such trials. To assess adherence to standard reporting guidelines among randomized controlled trials in dermatologic surgery. Systematic review. Data source was randomized controlled trials in the journal Dermatologic Surgery, per PubMed search, 1995 to 2014. Studies were appraised for the number of the 37 CONSORT 2010 Checklist criteria reported in each. Analysis included comparison of reporting across 4 consecutive periods. Three hundred sixty-three studies were eligible. The mean number of items reported per study increased monotonically from 14.5 in 1995 to 1999 to 16.2 in 2002 to 2004, 17.7 in 2005 to 2009, and 18.0 in 2010 to 2014 (p < .0001). A limitation was that study procedures may have been performed without being reported. Completeness of reporting in randomized controlled trials in dermatologic surgery has improved significantly during the preceding 2 decades. Some elements are still reported at lower rates.


Inducible COX-2-dependent apoptosis in human ovarian cancer cells.
Resveratrol is a naturally occurring trihydroxyl-diphenylethylene compound that has been shown experimentally to have beneficial effects in the treatment of cancer and cardiovascular disease. Resveratrol induces programmed cell death (apoptosis) in these cells and activates important signal transducing proteins including extracellular signal-regulated kinases (ERKs) 1 and 2 in cancer cells. Resveratrol also causes nuclear accumulation of the enzyme cyclooxygenase (COX)-2 and of the oncogene suppressor protein, p53. We have studied the molecular basis of the anticancer actions of resveratrol using human ovarian carcinoma (OVCAR-3) cells. Our findings include the following: (i) nuclear accumulation of COX-2 in resveratrol-treated cells is blocked by the ERK1/2 inhibitor, PD98059; (ii) an inhibitor of COX-2 activity, NS398, prevents accumulation of ERK1/2, COX-2, activated p53 and small ubiquitin-like modifier (SUMO-1) in the nucleus; (iii) apoptosis, quantitated by nucleosome enzyme-linked immunosorbent assay and the nuclear abundance of the pro-apoptotic protein, BcL-xs, were inhibited by NS398. This finding implicates nuclear COX-2 in p53-mediated apoptosis induced by resveratrol. Sumoylation is important to stabilization of p53 and a COX-2-SUMO-1 interaction suggests sumoylation of COX-2 in resveratrol-treated cells and (iv) chromatin immunoprecipitation studies showed binding of induced nuclear COX-2 to the promoter region of PIG3 and Bax, pro-apoptotic gene targets of transcriptionally active p53. Nuclear accumulation of activated ERK1/2 and sumolyated COX-2 are essential to resveratrol-induced pSer-15-p53-mediated apoptosis in human ovarian cancer cells.


Trace element profiles of the sea anemone Anemonia viridis living nearby a natural CO2 vent.
Ocean acidification (OA) is not an isolated threat, but acts in concert with other impacts on ecosystems and species. Coastal marine invertebrates will have to face the synergistic interactions of OA with other global and local stressors. One local factor, common in coastal environments, is trace element contamination. CO2 vent sites are extensively studied in the context of OA and are often considered analogous to the oceans in the next few decades. The CO2 vent found at Levante Bay (Vulcano, NE Sicily, Italy) also releases high concentrations of trace elements to its surrounding seawater, and is therefore a unique site to examine the effects of long-term exposure of nearby organisms to high pCO2 and trace element enrichment in situ. The sea anemone Anemonia viridis is prevalent next to the Vulcano vent and does not show signs of trace element poisoning/stress. The aim of our study was to compare A. viridis trace element profiles and compartmentalization between high pCO2 and control environments. Rather than examining whole anemone tissue, we analyzed two different body compartments-the pedal disc and the tentacles, and also examined the distribution of trace elements in the tentacles between the animal and the symbiotic algae. We found dramatic changes in trace element tissue concentrations between the high pCO2/high trace element and control sites, with strong accumulation of iron, lead, copper and cobalt, but decreased concentrations of cadmium, zinc and arsenic proximate to the vent. The pedal disc contained substantially more trace elements than the anemone's tentacles, suggesting the pedal disc may serve as a detoxification/storage site for excess trace elements. Within the tentacles, the various trace elements displayed different partitioning patterns between animal tissue and algal symbionts. At both sites iron was found primarily in the algae, whereas cadmium, zinc and arsenic were primarily found in the animal tissue. Our data suggests that A. viridis regulates its internal trace element concentrations by compartmentalization and excretion and that these features contribute to its resilience and potential success at the trace element-rich high pCO2 vent.


