Antigen-driven clonal proliferation of B cells within the target tissue of an autoimmune disease: the salivary glands of patients with Sjögren's syndrome

Structures resembling germinal centers are seen in the salivary glands of patients with Sjögren's syndrome, but it is not known whether the microenvironment of these cell clusters is sufficient for the induction of a germinal center response. Therefore, we cloned and sequenced rearranged Ig V genes expressed by B cells isolated from sections of labial salivary gland biopsies from two Sjögren's syndrome patients. Rearranged V genes from B cells within one cell cluster were polyclonal and most had few somatic mutations. Two adjacent clusters from another patient each contained one dominant B cell clone expressing hypermutated V genes. None of the rearranged V genes was found in both clusters, suggesting that cells are unable to migrate out into the surrounding tissue and seed new clusters. The ratios of replacement to silent mutations in the framework and complementarity determining regions suggest antigen selection of high-affinity mutants. These results show that an antigen-driven, germinal center-type B cell response is taking place within the salivary glands of Sjögren's syndrome patients. In view of the recent demonstration of a germinal center response within the rheumatoid synovial membrane and the existence of similar structures in the target tissues of other autoimmune. diseases, we propose that germinal center- type responses can be induced in the nonlymphoid target tissues of a variety of autoimmune diseases

Use of high-dimensional spectral data to evaluate organic matter, reflectance relationships in soils

Recent breakthroughs in remote sensing technology have led to the development of a spaceborne high spectral resolution imaging sensor, HIRIS, to be launched in the mid-1990s for observation of earth surface features. The effects of organic carbon content on soil reflectance over the spectral range of HIRIS, and to examine the contributions of humic and fulvic acid fractions to soil reflectance was evaluated. Organic matter from four Indiana agricultural soils was extracted, fractionated, and purified, and six individual components of each soil were isolated and prepared for spectral analysis. The four soils, ranging in organic carbon content from 0.99 percent, represented various combinations of genetic parameters such as parent material, age, drainage, and native vegetation. An experimental procedure was developed to measure reflectance of very small soil and organic component samples in the laboratory, simulating the spectral coverage and resolution of the HIRIS sensor. Reflectance in 210 narrow (10 nm) bands was measured using the CARY 17D spectrophotometer over the 400 to 2500 nm wavelength range. Reflectance data were analyzed statistically to determine the regions of the reflective spectrum which provided useful information about soil organic matter content and composition. Wavebands providing significant information about soil organic carbon content were located in all three major regions of the reflective spectrum: visible, near infrared, and middle infrared. The purified humic acid fractions of the four soils were separable in six bands in the 1600 to 2400 nm range, suggesting that longwave middle infrared reflectance may be useful as a non-destructive laboratory technique for humic acid characterization

A primary fish gill cell culture model to assess pharmaceutical uptake and efflux:evidence for passive and facilitated transport

AbstractThe gill is the principle site of xenobiotic transfer to and from the aqueous environment. To replace, refine or reduce (3Rs) the large numbers of fish used in in vivo uptake studies an effective in vitro screen is required that mimics the function of the teleost gill. This study uses a rainbow trout (Oncorhynchus mykiss) primary gill cell culture system grown on permeable inserts, which tolerates apical freshwater thus mimicking the intact organ, to assess the uptake and efflux of pharmaceuticals across the gill. Bidirectional transport studies in media of seven pharmaceuticals (propranolol, metoprolol, atenolol, formoterol, terbutaline, ranitidine and imipramine) showed they were transported transcellularly across the epithelium. However, studies conducted in water showed enhanced uptake of propranolol, ranitidine and imipramine. Concentration-equilibrated conditions without a concentration gradient suggested that a proportion of the uptake of propranolol and imipramine is via a carrier-mediated process. Further study using propranolol showed that its transport is pH-dependent and at very low environmentally relevant concentrations (ngL−1), transport deviated from linearity. At higher concentrations, passive uptake dominated. Known inhibitors of drug transport proteins; cimetidine, MK571, cyclosporine A and quinidine inhibited propranolol uptake, whilst amantadine and verapamil were without effect. Together this suggests the involvement of specific members of SLC and ABC drug transporter families in pharmaceutical transport

Assessing the reliability of uptake and elimination kinetics modelling approaches for estimating bioconcentration factors in the freshwater invertebrate, Gammarus pulex

