First Report of Powdery Mildew Caused by Sphaerotheca fusca on Tomatillo in California.
Tomatillo or husk tomato (Physalis ixocarpa Brot.) is an annual Solanaceous bush grown for its fruit, which are harvested when the fruit fill the enlarged calyx and are used primarily in Hispanic cooking. In the summer of 1997, commercial field-grown tomatillo in the Salinas Valley (Monterey County) was severely affected by a powdery mildew disease. Fungal growth was found on leaves, petioles, and calyces and resulted in twisting, desiccation, and premature senescence of the tissues. The mycelium was white to gray, ectophytic, amphigenous, and effuse. Mycelial appressoria were indistinct. Conidiophore foot cells were straight, cylindric, measured 36.1 to 61.1 µm (mean 47.0) × 11.1 to 13.9 µm (mean 11.7), and were followed by 1 to 3 shorter cells. Doliform conidia were formed in chains and measured 25.0 to 50.0 µm (mean 32.5) × 11.1 to 22.2 µm (mean 17.7). The length-to-width ratios of conidia generally were less than 2.0, and fibrosin bodies were present. Germ tubes usually were laterally inserted, lacked conspicuous appressoria, and were of the pannosa-type. Cleistothecia were not observed. Based on these characters, the fungus was identified as Sphaerotheca fusca (Fr.) Blumer, Beitr. Krypt.-Fl. Schweiz (1). Pathogenicity was confirmed by gently pressing infected leaves onto leaves of potted tomatillo. Inoculated plants were kept in a chamber at 100% humidity for 48 h, and then maintained in a greenhouse. Powdery mildew developed on inoculated plants after 12 to 14 days, while uninoculated plants did not develop disease. The experiment was conducted a second time and the results were the same. This is the first report of a powdery mildew disease of tomatillo in California. Reference: (1) U. Braun. Nova Hedwigia 89:1, 1987.


A qualitative study of obstacles to diaphragm and condom use in an HIV prevention trial in sub-Saharan Africa.
Consistent condom use and the substitution of condoms with potential HIV prevention methods of lower or unknown effectiveness are important concerns in the development of new prevention technologies. This qualitative study explored obstacles to consistent condom use with the diaphragm in MIRA, an HIV prevention trial in South Africa and Zimbabwe. We conducted 26 focus group discussions (FGDs) with 206 women and 7 FGDs and 10 in-depth interviews with 41 male partners of intervention-arm women. The belief that the diaphragm/gel prevented HIV, women's difficulties negotiating condom use, and men's unawareness that using the products together was recommended were obstacles to consistent condom use with the diaphragm/gel. Concerns about protection from HIV and pregnancy, recognition that the diaphragm was not yet proven to prevent HIV or sexually transmitted infections, and the trial context were facilitators. Understanding selective study product use in HIV prevention trials may inform improved adherence counseling and male involvement strategies.


Resveratrol ameliorates the chemical and microbial induction of inflammation and insulin resistance in human placenta, adipose tissue and skeletal muscle.
Gestational diabetes mellitus (GDM), which complicates up to 20% of all pregnancies, is associated with low-grade maternal inflammation and peripheral insulin resistance. Sterile inflammation and infection are key mediators of this inflammation and peripheral insulin resistance. Resveratrol, a stilbene-type phytophenol, has been implicated to exert beneficial properties including potent anti-inflammatory and antidiabetic effects in non-pregnant humans and experimental animal models of GDM. However, studies showing the effects of resveratrol on inflammation and insulin resistance associated with GDM in human tissues have been limited. In this study, human placenta, adipose (omental and subcutaneous) tissue and skeletal muscle were stimulated with pro-inflammatory cytokines TNF-α and IL-1β, the bacterial product lipopolysaccharide (LPS) and the synthetic viral dsRNA analogue polyinosinic:polycytidylic acid (poly(I:C)) to induce a GDM-like model. Treatment with resveratrol significantly reduced the expression and secretion of pro-inflammatory cytokines IL-6, IL-1α, IL-1β and pro-inflammatory chemokines IL-8 and MCP-1 in human placenta and omental and subcutaneous adipose tissue. Resveratrol also significantly restored the defects in the insulin signalling pathway and glucose uptake induced by TNF-α, LPS and poly(I:C). Collectively, these findings suggest that resveratrol reduces inflammation and insulin resistance induced by chemical and microbial products. Resveratrol may be a useful preventative therapeutic for pregnancies complicated by inflammation and insulin resistance, like GDM.


Indirubin-3'-monoxime inhibits beta-amyloid-induced neurotoxicity in neuroblastoma SH-SY5Y cells.
Increasing evidence suggests that the inappropriate activation of cyclin-dependent kinases (CDKs) could induce neuronal apoptosis in Alzheimer's disease (AD), which means that the pharmacological inhibitors of cell-cycle progression may effectively impede the development or progression of AD. Indirubin-3'-monoxime (IMX), a known effective inhibitor of CDKs, has been shown to have therapeutic effects on learning and memory deficits induced by beta-amyloid (Abeta) intracerebroventricular infusion in rats. In the present study, we investigated the neuroprotective effects of IMX on Abeta(25-35)-induced neuronal apoptosis and its potential mechanisms in human neuroblastoma SH-SY5Y cells. Abeta(25-35)-induced apoptosis, characterized by decreased cell viability, neuronal DNA condensation, and fragmentation, was associated with an increase in tau protein hyperphosphorylation. IMX, however, attenuated Abeta(25-35)-induced cell death in a dose-dependent manner. Furthermore, expression of hyperphosphorylation tau protein was significantly decreased with IMX treatment. Our study suggests that IMX may usefully prevent or delay the neuronal loss of AD.


Risk-based prioritization of ground water threatening point sources at catchment and regional scales.
Contaminated sites threaten ground water resources all over the world. The available resources for investigation and remediation are limited compared to the scope of the problem, so prioritization is crucial to ensure that resources are allocated to the sites posing the greatest risk. A flexible framework has been developed to enable a systematic and transparent risk assessment and prioritization of contaminant point sources, considering the local, catchment, or regional scales (Danish EPA, 2011, 2012). The framework has been tested in several catchments in Denmark with different challenges and needs, and two of these are presented. Based on the lessons learned, the Danish EPA has prepared a handbook to guide the user through the steps in a risk-based prioritization (Danish EPA, 2012). It provides guidance on prioritization both in an administratively defined area such as a Danish Region, and within the bounds of a specified ground water catchment. The handbook presents several approaches in order to prevent the prioritization from foundering because of a lack of data or an inappropriate level of complexity. The developed prioritization tools, possible graphical presentation and use of the results are presented using the case studies as examples. The methodology was developed by a broad industry group including the Danish EPA, the Danish Regions, the Danish Nature Agency, the Technical University of Denmark, and consultants - and the framework has been widely accepted by the professional community in Denmark. The concepts are quite general and can be applied in other countries facing similar challenges.


The H Syndrome: A Genodermatosis.
H syndrome (histiocytosis lymph adenopathy plus syndrome) is an autosomal recessive disorder caused by mutations in the SLC29A3 gene, encoding the human equilibrative nucleoside transporter (hENT3), characterized by cutaneous hyperpigmentation and hypertrichosis, hepatosplenomegaly, hearing loss, heart anomalies, hypogonadism, low height, hyperglycemia/insulin-dependent diabetes mellitus, and hallux valgus/flexion contractures. Exophthalmos, malabsorption, renal anomalies, flexion contractions of interphalangeal joints and hallux valgus, and lytic bone lesions, as well as osteosclerosis, are also seen. If these are lacking, the constellation of additional findings should raise suspicion for H syndrome. As most of the patients reported to date with H syndrome are from traditional, low-income populations, where consanguinity is common, it is highly important to develop a cheap and affordable technique for a mutation analysis. Two siblings presented to us, diagnosed as having insulin-dependent diabetes mellitus (IDDM) since the age of eight years and progressive flexion contracture of the small joints for seven-eight years. On examination, both had short stature. One also had bilateral cervical lymphadenopathy. The female had the Tanner stage of B3P3A2 M0 and the male had the Tanner stage of prepuberty. Laboratory workup, including antinuclear antibodies, rheumatoid factor, erythrocyte sedimentation rate, thyroid profile, and Celiac serology were negative. Genetic studies confirmed the diagnosis of H syndrome.


Offshore windmills and the effects of electromagnetic fields on fish.
With the large scale developments of offshore windpower the number of underwater electric cables is increasing with various technologies applied. A wind farm is associated with different types of cables used for intraturbine, array-to-transformer, and transformer-to-shore transmissions. As the electric currents in submarine cables induce electromagnetic fields there is a concern of how they may influence fishes. Studies have shown that there are fish species that are magneto-sensitive using geomagnetic field information for the purpose of orientation. This implies that if the geomagnetic field is locally altered it could influence spatial patterns in fish. There are also physiological aspects to consider, especially for species that are less inclined to move as the exposure could be persistent in a particular area. Even though studies have shown that magnetic fields could affect fish, there is at present limited evidence that fish are influenced by the electromagnetic fields that underwater cables from windmills generate. Studies on European eel in the Baltic Sea have indicated some minor effects. In this article we give an overview on the type of submarine cables that are used for electric transmissions in the sea. We also describe the character of the magnetic fields they induce. The effects of magnetic fields on fish are reviewed and how this may relate to the cables used for offshore wind power is discussed.


