The Mobilome; A Major Contributor to Escherichia coli stx2-Positive O26:H11 Strains Intra-Serotype Diversity.
Shiga toxin-producing Escherichia coli of serotype O26:H11/H- constitute a diverse group of strains and several clones with distinct genetic characteristics have been identified and characterized. Whole genome sequencing was performed using Illumina and PacBio technologies on eight stx2-positive O26:H11 strains circulating in France. Comparative analyses of the whole genome of the stx2-positive O26:H11 strains indicate that several clones of EHEC O26:H11 are co-circulating in France. Phylogenetic analysis of the French strains together with stx2-positive and stx-negative E. coli O26:H11 genomes obtained from Genbank indicates the existence of four clonal complexes (SNP-CCs) separated in two distinct lineages, one of which comprises the "new French clone" (SNP-CC1) that appears genetically closely related to stx-negative attaching and effacing E. coli (AEEC) strains. Interestingly, the whole genome SNP (wgSNP) phylogeny is summarized in the cas gene phylogeny, and a simple qPCR assay targeting the CRISPR array specific to SNP-CC1 (SP_O26-E) can distinguish between the two main lineages. The PacBio sequencing allowed a detailed analysis of the mobile genetic elements (MGEs) of the strains. Numerous MGEs were identified in each strain, including a large number of prophages and up to four large plasmids, representing overall 8.7-19.8% of the total genome size. Analysis of the prophage pool of the strains shows a considerable diversity with a complex history of recombination. Each clonal complex (SNP-CC) is characterized by a unique set of plasmids and phages, including stx-prophages, suggesting evolution through separate acquisition events. Overall, the MGEs appear to play a major role in O26:H11 intra-serotype clonal diversification.


Regulation of cellular sphingosine-1-phosphate by sphingosine kinase 1 and sphingosine-1-phopshate lyase determines chemotherapy resistance in gastroesophageal cancer.
Resistance to chemotherapy is common in gastroesophageal cancer. Mechanisms of resistance are incompletely characterised and there are no predictive biomarkers in clinical practice for cytotoxic drugs. We used new cell line models to characterise novel chemotherapy resistance mechanisms and validated them in tumour specimens to identify new targets and biomarkers for gastroesophageal cancer. Cell lines were selected for resistance to oxaliplatin, cisplatin and docetaxel and gene expression examined using Affymetrix Exon 1.0 ST arrays. Leads were validated by qRT-PCR and HPLC of tumour metabolites. Protein expression and pharmacological inhibition of lead target SPHK1 was evaluated in independent cell lines, and by immunohistochemistry in gastroesophageal cancer patients. Genes with differential expression in drug resistant cell lines compared to the parental cell line they were derived from, were identified for each drug resistant cell line. Biological pathway analysis of these gene lists, identified over-represented pathways, and only 3 pathways - lysosome, sphingolipid metabolism and p53 signalling- were identified as over-represented in these lists for all three cytotoxic drugs investigated. The majority of genes differentially expressed in chemoresistant cell lines from these pathways, were involved in metabolism of glycosphingolipids and sphingolipids in lysosomal compartments suggesting that sphingolipids might be important mediators of cytotoxic drug resistance in gastroeosphageal cancers . On further investigation, we found that drug resistance (IC50) was correlated with increased sphingosine kinase 1(SPHK1) mRNA and also with decreased sphingosine-1-phosphate lysase 1(SGPL1) mRNA. SPHK1 and SGPL1 gene expression were inversely correlated. SPHK1:SGPL1 ratio correlated with increased cellular sphingosine-1-phosphate (S1P), and S1P correlated with drug resistance (IC50). High SPHK1 protein correlated with resistance to cisplatin (IC50) in an independent gastric cancer cell line panel and with survival of patients treated with chemotherapy prior to surgery but not in patients treated with surgery alone. Safingol a SPHK1 inhibitor, was cytotoxic as a single agent and acted synergistically with cisplatin in gastric cancer cell lines. Agents that inhibit SPHK1 or S1P could overcome cytotoxic drug resistance in gastroesophageal cancer. There are several agents in early phase human trials including Safingol that could be combined with chemotherapy or used in patients progressing after chemotherapy.


Statins in adult patients with HIV: Protocol for a systematic review and network meta-analysis.
Patients with HIV have been found to suffer from lipid abnormalities, including elevated levels of total and LDL-cholesterol as well as triglyceride levels. Abnormal lipid levels are associated with an increased risk of developing cardiovascular diseases, which are significant causes of mortality among the general population. Therefore, the objective of the current study is to conduct a systematic review with network meta-analysis to compare the effects of statins classes on HIV patients. Randomized clinical trials (RCTs) and observational studies published in English up to 31 December 2017, and which include direct and/or indirect evidence, will be included. Studies will be retrieved by searching four electronic databases and cross-referencing. Dual selection and abstraction of data will occur. The primary outcome will all-cause mortality, new event of acute myocardial infarction, stroke (hemorrhagic and ischemic), hospitalization for acute coronary syndrome and urgent revascularization procedures and cardiovascular mortality. Secondary outcomes will be assessment of the differences in change of total cholesterol (TC), low-density lipoprotein (LDL-C), apolipoprotein B (ApoB), high density lipoprotein (HDL-C). Risk of bias will be assessed using the Cochrane Risk of Bias assessment instrument for RCTs and the Strengthening the Reporting of Observational Studies in Epidemiology instrument for observational studies. Network meta-analysis will be performed using multivariate random-effects meta-regression models. The surface under the cumulative ranking curve will be used to provide a hierarchy of statins that reduce cardiovascular mortality in HIV patients. A revised version of the Cochrane Risk of Bias tool (RoB 2.0) will be used to assess the risk of bias in eligible RCTs. Results will be synthesized and analyzed using network meta-analysis (NMA). Overall strength of the evidence and publication bias will be evaluated. Subgroup and sensitivity analysis will also be performed. Ethics approval was not required for this study because it was based on published studies. The results and findings of this study will be submitted and published in a scientific peer-reviewed journal. The evidence will determine which combination of interventions are most promising for current practice and further investigation. PROSPERO (CRD42017072996).


Serum Cytokine Profile in Asian Indian Patients with Takayasu Arteritis and its Association with Disease Activity.
Arterial inflammation Takayasu arteritis (TA) is an outcome of balance between pro- and anti-inflammatory cytokines. Comprehensive assessment of these cytokines is important for understanding pathogenesis and assessing disease activity. To study pro- and anti-inflammatory cytokines representing different T-helper cell pathway in serum samples of Asian Indian patients with TA and to assess their association with disease activity. Consecutive Indian patients with TA were assayed for serum interferon-γ, interleukin-6, interleukin-23, interleukin-17, interleukin-10 and transforming growth factor- β levels at baseline and follow up visit. Patients were grouped into active and stable disease based on Indian Takyasu Arteritis clinical Activity Score-2010. Serum levels of these cytokines between active and stable disease and between baseline and follow up visits were compared by non-parametric tests. Among 32 patients enrolled, 15 were classified as active while 17 as stable disease at baseline. IFN-γ levels were significantly higher in active disease than stable disease (p=0.0129) while other cytokines did not differ significantly between 2 groups. Serum levels of none of the cytokines changed significantly over 2 visits in both responders and non-responders. IL23 levels positively correlate with disease duration ((r=0.999; p<0.005). Modest correlation was observed between IFN-γ and IL23 levels at both baseline and follow up and between IFN-γ and IL-6 and CRP at follow up. IFN-γ levels are raised in active disease in TA and correlates well with other biomarkers of disease activity and proinflammatory cytokines. There is also a direct correlation between Il-23 levels and disease duration.


Heritability and seasonal variability of vitamin D concentrations in male twins.
Serum 25-hydroxyvitamin D [25(OH)D] concentrations can be affected by several environmental and individual factors. It is not clear to what extent genetic influences play a role in determining vitamin D status. Thus far, studies on the heritability of vitamin D have provided conflicting results. We estimated the heritability of vitamin D concentrations and the effect of season on heritability estimates. We measured serum 25(OH)D concentrations in 510 middle-aged, male twins (310 monozygotic and 200 dizygotic twins) selected from the Vietnam Era Twin Registry. Generalized estimating equations were used to test the association between 25(OH)D and other study factors. Structural equation modeling was used to estimate the heritability of 25(OH)D. The twins' mean (±SD) age was 55 ± 2.8 y. The mean (±SD) 25(OH)D concentration was 38.4 ± 23.3 ng/mL with a substantial seasonal variation (a 6.1-ng/mL lower value during the winter than during the summer, P = 0.003). Approximately 70% of the variation in 25(OH)D concentrations during the winter was explained by genetic factors. However, in the summer, 25(OH)D concentrations were not heritable. During the summer, 53% of the variation in 25(OH)D concentrations was due to shared environmental factors, and 47% of the variation in 25(OH)D concentrations was due to unique environmental factors. Serum 25(OH)D concentrations are highly heritable during the winter season only. In the summer, environmental conditions (eg, sun exposure) prevail over genetic backgrounds in determining serum 25(OH)D concentrations. This trial was registered at clinicaltrials.gov as NCT00017836.


Patient education for people with multiple sclerosis-associated fatigue: A systematic review.
Multiple Sclerosis (MS) is an inflammatory and neurodegenerative disease often causing decreased quality of life, social withdrawal and unemployment. Studies examining the effect of pharmacological interventions demonstrated only minor effects, whereas non-pharmacological interventions as e.g. patient education programs have shown promising results. We aim to systematically review the literature to determine the effect of patient education programs on fatigue in MS. We conducted a comprehensive search in PubMed for randomized controlled trials (RCTs) that evaluated patient education programs for MS-related fatigue. Interventions evaluating physical exercise and/or pharmacological treatments were not included. Meta-analyses were performed using the generic inverse variance method. The search identified 856 citations. After full-text screening we identified ten trials that met the inclusion criteria. Data of 1021 participants were analyzed. Meta-analyses showed significant positive effects on fatigue severity (weighted mean difference -0.43; 95% CI -0.74 to -0.11) and fatigue impact (-0.48; -0.82 to -0.15), but not for depression (-0.35 (95% CI -0.75 to 0.05; p = 0.08). Essentially, we categorized patient education programs into two types: firstly, interventions with a focus on cognitive-behavioral therapy (CBT) and secondly, interventions that teach patients ways of managing daily fatigue. CBT-based approaches seem to generate better results in reducing patient-reported fatigue severity. Analysing CBT studies only, the pooled weighted mean difference for fatigue severity was -0.60 (95% CI; -1.08 to -0.11) compared to non-CBT approaches (-0.20; 95% CI; -0.60 to -0.19). Furthermore, interventions employing an individual approach seem to reduce fatigue more effectively than group-based approaches (pooled weighted mean difference for fatigue severity in face-to-face studies was -0.80 (95% CI; -1.13 to -0.47) compared to group-based studies with -0,17 (95% CI; -0,39 to 0,05). Longest follow-up data were available for 12 months post-intervention. Overall, included studies demonstrated that educational programs and especially CBT-based approaches have a positive effect on reducing fatigue. Since fatigue is thought to be a multidimensional symptom, it should be treated with a multidimensional approach targeting patients' behavior as well as their emotional and mental attitude towards fatigue. However, the clinical relevance of the treatment effects i.e. the relevance for patients' daily functioning remains unclear and long-term effects, i.e. sustainability of effects beyond 6 months, warrants further work. This review has been registered in the PROSPERO international prospective register of systematic reviews data base (Registration number: CRD42014014224).