Persistent Postoperative Opioid Use in Older Head and Neck Cancer Patients.
Despite the epidemic of opioid overuse among American patients, there are limited data regarding the prevalence of such use among patients with head and neck cancer (HNC). Here, we report on the prevalence of persistent postoperative opioid (PPO) use and its risk factors among older patients with HNC undergoing surgery. Retrospective cohort study. Surveillance, Epidemiology, and End Results (SEER)-Medicare linked cancer registry-claims database. We identified patients aged 66 years or older who were diagnosed with HNC from 2008 to 2013, underwent primary surgical resection for their cancers, and met certain insurance and discharge criteria. The primary outcome was PPO use, defined as new opioid prescriptions 90 to 180 days postoperatively. We used multivariable logistic regression to evaluate associations between PPO use and factors such as demographics and postoperative treatment. Of the 1190 eligible patients with HNC, 866 (72.8%) received opioid prescriptions attributable to their surgery. Among these 866 patients, the prevalence of PPO use was 33.3% overall; it was 48.3% among the 428 patients with preoperative opioid use compared to 18.5% among the 438 opioid-naive patients (adjusted odds ratio [OR], 3.96; 95% confidence interval [CI], 2.80-5.59). Other factors associated with PPO use include postoperative radiotherapy (OR, 1.99; 95%, CI 1.33-2.98) and Charlson comorbidity index (OR, 1.20; 95% CI, 1.03-1.41). Postoperative chemotherapy (OR, 1.19; 95% CI, 0.73-1.95) was not significantly associated with PPO use. PPO use is a substantial problem in older surgical patients with HNC, one that warrants consideration of alternative treatment strategies and continued examination of prescription guidelines for patients with HNC.


What is hot in autoimmunity.
Late 2008 and 2009 have been rich of new developments in our knowledge in the pathogenesis, susceptibility, and putative treatments of autoimmune diseases. In general terms, it is now clear that the discovery pace in immunology in general and autoimmunity in particular is exponential and warrants a timely discussion. We herein review the major issues that have been addressed in the basic, clinical and translational fields of autoimmunity in the leading journals over the past 18 months. Of note, major scientific issues are being addressed with a tremendous effort, as in the case of the T helper 17 paradigm or the role of T regulatory cells or the long overlooked innate arm of the immune system, while an increasing number of translational works are being performed with promising data for a bedside impact. The ultimate implication from the recent literature is that autoimmunity is rapidly becoming a uniform scenario in which similarities significantly outnumber differences in terms of pathogenesis and mechanisms. For this reason a comprehensive yet brief review of the published reports encompassing all aspects of autoimmunity will prove helpful to basic scientist and clinicians alike to prompt new research directions.


Surgical lung cancer patients' views about smoking and support to quit after diagnosis: a qualitative study.
Evidence suggests that quitting smoking improves symptoms as well as disease-related mortality for cancer patients. However, smoking cessation support is typically not well integrated into routine cancer care even in the case of lung cancer.. We explored surgical lung cancer patients' views about smoking and about their preferences for support to help them to quit. We conducted semi-structured, qualitative interviews with 22 surgical lung cancer patients with a smoking history, after treatment with surgery. Data were analysed using the framework approach. Although diagnosis promoted a successful quit attempt in some, others continued smoking or relapsed after a quit attempt. Most participants wished they were a non-smoker but, in conflict with this, also felt that smoking was enjoyable, helped with psychological coping or had some health benefits. Some also demonstrated a fatalist attitude towards the potential detrimental health effects. However, all participants felt that it was important for health professionals to address smoking and some wanted cessation support although it was often not provided. Participants wanted support to start as early as possible and to continue for the first weeks after discharge. Surgical lung cancer patients often stop smoking during hospitalisation, and many want to remain quit but relapse shortly after discharge. Although it is often not provided, many patients want to be offered support to help them quit. Surveys suggest that clinicians believe that addressing smoking will be difficult and/or unwanted. However, these findings suggest that surgical lung cancer patients would tolerate, and most would prefer, integration of smoking cessation support into routine cancer care.