Down-regulation of the brain-specific cell-adhesion molecule contactin-3 in tuberous sclerosis complex during the early postnatal period.
The genetic disorder tuberous sclerosis complex (TSC) is frequently accompanied by the development of neuropsychiatric disorders, including autism spectrum disorder and intellectual disability, with varying degrees of impairment. These co-morbidities in TSC have been linked to the structural brain abnormalities, such as cortical tubers, and recurrent epileptic seizures (in 70-80% cases). Previous transcriptomic analysis of cortical tubers revealed dysregulation of genes involved in cell adhesion in the brain, which may be associated with the neurodevelopmental deficits in TSC. In this study we aimed to investigate the expression of one of these genes - cell-adhesion molecule contactin-3. Reverse transcription quantitative polymerase chain reaction for the contactin-3 gene (CNTN3) was performed in resected cortical tubers from TSC patients with drug-resistant epilepsy (n = 35, age range: 1-48 years) and compared to autopsy-derived cortical control tissue (n = 27, age range: 0-44 years), as well as by western blot analysis of contactin-3 (n = 7 vs n = 7, age range: 0-3 years for both TSC and controls) and immunohistochemistry (n = 5 TSC vs n = 4 controls). The expression of contactin-3 was further analyzed in fetal and postnatal control tissue by western blotting and in-situ hybridization, as well as in the SH-SY5Y neuroblastoma cell line differentiation model in vitro. CNTN3 gene expression was lower in cortical tubers from patients across a wide range of ages (fold change = - 0.5, p < 0.001) as compared to controls. Contactin-3 protein expression was lower in the age range of 0-3 years old (fold change = - 3.8, p < 0.001) as compared to the age-matched controls. In control brain tissue, contactin-3 gene and protein expression could be detected during fetal development, peaked around birth and during infancy and declined in the adult brain. CNTN3 expression was induced in the differentiated SH-SY5Y neuroblastoma cells in vitro (fold change = 6.2, p < 0.01). Our data show a lower expression of contactin-3 in cortical tubers of TSC patients during early postnatal period as compared to controls, which may affect normal brain development and might contribute to neuropsychiatric co-morbidities observed in patients with TSC.


Socioeconomic status and outcome from intensive care in England and Wales.
The objective of this study was to estimate the association between socioeconomic status (SES) and outcome for admissions to intensive care. Retrospective cohort study. We studied 51,572 admissions to 99 intensive-care units in England and Wales between 1995 and 2000. The SES of admissions was measured using Carstairs deprivation scores. Outcome was hospital mortality after adjustment for case mix using the APACHE II method. Admissions of lower SES were, on average, younger and less likely to be following surgery. There was evidence of a SES gradient for hospital mortality in admissions after elective surgery after adjusting for case mix (test for trend P <0.001), with higher SES associated with lower mortality. In the least-deprived quintile of SES, the odds ratio for hospital mortality was 0.70 (95% confidence interval, 0.58-0.84) compared with the most deprived quintile. There was no evidence of a SES gradient for hospital mortality in nonsurgical or emergency surgical admissions, and the decision to withdraw active treatment did not differ by SES. There is a SES gradient for hospital mortality in elective surgical admissions that is not explained by differences in case mix or the withdrawal of active treatment. Further research is required to establish if this finding can be explained by unmeasured differences in health status at admission to an intensive-care unit or differences in care and to establish the potential impact these results may have on interpreting comparative surgical performance data.


Social support, socio-economic status, health and abuse among older people in seven European countries.
Social support has a strong impact on individuals, not least on older individuals with health problems. A lack of support network and poor family or social relations may be crucial in later life, and represent risk factors for elder abuse. This study focused on the associations between social support, demographics/socio-economics, health variables and elder mistreatment. The cross-sectional data was collected by means of interviews or interviews/self-response during January-July 2009, among a sample of 4,467 not demented individuals aged 60-84 years living in seven European countries (Germany, Greece, Italy, Lithuania, Portugal, Spain, and Sweden). Multivariate analyses showed that women and persons living in large households and with a spouse/partner or other persons were more likely to experience high levels of social support. Moreover, frequent use of health care services and low scores on depression or discomfort due to physical complaints were indicators of high social support. Low levels of social support were related to older age and abuse, particularly psychological abuse. High levels of social support may represent a protective factor in reducing both the vulnerability of older people and risk of elder mistreatment. On the basis of these results, policy makers, clinicians and researchers could act by developing intervention programmes that facilitate friendships and social activities in old age.


Wegener granulomatosis: CT and MR findings.
To demonstrate the spectrum of CT and MR imaging findings in patients with Wegener granulomatosis and to determine how often these findings could be attributed to either direct extension from paranasal or orbital disease sites, remote granulomas, or central nervous system (CNS) vasculitis. We retrospectively reviewed the CT or MR studies of 15 patients with Wegener granulomatosis. Abnormal findings were seen in 7 patients (5 examined with MR imaging, 2 with CT). Findings included dural thickening and contrast enhancement (3 patients), infarcts (2 patients), regions of hyperintense signal on T2-weighted MR images (2 patients), and abnormal MR signal in the brain stem (2 patients). Three patients with imaging findings of dural enhancement and thickening were thought to have remote granulomatous lesions involving the dura. No patients had extension from sites external to the CNS or clinical findings suggestive of CNS vasculitis. The spectrum of CT and MR findings in Wegener granulomatosis includes dural thickening and enhancements cerebral infarction, and MR signal abnormalities in the brain stem and white matter. Presumed remote granulomatous lesions were the most common causes of CNS findings in this study. Complications related to non-CNS disease (eg, hypertension, endocarditis) also appear to have played a role in some patients.


Using landscape topology to compare continuous metaheuristics: a framework and case study on EDAs and ridge structure.
In this paper we extend a previously proposed randomized landscape generator in combination with a comparative experimental methodology to study the behavior of continuous metaheuristic optimization algorithms. In particular, we generate two-dimensional landscapes with parameterized, linear ridge structure, and perform pairwise comparisons of algorithms to gain insight into what kind of problems are easy and difficult for one algorithm instance relative to another. We apply this methodology to investigate the specific issue of explicit dependency modeling in simple continuous estimation of distribution algorithms. Experimental results reveal specific examples of landscapes (with certain identifiable features) where dependency modeling is useful, harmful, or has little impact on mean algorithm performance. Heat maps are used to compare algorithm performance over a large number of landscape instances and algorithm trials. Finally, we perform a meta-search in the landscape parameter space to find landscapes which maximize the performance between algorithms. The results are related to some previous intuition about the behavior of these algorithms, but at the same time lead to new insights into the relationship between dependency modeling in EDAs and the structure of the problem landscape. The landscape generator and overall methodology are quite general and extendable and can be used to examine specific features of other algorithms.


[Late-onset sporadic case of SPG4 (1726T>C mutant) accompanied by polyneuropathy with diabetes mellitus].
We report a 73-year-old man with SPG4. From aged 53 he had diabetes mellitus and at 64 he developed spastic paraparesis and urinary disturbance. At 70 years, he began to walk with a stick and noted abnormal sensations in bilateral feet. There was no relevant family history. Moderate spasticity with mild muscle weakness, markedly brisk tendon reflex with pathological reflexes, and mildly abnormal sensation in bilateral lower extremities, and markedly spastic gait were found. MRI showed mild C4-C7 spondylosis and L4-5 disk protrusion but no abnormality of the corpus callosum. Nerve conduction and needle EMG studies revealed various abnormalities in distal (MCV, SCV) and proximal (F-wave) peripheral nerves, but no neurogenic changes in limb muscles. We found a missense spastin gene mutation (1726T>C) that causes Leu534Pro substitution. This spastin gene mutation was novel in Japanese, but has been reported in an Italian family. The present case's neuropathy might be related to diabetes mellitus, because SPG4 is generally not associated with neuropathy. However, recent studies suggest that SPG4 patients sometimes have subclinical neuropathy, and longer disease duration may contribute to peripheral neuropathy. Further study of clinical characteristics associated with the Leu534Pro mutation will be necessary.


A general approach for haplotype phasing across the full spectrum of relatedness.
Many existing cohorts contain a range of relatedness between genotyped individuals, either by design or by chance. Haplotype estimation in such cohorts is a central step in many downstream analyses. Using genotypes from six cohorts from isolated populations and two cohorts from non-isolated populations, we have investigated the performance of different phasing methods designed for nominally 'unrelated' individuals. We find that SHAPEIT2 produces much lower switch error rates in all cohorts compared to other methods, including those designed specifically for isolated populations. In particular, when large amounts of IBD sharing is present, SHAPEIT2 infers close to perfect haplotypes. Based on these results we have developed a general strategy for phasing cohorts with any level of implicit or explicit relatedness between individuals. First SHAPEIT2 is run ignoring all explicit family information. We then apply a novel HMM method (duoHMM) to combine the SHAPEIT2 haplotypes with any family information to infer the inheritance pattern of each meiosis at all sites across each chromosome. This allows the correction of switch errors, detection of recombination events and genotyping errors. We show that the method detects numbers of recombination events that align very well with expectations based on genetic maps, and that it infers far fewer spurious recombination events than Merlin. The method can also detect genotyping errors and infer recombination events in otherwise uninformative families, such as trios and duos. The detected recombination events can be used in association scans for recombination phenotypes. The method provides a simple and unified approach to haplotype estimation, that will be of interest to researchers in the fields of human, animal and plant genetics.


Incidental Dose to Pelvic Nodes in Bladder-Only Radiotherapy: Is It Clinically Relevant?
Although there is a strong biological rationale to electively treat the pelvic nodes during bladder preservation, its clinical benefit is uncertain. This may be explained by the incidental dose received by the nodal regions when treating the bladder alone. This study was conducted to investigate the doses received by the different pelvic nodal regions when the bladder alone is treated by standard conformal radiotherapy. The computed tomography data sets of 20 patients with node-negative muscle-invasive bladder cancer treated in a bladder preservation protocol were studied. Patients were originally treated with conformal radiotherapy to the bladder alone. Replanning was done with additional delineation of the pelvic nodal regions namely common iliac (upper and lower), presacral, internal iliac, obturator, and external iliac. Dose volume parameters such as Dmean, Dmax, D100%, D66%, D33%, V40, and V50 to each of the nodal regions were estimated for all patients. The obturator nodes received the highest dose among all nodal regions. The mean dose received by obturator, external iliac, and internal iliac regions was 59, 45, and 36 Gy, respectively. The dose received by these 3 regions in the full bladder state was 63, 52, and 47 Gy, respectively. The dose received by all other pelvic nodal regions was low and not clinically relevant. The incidental dose received by obturator and external iliac nodes is clinically significant in bladder-only radiation, possibly enough to influence micrometastatic disease. This may be a reason for the lack of clear benefit seen with nodal irradiation in bladder cancer. Advances in Knowledge: This study highlights that the incidental dose received by obturator and external iliac nodes is clinically significant in bladder-only radiation. The obturator nodes received the highest dose among all nodal regions with mean dose of 59 Gy.