The relationship between leadership styles and empathy among student nurses.
Much of the nursing literature on leadership describes the qualities of existing nursing leaders, while emphasizing the need for leadership development in student nurses for both managerial and clinical practice. However, there is a lack of research literature on the characteristics of current students. Conducted by the University of Tennessee College of Nursing Empathy Research Group, this pilot study explores the relationship between leadership styles and empathy (cognitive and affective) levels. This correlational descriptive study involved self-report using 3 instruments. Hogan Empathy Scale (HES) and Emotional Empathy Tendency Scale (EETS) measured cognitive and affective empathy levels. The Multifactoral Leadership Questionnaire (MLQ-5x) was used to determine leadership style. Data analysis yielded evidence of a weak positive correlation between the predominant transformational leadership style and empathy levels in both junior and senior students. This correlation has implications for both nurse educators and future employers.


Adolescents' response to text-only tobacco health warnings: results from the 2008 UK Youth Tobacco Policy Survey.
As of June 2009 most (89%) European Union member states continue to use mandated text-only health warnings on tobacco products. This study assessed adolescent (aged 11-16 years) perceptions of and reactions to these text warnings on cigarette packs in the UK. Data comes from wave five of the cross-sectional Youth Tobacco Policy Survey in 2008. A total of 1401 adolescents were recruited and health warnings were assessed in terms of salience (noticing, reading), comprehension and credibility, memorability (recall), depth of processing (contemplating, discussing) and persuasiveness (put off smoking, make more likely to stop). Smokers were also asked about behavioural compliance (foregoing cigarettes due to warnings, avoidance of warnings) and perceptions of harm from their smoking (to indirectly assess possible knowledge gained from warnings). Despite moderately high salience of warnings, memorability and, in particular, depth of processing was quite low, with warnings only sometimes thought about and very rarely discussed. Warnings were however considered comprehensible, credible and a reasonable deterrent for occasional and never smokers. Additionally, a third of regular smokers indicated that, in the last month, warnings had stopped them from having a cigarette. However, only 6% of smokers indicated that warnings made them forego cigarettes frequently. Text warnings help to communicate the dangers associated with smoking and, resultantly, prompt a small number of smokers to forgo cigarettes and take action to avoid warnings, but depth of processing is low and warnings do not appear to be achieving their full potential among smokers.


Mapping low intake of micronutrients across Europe.
Achieving an understanding of the extent of micronutrient adequacy across Europe is a major challenge. The main objective of the present study was to collect and evaluate the prevalence of low micronutrient intakes of different European countries by comparing recent nationally representative dietary survey data from Belgium, Denmark, France, Germany, The Netherlands, Poland, Spain and the United Kingdom. Dietary intake information was evaluated for intakes of Ca, Cu, I, Fe, Mg, K, Se, Zn and the vitamins A, B₁, B₂, B₆, B₁₂, C, D, E and folate. The mean and 5th percentile of the intake distributions were estimated for these countries, for a number of defined sex and age groups. The percentages of those with intakes below the lower reference nutrient intake and the estimated average requirement were calculated. Reference intakes were derived from the UK and Nordic Nutrition Recommendations. The impact of dietary supplement intake as well as inclusion of apparently low energy reporters on the estimates was evaluated. Except for vitamin D, the present study suggests that the current intakes of vitamins from foods lead to low risk of low intakes in all age and sex groups. For current minerals, the study suggests that the risk of low intakes is likely to appear more often in specific age groups. In spite of the limitations of the data, the present study provides valuable new information about micronutrient intakes across Europe and the likelihood of inadequacy country by country.


TDP1 and PARP1 deficiency are cytotoxic to rhabdomyosarcoma cells.
Rhabdomyosarcoma is the most common soft tissue sarcoma in children. Metastatic rhabdomyosarcoma in children has a 5-year event-free survival rate of <30%, and a recent clinical trial with irinotecan, a topoisomerase I inhibitor, failed to improve outcome. Therefore, it was surmised that failure of irinotecan may be the result of overexpression of the DNA repair enzyme tyrosyl-DNA phosphodiesterase (TDP1), which processes topoisomerase I-DNA complexes resulting from topoisomerase I inhibitor treatment. Using human tissue microarrays and gene expression arrays, a marked overexpression of TDP1 protein and mRNA in RMS tumors was observed. Critically, knockdown of TDP1 or inhibition of poly(ADP-ribose) polymerase-1 (PARP-1), an enzyme in the same complex as TDP1, sensitized rhabdomyosarcoma cell lines to analogues of irinotecan. Interestingly, BRCA1/2 mutations or altered expression was not detectable in rhabdomyosarcoma cells; however, TDP1 knockdown and PARP-1 inhibition alone were cytotoxic to a subset of rhabdomyosarcoma cells, suggesting that they harbor genetic lesions in DNA repair components that have synthetic lethal interactions with loss of TDP1 or PARP1 function. Furthermore, culturing embryonal rhabdomyosarcoma cells in serum/nutrient-restricted medium increased cellular cytotoxicity upon PARP-1 inhibition and was intrinsically cytotoxic to alveolar, though not embryonal rhabdomyosarcoma cells. The results of these studies suggest a compensatory role for TDP1 in rhabdomyosarcoma after topoisomerase-I based therapy and further demonstrate that TDP1 knockdown, PARP-1 inhibition, and dietary restriction have therapeutic validity. Selective targeting of TDP1 and/or PARP-1 in rhabdomyosarcoma induces cytotoxicity and sensitizes to DNA damaging agents.


The potential for dams to impact lowland meandering river floodplain geomorphology.
The majority of the world's floodplains are dammed. Although some implications of dams for riverine ecology and for river channel morphology are well understood, there is less research on the impacts of dams on floodplain geomorphology. We review studies from dammed and undammed rivers and include influences on vertical and lateral accretion, meander migration and cutoff formation, avulsion, and interactions with floodplain vegetation. The results are synthesized into a conceptual model of the effects of dams on the major geomorphic influences on floodplain development. This model is used to assess the likely consequences of eight dam and flow regulation scenarios for floodplain geomorphology. Sediment starvation downstream of dams has perhaps the greatest potential to impact on floodplain development. Such effects will persist further downstream where tributary sediment inputs are relatively low and there is minimal buffering by alluvial sediment stores. We can identify several ways in which floodplains might potentially be affected by dams, with varying degrees of confidence, including a distinction between passive impacts (floodplain disconnection) and active impacts (changes in geomorphological processes and functioning). These active processes are likely to have more serious implications for floodplain function and emphasize both the need for future research and the need for an "environmental sediment regime" to operate alongside environmental flows.


Breast feeding in neonatal alloimmune thrombocytopenia.
Infants with neonatal alloimmune thrombocytopenia are at risk of severe intracranial haemorrhage. Placental transfer of maternal immunoglobulin G (IgG) directed against fetal platelet antigens is known to be the underlying mechanism. Since breast milk contains IgG it is theoretically possible that breast feeding of these infants could cause thrombocytopenia. The following case report shows that an infant with neonatal alloimmune thrombocytopenia may be safely breast fed, even when the breast milk contains the platelet specific antibody (HPA-1a).


Overview of impaired facial affect recognition in persons with traumatic brain injury.
To review the literature of affect recognition for persons with traumatic brain injury (TBI). It is suggested that impairment of affect recognition could be a significant problem for the TBI population and treatment strategies are recommended based on research for persons with autism. Research demonstrates that persons with TBI often have difficulty determining emotion from facial expressions. Studies show that poor interpersonal skills, which are associated with impaired affect recognition, are linked to a variety of negative outcomes. Theories suggest that facial affect recognition is achieved by interpreting important facial features and processing one's own emotions. These skills are often affected by TBI, depending on the areas damaged. Affect recognition impairments have also been identified in persons with autism. Successful interventions have already been developed for the autism population. Comparable neuroanatomical and behavioural findings between TBI and autism suggest that treatment approaches for autism may also benefit those with TBI. Impaired facial affect recognition appears to be a significant problem for persons with TBI. Theories of affect recognition, strategies used in autism and teaching techniques commonly used in TBI need to be considered when developing treatments to improve affect recognition in persons with brain injury.


Interobserver agreement after pipeline embolization device implantation.
Although flow diversion devices are popular in treatment of aneurysms, angiographic assessment with these devices has rarely been verified by interobserver variability study. The purpose of this study was to determine the interobserver agreement of a 3-point grading system for assessing the angiographic outcome after flow diversion therapy of intracranial, saccular aneurysms and to determine factors affecting such agreement. After approval by the institutional review board, 5 independent readers assessed pretreatment and follow-up digital subtraction angiograms from 96 patients treated with the Pipeline embolization device by using a 3-point grading system (complete, near-complete, and incomplete occlusion). "Minor discrepancy" was defined as a difference between any 2 readers of 1 grade, that is, complete vs near-complete or near-complete vs incomplete. "Major discrepancy" was defined as a difference between any 2 readers in which 1 reader noted complete occlusion and the other reader noted incomplete occlusion. We performed statistical analysis for the interobserver agreement by using the intraclass correlation coefficient. Subgroup analyses for discrepancy rate and ICC were performed for previously coiled aneurysms. The interobserver agreement was excellent (ICC, 0.76; 95% CI, 0.69-0.92). Among 96 cases, there was absolute agreement in 74 (77%), of which 67 had unanimous consensus of "complete" occlusion, 2 "near-complete" occlusion, and 5 "incomplete" occlusion. Discordance between any 2 readers was noted in 22 cases (23%), of which 7 (7.3%) revealed a major discrepancy. Subgroup analysis showed that minor discrepancies were more common among patients previously treated with coils vs those not previously treated with coils (37.5% vs 11.2%; P < .05). The observer agreement regarding occlusion after PED therapy is excellent. Only a minority of cases demonstrated discrepancy considered as major in this study.