Dissecting the roles of Raf- and PI3K-signalling pathways in melanoma formation and progression in a zebrafish model.
Deregulated Ras signalling is implicated in most human neoplasia, exemplified by melanoma. Whereas Raf activation occurs almost ubiquitously in benign and malignant melanocytic neoplasms, implying an involvement in tumour initiation, phosphoinositide 3-kinase (PI3K) activation occurs predominantly in malignant neoplasms, implying an involvement in malignant progression. Here, we dissect the contributions of these two pathways to tumourigenesis in vivo, by modulating their activities in zebrafish melanocytes. Misexpression of oncogenic Ras (V12RAS) in founder fish induced frequent melanoma, beginning at larval stages, with concomitant activation of Raf-Mek-Erk and PI3K-Akt signalling. Misexpression of effector-domain mutants of V12RAS, or of various downstream effectors, confirmed a selective role for the Raf-Mek-Erk pathway in initiating neoplasia, but highlighted the requirement for additional Ras effector pathways for malignancy. The phenotype of animals with germ-line transmission of V12RAS resembled familial atypical mole and melanoma (FAMM) syndrome: melanocytes displayed hyperplasia, dysplasia, altered terminal differentiation and spontaneously progressed to invasive melanoma. Co-expressing a dominant-interfering form of PI3K abolished V12RAS-induced malignancy, demonstrating a direct role for PI3K signalling in the malignant progression of melanoma in vivo, and highlighting PI3K as a promising target for melanoma therapy.


Dating of the human-ape splitting by a molecular clock of mitochondrial DNA.
A new statistical method for estimating divergence dates of species from DNA sequence data by a molecular clock approach is developed. This method takes into account effectively the information contained in a set of DNA sequence data. The molecular clock of mitochondrial DNA (mtDNA) was calibrated by setting the date of divergence between primates and ungulates at the Cretaceous-Tertiary boundary (65 million years ago), when the extinction of dinosaurs occurred. A generalized least-squares method was applied in fitting a model to mtDNA sequence data, and the clock gave dates of 92.3 +/- 11.7, 13.3 +/- 1.5, 10.9 +/- 1.2, 3.7 +/- 0.6, and 2.7 +/- 0.6 million years ago (where the second of each pair of numbers is the standard deviation) for the separation of mouse, gibbon, orangutan, gorilla, and chimpanzee, respectively, from the line leading to humans. Although there is some uncertainty in the clock, this dating may pose a problem for the widely believed hypothesis that the pipedal creature Australopithecus afarensis, which lived some 3.7 million years ago at Laetoli in Tanzania and at Hadar in Ethiopia, was ancestral to man and evolved after the human-ape splitting. Another likelier possibility is that mtDNA was transferred through hybridization between a proto-human and a proto-chimpanzee after the former had developed bipedalism.


Wandering in dementia: a longitudinal study.
This article analyzes the natural history of wandering behavior throughout the course of dementia. Prospective, 10-year, longitudinal study of wandering behavior in dementia, with autopsy follow-up. Participants with dementia, living at home with a carer. All lived in Oxfordshire, UK. Eighty-six people with dementia who were living at home with a carer and who were able to walk unaided at entry to study. At 4-monthly intervals, the carers were interviewed using the Present Behavioural Examination to assess wandering behavior in detail; participants with dementia were assessed cognitively. Nine types of "wandering" behavior were distinguished. Changes in wandering behavior were not generally related to gender, age, or time since onset of dementia. Onset of different types of wandering behavior showed some relationship with cognitive state. Various forms of increased walking first appeared during moderate dementia, each type typically persisting for 1 to 2 years. Late dementia was characterized by decreased walking and immobility. Wandering behavior in dementia can cause great problems for carers. There are different causes for such changes, some of which are related to cognitive ability, for example increased confusion results in ineffectual "pottering" and getting lost. Increased walking at night corresponds with disruption of diurnal rhythm.