Maternal depression and personality traits in association with child neuropsychological and behavioral development in preschool years: Mother-child cohort (Rhea Study) in Crete, Greece.
Poor perinatal maternal mental health has been linked with negative outcomes on early child development; however, the importance of maternal personality has been neglected thus far. We aimed to examine the effects of antenatal and postnatal maternal mental health, including assessment of maternal personality characteristics, on child neuropsychological and behavioral development at preschool years in a population based mother-child cohort (Rhea Study) in Crete, Greece. Self-reported measures of maternal depression (EPDS), trait anxiety (STAI-Trait) and personality traits (EPQ-R) were assessed in a sample of 288 women at 28-32 weeks of gestation. A larger sample of 642 mothers completed the EPDS scale at 8 weeks postpartum. Children's neuropsychological (MSCA) and behavioral (ADHDT and SDQ) development were assessed at 4 years of age. Linear regression analyses were used to estimate the associations between the exposures and outcomes of interest after adjustment for potential confounders. Regarding child neuropsychological development, increased postnatal depressive symptoms were associated with child's perceptual performance, whereas increased maternal psychoticism was linked with child's motor ability at 4 years of age. Furthermore, elevated levels of maternal depression during pregnancy and postpartum, and the predisposing personality characteristics of trait anxiety and neuroticism, were associated with children's behavioral difficulties. A clinical diagnostic instrument for maternal mental health was not used and assessment of children's behavior was based on maternal report. These findings suggest that poor perinatal maternal mental health and an adverse personality profile may be associated with impaired child neuropsychological and behavioral development at preschool years.


Experiments on the structure of an individual elementary particle.
Research begun in the early 1970s on geonium is reviewed. Genoium is a man-made atom, created at liquid-helium temperature in ultrahigh vacuum from an individual electron in magnetic and electric trapping fields. For this atom the electron gyromagnetic ratio g = 2. 000 000 000 110(60) has been measured in microwave spectroscopy experiments after subtraction of quantum electrodynamics shifts. The g - g(Dirac) = 11 x 10(-11) excess over the value g(Dirac) = 2 for the theoretical Dirac point electron suggests for the electron of nature a corresponding excess radius R(e) - R(Dirac) over the Dirac radius R(Dirac) = 0 and a spatial structure. From a plot of measured g and R values for the near-Dirac particles electron, proton, triton, and helium-3 an electron radius R(e) approximately 10(-20) centimeter is extrapolated. In a speculation, the triton-proton-quark model has been extended to the electron, to a succession of subquarks, and finally to the "cosmon." Rapid decay of a cosmon-anticosmon pair created from the "nothing" state in a spontaneous quantum jump initiated the Big Bang.


Financing universal health insurance: taxes, premiums, and the lessons of social insurance.
In a society with strong antitax sentiment and large government deficits, the enactment of universal health insurance is blocked by an impasse over financing. The two chief mechanisms for funding universal health insurance are taxes and insurance premiums. Taxes and premiums are not distinct entities; rather, a spectrum of financing methods exists with varying tax-like and premium-like features. Premium-like financing tends to be voluntary and earmarked for health care, with coverage contingent upon making payments and payments going to private insurance firms. Tax-like financing, in contrast, tends to be mandatory and not earmarked for health care, with coverage not dependent upon making payments and payments going to governments. Over the past century, most industrialized nations have developed highly popular social insurance programs to cover periods of retirement, disability, unemployment, and payment for medical care. Social insurance constitutes a blend of tax-like and premium-like features, offering lessons that might assist in breaking the current impasse over universal health insurance financing.


Osteoprotegerin in bone metastases: mathematical solution to the puzzle.
Bone is a common site for cancer metastasis. To create space for their growth, cancer cells stimulate bone resorbing osteoclasts. Cytokine RANKL is a key osteoclast activator, while osteoprotegerin (OPG) is a RANKL decoy receptor and an inhibitor of osteoclastogenesis. Consistently, systemic application of OPG decreases metastatic tumor burden in bone. However, OPG produced locally by cancer cells was shown to enhance osteolysis and tumor growth. We propose that OPG produced by cancer cells causes a local reduction in RANKL levels, inducing a steeper RANKL gradient away from the tumor and towards the bone tissue, resulting in faster resorption and tumor expansion. We tested this hypothesis using a mathematical model of nonlinear partial differential equations describing the spatial dynamics of OPG, RANKL, PTHrP, osteoclasts, tumor and bone mass. We demonstrate that at lower expression rates, tumor-derived OPG enhances the chemotactic RANKL gradient and osteolysis, whereas at higher expression rates OPG broadly inhibits RANKL and decreases osteolysis and tumor burden. Moreover, tumor expression of a soluble mediator inducing RANKL in the host tissue, such as PTHrP, is important for correct orientation of the RANKL gradient. A meta-analysis of OPG, RANKL and PTHrP expression in normal prostate, carcinoma and metastatic tissues demonstrated an increase in expression of OPG, but not RANKL, in metastatic prostate cancer, and positive correlation between OPG and PTHrP in metastatic prostate cancer. The proposed mechanism highlights the importance of the spatial distribution of receptors, decoys and ligands, and can be applied to other systems involving regulation of spatially anisotropic processes.


T cells recognize minor histocompatibility antigens on H-2 allogeneic cells.
B10.A animals were rendered tolerant to B10.M spleen cells by injection of (B10.A X B10.M)F1 cells into neonates. Adult animals accepted B10.M skin grafts and failed to generate cytotoxic effector cells in vitro against B10.M H-2 antigens. In vivo inoculation of tolerant animals with A.CA spleen cells, followed by in vitro challenge with similar cells, resulted in the generation of cytotoxic effector cells that had specificity for the A strain minor histocompatibility (H)-antigens in the context of the H-2f haplotype. If these animals were boosted in vitro with A strain spleen cells, cross-priming could be demonstrated, whereby the cytotoxic effect was restricted by the H-2a haplotype. These data indicate that at least two sets of T cells co-exist in tolerant animals, one capable of recognizing antigens in the context of the host H-2 haplotype, and the other able to recognize antigens in the context of the tolerated H-2-allogeneic haplotype. Because tolerant animals inoculated with A-strain spleen cells in vivo and boosted in vitro with A.CA spleen cells failed to generate a cytotoxic effect against A.CA, it is unlikely that minor H-antigens need to be processed by host lymphoreticular cells.


A review of the effectiveness of antidepressant medications for depressed nursing home residents.
Antidepressant medications are the most common psychopharmacologic therapy used to treat depressed nursing home (NH) residents. Despite a significant increase in the rate of antidepressant prescribing over the past several decades, little is known about the effectiveness of these agents in the NH population. To conduct a systematic review of the literature to examine and compare the effectiveness of antidepressant medications for treating major depressive symptoms in elderly NH residents. The following databases were searched with searches completed prior to January 2011 and no language restriction: MEDLINE, Embase, PsycINFO, CINHAL, CENTRAL, LILACS, ClinicalTrials.gov, International Standard Randomized Controlled Trial Number Register, and the WHO International Clinical Trial Registry Platform. Additional studies were identified from citations in evidence-based guidelines and reviews as well as book chapters on geriatric depression and pharmacotherapy from several clinical references. Studies were included if they described a clinical trial that assessed the effectiveness of any currently-marketed antidepressant for adults aged 65 years or older, who resided in the NH, and were diagnosed by DSM criteria and/or standardized validated screening instruments with Major Depressive Disorder, minor depression, dysthymic disorder, or Depression in Alzheimer's disease. A total of eleven studies, including four randomized and seven non-randomized open-label trials, met all inclusion and exclusion criteria. It was not feasible to conduct a meta-analysis because the studies were heterogeneous in terms of study design, operational definitions of depression, participant characteristics, pharmacologic interventions, and outcome measures. Of the four randomized trials, two had a control group and did not demonstrate a statistically-significant benefit for antidepressant pharmacotherapy over placebo. While six of the seven non-randomized studies identified a response to an antidepressant, their results must be interpreted with caution as they lacked a comparison group. The limited amount of evidence from randomized and non-randomized open-label trials suggests that depressed NH residents have a modest response to antidepressant medications. Further research using rigorous study designs are needed to examine the effectiveness and safety of antidepressants in depressed NH residents, and to determine the various facility, provider, and patient factors associated with response to treatment.


The provision of compulsory school physical activity: associations with physical activity, fitness and overweight in childhood and twenty years later.
To determine whether the provision of higher levels of compulsory school physical activity is associated with higher physical activity and fitness levels and less overweight in childhood and 20 years later. As part of the 1985 Australian Schools Health and Fitness Survey, 109 schools reported how much compulsory physical education (PE) and school sport they provided and were classified as low (<110 and <150 minutes/week for primary and secondary schools, respectively), medium (110-149 and 150-189 minutes/week for primary and secondary schools, respectively) or high (> or =150 and > or =190 minutes/week for primary and secondary schools, respectively) compulsory physical activity schools by tertile cutpoints. 6,412 children reported frequency and duration of school (PE and sport) and non-school (commuting and non-organised exercise) physical activity and had height and weight measured; overweight was defined using body mass index (BMI) (m/kg2) cutpoints. 9, 12 and 15 year-olds (n = 2,595) completed a cycle ergometer fitness test (physical working capacity at heart rate 170, PWC170). At follow-up in 2004-5, 2,346 participants kept a pedometer record, completed the International Physical Activity Questionnaire and/or a PWC170 fitness test; and had height and weight measured (overweight = BMI> or =25 m/kg2). At baseline and follow-up, median total physical activity, fitness and BMI were similar in participants who attended low, medium and high physical activity schools, and those attending high physical activity schools reported only modestly higher school physical activity. There was no difference in the prevalence of high total physical activity and fitness levels in childhood or adulthood across compulsory school physical activity categories. The prevalence of overweight in childhood and adulthood was similar across low, medium and high compulsory physical activity schools. The amount of compulsory physical activity reported by schools was not associated with total physical activity, fitness or overweight in childhood or in adulthood. Policies promoting amounts of compulsory school physical activity in this range may not be sufficient to increase physical activity and fitness or reduce the prevalence of obesity in children.