This study considers whether the current standard toxicokinetic methods are an accurate and applicable assessment of xenobiotic exposure in an aquatic freshwater invertebrate. An in vivo exposure examined the uptake and elimination kinetics for eight pharmaceutical compounds in the amphipod crustacean, Gammarus pulex by measuring their concentrations in both biological material and in the exposure medium over a 96 h period. Selected pharmaceuticals included two anti-inflammatories (diclofenac and ibuprofen), two beta-blockers (propranolol and metoprolol), an anti-depressant (imipramine), an anti-histamine (ranitidine) and two beta-agonists (formoterol and terbutaline). Kinetic bioconcentration factors (BCFs) for the selected pharmaceuticals were derived from a first-order one-compartment model using either the simultaneous or sequential modelling methods. Using the simultaneous method for parameter estimation, BCF values ranged from 12 to 212. In contrast, the sequential method for parameter estimation resulted in bioconcentration factors ranging from 19 to 4533. Observed toxicokinetic plots showed statistically significant lack-of-fits and further interrogation of the models revealed a decreasing trend in the uptake rate constant over time for rantidine, diclofenac, imipramine, metoprolol, formoterol and terbutaline. Previous published toxicokinetic data for 14 organic micro-pollutants were also assessed and similar trends were identified to those observed in this study. The decreasing trend of the uptake rate constant over time highlights the need to interpret modelled data more comprehensively to ensure uncertainties associated with uptake and elimination parameters for determining bioconcentration factors are minimised

Upgrade of the HadGEM3-A based attribution system to high resolution and a new validation framework for probabilistic event attribution

We present a substantial upgrade of the Met Office system for the probabilistic attribution of extreme weather and climate events with higher horizontal and vertical resolution (60 km mid-latitudes and 85 vertical levels), the latest Hadley Centre atmospheric and land model (ENDGame dynamics with GA6.0 science and JULES at GL6.0) as well as an updated forcings set. A new set of experiments designed for the evaluation and implementation of an operational attribution service are described which consist of pairs of multi-decadal stochastic physics ensembles continued on a season by season basis by large ensembles that are able to sample extreme at- mospheric states possible in the recent past. Diagnostics from these experiments form the HadGEM3-A contribution to the international Climate of the 20th Century Plus (C20Cþ) project and were analysed under the European Climate and Weather Events: Interpretation and Attribution (EUCLEIA) event attribution project as well as contributing to the Climate Science for Service Partnership (CSSP)-China programme. After discussing the framing issues surrounding questions that can be asked with our system we construct a novel approach to the evaluation of atmosphere-only ensembles intended for event attribution, in the process highlighting and clarifying the distinction between hindcast skill and model performance. A framework based around assessing model representation of predictable components and ensuring exchangeability of model and real world statistics leads to a form of detection and attribution to boundary condition forcing as a means of quantifying one degree of freedom of potential model error and allowing for the bias correction of event probabilities and resulting probability ratios. This method is then applied systematically across the globe to assess contributions from anthropogenic influence and specific boundary conditions to the changing probability of observed and record seasonal mean temperatures of four recent 3-month seasons from March 2016–February 2017

Unusual past dry and wet rainy seasons over Southern Africa and South America from a climate perspective

Southern Africa and Southern South America have experienced recent extremes in dry and wet rainy seasons which have caused severe socio-economic damages. Selected past extreme events are here studied, to estimate how human activity has changed the risk of the occurrence of such events, by applying an event attribution approach (Stott et al., 2004)comprising global climate models of Coupled Model Intercomparison Project 5 (CMIP5). Our assessment shows that models' representation of mean precipitation variability over Southern South America is not adequate to make a robust attribution statement about seasonal rainfall extremes in this region. Over Southern Africa, we show that unusually dry austral summers as occurred during 2002/2003 have become more likely, whereas unusually wet austral summers like that of 1999/2000 have become less likely due to anthropogenic climate change. There is some tentative evidence that the risk of extreme high 5-day precipitation totals (as observed in 1999/2000) have increased in the region. These results are consistent with CMIP5 models projecting a general drying trend over SAF during December–January–February (DJF) but also an increase in atmospheric moisture availability to feed heavy rainfall events when they do occur. Bootstrapping the confidence intervals of the fraction of attributable risk has demonstrated estimates of attributable risk are very uncertain, if the events are very rare. The study highlights some of the challenges in making an event attribution study for precipitation using seasonal precipitation and extreme 5-day precipitation totals and considering natural drivers such as ENSO in coupled ocean–atmosphere models