Absence of chronic effect of exposure to short-wave radio broadcast signal on salivary melatonin concentrations in dairy cattle.
A pilot study was conducted to investigate the influence of electromagnetic fields in the short-wave range (3-30 MHz) radio transmitter signals on salivary melatonin concentration in dairy cattle. The hypothesis to be tested was whether EMF exposure would lower salivary melatonin concentrations, and whether removal of the EMF source would be followed by higher concentration levels. For this pilot study, a controlled intervention trial was designed. Two commercial dairy herds at two farms were compared, one located at a distance of 500 m (exposed), the other at a distance of 4,000 m (unexposed) from the transmitter. At each farm, five cows were monitored with respect to their salivary melatonin concentrations over a period of ten consecutive days. Saliva samples were collected at two-hour intervals during the dark phase of the night. As an additional intervention, the short-wave transmitter was switched off during three of the ten days (off phase). The samples were analyzed using a radioimmunoassay. The average nightly field strength readings were 21-fold greater on the exposed farm (1.59 mA/m) than on the control farm (0.076 mA/m). The mean values of the two initial nights did not show a statistically significant difference between exposed and unexposed cows. Therefore, a chronic melatonin reduction effect seemed unlikely. However, on the first night of re-exposure after the transmitter had been off for three days, the difference in salivary melatonin concentration between the two farms (3.89 pg/ml, CI: 2.04, 7.41) was statistically significant, indicating a two- to seven-fold increase of melatonin concentration. Thus, a delayed acute effect of EMF on melatonin concentration cannot completely be excluded. However, results should be interpreted with caution and further trials are required in order to confirm the results.


Factors predictive of the status of sentinel lymph nodes in melanoma patients from a large multicenter database.
Numerous predictive factors for cutaneous melanoma metastases to sentinel lymph nodes have been identified; however, few have been found to be reproducibly significant. This study investigated the significance of factors for predicting regional nodal disease in cutaneous melanoma using a large multicenter database. Seventeen institutions submitted retrospective and prospective data on 3463 patients undergoing sentinel lymph node (SLN) biopsy for primary melanoma. Multiple demographic and tumor factors were analyzed for correlation with a positive SLN. Univariate and multivariate statistical analyses were performed. Of 3445 analyzable patients, 561 (16.3%) had a positive SLN biopsy. In multivariate analysis of 1526 patients with complete records for 10 variables, increasing Breslow thickness, lymphovascular invasion, ulceration, younger age, the absence of regression, and tumor location on the trunk were statistically significant predictors of a positive SLN. These results confirm the predictive significance of the well-established variables of Breslow thickness, ulceration, age, and location, as well as consistently reported but less well-established variables such as lymphovascular invasion. In addition, the presence of regression was associated with a lower likelihood of a positive SLN. Consideration of multiple tumor parameters should influence the decision for SLN biopsy and the estimation of nodal metastatic disease risk.


Crystal structure of the RIM1alpha C2B domain at 1.7 A resolution.
RIM proteins play critical roles in synaptic vesicle priming and diverse forms of presynaptic plasticity. The C-terminal C2B domain is the only module that is common to all RIMs but is only distantly related to well-studied C2 domains, and its three-dimensional structure and interactions have not been characterized in detail. Using NMR spectroscopy, we now show that N- and C-terminal extensions beyond the predicted C2B domain core sequence are necessary to form a folded, stable RIM1alpha C2B domain. We also find that the isolated RIM1alpha C2B domain is not sufficient for previously described protein-protein interactions involving the RIM1alpha C-terminus, suggesting that additional sequences adjacent to the C2B domain might be required for these interactions. However, analytical ultracentrifugation shows that the RIM1alpha C2B domain forms weak dimers in solution. The crystal structure of the RIM1alpha C2B domain dimer at 1.7 A resolution reveals that it forms a beta-sandwich characteristic of C2 domains and that the unique N- and C-terminal extensions form a small subdomain that packs against the beta-sandwich and mediates dimerization. Our results provide a structural basis to understand the function of RIM C2B domains and suggest that dimerization may be a crucial aspect of RIM function.


Plasma Amyloid as Prescreener for the Earliest Alzheimer Pathological Changes.
We investigated the association of plasma amyloid beta (Abeta)40, Abeta42, and total tau (tTau) with the presence of Alzheimer pathological changes in cognitively normal individuals with subjective cognitive decline (SCD). We included 248 subjects with SCD (61 ± 9 years, 42% female, Mini-Mental State Examination = 28 ± 2) from the SCIENCe project and Amsterdam Dementia Cohort. Subjects were dichotomized as amyloid abnormal by cerebrospinal fluid (CSF) and positron emission tomography (PET). Baseline plasma Abeta40, Abeta42, and tTau were measured using Simoa technology. Associations between plasma levels and amyloid status were assessed using logistic regression analyses and receiver operating characteristic analyses. Association of plasma levels with risk of clinical progression to mild cognitive impairment (MCI) or dementia was assessed using Cox proportional hazard models. Fifty-seven (23%) subjects were CSF-amyloid abnormal. Plasma Abeta42/Abeta40 ratio and plasma Abeta42 alone, but not tTau, identified abnormal CSF-amyloid status (plasma ratio: area under the curve [AUC] = 77%, 95% confidence interval [CI] = 69-84%; plasma Abeta42: AUC = 66%, 95% CI: 58-74%). Combining plasma ratio with age and apolipoprotein E resulted in AUC = 83% (95% CI = 77-89%). The Youden cutoff of the plasma ratio gave a sensitivity of 76% and specificity of 75%, and applying this as a prescreener would reduce the number of lumbar punctures by 51%. Using PET as outcome, a comparable reduction in number of PET scans would be achieved when applying the plasma ratio as prescreener. In addition, low plasma ratio was associated with clinical progression to MCI or dementia (hazard ratio = 2.0, 95% CI = 1.4-2.3). Plasma Abeta42/Abeta40 ratio has potential as a prescreener to identify Alzheimer pathological changes in cognitively normal individuals with SCD. Ann Neurol 2018;84:656-666.


Coffee consumption and risk of pancreatic cancer: a systematic review and dose-response meta-analysis.
The association between coffee consumption and pancreatic cancer risk has been extensively studied; however, there is no consistent conclusion. Therefore, this meta-analysis study sought to evaluate dose-response relationship between them. A search was conducted using the PubMed and Web of Science databases. Thirteen high-quality cohort studies were identified, involving in 959,992 study participants and 3831 pancreatic cancer cases. Comparing the highest with lowest categories of coffee intake, the pooled relative risk (RR) was 1.08 (95% CI 0.94-1.25). For dose-response analysis, no evidence of a nonlinear dose-response association between coffee consumption and pancreatic cancer (p for nonlinearity =0.171) was found. The risk of pancreatic cancer was increased by 5.87% (RR =1.06, 95% CI 1.05-1.07) with the increment of one cup/day. Coffee consumption was identified to be related with the increasing risk of pancreatic cancer in a dose-response manner. Nevertheless, further mechanistic studies are needed to clarify the concerned issues.


A randomized controlled trial comparing mupirocin versus Polysporin Triple for the prevention of catheter-related infections in peritoneal dialysis patients (the MP3 study).
Peritonitis remains the most serious complication of peritoneal dialysis (PD). Gram-positive organisms are among the most common causes of PD peritonitis; however, recent trends show increasing rates of gram-negative and fungal infections. Strategies to prevent peritonitis include the use of prophylactic topical mupirocin at the site where the PD catheter exits from the abdominal wall; however, mupirocin does not afford protection against gram-negative or fungal infections. The aim of this study is to determine if the incidence of catheter-related infections (exit-site infection, tunnel infection, or peritonitis) is significantly reduced by the routine application of Polysporin Triple antibiotic ointment (Pfizer Canada, Markham, Ontario, Canada) in comparison to mupirocin ointment. The Mupirocin Versus Polysporin Triple Study (MP3) is a multicenter, randomized, double-blinded controlled study comparing Polysporin Triple (P3) against the current standard of care. The aim of the study is to recruit 200 patients being treated with or starting on PD and randomize them to receive either mupirocin or P3 at the catheter exit site. Patients will be followed for 18 months or until death or transfer from PD to an alternate treatment modality. The primary outcome will be the time to first catheter-related infection. Catheter-related infections will be strictly defined using current guidelines and categorized into exit-site infections, infective peritonitis, or tunnel infections. The primary analysis will be an intention-to-treat analysis. The results of this study will help determine if the use of P3 is superior to mupirocin ointment in the prevention of catheter-related infections and will help guide evidence-based best practices.


Linear motif atlas for phosphorylation-dependent signaling.
Systematic and quantitative analysis of protein phosphorylation is revealing dynamic regulatory networks underlying cellular responses to environmental cues. However, matching these sites to the kinases that phosphorylate them and the phosphorylation-dependent binding domains that may subsequently bind to them remains a challenge. NetPhorest is an atlas of consensus sequence motifs that covers 179 kinases and 104 phosphorylation-dependent binding domains [Src homology 2 (SH2), phosphotyrosine binding (PTB), BRCA1 C-terminal (BRCT), WW, and 14-3-3]. The atlas reveals new aspects of signaling systems, including the observation that tyrosine kinases mutated in cancer have lower specificity than their non-oncogenic relatives. The resource is maintained by an automated pipeline, which uses phylogenetic trees to structure the currently available in vivo and in vitro data to derive probabilistic sequence models of linear motifs. The atlas is available as a community resource (http://netphorest.info).


Design of discrete, nearly-uniform Bragg gratings in planar waveguides.
In this paper we present an efficient method for designing discrete, nearly-uniform Bragg gratings in generic planar waveguides. Various schemes have already been proposed to design continuous Bragg gratings in optical fibers, but a general scheme for creating their discrete counterpart is still lacking. Taking a continuous Bragg grating as our starting point, we show that the same grating functionalities can also be realized in any planar waveguide by discretizing it into a series of air holes. The relationship between the two gratings is established in terms of grating strength and local grating period.