Shared attentional resources for global and local motion processing.
One of the most important aspects of visual attention is its flexibility; our attentional "window" can be tuned to different spatial scales, allowing us to perceive large-scale global patterns and local features effortlessly. We investigated whether the perception of global and local motion competes for a common attentional resource. Subjects viewed arrays of individual moving Gabors that group to produce a global motion percept when subjects attended globally. When subjects attended locally, on the other hand, they could identify the direction of individual uncrowded Gabors. Subjects were required to devote their attention toward either scale of motion or divide it between global and local scales. We measured direction discrimination as a function of the validity of a precue, which was varied in opposite directions for global and local motion such that when the precue was valid for global motion, it was invalid for local motion and vice versa. There was a trade-off between global and local motion thresholds, such that increasing the validity of precues at one spatial scale simultaneously reduced thresholds at that spatial scale but increased thresholds at the other spatial scale. In a second experiment, we found a similar pattern of results for static-oriented Gabors: Attending to local orientation information impaired the subjects' ability to perceive globally defined orientation and vice versa. Thresholds were higher for orientation compared to motion, however, suggesting that motion discrimination in the first experiment was not driven by orientation information alone but by motion-specific processing. The results of these experiments demonstrate that a shared attentional resource flexibly moves between different spatial scales and allows for the perception of both local and global image features, whether these features are defined by motion or orientation.


Transmissible mink encephalopathy species barrier effect between ferret and mink: PrP gene and protein analysis.
Experimental infection of transmissible mink encephalopathy (TME) in two closely related mustelids, black ferret (Mustela putorius furo) and mink (Mustela visa), revealed differences in their susceptibility to the TME agent. When challenged with the Stetsonville TME agent, a longer incubation period was observed in ferrets (28 to 38 months) than mink (4 months). Western blot analysis of ferret and mink prion proteins (PrP) demonstrated no detectable differences between the proteins. Northern blot analysis of ferret brain RNA indicated that PrP mRNA abundance is similar in infected and uninfected individuals. We amplified the PrP coding region from ferret DNA using the polymerase chain reaction and compared the deduced amino acid sequence of the ferret PrP gene with the mink PrP gene. This comparison revealed six silent base changes and two amino acid changes between mink and ferret: Phe-->Lys at codon 179 and Arg-->Gln at codon 224, respectively. These changes may indicate the region of PrP that is responsible for the species barrier effect between mink and ferret.


Odorant-induced oscillations in the mushroom bodies of the locust.
Kenyon cells are the intrinsic interneurons of the mushroom bodies in the insect brain, a center for olfactory and multimodal processing and associative learning. These neurons are small (3-8 microns soma diameter) and numerous (340,000 and 400,000 in the bee and cockroach brains, respectively). In Drosophila, Kenyon cells are the dominant site of expression of the dunce, DC0, and rutabaga gene products, enzymes in the cAMP cascade whose absence leads to specific defects in olfactory learning. In honeybees, the volume of the mushroom body neurophils may depend on the age or social status of the individual. Although the anatomy of these neurons has been known for nearly a century, their physiological properties and the principles of information processing in the circuits that they form are totally unknown. This article provides a first such characterization. The activity of Kenyon cells was recorded in vivo from locust brains with intracellular and local field potential electrodes during olfactory processing. Kenyon cells had a high input impedance (approximately 1 G omega at the soma). They produced action potentials upon depolarization, and consistently showed spike adaptation during long depolarizing current pulses. They generally displayed a low resting level of spike activity in the absence of sensory stimulation, despite a large background of spontaneous synaptic activity, and showed no intrinsic bursting behavior. Presentation of an airborne odor, but not air alone, to an antenna evoked spatially coherent field potential oscillations in the ipsilateral mushroom body, with a frequency of approximately 20 Hz. The frequency of these oscillations was independent of the nature of the odorant. Short bouts of oscillations sometimes occurred spontaneously, that is, in the absence of odorant stimulation. Autocorrelograms of the local field potentials in the absence of olfactory stimulation revealed small peaks at +/- 50 msec, suggesting an intrinsic tendency of the mushroom body networks to oscillate at 20 Hz. Such oscillatory behavior could not be seen from local field potential recordings in the antennal lobes, and may thus be generated in the mushroom body, or via feedback interactions with downstream neurons in the protocerebrum. During the odor-induced oscillations, the membrane potential of Kenyon cells oscillated around the resting level, under the influence of excitatory inputs phase-locked to the field activity. Each phasic wave of depolarization in a Kenyon cell could be amplified by intrinsic excitable properties of the dendritic membrane, and sometimes led to one action potential, whose timing was phase-locked to the population oscillations.(ABSTRACT TRUNCATED AT 400 WORDS)


Stimulation of neutrophils by tumor necrosis factor.
Human recombinant tumor necrosis factor (TNF) was shown to be a weak direct stimulus of the neutrophil respiratory burst and degranulation. The stimulation, as measured by iodination, H2O2 production, and lysozyme release, was considerably increased by the presence of unopsonized zymosan in the reaction mixture, an effect which was associated with the increased ingestion of the zymosan. TNF does not act as an opsonin but, rather, reacts with the neutrophil to increase its phagocytic activity. TNF-dependent phagocytosis, as measured indirectly by iodination, is inhibited by monoclonal antibodies (Mab) 60.1 and 60.3, which recognize different epitopes on the C3bi receptor/adherence-promoting surface glycoprotein of neutrophils. Other neutrophil stimulants, namely N-formyl-methionyl-leucyl-phenylalanine, the Ca2+ ionophore A23187, and phorbol myristic acetate, also increase iodination in the presence of zymosan; as with TNF, the effect of these stimulants is inhibited by Mab 60.1 and 60.3, whereas, in contrast to that of TNF, their stimulation of iodination is unaffected by an Mab directed against TNF. TNF may be a natural stimulant of neutrophils which promotes adherence to endothelial cells and to particles, leading to increased phagocytosis, respiratory burst activity, and degranulation.


Ancestral developmental potential facilitates parallel evolution in ants.
Complex worker caste systems have contributed to the evolutionary success of advanced ant societies; however, little is known about the developmental processes underlying their origin and evolution. We combined hormonal manipulation, gene expression, and phylogenetic analyses with field observations to understand how novel worker subcastes evolve. We uncovered an ancestral developmental potential to produce a "supersoldier" subcaste that has been actualized at least two times independently in the hyperdiverse ant genus Pheidole. This potential has been retained and can be environmentally induced throughout the genus. Therefore, the retention and induction of this potential have facilitated the parallel evolution of supersoldiers through a process known as genetic accommodation. The recurrent induction of ancestral developmental potential may facilitate the adaptive and parallel evolution of phenotypes.


Hyperresponsiveness of airway muscle to acetylcholine in asthmatic and non-asthmatic subjects.
Despite a long-standing recognition, the bronchial hyperresponsiveness (BHR) of airway smooth muscle, in asthmatic and non-asthmatic subjects is still under investigation. In order to better understand the mechanism regulating the airway function, some results obtained with cellular physiology techniques are compared, for some non-asthmatic without BHR subjects and other subjects suffering from real bronchial asthma. Eighteen subjects without chronic or acute bronchopathy and seven patients with a typical history of bronchial asthma were considered. All of them were non-smokers, with a wide range of in vivo hyperresponsiveness to Acetylcholine (ACh). Owing to neoplastic lesions, all patients underwent a thoracic surgery. In vitro hyperresponsiveness of airway-smooth-muscle chains was assessed with isotonic contractions to incremental doses of ACh, in accordance with a non-cumulative dose-response technique. Regression between muscle contractions and ACh doses was studied for both groups, and it turned out to be linear in both cases. The slopes and elevations of the regression lines of the two groups were statically identical. There was no correlation between in vivo hyperresponsiveness (as PD20-ACh-FEV1) and in vitro responses (as EC50), for both asthmatic and non-asthmatic group. (i) in vitro, the same BHR of smooth-muscle resulted, for both asthmatic and non-asthmatic subjects, (ii) in vivo, a different BHR of the former group resulted. This can be explained with the peculiarity of the micro-environmental surrounding the bronchial tissue, not with an intrinsic defect of the isolated bronchial tissue.


Soyfood intake during adolescence and subsequent risk of breast cancer among Chinese women.
Many experimental but few epidemiological studies have suggested that soyfoods and their constituents have cancer-inhibitory effects on breast cancer. No epidemiological study has evaluated the association of adolescent soyfood intake with the risk of breast cancer. To evaluate the effect of soyfood intake during adolescence, one of the periods that breast tissue is most sensitive to environmental stimuli, on subsequent risk of breast cancer, we analyzed data from a population-based case-control of 1459 breast cancer cases and 1556 age-matched controls (respective response rates were 91.1% and 90.3%). Information on dietary intake from ages 13-15 years was obtained by interview from all study participants and, in addition, from mothers of subjects less than 45 years of age (296 cases and 359 controls). Odds ratios (ORs) and 95% confidence intervals (CIs) derived from unconditional logistic models were used to measure soyfood intake and breast cancer risk. After adjustment for a variety of other risk factors, adolescent soyfood intake was inversely associated with risk, with ORs of 1.0 (reference), 0.75 (95% CI, 0.60-0.93), 0.69 (95% CI, 0.55-0.87), 0.69 (95% CI, 0.55-0.86), and 0.51 (95% CI, 0.40-0.65), respectively, for the lowest to highest quintiles of total soyfood intake (trend test, P < 0.001). The inverse association was observed for each of the soyfoods examined and existed for both pre- and postmenopausal women. Adolescent soyfood intakes reported by participants' mothers were also inversely associated with breast cancer risk (P for trend < 0.001), with an OR of 0.35 (95% CI, 0.21-0.60) for women in the highest soyfood intake group. Adjustment for rice and wheat products, the major energy source in the study population, and usual adult soyfood intake did not change the soyfood associations. Our study suggests that high soy intake during adolescence may reduce the risk of breast cancer in later life.


