Long-Lived Plasma Cells and Memory B Cells Produce Pathogenic Anti-GAD65 Autoantibodies in Stiff Person Syndrome

Stiff person syndrome (SPS) is a rare, neurological disorder characterized by sudden cramps and spasms. High titers of enzyme-inhibiting IgG autoantibodies against the 65 kD isoform of glutamic acid decarboxylase (GAD65) are a hallmark of SPS, implicating an autoimmune component in the pathology of the syndrome. Studying the B cell compartment and the anti-GAD65 B cell response in two monozygotic twins suffering from SPS, who were treated with the B cell-depleting monoclonal anti-CD20 antibody rituximab, we found that the humoral autoimmune response in SPS is composed of a rituximab-sensitive part that is rapidly cleared after treatment, and a rituximab-resistant component, which persists and acts as a reservoir for autoantibodies inhibiting GAD65 enzyme activity. Our data show that these potentially pathogenic anti-GAD65 autoantibodies are secreted by long-lived plasma cells, which may either be persistent or develop from rituximab-resistant memory B lymphocytes. Both subsets represent only a fraction of anti-GAD65 autoantibody secreting cells. Therefore, the identification and targeting of this compartment is a key factor for successful treatment planning of SPS and of similar autoimmune diseases

Assessing Natural Resource Use by Forest-Reliant Communities in Madagascar Using Functional Diversity and Functional Redundancy Metrics

Biodiversity plays an integral role in the livelihoods of subsistence-based forest-dwelling communities and as a consequence it is increasingly important to develop quantitative approaches that capture not only changes in taxonomic diversity, but also variation in natural resources and provisioning services. We apply a functional diversity metric originally developed for addressing questions in community ecology to assess utilitarian diversity of 56 forest plots in Madagascar. The use categories for utilitarian plants were determined using expert knowledge and household questionnaires. We used a null model approach to examine the utilitarian (functional) diversity and utilitarian redundancy present within ecological communities. Additionally, variables that might influence fluctuations in utilitarian diversity and redundancy—specifically number of felled trees, number of trails, basal area, canopy height, elevation, distance from village—were analyzed using Generalized Linear Models (GLMs). Eighteen of the 56 plots showed utilitarian diversity values significantly higher than expected. This result indicates that these habitats exhibited a low degree of utilitarian redundancy and were therefore comprised of plants with relatively distinct utilitarian properties. One implication of this finding is that minor losses in species richness may result in reductions in utilitarian diversity and redundancy, which may limit local residents' ability to switch between alternative choices. The GLM analysis showed that the most predictive model included basal area, canopy height and distance from village, which suggests that variation in utilitarian redundancy may be a result of local residents harvesting resources from the protected area. Our approach permits an assessment of the diversity of provisioning services available to local communities, offering unique insights that would not be possible using traditional taxonomic diversity measures. These analyses introduce another tool available to conservation biologists for assessing how future losses in biodiversity will lead to a reduction in natural resources and provisioning services from forests

An investigation of the apparent breast cancer epidemic in France: screening and incidence trends in birth cohorts

<p>Abstract</p> <p>Background</p> <p>Official descriptive data from France showed a strong increase in breast-cancer incidence between 1980 to 2005 without a corresponding change in breast-cancer mortality. This study quantifies the part of incidence increase due to secular changes in risk factor exposure and in overdiagnosis due to organised or opportunistic screening. Overdiagnosis was defined as non progressive tumours diagnosed as cancer at histology or progressive cancer that would remain asymptomatic until time of death for another cause.</p> <p>Methods</p> <p>Comparison between age-matched cohorts from 1980 to 2005. All women residing in France and born 1911-1915, 1926-1930 and 1941-1945 are included. Sources are official data sets and published French reports on screening by mammography, age and time specific breast-cancer incidence and mortality, hormone replacement therapy, alcohol and obesity. Outcome measures include breast-cancer incidence differences adjusted for changes in risk factor distributions between pairs of age-matched cohorts who had experienced different levels of screening intensity.</p> <p>Results</p> <p>There was an 8-fold increase in the number of mammography machines operating in France between 1980 and 2000. Opportunistic and organised screening increased over time. In comparison to age-matched cohorts born 15 years earlier, recent cohorts had adjusted incidence proportion over 11 years that were 76% higher [95% confidence limits (CL) 67%, 85%] for women aged 50 to 64 years and 23% higher [95% CL 15%, 31%] for women aged 65 to 79 years. Given that mortality did not change correspondingly, this increase in adjusted 11 year incidence proportion was considered as an estimate of overdiagnosis.</p> <p>Conclusions</p> <p>Breast cancer may be overdiagnosed because screening increases diagnosis of slowly progressing non-life threatening cancer and increases misdiagnosis among women without progressive cancer. We suggest that these effects could largely explain the reported "epidemic" of breast cancer in France. Better predictive classification of tumours is needed in order to avoid unnecessary cancer diagnoses and subsequent procedures.</p