How will climate change affect endangered Mediterranean waterbirds?
Global warming and direct anthropogenic impacts, such as water extraction, largely affect water budgets in Mediterranean wetlands, thereby increasing wetland salinities and isolation, and decreasing water depths and hydroperiods (duration of the inundation period). These wetland features are key elements structuring waterbird communities. However, the ultimate and net consequences of these dynamic conditions on waterbird assemblages are largely unknown. We combined regular sampling of waterbird presence through one annual cycle with in-situ data on relevant environmental predictors of waterbird distribution to model habitat selection for 69 species in a typical Mediterranean wetland network in southwestern Spain. Species associations with environmental features were subsequently used to predict changes in habitat suitability for each species under three climate change scenarios (encompassing changes in environmental predictors that ranged from 10% to 50% change as predicted by regional climatic models). Waterbirds distributed themselves unevenly throughout environmental gradients and water salinity was the most important gradient structuring the distribution of the community. Environmental suitability for the guilds of diving birds and vegetation gleaners will decline in future climate scenarios, while many small wading birds will benefit from changing conditions. Resident species and those that breed in this wetland network will also be more negatively impacted than those using this area for wintering or stopover. We provide a tool that can be used in a horizon-scanning framework to identify emerging issues in waterbird conservation and to anticipate suitable management actions.


Inpatient forensic-psychiatric care: Legal frameworks and service provision in three European countries.
Laws governing the detention and treatment of mentally disordered offenders (MDOs) vary widely across Europe, yet little information is available about the features of these laws and their comparative advantages and disadvantages. The purpose of this article is to compare the legal framework governing detention in forensic psychiatric care in three European countries with long-established services for MDOs, England, Germany and the Netherlands. A literature review was conducted alongside consultation with experts from each country. We found that the three countries differ in several areas, including criteria for admission, review of detention, discharge process, the concept of criminal responsibility, service provision and treatment philosophy. Our findings suggest a profound difference in how each country relates to MDOs, with each approach contributing to different pathways and potentially different outcomes for the individual. Hopefully making these comparisons will stimulate debate and knowledge exchange on an international level to aid future research and the development of best practice in managing this population.


Pancreatic Polypeptide but Not Other Members of the Neuropeptide Y Family Shows a Moderate Association With Perceived Anxiety in Obese Men.
Neuropeptide Y (NPY), peptide tyrosine tyrosine (PYY), and pancreatic polypeptide (PP) are important mediators in the bidirectional communication along the gut-brain-axis. Best known for their role in the regulation of appetite and food intake they are considered to play a crucial role in the development of obesity. Additionally, mounting evidence indicates a regulatory function in anxiety, mood and stress resilience with potential sex differences. In the present study, we examined the associations of NPY, PYY, and PP plasma levels with anxiety, depressiveness and perceived stress in obese patients. We analyzed 144 inpatients (90 female, 54 male, BMI mean: 49.4 kg/m2) in a naturalistic treatment setting for obesity and its somatic and mental comorbidities. Fasting blood samples were taken, and patients completed psychometric self-assessment questionnaires (GAD-7, PHQ-9, PSQ-20) within the first week after admission and before discharge. Plasma concentrations of the peptides were measured by ELISA. Women showed significant higher anxiety (GAD-7: 8.13 ± 5.67 vs. 5.93 ± 5.42, p = 0.04) and stress scores (PSQ-20: 52.62 ± 23.5 vs. 41.23 ± 22.53, p = 0.01) than men. In the longitudinal analysis women with a clinically relevant improvement of anxiety (≥ 5 points on GAD-7, p < 0.001) also showed significant improvements in depression (PHQ-9: 38%, p = 0.002) and PSQ-20 scores (23%, p = 0.005) while anxiety-improved male patients only improved in the subscale tension of the PSQ-20 (34%, p = 0.02). In men we observed a positive correlation of PP with anxiety scores (GAD-7: r = 0.41, p = 0.007) and with age (r = 0.49, p = 0.001) on admission while NPY negatively correlated with age (r = -0.38, p = 0.01). In contrast, there were no significant associations (p > 0.05) in female subjects in the cross-sectional as well as in the longitudinal analysis. In conclusion, women suffering from morbid obesity showed greater psychological comorbidity and considerable interactions among them. Despite that we solely observed associations of PP with anxiety and age with NPY and PP in men, suggesting a possible influence of sex hormones on the NPY system. However, improvement of anxiety scores did not lead to significant changes in NPY.


Functional results of primary closure vs flaps in oropharyngeal reconstruction: a prospective study of speech and swallowing.
The preservation of speech and swallowing function is the primary goal when reconstructing soft tissue defects in the oral cavity or oropharynx. The type of reconstructive procedure used should be based on outcome data examining speech and swallowing function; yet, there is a paucity of such information. To present the results of a multi-institutional prospective study of speech and swallowing function before and after soft tissue reconstruction of the oral cavity and oropharynx, and to compare 3 methods of reconstruction with respect to speech and swallowing function: primary closure, distal myocutaneous flap, and microvascular free flap. Prospective case-comparison study. Four leading head and neck cancer institutions. The patients were selected from a database of 284 patients treated at the different institutions. The patients were matched for the location of the oral cavity or oropharyngeal defect and the percentage of oral tongue and tongue base resection. Those patients who had previous speech and swallowing deficits and patients in whom postoperative fistulas or wound infections developed were excluded from the study. The patients underwent speech and swallowing evaluation preoperatively and 3 months after healing. This evaluation included videofluoroscopic studies of swallowing and tests of speech intelligibility and sentence articulation. Videofluoroscopy provided measures of swallowing efficiency and bolus movement. Liquid and paste consistencies were used in evaluating swallowing function. The functional results of the reconstruction. Patients who had primary closure were more efficient at swallowing liquids, had less pharyngeal residue, a longer oral transit time with paste, and higher conversational intelligibility than patients who underwent reconstruction with a distal flap. Compared with patients who underwent reconstruction with a free flap, those who had primary closure had more efficient swallowing of liquids, less pharyngeal residue, and shorter pharyngeal delay times with paste. No difference in the speech and swallowing function existed between patients treated with distal myocutaneous flaps and those treated with microvascular free flaps. Contrary to the current theory of oral and oropharyngeal reconstruction, we found that the use of primary closure resulted in equal or better function than the use of flap reconstruction in patients with a comparable locus of resection and percentage of oral tongue and tongue base resection.


Thermal stability of trihexyl(tetradecyl)phosphonium chloride.
Dynamic TGA studies of phosphonium ionic liquids have reported thermal stabilities of 300 °C or higher for these compounds. This is often an overestimation of the real thermal stability. The chosen technique as well as the experimental parameters can influence the thermal stability. In this paper, the thermal stability of commercially available Cyphos IL 101 is studied. The effect of the nature of the atmosphere (air or inert gas), the purity of the sample, the heating rate and presence of a metal on the short-term and long-term stability of commercial Cyphos IL 101 is investigated. The thermal decomposition products are characterized using thermogravimetric analysis coupled to mass spectrometry (TGA-MS). Impurities present and higher heating rates lead to an under- and overestimation of the thermal stability, respectively. The presence of oxygen leads to a lower thermal stability. In contrast, adding metal chlorides to the ionic liquid causes an increase in the thermal stability. The chloride anions are coordinated to the metal ion, so that the Lewis basicity of the anions is reduced. Also this paper gives insights in the behavior of Cyphos IL 101 at high temperatures, which is of relevance for possible application of this ionic liquid in high-temperature industrial processes.


Cooperation, control, and concession in meerkat groups.
"Limited control" models of reproductive skew in cooperative societies suggest that the frequency of breeding by subordinates is determined by the outcome of power struggles with dominants. In contrast, "optimal skew" models suggest that dominants have full control of subordinate reproduction and allow subordinates to breed only when this serves to retain subordinates' assistance with rearing dominants' own litters. The results of our 7-year field study of cooperative meerkats, Suricata suricatta, support the predictions of limited control models and provide no indication that dominant females grant reproductive concessions to subordinates to retain their assistance with future breeding attempts.


Distribution of 1,3-bis(2-chloroethyl)-1-nitrosourea and tracers in the rabbit brain after interstitial delivery by biodegradable polymer implants.
Intracranial tumors, such as glioblastoma multiforme and astrocytomas, are among the most aggressive and difficult to cure. In the present study, we evaluated the intracranial distribution of released agents during the first 3 days after implantation. Polymer implants containing [3H]-1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), [3H]dextran (MW 70,000) or [14C]iodoantipyrene (IAP) were implanted into the brains of rabbits; autoradiography was used to measure the distribution of radiolabels within the brain at 6, 24 and 72 hr after implantation. For all of the agents studied, the majority of the radioactivity was found within the region 1 to 2 mm from the surface of the polymer. Dextran, however, penetrated farther into the brain than either IAP or BCNU. The distribution of radiolabel on an anteroposterior axis was determined by examining serial coronal images: after 72 hr, significant radioactivity (< 2 S.D. above background) extended > 17 mm in animals with [3H]dextran implants and approximately mm in animals receiving [3H]BCNU or [14C]IAP. Concentration profiles were also measured on coronal images obtained at the implant site: radioactivity dropped to a 10% maximum value 1.7 mm from the surface of the pellet in [3H]dextran-treated animals and < 1.2 mm in [3H]BCNU or [14C]IAP-treated animals. Measured concentration profiles near the polymer were compared to mathematical models of drug diffusion and elimination. These results demonstrate that the majority of agents delivered into the brain by intracranially implanted polymers accumulates in the tissue within 1 to 2 mm of the implant, but that the size of the treated region depends on physicochemical properties of the agents.(ABSTRACT TRUNCATED AT 250 WORDS)


Imprinting of Igf2 and H19 from a 130 kb YAC transgene.
A stringent test for imprint control elements is to examine their function at ectopic loci in transgenic experiments. Igf2 and H19 are part of a larger imprinting region and as a first step, we examined these reciprocally imprinted genes in transgenic experiments using a 130 kb YAC clone. After paternal inheritance, H19 was appropriately repressed and Igf2 was expressed, irrespective of copy number or genetic background. After maternal inheritance H19 was consistently expressed, albeit with some variability. The levels of H19 expression per copy of the transgene inversely correlated with Igf2 (-lacZ) expression in cis. The consistent imprinting of H19 from this YAC contrasts with the previously described imprinting of mini-H19 transgenes, which only occurs at multi-copy loci, is inconsistent, and is prone to genetic background effects. We propose a novel model in which silencing of the H19 gene is the default state and its activation after maternal inheritance is the key mechanistic event for imprinting in this region. In addition, in situ analysis of the Igf2-lacZ reporter indicates that additional mesoderm-specific enhancers are present within the YAC clone. No obvious phenotype was detected from the excess gene dosage of H19.