Is testosterone treatment good for the prostate? Study of safety during long-term treatment.
For men with androgen deficiency on testosterone replacement therapy (TRT), clinical concern relates to the development of prostate cancer (PCa). An updated audit of prostate safety from the UK Androgen Study was carried out to analyze the incidence of PCa during long-term TRT. Diagnosis of PCa in men receiving TRT, by serum prostate-specific antigen (PSA) testing and digital rectal examination (DRE), and its relation to different testosterone preparations. One thousand three hundred sixty-five men aged 28-87 (mean 55) years with symptomatic androgen deficiency and receiving TRT have been monitored for up to 20 years. All patients were prescreened for PCa by DRE and PSA along with endocrine, biochemical, hematological, and urinary profiles at baseline and every 6 months. Abnormal findings or rising PSA were investigated by transrectal ultrasound and prostate biopsy. The data were compared for the four different testosterone preparations used in TRT, including pellet implants, Restandol, mesterolone, and Testogel. Fourteen new cases of PCa were diagnosed at one case per 212 years treatment, after 2,966 man-years of treatment (one case per 212 years). Time to diagnosis ranged from 1 to 12 years (mean 6.3 years). All tumors were clinically localized and suitable for potentially curative treatment. Initiating testosterone treatment had no statistically significant effect on total PSA, free PSA or free/total PSA ratio, and any initial PSA change had no predictive relationship to subsequent diagnosis of cancer. The incidence of PCa during long-term TRT was equivalent to that expected in the general population. This study adds to the considerable weight of evidence that with proper clinical monitoring, testosterone treatment is safe for the prostate and improves early detection of PCa. Testosterone treatment with regular monitoring of the prostate may be safer for the individual than any alternative without surveillance.


Antibiotic Therapy in Adults with Malaria (ANTHEM): High Rate of Clinically Significant Bacteremia in Hospitalized Adults Diagnosed with Falciparum Malaria.
It has been believed that concomitant bacteremia is uncommon in adults hospitalized with falciparum malaria. Accordingly, the World Health Organization treatment guidelines presently only recommended additional antibacterial therapy in these patients if they have a clinical syndrome compatible with serious bacterial infection. Admission blood cultures were collected from 20 consecutive adults in Myanmar, hospitalized with a positive immunochromatographic test and blood film, suggesting a diagnosis of falciparum malaria; four (20%) had bacteremia with a clinically significant pathogen. These case series' data were pooled with a previously published multicenter study from Myanmar which had also collected blood cultures in adults hospitalized with a diagnosis of falciparum malaria. Among 87 patients in the two studies, 13 (15%) had clinically significant bacteremia on admission, with Gram-negative organisms in 10 (77%) and Staphylococcus aureus in the remaining three (23%). Bacteremic patients had more severe disease than non-bacteremic patients (median [interquartile range] respiratory coma acidosis malaria score 2 [1-4] versus 1 [1-2], P = 0.02) and were more likely to die (2/13 [15%] versus 1/74 [1%], P = 0.01). However, bacterial coinfection was suspected clinically in a minority of bacteremic patients (5/13 [38%] compared with 13/70 [19%] of non-bacteremic patients, P = 0.11). Concomitant bacteremia in adults diagnosed with falciparum malaria may be more common than previously believed and is difficult to identify clinically in resource-poor settings. Death is more common in these patients, suggesting that clinicians should have a lower threshold for commencing empirical antibacterial therapy in adults diagnosed with falciparum malaria in these locations than is presently recommended.


The virtue matrix. Calculating the return on corporate responsibility.
Executives who want to make their organizations better corporate citizens face many obstacles: If they undertake costly initiatives that their rivals don't embrace, they risk eroding their company's competitive position. If they invite government oversight, they may be hampered by costly regulations. And if they adopt wage scales and working conditions that prevail in the wealthiest democracies, they may drive jobs to countries with less stringent standards. Such dilemmas call for clear, hard thinking. To aid in that undertaking, Roger Martin introduces the virtue matrix--a tool to help executives analyze corporate responsibility by viewing it as a product or service. The author uses real-life examples to explore the forms and degrees of corporate virtue. He cites Aaron Feuerstein, CEO of Malden Mills, a textile company whose plant was destroyed by fire in 1995. Rather than move operations to a lower-wage region, Feuerstein continued to pay his idled workforce and rebuilt the plant. Unlike the typical CEO of a publicly held corporation, who is accountable to hundreds or thousands of shareholders, Feuerstein was free to act so generously because he had only a few family members to answer to. But as Martin points out, corporations don't operate in a universe composed solely of shareholders. They can be subject to pressure from citizens, employees, and political authorities. The virtue matrix provides a way to assess these forces and how they interact. Martin uses it to examine why the public clamor for more responsible corporate conduct never seems to abate. Another issue the author confronts is anxiety over globalization. Finally, Martin applies the virtue matrix to two crucial questions: What are the barriers to increasing the supply of corporate virtue? And what can companies do to remove those barriers?


Improvement in Outcomes After Cardiac Arrest and Resuscitation by Inhibition of S-Nitrosoglutathione Reductase.
The biological effects of nitric oxide are mediated via protein S-nitrosylation. Levels of S-nitrosylated protein are controlled in part by the denitrosylase, S-nitrosoglutathione reductase (GSNOR). The objective of this study was to examine whether GSNOR inhibition improves outcomes after cardiac arrest and cardiopulmonary resuscitation (CA/CPR). Adult wild-type C57BL/6 and GSNOR-deleted (GSNOR-/-) mice were subjected to potassium chloride-induced CA and subsequently resuscitated. Fifteen minutes after a return of spontaneous circulation, wild-type mice were randomized to receive the GSNOR inhibitor, SPL-334.1, or normal saline as placebo. Mortality, neurological outcome, GSNOR activity, and levels of S-nitrosylated proteins were evaluated. Plasma GSNOR activity was measured in plasma samples obtained from post-CA patients, preoperative cardiac surgery patients, and healthy volunteers. GSNOR activity was increased in plasma and multiple organs of mice, including brain in particular. Levels of protein S-nitrosylation were decreased in the brain 6 hours after CA/CPR. Administration of SPL-334.1 attenuated the increase in GSNOR activity in brain, heart, liver, spleen, and plasma, and restored S-nitrosylated protein levels in the brain. Inhibition of GSNOR attenuated ischemic brain injury and improved survival in wild-type mice after CA/CPR (81.8% in SPL-334.1 versus 36.4% in placebo; log rank P=0.031). Similarly, GSNOR deletion prevented the reduction in the number of S-nitrosylated proteins in the brain, mitigated brain injury, and improved neurological recovery and survival after CA/CPR. Both GSNOR inhibition and deletion attenuated CA/CPR-induced disruption of blood brain barrier. Post-CA patients had higher plasma GSNOR activity than did preoperative cardiac surgery patients or healthy volunteers ( P<0.0001). Plasma GSNOR activity was positively correlated with initial lactate levels in postarrest patients (Spearman correlation coefficient=0.48; P=0.045). CA and CPR activated GSNOR and reduced the number of S-nitrosylated proteins in the brain. Pharmacological inhibition or genetic deletion of GSNOR prevented ischemic brain injury and improved survival rates by restoring S-nitrosylated protein levels in the brain after CA/CPR in mice. Our observations suggest that GSNOR is a novel biomarker of postarrest brain injury as well as a molecular target to improve outcomes after CA.


Dynamic analysis of the righting reflex in toads; recovery after hemilabyrinthectomy.
Static and dynamic measurements of the righting reflex were performed in intact toads (Bufo arenarum platensis) and at different stages of recovery from hemilabyrinthectomy. Reflex activity was evaluated by the toad's capacity to maintain a horizontal head position while rolled sideways. Static data were obtained from frontal photographs. In dynamic experiments platform position (stimulus) was measured through a potentiometer, while a linear accelerometer glued to the cranium was used to record head tilts. The dynamic study included a linear systems analysis using sinusoids of 0.5-3 Hz with rolls of up to 30° to each side. Hemilabyrinthectomy produced a head tilt towards the lesioned side, and gain decay and phase lag increase in the dynamic response. All postural defects recovered progressively within 30-60 days as already described in other species. Nevertheless, the tonic head deviation produced by dynamic stimuli of frequencies above 1 Hz did not recover. This remnant defect has not been observed in previous studies in which only static observations were performed. The involvement of a frequency-dependent rectifying mechanism in postural compensation is discussed.


Ocean acidification as a driver of community simplification via the collapse of higher-order and rise of lower-order consumers.
Increasing oceanic uptake of CO2 is predicted to drive ecological change as both a resource (i.e. CO2 enrichment on primary producers) and stressor (i.e. lower pH on consumers). We use the natural ecological complexity of a CO2 vent (i.e. a seagrass system) to assess the potential validity of conceptual models developed from laboratory and mesocosm research. Our observations suggest that the stressor-effect of CO2 enrichment combined with its resource-effect drives simplified food web structure of lower trophic diversity and shorter length. The transfer of CO2 enrichment from plants to herbivores through consumption (apparent resource-effect) was not compensated by predation, because carnivores failed to contain herbivore outbreaks. Instead, these higher-order consumers collapsed (apparent stressor-effect on carnivores) suggesting limited trophic propagation to predator populations. The dominance of primary producers and their lower-order consumers along with the loss of carnivores reflects the duality of intensifying ocean acidification acting both as resource-effect (i.e. bottom-up control) and stressor-effect (i.e. top-down control) to simplify community and trophic structure and function. This shifting balance between the propagation of resource enrichment and its consumption across trophic levels provides new insights into how the trophic dynamics might stabilize against or propagate future environmental change.


The effect of feedback delay and feedback type on perceptual category learning: the limits of multiple systems.
Evidence that learning rule-based (RB) and information-integration (II) category structures can be dissociated across different experimental variables has been used to support the view that such learning is supported by multiple learning systems. Across 4 experiments, we examined the effects of 2 variables, the delay between response and feedback and the informativeness of feedback, which had previously been shown to dissociate learning of the 2 types of category structure. Our aim was twofold: first, to determine whether these dissociations meet the more stringent inferential criteria of state-trace analysis and, second, to determine the conditions under which they can be observed. Experiment 1 confirmed that a mask-filled feedback delay dissociated the learning of RB and II category structures with minimally informative (yes/no) feedback and also met the state-trace criteria for the involvement of multiple latent variables. Experiment 2 showed that this effect is eliminated when a less similar, fixed pattern mask is presented in the interval between response and feedback. Experiment 3 showed that the selective effect of feedback delay on II learning is reduced with fully informative feedback (in which the correct category is specified after an incorrect response) and that feedback type did not dissociate RB and II learning. Experiment 4 extended the results of Experiment 2, showing that the differential effect of feedback delay is eliminated when a fixed pattern mask is used. These results pose important challenges to models of category learning, and we discuss their implications for multiple learning system models and their alternatives.