Autism in England: assessing underdiagnosis in a population- based cohort study of prospectively collected primary care data

Background: Autism has long been viewed as a paediatric condition, meaning that many autistic adults missed out on a diagnosis as children when autism was little known. We estimated numbers of diagnosed and undiagnosed autistic people in England, and examined how diagnostic rates differed by socio-demographic factors. Methods: This population-based cohort study of prospectively collected primary care data from IQVIA Medical Research Data (IMRD) compared the prevalence of diagnosed autism to community prevalence to estimate underdiagnosis. 602,433 individuals registered at an English primary care practice in 2018 and 5,586,100 individuals registered between 2000 and 2018 were included. Findings: Rates of diagnosed autism in children/young people were much higher than in adults/older adults. As of 2018, 2.94% of 10- to 14-year-olds had a diagnosis (1 in 34), vs. 0.02% aged 70+ (1 in 6000). Exploratory projections based on these data suggest that, as of 2018, 463,500 people (0.82% of the English population) may have been diagnosed autistic, and between 435,700 and 1,197,300 may be autistic and undiagnosed (59–72% of autistic people, 0.77%–2.12% of the English population). Age-related inequalities were also evident in new diagnoses (incidence): c.1 in 250 5- to 9-year-olds had a newly-recorded autism diagnosis in 2018, vs. c.1 in 4000 20- to 49-year-olds, and c.1 in 18,000 people aged 50+. Interpretation: Substantial age-related differences in the proportions of people diagnosed suggest an urgent need to improve access to adult autism diagnostic services. Funding: Dunhill Medical Trust, Economic and Social Research Council, Medical Research Council, National Institute for Health Research, the Wellcome Trust, and the Royal College of Psychiatrists.</p

Does Pain at an Earlier Stage of Chondropathy Protect Female Mice Against Structural Progression After Surgically Induced Osteoarthritis?

OBJECTIVE: Female C57BL/6 mice exhibit less severe chondropathy than male mice. This study was undertaken to test the robustness of this observation and explore underlying mechanisms. METHODS: Osteoarthritis was induced in male and female C57BL/6 or DBA/1 mice (n = 6-15 per group) by destabilization of the medial meniscus (DMM) or partial meniscectomy (PMX). Some mice were ovariectomized (OVX) (n = 30). In vivo repair after focal cartilage defect or joint immobilization (sciatic neurectomy) following DMM was assessed. Histologic analysis, evaluation of gene expression in whole knees, and behavioral analysis using Laboratory Animal Behavior Observation Registration and Analysis System (LABORAS) and Linton incapacitance testing (n = 7-10 mice per group) were performed. RESULTS: Female mice displayed less severe chondropathy (20-75% reduction) across both strains and after both surgeries. Activity levels after PMX were similar for male and female mice. Some repair-associated genes were increased in female mouse joints after surgery, but no repair differences were evident in vivo. Despite reduced chondropathy, female mice developed pain-like behavior at the same time as male mice. At the time of established pain-like behavior (10 weeks after PMX), pain-associated genes were significantly up-regulated in female mice, including Gdnf (mean ± SEM fold change 2.54 ± 0.30), Nrtn (6.71 ± 1.24), Ntf3 (1.92 ± 0.27), and Ntf5 (2.89 ± 0.48) (P < 0.01, P < 0.01, P < 0.05, and P < 0.001, respectively, versus male mice). Inflammatory genes were not regulated in painful joints in mice of either sex. CONCLUSION: We confirm strong structural joint protection in female mice that is not due to activity or intrinsic repair differences. Female mice develop pain at the same time as males, but induce a distinct set of neurotrophins. We speculate that heightened pain sensitivity in female mice protects the joint by preventing overuse

Bonfires and barbecues:coalition governance and the politics of Quango reform

The use of arm's-length bodies to deliver certain services, to regulate certain sectors or to assume responsibility for particularly salient political issues is neither new in historical terms or a feature unique to the UK in comparative terms. What is particularly distinctive, however, is the Coalition Government's attempts since 2010 to reduce the number of ‘quangos’ while also strengthening the capacity of the core executive and sponsor departments to control and co-ordinate this dense and fragmented sphere of delegated governance. Drawing upon the findings of the first research project to analyse the current Public Bodies Reform Agenda, this article provides an account of the ‘filling-in’ of the ‘hollowing out’. It argues that when viewed through a historical lens, the Coalition Government has adopted a distinctive approach to ‘the quango problem’