The genetic architecture of schizophrenia is complex, involving risk alleles ranging from common alleles of weak effect to rare alleles of large effect, the best exemplar of the latter being large ...copy number variants (CNVs). It is currently unknown whether pathophysiology in those with defined rare mutations overlaps with that in other individuals with the disorder who do not share the same rare mutation. Under an extreme heterogeneity model, carriers of specific high-penetrance mutations form distinct subgroups. In contrast, under a polygenic threshold model, high-penetrance rare allele carriers possess many risk factors, of which the rare allele is the only one, albeit an important, factor. Under the latter model, cases with rare mutations can be expected to share some common risk alleles, and therefore pathophysiological mechanisms, with cases without the same mutation. Here we show that, compared with controls, individuals with schizophrenia who have known pathogenic CNVs carry an excess burden of common risk alleles (P=2.25 × 10(-17)) defined from a genome-wide association study largely based on individuals without known CNVs. Our finding is not consistent with an extreme heterogeneity model for CNV carriers, but does offer support for the polygenic threshold model of schizophrenia. That this is so provides support for the notion that studies aiming to model the effects of rare variation may uncover pathophysiological mechanisms of relevance to those with the disorder more widely.
Issue Title: The Hinode (Solar-B) Mission / Edited by Takashi Sakurai see e-mail The EUV Imaging Spectrometer (EIS) on Hinode will observe solar corona and upper transition region emission lines in ...the wavelength ranges 170-210 Å and 250-290 Å. The line centroid positions and profile widths will allow plasma velocities and turbulent or non-thermal line broadenings to be measured. We will derive local plasma temperatures and densities from the line intensities. The spectra will allow accurate determination of differential emission measure and element abundances within a variety of corona and transition region structures. These powerful spectroscopic diagnostics will allow identification and characterization of magnetic reconnection and wave propagation processes in the upper solar atmosphere. We will also directly study the detailed evolution and heating of coronal loops. The EIS instrument incorporates a unique two element, normal incidence design. The optics are coated with optimized multilayer coatings. We have selected highly efficient, backside-illuminated, thinned CCDs. These design features result in an instrument that has significantly greater effective area than previous orbiting EUV spectrographs with typical active region 2-5 s exposure times in the brightest lines. EIS can scan a field of 6×8.5 arcmin with spatial and velocity scales of 1 arcsec and 25 kms^sup -1^ per pixel. The instrument design, its absolute calibration, and performance are described in detail in this paper. EIS will be used along with the Solar Optical Telescope (SOT) and the X-ray Telescope (XRT) for a wide range of studies of the solar atmosphere. PUBLICATION ABSTRACT
Circadian clocks are endogenous timers adjusting behaviour and physiology with the solar day. Synchronized circadian clocks improve fitness and are crucial for our physical and mental well-being. ...Visual and non-visual photoreceptors are responsible for synchronizing circadian clocks to light, but clock-resetting is also achieved by alternating day and night temperatures with only 2-4 °C difference. This temperature sensitivity is remarkable considering that the circadian clock period (~24 h) is largely independent of surrounding ambient temperatures. Here we show that Drosophila Ionotropic Receptor 25a (IR25a) is required for behavioural synchronization to low-amplitude temperature cycles. This channel is expressed in sensory neurons of internal stretch receptors previously implicated in temperature synchronization of the circadian clock. IR25a is required for temperature-synchronized clock protein oscillations in subsets of central clock neurons. Extracellular leg nerve recordings reveal temperature- and IR25a-dependent sensory responses, and IR25a misexpression confers temperature-dependent firing of heterologous neurons. We propose that IR25a is part of an input pathway to the circadian clock that detects small temperature differences. This pathway operates in the absence of known 'hot' and 'cold' sensors in the Drosophila antenna, revealing the existence of novel periphery-to-brain temperature signalling channels.
The antipsychotic clozapine is uniquely effective in the management of schizophrenia; however, its use is limited by its potential to induce agranulocytosis. The causes of this, and of its precursor ...neutropenia, are largely unknown, although genetic factors have an important role. We sought risk alleles for clozapine-associated neutropenia in a sample of 66 cases and 5583 clozapine-treated controls, through a genome-wide association study (GWAS), imputed human leukocyte antigen (HLA) alleles, exome array and copy-number variation (CNV) analyses. We then combined associated variants in a meta-analysis with data from the Clozapine-Induced Agranulocytosis Consortium (up to 163 cases and 7970 controls). In the largest combined sample to date, we identified a novel association with rs149104283 (odds ratio (OR)=4.32, P=1.79 × 10
), intronic to transcripts of SLCO1B3 and SLCO1B7, members of a family of hepatic transporter genes previously implicated in adverse drug reactions including simvastatin-induced myopathy and docetaxel-induced neutropenia. Exome array analysis identified gene-wide associations of uncommon non-synonymous variants within UBAP2 and STARD9. We additionally provide independent replication of a previously identified variant in HLA-DQB1 (OR=15.6, P=0.015, positive predictive value=35.1%). These results implicate biological pathways through which clozapine may act to cause this serious adverse effect.