Elastocapillary deformation of thin elastic ribbons in 2D foam columns.
The ability of liquid interfaces to shape slender elastic structures provides powerful strategies to control the architecture of mechanical self assemblies. However, elastocapillarity-driven intelligent design remains unexplored in more complex architected liquids - such as foams. Here we propose a model system which combines an assembly of bubbles and a slender elastic structure. Arrangements of soap bubbles in confined environments form well-defined periodic structures, dictated by Plateau's laws. We consider a 2D foam column formed in a container with square cross-section in which we introduce an elastomer ribbon, leading to architected structures whose geometry is guided by a competition between elasticity and capillarity. In this system, we quantify both experimentally and theoretically the equilibrium shapes, using X-ray micro-tomography and energy minimisation techniques. Beyond the understanding of the amplitude of the wavy elastic ribbon deformation, we provide a detailed analysis of the profile of the ribbon, and show that such a setup can be used to grant a shape to a UV-curable composite slender structure, as a foam-forming technique suitable to miniaturisation. In more general terms, this work provides a stepping stone towards an improved understanding of the interactions between liquid foams and slender structures.


Apparent power-law behavior of water's isothermal compressibility and correlation length upon supercooling.
The isothermal compressibility and correlation length of supercooled water obtained from small-angle X-ray scattering (SAXS) were analyzed by fits based on an apparent power-law in the temperature range from 280 K down to the temperature of maximum compressibility at 229 K. Although the increase in thermodynamic response functions is not towards a critical point, it is still possible to obtain an apparent power law all the way to the maximum values with best-fit exponents of γ = 0.40 ± 0.01 for the isothermal compressibility and ν = 0.26 ± 0.03 for the correlation length. The ratio between these exponents is close to a value of ≈0.5, as expected for a critical point, indicating the proximity of a potential second critical point. Comparison of γ obtained from experiment with molecular dynamics simulations on the iAMOEBA water model shows that it would be located at pressures in the neighborhood of 1 kbar. The high value and sharpness of the compressibility maximum observed in the experiment are not reproduced by any of the existing classical water models, thus inviting further development of simulation models of water.


Sustained elevation of serum cortisol level causes sensitization of coronary vasoconstricting responses in pigs in vivo: a possible link between stress and coronary vasospasm.
Vasospastic angina is induced by stress, for which cortisol secreted by activated hypothalamic/pituitary/adrenal axis may play an important role. However, direct evidence for this notion is still lacking. In this study, we examined whether sustained elevation of serum cortisol level sensitizes coronary vasoconstricting responses in pigs in vivo and, if so, whether Rho-kinase, which we found is a key molecule of coronary vasospasm, is involved. Oral administration of cortisol (20 mg/kg per day) increased its serum level to that seen in restraint stress in pigs. Thus, we examined coronary vasomotor responses in the following 4 groups: (1) control (without cortisol); (2) cortisol (20 mg/kg per day, p.o.) for 9 days; (3) cortisol plus RU38486 (a glucocorticoids receptor antagonist, 10 mg/kg per day, p.o.) for 9 days; and (4) cortisol for 9 days followed by 6-week withdrawal. Coronary angiography showed that intracoronary serotonin caused coronary hyperconstriction and reduction in coronary blood flow associated with ischemic ECG changes (coronary vasospasm) in only the cortisol group. All of these responses were abolished by hydroxyfasudil, a specific Rho-kinase inhibitor, in vivo. Organ chamber experiments demonstrated that serotonin concentration-dependently caused hypercontractions of coronary vascular smooth muscle associated with Rho-kinase activation (as evidenced by the enhanced phosphorylation of myosin binding subunit, a substrate of Rho-kinase) in only the cortisol group. All of these responses were again inhibited by hydroxyfasudil in vitro. These results indicate that sustained elevation of serum cortisol level sensitizes coronary vasoconstricting responses through Rho-kinase activation, suggesting the link between stress and coronary vasospasm.


Intraoperative radiotherapy for recurrent and/or residual colorectal cancer.
Intraoperative radiotherapy (IORT) is an attractive boosting modality in the combined treatment of recurrent and/or residual colorectal cancer. Twenty seven patients treated with IORT are analysed. Residual disease following resection of the primary tumor was treated in 11 cases (group I). Localized recurrent disease without previous radiotherapy was treated in 11 cases (group II). IORT was used in five additional patients with local recurrences in previously irradiated areas (group III). The treatment program consisted of maximal tumor resection, IORT (10-30 Gy) to the area of residual disease and external beam radiotherapy (46-50 Gy). The median follow-up time for the entire series of patients is 11 months. Local tumor control rates are 90% in group I, 63% in group II and 60% in group III. Toxicity and complications related to IORT observed in this initial experience have been pelvic pain (29%) and lower extremity neuropathy (3%). These early clinical results suggest that the IORT combined with surgery and external beam radiotherapy is feasible in primary and recurrent disease. Local control rates obtained in patients not suitable for curative surgery are encouraging.


Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia.
Although manganese is an essential trace metal, little is known about its transport and homeostatic regulation. Here we have identified a cohort of patients with a novel autosomal recessive manganese transporter defect caused by mutations in SLC39A14. Excessive accumulation of manganese in these patients results in rapidly progressive childhood-onset parkinsonism-dystonia with distinctive brain magnetic resonance imaging appearances and neurodegenerative features on post-mortem examination. We show that mutations in SLC39A14 impair manganese transport in vitro and lead to manganese dyshomeostasis and altered locomotor activity in zebrafish with CRISPR-induced slc39a14 null mutations. Chelation with disodium calcium edetate lowers blood manganese levels in patients and can lead to striking clinical improvement. Our results demonstrate that SLC39A14 functions as a pivotal manganese transporter in vertebrates.


Beta adrenergic receptor response coupling in hypertrophied hearts.
Reports in the literature have indicated that inotropic responsiveness to isoproterenol (ISO) of hypertrophied rat myocardium is decreased. We have studied possible biochemical mechanisms to explain this. Adenylate cyclase activity in myocardial membranes from 13-week-old spontaneously hypertensive rats (SHR) was unchanged compared to enzyme activity in Wystar-Kyoto (WKY) when measured under basal conditions or following NaF, a guanosine triphosphate analog, MnCl2, or forskolin stimulation. However, ISO-stimulated cyclase activity was decreased as were beta-adrenergic receptor density with no change in receptor affinity. On the other hand, hearts from two-kidney, one clip renal hypertensive rats 6 weeks after initiation of hypertension showed decreased basal, ISO, NaF, and GTP analog-stimulated cyclase activity with no change in Mn++ or forskolin-stimulated activity. In this model, receptor density increased. When the clipped kidney was removed, these changes returned toward normal as did the blood pressure and heart weight. We interpret these data to indicate that in SHR the biochemical defect leading to decreased inotropic responsiveness of hypertrophied hearts is due to decreased beta-adrenergic receptor density, leading to decreased ISO-stimulated cyclase activity. The nucleotide regulatory protein component (N) and the catalytic subunit (C) are not changed. In the renal hypertensive rat, on the other hand, although the C is unchanged, there is a decrease in the activity of N, and this is probably the primary reason why inotropic responsiveness to ISO is decreased. Increases in receptor density seen in this model may possibly be compensatory.


Towards a rigorous understanding of societal responses to climate change.
A large scholarship currently holds that before the onset of anthropogenic global warming, natural climatic changes long provoked subsistence crises and, occasionally, civilizational collapses among human societies. This scholarship, which we term the 'history of climate and society' (HCS), is pursued by researchers from a wide range of disciplines, including archaeologists, economists, geneticists, geographers, historians, linguists and palaeoclimatologists. We argue that, despite the wide interest in HCS, the field suffers from numerous biases, and often does not account for the local effects and spatiotemporal heterogeneity of past climate changes or the challenges of interpreting historical sources. Here we propose an interdisciplinary framework for uncovering climate-society interactions that emphasizes the mechanics by which climate change has influenced human history, and the uncertainties inherent in discerning that influence across different spatiotemporal scales. Although we acknowledge that climate change has sometimes had destructive effects on past societies, the application of our framework to numerous case studies uncovers five pathways by which populations survived-and often thrived-in the face of climatic pressures.


The Virginia Slims identity crisis: an inside look at tobacco industry marketing to women.
Because no prior studies have comprehensively analysed previously secret tobacco industry documents describing marketing female brands, the Virginia Slims brand was studied to explore how Philip Morris and competitors develop and adapt promotional campaigns targeting women. Analysis of previously secret tobacco industry documents. The majority of the documents used were from Philip Morris. The key to Virginia Slims advertising was creating an aspirational image which women associated with the brand. Virginia Slims co-opted women's liberation slogans to build a modern female image from 1968 through to the 1980s, and its market share grew from 0.24% to 3.16% during that time period. Ironically, the feminist image that worked very well for the brand was also the reason for its subsequent problems. Philip Morris experienced unprecedented losses in market share in the early 1990s, with a decline in market share for four consecutive years from 3.16% to 2.26%; they attributed this decline to both the fact that the brand's feminist image no longer appealed to young women aged 18-24 years, and increased competition from more contemporary and lower priced competitors. Throughout the 1990s, attempts to reacquire young women while retaining Virginia Slims loyal (now older) smokers were made using a "King Size" line extension, new slogans, and loyalty building promotions. Tobacco advertisers initially created distinct female brands with aspirational images; continued appeal to young women was critical for long term growth. The need for established brands to evolve to maintain relevance to young women creates an opportunity for tobacco counter-marketing, which should undermine tobacco brand imagery and promote aspirational smoke-free lifestyle images. Young women age 18-24 are extremely valuable to the tobacco industry and should be a focus for tobacco control programmes.


Elbow septic arthritis in an infant: an unusual presentation of invasive pneumococcal disease.
Acute septic arthritis is a rare, potentially severe infection that requires immediate treatment to avoid long-term morbidity. Most common aetiological agents are commonly used for empirical treatment, but the choice of antibiotics may be influenced by other factors, such as the patient's age and the epidemiological context.We report an infant with elbow arthritis, whose treatment was changed after Streptococcus pneumoniae serotype 9N was isolated in the blood and synovial fluid. The child underwent arthrocentesis and received intravenous ampicillin followed by oral amoxicillin, with a favourable response and no sequelae at 1-year follow-up.We report an uncommon manifestation of invasive pneumococcal disease in a young immunised healthy infant caused by a non-vaccine serotype. The presence of S. pneumoniae should be considered in joint infections, especially in infants and those with a history of respiratory symptoms.