Collagenase Dupuytren Contracture: Achieving Single Treatment Success with a Hand Therapist-Based Protocol.
Surgery remains the gold standard in the treatment of Dupuytren contracture but is technically demanding, carries significant risk of complications, and requires prolonged recovery time. Collagenase injection is an efficacious alternative to surgery; however, contracture release often requires multiple treatments spaced a month apart. We report our experience with a new collagenase treatment protocol aimed to minimize the total treatment time per joint contracture. We performed a single institution retrospective review of patients with Dupuytren contracture treated with collagenase using our protocol from 2011 to 2013. Patients returned 24 hours after collagenase injection for cord manipulation by a certified hand therapist while under digital block. Treatment success was defined as reduction in contracture to 5 degrees or less. Successfully treated joints were evaluated for recurrence (>10 degrees contracture) at 30-day and 6-month follow-up appointments. Serious adverse events, including skin tears, were recorded. Success was achieved in 36 of 47 treated joints (76.6%) after a single injection. There were 2 recurrences in 32 joints at 30-day follow-up (6.2%) and no recurrences in 17 joints available at 6-month follow-up. Skin tears were the only serious adverse event occurring in 18 of 47 cord ruptures (38.3%). All healed secondarily without complication. Our protocol preserves treatment efficacy while maximizing efficiency. Achieving successful cord rupture with a single injection allows earlier return of function, reduced cost of treatment, and increased convenience for the patient. Patients, particularly those with greater contractures, should be counseled regarding the risk of skin tear during cord manipulation.


Magnetically responsive microbubbles as delivery vehicles for targeted sonodynamic and antimetabolite therapy of pancreatic cancer.
Magnetically responsive microbubbles (MagMBs), consisting of an oxygen gas core and a phospholipid coating functionalised with Rose Bengal (RB) and/or 5-fluorouracil (5-FU), were assessed as a delivery vehicle for the targeted treatment of pancreatic cancer using combined antimetabolite and sonodynamic therapy (SDT). MagMBs delivering the combined 5-FU/SDT treatment produced a reduction in cell viability of over 50% when tested against a panel of four pancreatic cancer cell lines in vitro. Intravenous administration of the MagMBs to mice bearing orthotopic human xenograft BxPC-3 tumours yielded a 48.3% reduction in tumour volume relative to an untreated control group (p<0.05) when the tumour was exposed to both external magnetic and ultrasound fields during administration of the MagMBs. In contrast, application of an external ultrasound field alone resulted in a 27% reduction in tumour volume. In addition, activated caspase and BAX protein levels were both observed to be significantly elevated in tumours harvested from animals treated with the MagMBs in the presence of magnetic and ultrasonic fields when compared to expression of those proteins in tumours from either the control or ultrasound field only groups (p<0.05). These results suggest MagMBs have considerable potential as a platform to enable the targeted delivery of combined sonodynamic/antimetabolite therapy in pancreatic cancer.


Use of an iPad App to simulate pressure-volume loops and cardiovascular physiology.
The purpose of this laboratory exercise is to model the changes in preload, afterload, and contractility on a simulated pressure-volume loop and to correlate those findings with common measurements of clinical cardiovascular physiology. Once students have modeled these changes on a healthy heart, the students are asked to look at a simulated case of cardiogenic shock. Effects on preload, contractility, and afterload are explored, as well as the hemodynamic effects of a number of student-suggested treatment strategies.


Structure and functions of endotoxin-binding peptides derived from CAP18.
CAP18 (cationic antimicrobial protein, 18kDa) is a 142 amino acid protein originally isolated from rabbit granulocytes using agglutination of LPS-coated erythrocytes as an assay. CAP-18 is composed of an N-terminal domain of unknown function (CAP181-105) and a C-terminal LPS-binding domain (CAP18106-142). Synthetic CAP18106-142 and CAP18106-137, a 32-amino acid peptide resulting from the truncation of 5 amino acids from the C-terminus of CAP18106-142, inhibited LPS-induced tissue factor generation, nitric oxide production and TNF release by macrophages. Mice treated with CAP18106-142 or CAP18106-137 were significantly protected from LPS lethality. Although CAP18106-142 and CAP18106-137 were highly active, other fragments of CAP18106-142, including CAP18110-142 with a truncated N-terminus, did not exhibit LPS-binding and LPS-neutralizing activities. Both peptides had broad anti-microbial activity against both Gram-negative bacteria such as Escherichia coli, Salmonella typhimurium, Klebsiella pneumoniae, Pseudomonas aeruginosa (IC50; 40-100 nM) and Gram-positive bacteria such as Staphylococcus aureus(Methicillin sensitive and resistant strains) and Streptococcus pneumoniae (IC50; 100-200nM). We cloned a CAP18 family protein from human granulocytes. The cloned cDNA encoded 140 amino acid residues. Human CAP18 (CAP181-140) was highly homologous to that of rabbit. A 32- amino-acid C-terminal fragment (CAP18104-135) was shown to bind LPS, inhibit LPS-induced tissue factor generation by murine macrophages, and protect mice from LPS lethality. This peptide exhibited antimicrobial activity against both Gram-negative and Gram-positive bacteria. We hypothesize that CAP18 and the derived peptides bind to LPS and alter the capacity of LPS to initiate disseminated intravascular coagulation. In this regard, CAP may act as host defense protein against infectious diseases, and have therapeutic potential for sepsis and endotoxin shock.


Efficacy of a Process Improvement Intervention on Inmate Awareness of HIV Services: A Multi-Site Trial.
The prevalence of HIV among U.S. inmates is much greater than in the general population, creating public health concerns and cost issues for the criminal justice system. The HIV Services and Treatment Implementation in Corrections protocol of the NIDA funded Criminal Justice Drug Abuse Treatment Studies cooperative tested the efficacy of an organizational process improvement strategy on improving HIV services in correctional facilities. For this paper, we analyzed efficacy of this strategy on improving inmate awareness and perceptions of HIV services. The study used a multi-site (n=28) clustered randomized trial approach. Facilities randomized to the experimental condition used a coach-driven local change team approach to improve HIV services at their facility. Facilities in the control condition were given a directive to improve HIV services on their own. Surveys about awareness and perceptions of HIV services were administered anonymously to inmates who were incarcerated in study facilities at baseline (n=1253) and follow-up (n=1048). A series of one-way ANOVAs were run to test whether there were differences between inmates in the experimental and control facilities at baseline and follow-up. Differences were observed at baseline, with the experimental group having significantly lower scores than the control group on key variables. But, at post-test, following the intervention, these differences were no longer significant. Taken in context of the findings from the main study, these results suggest that the change team approach to improving HIV services in correctional facilities is efficacious for improving inmates' awareness and perceptions of HIV services.


Serum vitamin D metabolites and their binding protein in patients with liver cirrhosis.
Serum parameters of calcium metabolism were measured in 32 consecutive patients with biopsy-proven cirrhosis due to either hepatitis (n = 13), alcohol abuse (n = 11), Wilson's disease (n = 3), or primary or secondary biliary cirrhosis (n = 5). All measurements were normal in the small group of patients with Wilson's disease. The serum concentrations of albumin, vitamin D-binding protein, total calcium, phosphorus, and 1,25-dihydroxyvitamin D3 (1,25-(OH2)D3) were decreased in the other patients with cirrhosis, but their mean serum concentrations of ionized calcium, 25-hydroxyvitamin D3 (25-OHD3) and free 1,25-(OH2)D3 index were normal. A slight but significant increase in the serum PTH measured using a carboxyl-terminal antiserum was found. A significant correlation was found between the serum concentration of either albumin or vitamin D-binding protein and the serum concentrations of total calcium, 25-OHD3, 1,25-(OH2)D3, and PTH but not with ionized calcium or free 1,25-(OH2)D3 index. The observed abnormalities of calcium metabolism in unselected patients with cirrhosis were mainly due to decreased protein synthesis. Only the patients with severe cirrhosis had decreased concentrations of 25-OHD3 but they were nevertheless able to maintain a normal ionized serum calcium and free 1,25-(OH2)D3 level, possibly by means of compensatory hyperparathyroidism.


The absence of disease-specific polymorphisms within the HLA-B51 gene that is the susceptible locus for Behçet's disease.
Behçet's disease is known to be associated with HLA-B51 in many different populations. Genetic evidence supports that the susceptible gene for Behçet's disease is the HLA-B51 allele at the HLA-B locus. This study was aimed to determine the HLA-B51 nucleotide sequence variation in three Behçet's disease patients and three healthy controls in order to elucidate if any disease specific mutations or polymorphisms may exist in the HLA-B51 gene of patients. Long-range polymerase chain reaction (PCR) was first carried out to give a PCR-amplified product of 9.5 kb which was then used as a template for nested PCR to give a final amplified product of 4.2 kb. This final product containing the 1.3-kb promoter/enhancer region and the entire HLA-B gene except for a 363-bp 3' terminal end segment encoding the 3' untranslated region was subcloned by the BP cloning technique and sequenced. The sequencing results showed that all the patients possessed the HLA-B*51011 allele, and there were no differences in the exonic nucleotide sequences between the three Behçet's disease patients and the three healthy controls. The HLA-B*51011 intronic and promoter/enhancer nucleotide sequences from the three patients had 22 single nucleotide polymorphisms (SNPs), a single insertion of 6 bp and a single deletion of 2 bp. On the other hand, the three healthy controls had 24 SNPs in their intronic and promoter/enhancer regions. However, none of these polymorphisms in the patients were specific for the disease. Therefore, these results clearly demonstrate that the HLA-B exonic sequence that encodes the HLA-B51 allele is the real pathogenic factor in Behçet's disease.