Online chemical modeling environment (OCHEM): web platform for data storage, model development and publishing of chemical information.
The Online Chemical Modeling Environment is a web-based platform that aims to automate and simplify the typical steps required for QSAR modeling. The platform consists of two major subsystems: the database of experimental measurements and the modeling framework. A user-contributed database contains a set of tools for easy input, search and modification of thousands of records. The OCHEM database is based on the wiki principle and focuses primarily on the quality and verifiability of the data. The database is tightly integrated with the modeling framework, which supports all the steps required to create a predictive model: data search, calculation and selection of a vast variety of molecular descriptors, application of machine learning methods, validation, analysis of the model and assessment of the applicability domain. As compared to other similar systems, OCHEM is not intended to re-implement the existing tools or models but rather to invite the original authors to contribute their results, make them publicly available, share them with other users and to become members of the growing research community. Our intention is to make OCHEM a widely used platform to perform the QSPR/QSAR studies online and share it with other users on the Web. The ultimate goal of OCHEM is collecting all possible chemoinformatics tools within one simple, reliable and user-friendly resource. The OCHEM is free for web users and it is available online at http://www.ochem.eu.


β1 integrin inhibition elicits a prometastatic switch through the TGFβ-miR-200-ZEB network in E-cadherin-positive triple-negative breast cancer.
Interactions with the extracellular matrix (ECM) through integrin adhesion receptors provide cancer cells with physical and chemical cues that act together with growth factors to support survival and proliferation. Antagonists that target integrins containing the β1 subunit inhibit tumor growth and sensitize cells to irradiation or cytotoxic chemotherapy in preclinical breast cancer models and are under clinical investigation. We found that the loss of β1 integrins attenuated breast tumor growth but markedly enhanced tumor cell dissemination to the lungs. When cultured in three-dimensional ECM scaffolds, antibodies that blocked β1 integrin function or knockdown of β1 switched the migratory behavior of human and mouse E-cadherin-positive triple-negative breast cancer (TNBC) cells from collective to single cell movement. This switch involved activation of the transforming growth factor-β (TGFβ) signaling network that led to a shift in the balance between miR-200 microRNAs and the transcription factor zinc finger E-box-binding homeobox 2 (ZEB2), resulting in suppressed transcription of the gene encoding E-cadherin. Reducing the abundance of a TGFβ receptor, restoring the ZEB/miR-200 balance, or increasing the abundance of E-cadherin reestablished cohesion in β1 integrin-deficient cells and reduced dissemination to the lungs without affecting growth of the primary tumor. These findings reveal that β1 integrins control a signaling network that promotes an epithelial phenotype and suppresses dissemination and indicate that targeting β1 integrins may have undesirable effects in TNBC.


Fast Compressive Tracking.
It is a challenging task to develop effective and efficient appearance models for robust object tracking due to factors such as pose variation, illumination change, occlusion, and motion blur. Existing online tracking algorithms often update models with samples from observations in recent frames. Despite much success has been demonstrated, numerous issues remain to be addressed. First, while these adaptive appearance models are data-dependent, there does not exist sufficient amount of data for online algorithms to learn at the outset. Second, online tracking algorithms often encounter the drift problems. As a result of self-taught learning, misaligned samples are likely to be added and degrade the appearance models. In this paper, we propose a simple yet effective and efficient tracking algorithm with an appearance model based on features extracted from a multiscale image feature space with data-independent basis. The proposed appearance model employs non-adaptive random projections that preserve the structure of the image feature space of objects. A very sparse measurement matrix is constructed to efficiently extract the features for the appearance model. We compress sample images of the foreground target and the background using the same sparse measurement matrix. The tracking task is formulated as a binary classification via a naive Bayes classifier with online update in the compressed domain. A coarse-to-fine search strategy is adopted to further reduce the computational complexity in the detection procedure. The proposed compressive tracking algorithm runs in real-time and performs favorably against state-of-the-art methods on challenging sequences in terms of efficiency, accuracy and robustness.