The effect of HMGA1 in LPS-induced Myocardial Inflammation.
Aims: The High Mobility Group A1 (HMGA1) proteins, serving as a dynamic regulator of gene transcription and chromatin remodeling, play an influential part in the pathological process of a large number of cardiovascular diseases. However, the precise role of HMGA1 in sepsis induced cardiomyopathy (SIC) remains unintelligible. This research was designed to illustrate the effect of HMGA1 involved in SIC. Methods and Results: Cardiomyocyte-specific HMGA1 overexpression was obtained using an adeno-associated virus system with intramyocardial injection in mice heart. The model of SIC in mice was constructed via intraperitoneal injection of lipopolysaccharide (LPS) for 6h. H9c2 rat cardiomyocytes was stimulated with LPS for 12h. HMGA1 expression was upregulated in murine inflammatory hearts as well as LPS stimulated H9c2 cardiomyocytes. HMGA1-overexpressing exhibited aggravated cardiac dysfunction, cardiac inflammation as well as cells apoptosis following LPS treatment both in vivo and in vitro experiment. Interestingly, HMGA1 knockdown in H9c2 cardiomyocytes attenuated LPS-induced cardiomyocyte inflammation, but aggravated cell apoptosis. Mechanistically, we found that overexpression of HMGA1 induced increased expression of cyclooxygenase-2 (COX-2). COX-2 inhibitor alleviated the aggravation of inflammation and apoptosis in HMGA1 overexpressed H9c2 cardiomyocytes whereas HMGA1 knockdown induced a reduction in signal transducer and activators of transcription 3 (STAT3) expression. STAT3 agonist reversed HMGA1 silence induced anti-inflammatory effects, while ameliorated cell apoptosis induced by LPS. Conclusion: In conclusion, our results suggest that overexpression of HMGA1 aggravated cardiomyocytes inflammation and apoptosis by up-regulating COX-2 expression, while silence of HMGA1 expression attenuated inflammation but aggregated cell apoptosis via down-regulation of STAT3.


Differential localization of GABA(A) receptor subunits in relation to rat striatopallidal and pallidopallidal synapses.
As a central integrator of basal ganglia function, the external segment of the globus pallidus (GP) plays a critical role in the control of voluntary movement. The GP is composed of a network of inhibitory GABA-containing projection neurons which receive GABAergic input from axons of the striatum (Str) and local collaterals of GP neurons. Here, using electrophysiological techniques and immunofluorescent labeling we have investigated the differential cellular distribution of α1, α2 and α3 GABA(A) receptor subunits in relation to striatopallidal (Str-GP) and pallidopallidal (GP-GP) synapses. Electrophysiological investigations showed that zolpidem (100 nm; selective for the α1 subunit) increased the amplitude and the decay time of both Str-GP and GP-GP IPSCs, indicating the presence of the α1 subunits at both synapses. However, the application of drugs selective for the α2, α3 and α5 subunits (zolpidem at 400 nm, L-838,417 and TP003) revealed differential effects on amplitude and decay time of IPSCs, suggesting the nonuniform distribution of non-α1 subunits. Immunofluorescence revealed widespread distribution of the α1 subunit at both soma and dendrites, while double- and triple-immunofluorescent labeling for parvalbumin, enkephalin, gephyrin and the γ2 subunit indicated strong immunoreactivity for GABA(A) α3 subunits in perisomatic synapses, a region mainly targeted by local axon collaterals. In contrast, immunoreactivity for synaptic GABA(A) α2 subunits was observed in dendritic compartments where striatal synapses are preferentially located. Due to the kinetic properties which each GABA(A) α subunit confers, this distribution is likely to contribute differentially to both physiological and pathological patterns of activity.


Psychiatric consequences of road traffic accidents.
To determine the psychiatric consequences of being a road traffic accident victim. Follow up study of road accident victims for up to one year. Emergency department of the John Radcliffe Hospital, Oxford. 188 consecutive road accident victims aged 18-70 with multiple injuries (motorcycle or car) or whiplash neck injury, who had not been unconscious for more than 15 minutes, and who lived in the catchment area. Present state examination "caseness"; post-traumatic stress disorder and travel anxiety; effects on driving and on being a passenger. Acute, moderately severe emotional distress was common. Almost one fifth of subjects, however, suffered from an acute stress syndrome characterised by mood disturbance and horrific memories of the accident. Anxiety and depression usually improved over the 12 months, though one tenth of patients had mood disorders at one year. In addition, specific post-traumatic symptoms were common. Post-traumatic stress disorder occurred during follow up in one tenth of patients, and phobic travel anxiety as a driver or passenger was more common and frequently disabling. Emotional disorder was associated with having pre-accident psychological or social problems and, in patients with multiple injuries, continuing medical complications. Post-traumatic syndromes were not associated with a neurotic predisposition but were strongly associated with horrific memories of the accident. They did not occur in subjects who had been briefly unconscious and were amnesic for the accident. Mental state at three months was highly predictive of mental state at one year. Psychiatric symptoms and disorder are frequent after major and less severe road accident injury. Post-traumatic symptoms are common and disabling. Early information and advice might reduce psychological distress and travel anxiety and contribute to road safety and assessing "nervous shock."


Hydrogeological characterization of an alpine aquifer system in the Canadian Rocky Mountains.
Groundwater storage in alpine regions is essential for maintaining baseflows in mountain streams. Recent studies have shown that common alpine landforms (e.g., talus and moraine) have substantial groundwater storage capacity, but the hydrogeological connectivity between individual landforms has not been understood. This study characterizes the hydrogeology of an alpine cirque basin in the Canadian Rocky Mountains that contains typical alpine landforms (talus, meadow, moraines) and hydrological features (tarn, streams, and springs). Geological, hydrological, and hydrochemical observations were used to understand the overall hydrogeological setting of the study basin, and three different geophysical methods (electrical resistivity tomography, seismic refraction tomography, and ground penetrating radar) were used to characterize the subsurface structure and connectivity, and to develop a hydrogeological conceptual model. Geophysical imaging shows that the talus is typically 20-40 m thick and highly heterogeneous. The meadow sediments are only up to 11 m thick but are part of a 30-40-m-thick accumulation of unconsolidated material that fills a bedrock overdeepening (i.e. a closed, subglacial basin). A minor, shallow groundwater system feeds springs on the talus and streams on the meadow, whereas a deep system in the moraine supplies most of the water to the basin outlet springs, thereby serving as a 'gate keeper' of the basin. Although the hydrologic functions of the talus in this study are substantially different from other locations, primarily due to differences in bedrock lithology and geomorphic processes, the general conceptual framework developed in this study is expected to be applicable to other alpine regions.


Understanding medical student evidence-based medicine information seeking in an authentic clinical simulation.
Evidence-based medicine practices of medical students in clinical scenarios are not well understood. Optimal foraging theory (OFT) is one framework that could be useful in breaking apart information-seeking patterns to determine effectiveness and efficiency of different methods of information seeking. The aims of this study were to use OFT to determine the number and type of resources used in information seeking when medical students answer a clinical question, to describe common information-seeking patterns, and identify patterns associated with higher quality answers to a clinical question. Medical students were observed via screen recordings while they sought evidence related to a clinical question and provided a written response for what they would do for that patient based on the evidence that they found. Half (51%) of study participants used only 1 source before answering the clinical question. While the participants were able to successfully and efficiently navigate point-of-care tools and search engines, searching PubMed was not favored, with only half (48%) of PubMed searches being successful. There were no associations between information-seeking patterns and the quality of answers to the clinical question. Clinically experienced medical students most frequently relied on point-of-care tools alone or in combination with PubMed to answer a clinical question. OFT can be used as a framework to understand the information-seeking practices of medical students in clinical scenarios. This has implications for both teaching and assessment of evidence-based medicine in medical students.


Rationale and Design of a Clinical Trial Investigating Tolvaptan Safety and Efficacy in Autosomal Dominant Polycystic Kidney Disease.
In TEMPO 3:4, the vasopressin V2-receptor antagonist tolvaptan slowed kidney growth and function decline in autosomal dominant polycystic kidney disease (ADPKD) patients with relatively preserved kidney function. Prospective, phase 3b, multi-center, randomized-withdrawal, placebo-controlled, double-blind trial of tolvaptan in ADPKD patients with late stage 2 to early stage 4 chronic kidney disease (CKD). The primary endpoint was estimated glomerular filtration rate (eGFR) change from pre-treatment baseline to post-treatment follow-up. Secondary endpoints included annualized eGFR slope, incidence of ADPKD complications, and overall and hepatic safety profiles. Participants were 18-55 year-old ADPKD patients with baseline eGFR ≥25 and ≤65 mL/min/1.73 m2 or 56-65 year-old with eGFR ≥25 and ≤44 mL/min/1.73 m2 and evidence of eGFR decline >2.0 mL/min/1.73 m2 per year. Daily split doses of tolvaptan were titrated to tolerance (30/15, 45/15, 60/30, or 90/30 mg) and maintained for 12 months, after an 8-week pre-randomization period to screen out subjects unable to tolerate at least 60/30 mg for 3 weeks. Of 1,495 subjects who entered the tolvaptan titration period, 125 (8.4%) discontinued the study before randomization. One thousand three hundred seventy subjects (684 tolvaptan, 686 placebo) from 213 centers across 21 countries were randomized. Baseline demographics were well balanced across treatment arms. Information collected during the study included eGFR, survey scores (PKD history and outcome), adverse events, vital signs, hematology, urinalysis, and serum chemistry tests. Replicating Evidence of Preserved Renal Function: An Investigation of Tolvaptan Safety and Efficacy (REPRISE) determines whether tolvaptan administered over 1 year exhibits disease-modifying properties in ADPKD patients with late stage 2 to early stage 4 CKD, which provides an important therapeutic advancement for this difficult-to-treat disease.