Abstract Frozen shoulder is a specific, painful and debilitating condition effecting patients mainly in middle age. While it has been recognised for over 100 years, it is still mis-diagnosed, with a ...natural history that is poorly understood and with limited evidence for the efficacy for various treatments. This review considers what is known about this common painful condition and the treatments available.
Large (>100 kb), rare (<1% in the population) copy number variants (CNVs) have been shown to confer risk for schizophrenia (SZ), but the findings for bipolar disorder (BD) are less clear. In a new BD ...sample from the United Kingdom (n=2591), we have examined the occurrence of CNVs and compared this with previously reported samples of 6882 SZ and 8842 control subjects. When combined with previous data, we find evidence for a contribution to BD for three SZ-associated CNV loci: duplications at 1q21.1 (P=0.022), deletions at 3q29 (P=0.03) and duplications at 16p11.2 (P=2.3 × 10(-4)). The latter survives multiple-testing correction for the number of recurrent large CNV loci in the genome. Genes in 20 regions (total of 55 genes) were enriched for rare exonic CNVs among BD cases, but none of these survives correction for multiple testing. Finally, our data provide strong support for the hypothesis of a lesser contribution of very large (>500 kb) CNVs in BD compared with SZ, most notably for deletions >1 Mb (P=9 × 10(-4)).
Abstract
Background
Chemoradiation with capecitabine followed by surgery is standard care for locally advanced rectal cancer (LARC). Severe diarrhea is considered a dose-limiting toxicity of adding ...capecitabine to radiation therapy. The aim of this study was to describe the risk factors and the impact of body composition on severe diarrhea in patients with LARC during preoperative chemoradiation with capecitabine.
Methods
A single centre retrospective cohort study was conducted in a tertiary referral centre. All patients treated with preoperative chemoradiation with capecitabine for LARC from 2009 to 2015 were included. Patients with locally recurrent rectal cancer who received chemoradiation for the first time were included as well. Logistic regression analyses were performed to identify risk factors for severe diarrhea.
Results
A total of 746 patients were included. Median age was 64 years (interquartile range 57–71) and 477 patients (64%) were male. All patients received a radiation dosage of 25 × 2 Gy during a period of five weeks with either concomitant capecitabine administered on radiation days or continuously during radiotherapy. In this cohort 70 patients (9%) developed severe diarrhea. In multivariable logistic regression analyses female sex (OR: 4.42, 95% CI 2.54–7.91) and age ≥ 65 (OR: 3.25, 95% CI 1.85–5.87) were the only risk factors for severe diarrhea.
Conclusions
Female patients and patients aged sixty-five or older had an increased risk of developing severe diarrhea during preoperative chemoradiation therapy with capecitabine. No relation was found between body composition and severe diarrhea.
Two methods of estimating stratum corneum thickness using reflectance confocal microscopy were examined, and epidermal thickness measurements at multiple body sites were compared. Measurements of ...stratum corneum thickness were made using the derivative method, which is based on the rate of change of image intensity as a proxy for keratin concentration, and simple visual analysis of confocal images. To compare epidermal thickness we collected 1491 z-axis stacks of confocal images from 10 body sites in 39 subjects. An artefact associated with the imaging process interfered with the derivative method for stratum corneum thickness, and simple visual analysis is to be preferred. Although some epidermal properties varied by site, the most striking finding was the degree of within-site variation, which accounted for between 50% and 74% of the total variation observed. The majority of this variation was not due to measurement error, and represents genuine topographical irregularity. This fine-scale variation limits the ease of use of reflectance confocal microscopy for quantitative studies of the epidermis and stratum corneum.
Summary
Successfully delivering medical care and acquiring and disseminating the new knowledge that underpins clinical advance requires dealing with a number of both theoretical and organizational ...issues that may impede progress. Firstly, we have to move beyond the idea that biology and medicine are synonymous, and realize that tropes such as ‘bench to bedside’ or ‘translational’ frequently do not capture the way medical advance occurs. Medicine is more engineering than science, and the constraints imposed by society and economics, as well as historical models of working, may all delay improvements in healthcare delivery. Secondly, the generation of new ideas is influenced by the social organization and financial underpinning of science. Comparisons with other areas of science and technology suggest that medical science is dysfunctional and lacking in genuine innovation, particularly when cost is factored in as a key denominator. There are reasons to believe that matters are getting worse, and that the climate for revolutionary discovery is less supportive in both academia and industry than it was in the mid‐to‐late twentieth century. Thirdly, healthcare delivery is subject to a number of factors that limit cheap and effective care. These include payment systems that encourage unnecessary care, self‐interest by medical guilds and insurers, and regulators that seek to limit new ways of working. Finally, there is also a striking failure to study and understand medical competence, how we educate doctors and other clinicians, and how technology might help to reduce costs.
A number of large, rare copy number variants (CNVs) are deleterious for neurodevelopmental disorders, but large, rare, protective CNVs have not been reported for such phenotypes. Here we show in a ...CNV analysis of 47 005 individuals, the largest CNV analysis of schizophrenia to date, that large duplications (1.5-3.0 Mb) at 22q11.2--the reciprocal of the well-known, risk-inducing deletion of this locus--are substantially less common in schizophrenia cases than in the general population (0.014% vs 0.085%, OR=0.17, P=0.00086). 22q11.2 duplications represent the first putative protective mutation for schizophrenia.
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