Steps towards constructing a global comparative risk analysis for alcohol consumption: determining indicators and empirical weights for patterns of drinking, deciding about theoretical minimum, and dealing with different consequences.
In order to conduct a comparative risk analysis for alcohol within the Global Burden of Disease Study (GBD 2000), several questions had to be answered. (1) What are the appropriate dimensions for alcohol consumption and how can they be categorized? The average volume of alcohol and patterns of drinking were selected as dimensions. Both dimensions could be looked upon as continuous but were categorized for practical purposes. The average volume of drinking was categorized into the following categories: abstention; drinking 1 (> 0-19.99 g pure alcohol daily for females, > 0-39.99 g for males); drinking 2 (20-39.99 g for females, 40-59.99 g for males), and drinking 3 (> or =40 g for females, > or =60 g for males). Patterns of drinking were categorized into four levels of detrimental impact based on an optimal scaling analysis of key informant ratings. (2) What is the theoretical minimum for both dimensions? A pattern of regular light drinking (at most 1 drink every day) was selected as theoretical minimum for established market economies for all people above age 45. For all other regions and age groups, the theoretical minimum was set to zero. Potential problems and uncertainties with this selection are discussed. (3) What are the health outcomes for alcohol and how do they relate to the dimensions? Overall, more than 60 disease conditions were identified as being related to alcohol consumption. Most chronic conditions seem to be related to volume only (exceptions are coronary heart disease and ischemic stroke), and most acute conditions seem to be related to volume and patterns. In addition, using methodology based on aggregate data, patterns were relevant for attributing harms for men but not women.


Evidence for horizontal gene transfer of two antigenically distinct O antigens in Bordetella bronchiseptica.
Host immunity is a major driving force of antigenic diversity, resulting in pathogens that can evade immunity induced by closely related strains. Here we show that two Bordetella bronchiseptica strains, RB50 and 1289, express two antigenically distinct O-antigen serotypes (O1 and O2, respectively). When 18 additional B. bronchiseptica strains were serotyped, all were found to express either the O1 or O2 serotype. Comparative genomic hybridization and PCR screening showed that the expression of either the O1 or O2 serotype correlated with the strain containing either the classical or alternative O-antigen locus, respectively. Multilocus sequence typing analysis of 49 B. bronchiseptica strains was used to build a phylogenetic tree, which revealed that the two O-antigen loci did not associate with a particular lineage, evidence that these loci are horizontally transferred between B. bronchiseptica strains. From experiments using mice vaccinated with purified lipopolysaccharide from strain RB50 (O1), 1289 (O2), or RB50Deltawbm (O antigen deficient), our data indicate that these O antigens do not confer cross-protection in vivo. The lack of cross-immunity between O-antigen serotypes appears to contribute to inefficient antibody-mediated clearance between strains. Together, these data are consistent with the idea that the O-antigen loci of B. bronchiseptica are horizontally transferred between strains and encode antigenically distinct serotypes, resulting in inefficient cross-immunity.


Behavioral sensitization to cocaine is associated with increased AMPA receptor surface expression in the nucleus accumbens.
Regulation of AMPA receptor trafficking is important for many forms of neuronal plasticity. In this study, a protein cross-linking assay was used to evaluate the contribution of AMPA receptor trafficking to plasticity associated with behavioral sensitization, an animal model of drug addiction. Cross-linking was used to distinguish between cell surface and intracellular AMPA receptors in nucleus accumbens (NAc) tissue obtained from rats treated repeatedly with saline or cocaine. Surface/intracellular (S/I) ratios for glutamate receptor 1 (GluR1) and GluR2/3 subunits were increased 21 d after the last injection in cocaine-sensitized rats but not rats that failed to sensitize, and the magnitude of the S/I ratio for cocaine-sensitized rats was positively correlated with the magnitude of behavioral sensitization. At the 1 d withdrawal time, cocaine did not alter S/I ratios, and there was no correlation between S/I ratios and behavioral sensitization. The majority of surface-expressed GluR1 detected with this assay was associated with synapses, based on coimmunoprecipitation with postsynaptic density protein of 95 kDa. These findings suggest that behavioral sensitization to cocaine is associated with a slowly developing redistribution of AMPA receptors to the surface of NAc neurons. Motor execution of drug-seeking responses depends on activation of AMPA receptors on NAc neurons by glutamate afferents originating in cortical and limbic regions. We propose that drug-seeking responses are more effectively triggered in cocaine-sensitized rats because of increased cell surface expression of AMPA receptors.