Developmental change in tone perception in Mandarin monolingual, English monolingual, and Mandarin-English bilingual infants: Divergences between monolingual and bilingual learners.
Most languages use lexical tone to discriminate the meanings of words. There has been recent interest in tracking the development of tone categories during infancy. These studies have focused largely on monolingual infants learning either a tone language or a non-tone language. It remains to be seen how bilingual infants learning one tone language (e.g., Mandarin) and one non-tone language (e.g., English) discriminate tones. Here, we examined infants' discrimination of two Mandarin tones pairs: one salient and one subtle. Discrimination was investigated in three groups: Mandarin-English bilinguals, English monolinguals, and Mandarin monolinguals at 6 months and 9 months of age in a cross-sectional design. Results demonstrated relatively strong Mandarin tone discrimination in Mandarin monolinguals, with salient tone discrimination at 6 months and both salient and subtle tone discrimination at 9 months. English monolinguals discriminated neither contrast at 6 months but discriminated the salient contrast at 9 months. Surprisingly, there was no evidence for tone discrimination in Mandarin-English bilingual infants. In a second experiment, 12- and 13-month-old Mandarin-English bilingual and English monolingual infants were tested to determine whether bilinguals would demonstrate tone sensitivity at a later age. Results revealed a lack of tone sensitivity at 12 or 13 months in bilingual infants, yet English monolingual infants were sensitive to both salient and subtle Mandarin tone contrasts at 12 or 13 months. Our findings provide evidence for age-related convergence in Mandarin tone discrimination in English and Mandarin monolingual infants and for a distinct pattern of tone discrimination in bilingual infants. Theoretical implications for phonetic category acquisition are discussed.


Search for primary infection by Pneumocystis carinii in a cohort of normal, healthy infants.
To determine whether Pneumocystis carinii is associated with clinical illness in the competent host, 107 normal, healthy infants were enrolled in a 2-year prospective cohort study in Chile. P. carinii was identified by specific stains and nested--deoxyribonucleic acid (DNA) amplification of the large subunit mitochondrial ribosomal ribonucleic acid gene of P. carinii f. sp. hominis, and seroconversion was assessed by enzyme-linked immunosorbent assay of serum samples drawn every 2 months. P. carinii DNA was identified in nasopharyngeal aspirates obtained during episodes of mild respiratory infection in 24 (32%) of 74 infants from whom specimens were available for testing. Three (12.5%) of those 24 infants versus 0 of 50 infants who tested negative for P. carinii had apnea episodes. Seroconversion developed in 67 (85%) of 79 infants who remained in the study by 20 months of age and occurred in the absence of any symptoms of disease in 14 (20.8%). The study indicates that P. carinii DNA can be frequently detected in healthy infants, and it raises the hypothesis that they may be an infectious reservoir of P. carinii in the community. Further investigation is needed to identify whether P. carinii causes overt respiratory disease in infants.


Crowd-out in the State Children's Health Insurance Program (SCHIP): incidence, enrollee characteristics and experiences, and potential impact on New York's SCHIP.
The extent to which the State Children's Health Insurance Program (SCHIP) crowds our private insurance is poorly understood. To assess the incidence of crowd-out and enrollee characteristics associated with crowd-out. Parent telephone survey for 2,644 children after enrollment in NY SCHIP. MEASURES AND ANALYSES: Crowd-out is measured based on enrollee reports of coverage (and loss of coverage) before SCHIP. Multivariate logistic regression is used to relate crowd-out to enrollee characteristics. Only 7.1 percent of SCHIP enrollees dropped private coverage < or =6 months before SCHIP, suggesting relatively modest crowd-out. Crowd-out was associated with some enrollee traits including income, but not with health status. Most movement from private to public insurance in NY was not crowd-out. Under current program structure in NY, crowd-out concerns should not dampen enthusiasm for SCHIP.


Quantitative glycomics using liquid phase separations coupled to mass spectrometry.
Post-translational modification of proteins by the attachment of glycans is governed by a variety of highly specific enzymes and is associated with fundamental impacts on the parent protein's physical, chemical and biological properties. The inherent connection between cellular physiology and specific glycosylation patterns has been shown to offer potential for diagnostic and prognostic monitoring of altered glycosylation in the disease state. Conversely, glycoprotein based biopharmaceuticals have emerged as dominant therapeutic strategies in the treatment of intricate diseases. Glycosylation present on these biopharmaceuticals represents a major critical quality attribute with impacts on both pharmacokinetics and pharmacodynamics. The structural variety of glycans, based upon their non-template driven assembly, poses a significant analytical challenge for both qualitative and quantitative analysis. Labile monosaccharide constituents, isomeric species and often low sample availability from biological sources necessitates meticulous sample handling, ultra-high-resolution analytical separation and sensitive detection techniques, respectively. In this article a critical review of analytical quantitation approaches using liquid phase separations coupled to mass spectrometry for released glycans of biopharmaceutical and biomedical significance is presented. Considerations associated with sample derivatisation strategies, ionisation, relative quantitation through isotopic as well as isobaric labelling, metabolic/enzymatic incorporation and targeted analysis are all thoroughly discussed.


Piezoelectric enhancement under negative pressure.
Enhancement of ferroelectric properties, both spontaneous polarization and Curie temperature under negative pressure had been predicted in the past from first principles and recently confirmed experimentally. In contrast, piezoelectric properties are expected to increase by positive pressure, through polarization rotation. Here we investigate the piezoelectric response of the classical PbTiO3, Pb(Zr,Ti)O3 and BaTiO3 perovskite ferroelectrics under negative pressure from first principles and find significant enhancement. Piezoelectric response is then tested experimentally on free-standing PbTiO3 and Pb(Zr,Ti)O3 nanowires under self-sustained negative pressure, confirming the theoretical prediction. Numerical simulations verify that negative pressure in nanowires is the origin of the enhanced electromechanical properties. The results may be useful in the development of highly performing piezoelectrics, including lead-free ones.


Kyrpidia spormannii sp. nov., a thermophilic, hydrogen-oxidizing, facultative autotroph, isolated from hydrothermal systems at São Miguel Island, and emended description of the genus Kyrpidia.
A Gram-stain-positive, rod-shaped, non-motile, spore-forming bacterium, strain EA-1T, was isolated from hydrothermal sediment samples from the Azores (São Miguel, Portugal). 16S rRNA gene sequence analysis of the isolated bacterium revealed a phylogenetic affiliation with the genus Kyrpidia. The sequence similarity of the five 16S rRNA gene copies to its closest relative, Kyrpidia tusciae, ranged from 97.79 to 97.85 %. The in silico estimate of DNA-DNA hybridization was 56.0 %. The dominant fatty acids of the novel isolate were anteiso-C17 : 0 (49.9 %), iso-C17 : 0 (23.0 %) and iso-C16 : 0 (13.3 %), while the quinone detected was menaquinone MK-7. Analysis of polar lipids identified phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine and additional unidentified compounds comprising two glycolipids, two phospholipids and two lipids. The presence of meso-diaminopimelic acid in the peptidoglycan and mannose, arabinose and ribose in the cell wall of strain EA-1T were detected. The strain was able to grow heterotrophically as well as autotrophically with carbon dioxide as the sole carbon source and with hydrogen and oxygen as electron donor and acceptor, respectively. Based on its chemotaxonomic, physiological and genomic characteristics, the new strain is considered to represent a novel species within the genus Kyrpidia, for which the name Kyrpidiaspormannii sp. nov. is proposed. The type strain is strain EA-1T (=DSM 106492T=CCOS1194T).


A comparison of fresh and used aircraft oil for the identification of toxic substances linked to aerotoxic syndrome.
Fresh and used aircraft engine lubricants (Mobil Jet Oil II) were analysed using a Fourier Transform Ion Cyclotron Resonance Mass Spectrometer (FTICRMS) and comprehensive two dimensional gas chromatography with high resolution time of flight mass spectrometry (GCxGC-HRTOFMS). The composition of the fresh oil was established, with special focus to its tricresyl phosphate (TCP) content as this has formed the focus for most investigations into aerotoxic syndrome. The results showed that only four TCP isomers were present at detectable levels in the fresh oil: mmm-TCP, mmp-TCP, ppm-TCP and ppp-TCP. The results indicate that the formulation of Mobile Jet Oil II does not contain the more toxic ortho substituted TCP isomers at concentrations above 0.0005%. The temperatures of jet engines during operation are greater than 200 °C which creates the potential to alter the composition of the original oil and create other toxic compounds. The results show there may be a significant risk from alkylated cresyl phosphates, which were identified in the used oils at concentrations calculated in the range of 0.13-0.69%. w/w. Several xylenyl and ethylphenyl phosphates have been shown to exhibit a similar toxicity to ortho substituted TCP isomers which makes there discovery in used oil significant. These compounds should be included in future aircraft air quality studies and when assessing the risks and causes of aerotoxic syndrome.


Modulation of vection latencies in the full-body illusion.
Current neuroscientific models of bodily self-consciousness (BSC) argue that inaccurate integration of sensory signals leads to altered states of BSC. Indeed, using virtual reality technology, observers viewing a fake or virtual body while being exposed to tactile stimulation of the real body, can experience illusory ownership over-and mislocalization towards-the virtual body (Full-Body Illusion, FBI). Among the sensory inputs contributing to BSC, the vestibular system is believed to play a central role due to its importance in estimating self-motion and orientation. This theory is supported by clinical evidence that vestibular loss patients are more prone to altered BSC states, and by recent experimental evidence that visuo-vestibular conflicts can disrupt BSC in healthy individuals. Nevertheless, the contribution of vestibular information and self-motion perception to BSC remains largely unexplored. Here, we investigate the relationship between alterations of BSC and self-motion sensitivity in healthy individuals. Fifteen participants were exposed to visuo-vibrotactile conflicts designed to induce an FBI, and subsequently to visual rotations that evoked illusory self-motion (vection). We found that synchronous visuo-vibrotactile stimulation successfully induced the FBI, and further observed a relationship between the strength of the FBI and the time necessary for complete vection to arise. Specifically, higher self-reported FBI scores across synchronous and asynchronous conditions were associated to shorter vection latencies. Our findings are in agreement with clinical observations that vestibular loss patients have higher FBI susceptibility and lower vection latencies, and argue for increased visual over vestibular dependency during altered states of BSC.