The glycosylphosphatidylinositol (GPI) signal sequence of human placental alkaline phosphatase is not recognized by human Gpi8p in the context of the yeast GPI anchoring machinery.
Biosynthesis of glycosylphosphatidylinositol (GPI)-anchored proteins involves the action of a GPI trans-amidase, which replaces the C-terminal GPI signal sequence (GPI-SS) of the primary translation product with a preformed GPI lipid. The transamidation depends on a complex of four proteins, Gaa1p, Gpi8p, Gpi16p and Gpi17p. Although the GPI anchoring pathway is conserved throughout the eukaryotic kingdom, it has been reported recently that the GPI-SS of human placental alkaline phosphatase (hPLAP) is not recognized by the yeast transamidase, but is recognized in yeast that contain the human Gpi8p homologue. This finding suggests that Gpi8p is intimately involved in the recognition of GPI precursor proteins and may also be responsible for the subtle taxon-specific differences in transamidase specificity that sometimes prevent the efficient GPI anchoring of heterologously expressed GPI proteins. Here, we confirm that the GPI signal sequence of hPLAP is indeed not recognized by the yeast GPI-anchoring machinery. However, in our hands, GPI attachment cannot be restored by the co-expression of human Gpi8p in yeast cells under any circumstances.


Urinary 1-hydroxypyrene and Skin Contamination in Firefighters Deployed to the Fort McMurray Fire.
In May 2016, firefighters from the province of Alberta, Canada deployed to a fire that engulfed the urban area of Fort McMurray. During the first days of the fire, firefighters experienced heavy smoke exposures during greatly extended work shifts. Urinary samples were collected post-deployment from three fire services for estimation of 1-hydroxypyrene (1-HP) concentration, reflecting exposure to polycyclic aromatic hydrocarbons (PAHs), to determine the effects of respiratory protective equipment (RPE) and skin hygiene in reducing internal dose. Urine samples from one fire service (n = 62) were analyzed for 1-HP by two laboratories, using different assays (LC-MS/MS: GC-MS): remaining samples were analyzed just by LC-MS/MS. A Skin Exposure Mitigation Index (SEMI) was computed from questions on opportunities for changing clothing, showering, and washing during breaks. Regression analyses, using 1-HP ng/g creatinine as the dependent variable, assessed the effect of RPE and skin factors on PAH absorption, allowing for environmental exposure and potential confounders. Stratification identified key groups with equal delay in sample collection. 1-HP was detected in 71.0% of 62 samples by LC-MS/MS and 98.4% by GC-MS, with good mutual agreement between the methods. In 171 post-fire samples, 1-HP corrected for creatinine was related to current cigarette smoking and recent barbeque. Among those with samples collected within 48 h, urinary 1-HP was correlated with estimated exposure(r = 0.53, P < 0.001). In those with only one rotation before urine sample collection, no effect was seen of RPE use but I-HP was significantly lower (P = 0.003) in those with those with a high score on the SEMI scale, indicating better access to factors mitigating skin absorption. Skin exposure to PAHs is an important route of absorption in firefighters, which can be mitigated by good skin hygiene.


Automatic patient registration for port placement in minimally invasive endoscopic surgery.
Optimal port placement is a delicate issue in minimally invasive endoscopic surgery, particularly in robotically assisted surgery. A good choice of the instruments' and endoscope's ports can avoid time-consuming consecutive new port placement. We present a novel method to intuitively and precisely plan the port placement. The patient is registered to its pre-operative CT by just moving the endoscope around fiducials, which are attached to the patient's thorax and are visible in its CT. Their 3D positions are automatically reconstructed. Without prior time-consuming segmentation, the pre-operative CT volume is directly rendered with respect to the endoscope or instruments. This enables the simulation of a camera flight through the patient's interior along the instruments' axes to easily validate possible ports.


Screen-detected and interval colorectal cancers in England: Associations with lifestyle and other factors in women in a large UK prospective cohort.
Faecal occult blood (FOB) - based screening programmes for colorectal cancer detect about half of all cancers. Little is known about individual health behavioural characteristics which may be associated with screen-detected and interval cancers. Electronic linkage between the UK National Health Service Bowel Cancer Screening Programme (BCSP) in England, cancer registration and other national health records, and a large on-going UK cohort, the Million Women Study, provided data on 628,976 women screened using a guaiac-FOB test (gFOBt) between 2006 and 2012. Relative risks (RRs) and 95% confidence intervals (CIs) were estimated by logistic and Cox regression for associations between individual lifestyle factors and risk of colorectal tumours. Among screened women, 766 were diagnosed with screen-detected colorectal cancer registered within 2 years after a positive gFOBt result, and 749 with interval colorectal cancers registered within 2 years after a negative gFOBt result. Current smoking was significantly associated with risk of interval cancer (RR 1.64, 95%CI 1.35-1.99) but not with risk of screen-detected cancer (RR 1.03, 0.84-1.28), and was the only factor of eight examined to show a significant difference in risk between interval and screen-detected cancers (p for difference, 0.003). Compared to screen-detected cancers, interval cancers tended to be sited in the proximal colon or rectum, to be of non-adenocarcinoma morphology, and to be of higher stage.


A real-time RT-PCR for rapid detection and quantification of mosquito-borne alphaviruses.
Mosquito-borne alphaviruses are widely distributed throughout the world, causing important human illnesses. Therefore, the development of methods to enable early diagnosis of infections by alphavirus is essential. We show here the development and evaluation of a quantitative real-time RT-PCR using genus-specific primers to the nsP1 viral gene of all mosquito-borne alphaviruses. The specificity and sensitivity of the assay were tested using seven alphaviruses and RNA transcribed from Venezuelan equine encephalitis virus. The detection limits of real-time RT-PCR ranged from 10 to 76 copies per ml. The melting temperature (TM) values for amplification of the alphavirus genomes were 83.05 °C and 85.28 °C. Interestingly, the assay suggested the possibility the arthritogenic alphaviruses with TM peaks of 84.83 to 85.28 °C and encephalitic alphaviruses of 83.34 °C to 84.68 °C could be discriminated both diseases. Real-time RT-PCR may prove very useful for the screening and preliminary diagnosis in outbreaks and surveillance studies as well as for measuring the viral load in pathogenesis studies.


The medial nucleus of the trapezoid body in the gerbil is more than a relay: comparison of pre- and postsynaptic activity.
The medial nucleus of the trapezoid body (MNTB) plays an important role in the processing of interaural intensity differences, a feature that is critical for the localization of sound sources. It is generally believed that the MNTB functions primarily as a passive relay in converting excitatory input originating from the contralateral cochlear nucleus (CN) into an inhibitory input to the ipsilateral lateral superior olive. However, studies showing that the MNTB itself is also the target of inhibitory input suggest that the MNTB may serve more than a sign-converting function. To examine the fidelity of signal transmission at the CN-MNTB synapse, presynaptic calyceal potentials ("prepotentials"), reflecting the excitatory input to the MNTB neuron, and postsynaptic action potentials were simultaneously monitored with the same electrode during in vivo extracellular recordings from the gerbil's MNTB. Presynaptic activity differed from postsynaptic activity in several respects: (1) Spontaneous and sound-evoked discharge rates were greater presynaptically than postsynaptically. (2) Frequency tuning was sharper postsynaptically than presynaptically. (3) Calyceal terminals and MNTB neurons both showed phasic-tonic response patterns to tonal stimulation, but the duration of the onset response and the level of the tonic component were reduced postsynaptically. (4) Phase-locking to sound frequencies up to 1 kHz was greater postsynaptically than presynaptically. (5) The rate-intensity characteristics of pre- and postsynaptic activities differed significantly from each other in half of the MNTB neurons. To test the hypothesis that acoustically evoked inhibition of MNTB neurons contributed to the relatively lower levels of postsynaptic discharge, two-tone stimulation was applied, wherein the response to one tone-burst, set at the neuron's characteristic frequency, can be reduced by addition of a second "inhibitory" tone. The inhibitory tone caused a much larger reduction in post- than in presynaptic activity, indicating an acoustically evoked inhibitory influence directly on MNTB units. These findings show that transmission at the CN-MNTB synapse does not occur in a fixed one-to-one manner and that the response of MNTB neurons reflects the integration of their excitatory and inhibitory inputs.


Laser induced damage of fused silica polished optics due to a droplet forming organic contaminant.
We report on the effect of organic molecular contamination on single shot laser induced damage density at the wavelength of 351 nm, with a 3 ns pulse length. Specific contamination experiments were made with dioctylphthalate (DOP) in liquid or gaseous phase, on the surface of fused silica polished samples, bare or solgel coated. Systematic laser induced damage was observed only in the case of liquid phase contamination. Different chemical and morphological characterization methods were used to identify and understand the damage process. We demonstrate that the contaminant morphology, rather than its physicochemical nature, can be responsible for the decrease of laser induced damage threshold of optics.


Thermodynamic characterization of a tetrahaem cytochrome isolated from a facultative aerobic bacterium, Shewanella frigidimarina: a putative redox model for flavocytochrome c3.
The facultative aerobic bacterium Shewanella frigidimarina produces a small c-type tetrahaem cytochrome (86 residues) under anaerobic growth conditions. This protein is involved in the respiration of iron and shares 42% sequence identity with the N-terminal domain of a soluble flavocytochrome, isolated from the periplasm of the same bacterium, which also contains four c -type haem groups. The thermodynamic properties of the redox centres and of an ionizable centre in the tetrahaem cytochrome were determined using NMR and visible spectroscopy techniques. This is the first detailed thermodynamic study performed on a tetrahaem cytochrome isolated from a facultative aerobic bacterium and reveals that this protein presents unique features. The redox centres have negative and different redox potentials, which are modulated by redox interactions between the four haems (covering a range of 8-56 mV) and by redox-Bohr interactions between the haems and an ionizable centre (-4 to -36 mV) located in close proximity to haem III. All of the interactions between the five centres are clearly dominated by electrostatic effects and the microscopic reduction potential of haem III is the one most affected by the oxidation of the other haems and by the protonation state of the molecule. Altogether, this study indicates that the tetrahaem cytochrome isolated from S. frigidimarina (Sfc) has the thermodynamic properties to work as an electron wire between its redox partners. Considering the high degree of sequence identity between Sfc and the cytochrome domain of flavocytochrome c(3), the structural similarities of the haem core, and that the macroscopic potentials are also identical, the results obtained in this work are rationalized in order to put forward a putative redox model for flavocytochrome c(3).