Chromatin as a Platform for Modulating the Replication Stress Response.
Eukaryotic DNA replication occurs in the context of chromatin. Recent years have seen major advances in our understanding of histone supply, histone recycling and nascent histone incorporation during replication. Furthermore, much is now known about the roles of histone remodellers and post-translational modifications in replication. It has also become clear that nucleosome dynamics during replication play critical roles in genome maintenance and that chromatin modifiers are important for preventing DNA replication stress. An understanding of how cells deploy specific nucleosome modifiers, chaperones and remodellers directly at sites of replication fork stalling has been building more slowly. Here we will specifically discuss recent advances in understanding how chromatin composition contribute to replication fork stability and restart.


Do mycoplasmas cause human cancer?
A linkage between mycoplasmas and malignancy was mainly proposed in the 1960s when human-associated mycoplasmas were becoming of interest given the novel characterization of the human respiratory pathogen Mycoplasma pneumoniae. Associations with leukemia and other malignancies, however, were largely ascribed to tissue-culture contamination, which is now recognized as a significant potential problem in molecular biology circles. A few epidemiological studies, however, continue to raise concern over such a linkage. As well, in vitro data have demonstrated the potential for some mycoplasmas to induce karyotypic changes and malignant transformation during chronic tissue-culture infestation. As cellular and molecular mechanisms for such transformation become studied, a resurgence of interest in this area is inevitable. A role for mycoplasmas in malignancy of any sort is conjectural, but there remains a need to continue with focussed epidemiological and laboratory investigations.


Amyloid - membrane interactions: experimental approaches and techniques.
The growing interest in membrane interactions of amyloidogenic peptides and proteins emanates from the realization that lipids and membranes play important, potentially central, roles in the toxicity and pathological pathways of amyloid diseases. Expanding body of evidence indicates that lipid binding of amyloidogenic peptides and amyloid peptide association with cellular membranes is critical in the onset and progression of amyloid diseases. Advancing the understanding in this field goes hand in hand with application of varied biophysical and biological techniques designed to probe the characteristics and underlying mechanisms of membrane-peptide interactions. This review summarizes experimental approaches and technical aspects employed in recent years for investigating the interaction of amyloid peptides and fibrillar species with lipid bilayers, and the reciprocal contribution of membranes to fibrillation processes and amyloidogenesis.


Effects of encainide on the determinants of cardiac excitability in sheep Purkinje fibers.
Encainide is a benzanilide derivative that is effective against ventricular arrhythmias but, at times, may be arrhythmogenic. The microelectrode technique of intracellular current application and transmembrane voltage recording was used to study the effects of encainide, in a concentration equivalent to a clinically effective antiarrhythmic plasma level, on the determinants of cardiac excitability in sheep Purkinje fibers. A rapid, on-line computerized data analysis system was used to track the alterations in the active and passive membrane properties relevant to excitability in time. Cardiac excitability was defined experimentally in terms of the current required to attain threshold and/or the shift in strength- or change-duration curves. Encainide produced multiphasic changes in cardiac excitability, the final state of excitability depended on the balance between altered passive and active membrane properties. Encainide could enhance excitability by increasing membrane and slope resistance without altering the nonlinearities of the current-voltage relationship despite an actual depression of the sodium system. Encainide could decrease excitability by 1) depressing the sodium system; 2) decreasing membrane resistance without altering the nonlinearities of the subthreshold current-voltage relationship; 3) altering the nonlinearities of the current-voltage relationship; and 4) by a combination of these actions. During washout, excitability could remain altered despite a return of descriptive parameters such as the maximal rate of rise of phase 0, overshoot and action potential duration to normal. The study demonstrated the importance of time-related changes of an antiarrhythmic drug at a constant concentration. The results explain, in part, the antiarrhythmic actions and arrhythmogenic potential of encainide.