Low doses of chlorpyrifos interfere with spermatogenesis of rats through reduction of sex hormones.
Use of pesticides results in indirect effects on human health. We aimed to evaluate implications of toxicological effects of subchronic chlorpyrifos exposure on reproductive function in male rats. A total of 48 adult Wistar male rats were separated into four groups (n = 12). Animals were gavaged with 2.5 mg/kg (T1), 5 mg/kg (T2), or 10 mg/kg (T3) body weight of chlorpyrifos (CPF) or distilled water (control) daily for 30 days. Organ weights, epididymal sperm parameters, DNA integrity, sex hormonal (FHS and LH) levels, and alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and creatinine concentrations were determined on day 31. Another two sets of (four groups/set; n = 10) animals were orally treated with the same doses of CPF, control animal groups were treated with distilled water only for 30 days, and fertility indices and blood plasma acetylcholine esterase (AchE) were determined on day 31. Exposure to CPF resulted in a significant (p < 0.05) decrease in weights of testis and epididymis. An increase in liver weight resulted in reduced sperm counts and sperm motility and an increase in sperm abnormalities. Significant reduction in serum testosterone (p < 0.01), luteinizing hormone (p < 0.05), and follicular stimulating hormone (p < 0.05) levels was evident in animals treated with the highest dose. A significant decrease in the number of viable implantation sites and pups was observed in female rats mated with the T3 (p < 0.01) and T2 (p < 0.05) males. The ALT, AST, GGT, and creatinine contents were significantly increased (p < 0.05 and p < 0.01, respectively) on CPF exposure. A significant (p < 0.01) reduction in blood plasma AchE enzyme was observed with the highest dose. Our results demonstrated that prolonged exposure of CPF induces spermatogenesis damage, possibly through interference with sex hormones and AchE enzyme resulting in reduction of fertility. Therefore, awareness programs on handling CPF (pesticides) to enhance safety warrant minimization of its hazards.


Recognizing and investigating iron-deficiency anemia in hospitalized elderly people.
To determine whether anemia is documented and appropriately investigated for iron deficiency in hospitalized elderly people. Retrospective chart review. Medical clinical teaching unit (CTU) in secondary care hospital in Hamilton, Ont. Consecutive patients 65 years of age or older admitted between April 1992 and March 1993. Proportion of anemic patients for whom documentation was adequate (included in problem list in patient chart) and for whom adequate investigations were performed (measurement of serum ferritin level in anemic patients in whom iron deficiency was suspected, bone-marrow aspiration for those with intermediate probability of iron deficiency after determination of serum ferritin level, and endoscopy of upper or lower gastrointestinal tract, or both, in patients with iron deficiency). Of 183 eligible patients admitted to the CTU 66 (36%) had anemia, in 47 cases (71%) the anemia was documented by house staff or attending physicians. Of the 66 anemic patients 49 had a non-macrocytic anemia of unknown cause: 26 had their serum ferritin level measured, 5 underwent bone-marrow aspiration, and 21 were referred for gastrointestinal endoscopy. Six of eight patients with probable iron deficiency (i.e., a serum ferritin level that was diagnostic [less than 18 micrograms/L] or suggestive [18 to 45 micrograms/L]) underwent endoscopy, two were found to have cancer of the stomach or cecum. Only 26 of the 49 patients had adequate investigation. Anemia is common among elderly patients in hospital. However, iron deficiency is underrecognized and underinvestigated.


Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy.
Glycogen synthase kinase 3 (GSK3) is a multifunctional serine/threonine kinase that participates in numerous signalling pathways involved in diverse physiological processes. Several of these pathways are implicated in disease pathogenesis, which has prompted efforts to develop GSK3-specific inhibitors for therapeutic applications. However, before now, there has been no strong rationale for targeting GSK3 in malignancies. Here we report pharmacological, physiological and genetic studies that demonstrate an oncogenic requirement for GSK3 in the maintenance of a specific subtype of poor prognosis human leukaemia, genetically defined by mutations of the MLL proto-oncogene. In contrast to its previously characterized roles in suppression of neoplasia-associated signalling pathways, GSK3 paradoxically supports MLL leukaemia cell proliferation and transformation by a mechanism that ultimately involves destabilization of the cyclin-dependent kinase inhibitor p27(Kip1). Inhibition of GSK3 in a preclinical murine model of MLL leukaemia provides promising evidence of efficacy and earmarks GSK3 as a candidate cancer drug target.


A Markovian analysis of bacterial genome sequence constraints.
The arrangement of nucleotides within a bacterial chromosome is influenced by numerous factors. The degeneracy of the third codon within each reading frame allows some flexibility of nucleotide selection; however, the third nucleotide in the triplet of each codon is at least partly determined by the preceding two. This is most evident in organisms with a strong G + C bias, as the degenerate codon must contribute disproportionately to maintaining that bias. Therefore, a correlation exists between the first two nucleotides and the third in all open reading frames. If the arrangement of nucleotides in a bacterial chromosome is represented as a Markov process, we would expect that the correlation would be completely captured by a second-order Markov model and an increase in the order of the model (e.g., third-, fourth-…order) would not capture any additional uncertainty in the process. In this manuscript, we present the results of a comprehensive study of the Markov property that exists in the DNA sequences of 906 bacterial chromosomes. All of the 906 bacterial chromosomes studied exhibit a statistically significant Markov property that extends beyond second-order, and therefore cannot be fully explained by codon usage. An unrooted tree containing all 906 bacterial chromosomes based on their transition probability matrices of third-order shares ∼25% similarity to a tree based on sequence homologies of 16S rRNA sequences. This congruence to the 16S rRNA tree is greater than for trees based on lower-order models (e.g., second-order), and higher-order models result in diminishing improvements in congruence. A nucleotide correlation most likely exists within every bacterial chromosome that extends past three nucleotides. This correlation places significant limits on the number of nucleotide sequences that can represent probable bacterial chromosomes. Transition matrix usage is largely conserved by taxa, indicating that this property is likely inherited, however some important exceptions exist that may indicate the convergent evolution of some bacteria.


Discovery and mapping of single feature polymorphisms in wheat using Affymetrix arrays.
Wheat (Triticum aestivum L.) is a staple food crop worldwide. The wheat genome has not yet been sequenced due to its huge genome size (approximately 17,000 Mb) and high levels of repetitive sequences; the whole genome sequence may not be expected in the near future. Available linkage maps have low marker density due to limitation in available markers; therefore new technologies that detect genome-wide polymorphisms are still needed to discover a large number of new markers for construction of high-resolution maps. A high-resolution map is a critical tool for gene isolation, molecular breeding and genomic research. Single feature polymorphism (SFP) is a new microarray-based type of marker that is detected by hybridization of DNA or cRNA to oligonucleotide probes. This study was conducted to explore the feasibility of using the Affymetrix GeneChip to discover and map SFPs in the large hexaploid wheat genome. Six wheat varieties of diverse origins (Ning 7840, Clark, Jagger, Encruzilhada, Chinese Spring, and Opata 85) were analyzed for significant probe by variety interactions and 396 probe sets with SFPs were identified. A subset of 164 unigenes was sequenced and 54% showed polymorphism within probes. Microarray analysis of 71 recombinant inbred lines from the cross Ning 7840/Clark identified 955 SFPs and 877 of them were mapped together with 269 simple sequence repeat markers. The SFPs were randomly distributed within a chromosome but were unevenly distributed among different genomes. The B genome had the most SFPs, and the D genome had the least. Map positions of a selected set of SFPs were validated by mapping single nucleotide polymorphism using SNaPshot and comparing with expressed sequence tags mapping data. The Affymetrix array is a cost-effective platform for SFP discovery and SFP mapping in wheat. The new high-density map constructed in this study will be a useful tool for genetic and genomic research in wheat.


[Neoadjuvant intraarterial chemotherapy with nedaplatin, peplomycin and mitomycin C for advanced cervical cancer].
The aim of the present study was to examine the usefulness of neoadjuvant intraarterial chemotherapy (NAC) using nedaplatin as key drug to improve the prognosis in case of advanced cervical cancer. Twenty-five cases of advanced cervical cancer (15 cases of stage II with high risks, 10 of stage III, referred to as the 254-S group) treated by NAC using nedaplatin, mitomycin C and peplomycin were compared with 30 cases (22 cases of stage II with high risks, 8 of stage III, referred to as the CDDP group) treated using cisplatin and mitomycin C which is the conventional regimen, in terms of measurable response, pathological response, rate of lymph node metastasis, cumulative survival rate, side effects and relapse style. According to the evaluation by measurable responses, the response rate was 90% (CR 52%) in the 254-S group and 75% (CR 15%) in the CDDP group. For pathological response of the specimen, the CR rate was 16% in the 254-S group and 23% in the CDDP group. The rate of lymph node metastasis extracted surgically was 33% and 41%, respectively. The cumulative survival rate in the 254-S group was about 10% better than in the CDDP group, but no significant difference was found. Leucopenia of both groups was of the same grade. In the 254-S group, although thrombocytopenia was more critical than in the CDDP group, there was a slight tendency to kidney toxicity. The locoregional recurrence rate was 12% in the 254-S group and 30% in the CDDP group. The distant metastasis rate was 16% and 27%, respectively. Although neoadjuvant intraarterial chemotherapy using nedaplatin as a key drug was useful to improve the prognosis of advanced cervical cancer, measures against recurrence outside the pelvis and individualization of medical treatment were considered to lead to a further improvement of the prognosis.


Enlarged vestibular aqueducts and other inner-ear abnormalities in patients with Down syndrome.
Histopathological anomalies of inner-ear structures in individuals with Down syndrome have been well documented; however, few studies have examined the radiological features. A retrospective study was conducted of temporal bone computed tomography images in 38 individuals (75 ears) with Down syndrome to evaluate the prevalence of inner-ear abnormalities and assess vestibular aqueduct widths. Inner-ear anomalies were identified in 20 of the 38 individuals (52.6 per cent). Seven of the 75 temporal bones (9.3 per cent) were found to have higher than previously reported. A dilated internal auditory canal and vestibule were more common among the present study group, while prior studies have demonstrated internal auditory canal stenosis and decreased vestibule size. Down syndrome patients exhibit a high prevalence of dysplastic inner-ear features that confer substantial risk of sensorineural hearing loss. Computed tomography is a useful screening aid to detect inner-ear abnormalities, particularly enlarged vestibular aqueducts, which cause preventable sensorineural hearing loss in this population.


Protection against mucoid Pseudomonas aeruginosa in rodent models of endobronchial infections.
Chronic endobronchial infection with mucoid Pseudomonas aeruginosa accounts for much of the morbidity and mortality in patients with cystic fibrosis (CF). Reduced morbidity is observed when infection is absent. Clinical investigations have implicated opsonizing antibody specific for the mucoid exopolysaccharide (MEP) surrounding these bacteria as a potential immunologic protective mechanism, whereas nonopsonizing antibody to MEP is not protective. Mice and rats immunized with doses of MEP that elicited opsonizing antibody had reduced levels of infection compared with nonimmune controls after intratracheal challenge with mucoid P. aeruginosa enmeshed in agar beads. Doses of MEP that elicited nonopsonizing antibody were not protective. Parallel experiments in which passive transfer of polyclonal and monoclonal opsonizing and nonopsonizing antibody were used yielded similar results. These data indicate that MEP-specific opsonizing antibody can protect against chronic P. aeruginosa infection in this model of disease.


Traditional Chinese Medicine Moxibustion in the Treatment of Infantile Diarrhea.
The main contribution of this research paper is to summarize the results of Meta-analysis of moxibustion in the treatment of infantile diarrhea which is one the common disease and requires considerable attention from the research community and funding organizations. In order to verify that the proposed scheme has merits, a comprehensive searching methodology was adopted by considering various databases such as China Biomedical Literature Database (CBM), China National Knowledge Network Infrastructure (CNKI), Wanfang Database, Pub Med Database, Google Academic, and Cochrane Library. It is important to note that a powerful computer has been utilized to carry out this searching. Finally, only those literature contents are selected which meet the inclusion criteria. Likewise, exclusion criteria was used to exclude irrelevant contents of the literature. RevMan 5.3 was used to analyze the collected data and after reading the titles and abstracts, 29 well-designed studies were selected. Through searching the full text, reading literature, and quality evaluation, 17 papers were finally included. Response rates were reported in all 17 studies, and subgroup analysis was performed based on whether or not other therapies were combined. 7 studies compared the effectiveness of simple moxibustion and conventional therapy in the treatment of infantile diarrhea, and the results showed statistically significant differences [OR = 4.01, 95% CI (2.03, 7.84), P < 0.0001]; 10 studies compared the effectiveness of moxibustion combined with other therapies and conventional therapies in the treatment of diarrhea in children, and the results showed that the difference had general meaning [OR = 4.45, 95% CI (2.83, 7.10), P < 0.00001]. The funnel plot (in Figure) showed that the distribution of included studies was asymmetrical on both sides of the baseline, which could be considered as publication bias. Traditional Chinese medicine moxibustion could effectively relieve the symptoms of infantile diarrhea, and the effect was significant.


beta-Catenin is required for specification of proximal/distal cell fate during lung morphogenesis.
The lungs are divided, both structurally and functionally, into two distinct components, the proximal airways, which conduct air, and the peripheral airways, which mediate gas exchange. The mechanisms that control the specification of these two structures during lung development are currently unknown. Here we show that beta-catenin signaling is required for the formation of the distal, but not the proximal, airways. When the gene for beta-catenin was conditionally excised in epithelial cells of the developing mouse lung prior to embryonic day 14.5, the proximal lung tubules grew and differentiated appropriately. The mice, however, died at birth because of respiratory failure. Analysis of the lungs by in situ hybridization and immunohistochemistry, using molecular markers of the epithelial and mesenchymal components of both proximal and peripheral airways, showed that the lungs were composed primarily of proximal airways. These observations establish, for the first time, both the sites and timing of specification of the proximal and peripheral airways in the developing lung, and that beta-catenin is one of the essential components of this specification.


Needlescopic, laparoscopic, and open appendectomy: a comparative study.
The benefits of laparoscopic appendectomy appear to be controversial. Since 1994, several abdominal procedures have been completed by using the needlescopic technique, but there appear to be no prospective studies to demonstrate the perceived benefits of needlescopic appendectomy. The authors compared open, laparoscopic, and needlescopic appendectomy in a randomized fashion with regard to duration of surgery, length of hospitalization, analgesic dosage, and surgery-associated complications. From March to July 1998, 75 patients admitted at the emergency station of the authors' hospital with a final diagnosis of acute appendicitis without tumor formation were randomized to receive one of the three treatment categories: open (OA), laparoscopic (LA), and needlescopic (nLA) appendectomy. Laparoscopic and needlescopic appendectomy were performed by using a three-port technique, although the size of the trocar used varied. There were 26 patients in the OA group, 23 in the LA group, and 26 in the nLA group. The mean operation durations for the OA, LA, and nLA groups were 55.4 +/- 28.0 minutes, 69.1 +/- 48.8 minutes, and 62.3 +/- 26.3 minutes, respectively, and these were not significantly different from one another. The mean number of the analgesic doses (Pethidine 1 mg/kg) required was 1.3 +/- 1.2 mg/kg, 0.5 +/- 0.8 mg/kg, and 0.2 +/- 0.6 mg/kg, respectively. Significant differences were noted when comparing the OA with the LA or nLA groups (OA vs. LA, P = 0.02; OA vs. nLA, P = 0.0002; LA vs. nLA, P = 0.06). The mean oral intake durations were 32.2 +/- 16.9 hours, 21.0 +/- 14.6 hours, and 20.8 +/- 16.4 hours, respectively, after surgery for the OA, LA, and nLA groups, and the between-group differences were statistically significant for the OA versus LA group ( P = 0.004) and for the OA versus nLA group ( P = 0.003). The mean durations of hospitalization for the OA, LA, and nLA groups were 3.6 +/-1.8 days, 2.8 +/- 1.4 days, and 2.4 +/- 0.9 days, and difference was detected between the OA and the nLA groups ( P = 0.02). The OA group rendered a greater wound-complication rate and ileus than did the other two groups, but the differences were not detected between the three categories ( P = 0.065, 0.6935). The result of the current study confirmed that the nLA procedure is a feasible and safe one. The nLA procedure provided substantial advantages over the OA procedure in the contexts of diminished postoperative pain and shorter hospital stay without significant increases in postoperative complication rate or surgical time.


Vitamin D and common mental disorders in mid-life: cross-sectional and prospective findings.
The relationship between vitamin D and common mental disorders (CMDs) remains unclear. We aimed to determine if behaviours affecting vitamin D concentrations differ between individuals with or without CMDs and evaluate, cross-sectionally and prospectively, the extent to which the association between 25(OH)D and CMDs are explained by these behaviours. Data are from the 1958 British birth cohort (n = 7401). Behaviours were ascertained by questionnaire at age 45 years. CMDs (depression, anxiety, panic, phobia) were assessed using the Clinical Interview Schedule-Revised at 45 years and depression using Mental Health Inventory-5 at 50 years. Participants with CMDs at 45 years differed from others on some but not all vitamin D related behaviours. There were inverse, cross-sectional associations at 45 years of 25(OH)D with depression and panic, which persisted after adjustment for vitamin D related behaviours (OR = 0.57, 95% CI: 0.40,0.81 and OR = 0.33, 95% CI: 0.40,0.81, respectively). Association between 25(OH)D and subsequent (50 years) risk of depression was non-linear (p = 0.01), with lower risk for participants with 25(OH)D between 50 and 85 nmol/l compared with those with lower or higher concentrations. This study provides support for an association of low 25(OH)D concentrations with current and subsequent risk of depression in mid-adulthood.


Inhibition of the spindle assembly checkpoint kinase Mps-1 as a novel therapeutic strategy in malignant mesothelioma.
Malignant mesothelioma (MM) is an aggressive malignancy, highly resistant to current medical and surgical therapies, whose tumor cells characteristically show a high level of aneuploidy and genomic instability. We tested our hypothesis that targeting chromosomal instability in MM would improve response to therapy. Thr/Tyr kinase (TTK)/monopolar spindle 1 kinase (Mps-1) is a kinase of the spindle assembly checkpoint that controls cell division and cell fate. CFI-402257 is a novel, selective inhibitor of Mps-1 with antineoplastic activity. We found that CFI-402257 suppresses MM growth. We found that Mps-1 is overexpressed in MM and that its expression correlates with poor patients' outcome. In vitro, CFI-402257-mediated inhibition of Mps-1 resulted in abrogation of the mitotic checkpoint, premature progression through mitosis, marked aneuploidy and mitotic catastrophe. In vivo, CFI-402257 reduced MM growth in an orthotopic, syngeneic model, when used as a single agent, and more so when used in combination with cisplatin+pemetrexed, the current standard of care. Our preclinical findings indicate that CFI-402257 is a promising novel therapeutic agent to improve the efficacy of the current chemotherapeutic regimens for MM patients.


No impact of fish oil supplements on bleeding risk: a systematic review.
Fish oil supplementation may inhibit platelet aggregation and can potentially increase the risk of bleeding. The aim of the present systematic review was to evaluate the effect of fish oil supplements on haemostasis and bleeding risk, and to provide recommendations on whether it is necessary to discontinue fish oil supplementation prior to surgery. Studies were identified through PubMed and Embase searches and by reviewing the reference lists of the included papers. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used. Included in the review were publications including a minimum of 20 healthy subjects and studies on patients who were undergoing surgery and who had fish oil exposure. In total, 52 publications were included; 32 publications on healthy subjects and 20 publications on patients undergoing surgery. The majority of the included studies were randomised controlled trials or included a control group. Overall, fish oil supplements reduced platelet aggregation in healthy subjects. Fish oil exposure in surgical patients did not increase bleeding or blood transfusions either during or after surgery. Fish oil supplements reduced platelet aggregation in healthy subjects. This biochemical effect was not reflected in increased bleeding risk during or after surgery evaluated in randomised controlled trials. Consequently, this systematic review does not support the need for discontinuation of fish oil supplements prior to surgery or other invasive procedures.


Tau phosphorylation in human brain: relationship to behavioral disturbance in dementia.
Agitation and aggressive behavior are common symptoms of Alzheimer's disease (AD), and tangle density in frontal cortex is a possible regional substrate of these behaviors. To investigate this further, 16 AD patients, 8 patients with non-AD dementia, and 13 age-matched control subjects for frontal cortex and, respectively, 21, 7, and 6 patients for parietal cortex were analyzed for tau and phospho-tau by enzyme-linked immunosorbent assay (ELISA). Agitation/aggression was determined by the Present Behavioural Examination. In a subset of cases, glycogen synthase kinase-3β (GSK-3β) phosphorylation and protein phosphatase 2A (PP2A) expression were measured. Phospho-tau and the phospho-tau/total tau ratio were elevated in AD in both cortical regions. In keeping with our hypothesis, the phospho-tau/total tau ratio was elevated in the frontal cortex of those patients with agitation/aggression during life, and there was a significant correlation (p = 0.024) between these behaviors and the phospho-tau/total tau ratio in the cortex. PP2A expression was lower (p < 0.01) in the frontal cortex of patients with high tau phosphorylation. This study confirms a link between tau phosphorylation and agitation/aggression and suggests that reducing tau phosphorylation may provide symptomatic relief.