High Affinity Antigen Recognition of the Dual Specific Variants of Herceptin Is Entropy-Driven in Spite of Structural Plasticity

The antigen-binding site of Herceptin, an anti-human Epidermal Growth Factor Receptor 2 (HER2) antibody, was engineered to add a second specificity toward Vascular Endothelial Growth Factor (VEGF) to create a high affinity two-in-one antibody bH1. Crystal structures of bH1 in complex with either antigen showed that, in comparison to Herceptin, this antibody exhibited greater conformational variability, also called “structural plasticity”. Here, we analyzed the biophysical and thermodynamic properties of the dual specific variants of Herceptin to understand how a single antibody binds two unrelated protein antigens. We showed that while bH1 and the affinity-improved bH1-44, in particular, maintained many properties of Herceptin including binding affinity, kinetics and the use of residues for antigen recognition, they differed in the binding thermodynamics. The interactions of bH1 and its variants with both antigens were characterized by large favorable entropy changes whereas the Herceptin/HER2 interaction involved a large favorable enthalpy change. By dissecting the total entropy change and the energy barrier for dual interaction, we determined that the significant structural plasticity of the bH1 antibodies demanded by the dual specificity did not translate into the expected increase of entropic penalty relative to Herceptin. Clearly, dual antigen recognition of the Herceptin variants involves divergent antibody conformations of nearly equivalent energetic states. Hence, increasing the structural plasticity of an antigen-binding site without increasing the entropic cost may play a role for antibodies to evolve multi-specificity. Our report represents the first comprehensive biophysical analysis of a high affinity dual specific antibody binding two unrelated protein antigens, furthering our understanding of the thermodynamics that drive the vast antigen recognition capacity of the antibody repertoire

Prevalence and factors associated with alcohol and drug-related disorders in prison: a French national study

BACKGROUND: Most studies measuring substance-use disorders in prisons focus on incoming or on remand prisoners and are generally restricted to drugs. However, there is evidence that substance use initiation or continuation occurs in prison, and that alcohol use is common. The aim of this study is 1) to assess prevalence of both drug and alcohol abuse and dependence (DAD/AAD) in a national randomised cohort of French prisoners, short or long-term sentence 2) to assess the risk factors associated with DAD/AAD in prison. a stratified random strategy was used to select 1) 23 prisons among the different types of prison 2) 998 prisoners. Diagnoses were assessed according to a standardized procedure, each prisoner being assessed by two psychiatrists, one junior, using a structured interview (MINI 5 plus), and one senior, completing the procedure with an open clinical interview. At the end of the interview the clinicians met and agreed on a list of diagnoses. Cloninger's Temperament and Character Inventory (TCI) was also used. RESULTS: More than a third of prisoners presented either AAD or DAD in the last 12 months. Cannabis was the most frequent drug and just under a fifth of prisoners had AAD. AAD and DAD were clearly different for the following: socio-demographic variables, childhood history, imprisonment characteristics, psychiatric comorbidity and Cloninger's TCI. Profiles of AAD in prison are similar to type II alcoholism. CONCLUSION: Regular screening of AAD/DAD in prison, and specific treatment programmes taking into account differences between prisoners with an AAD and prisoners with a DAD should be a public health priority in priso

Different Pattern of Immunoglobulin Gene Usage by HIV-1 Compared to Non-HIV-1 Antibodies Derived from the Same Infected Subject

A biased usage of immunoglobulin (Ig) genes is observed in human anti-HIV-1 monoclonal antibodies (mAbs) resulting probably from compensation to reduced usage of the VH3 family genes, while the other alternative suggests that this bias usage is due to antigen requirements. If the antigen structure is responsible for the preferential usage of particular Ig genes, it may have certain implications for HIV vaccine development by the targeting of particular Ig gene-encoded B cell receptors to induce neutralizing anti-HIV-1 antibodies. To address this issue, we have produced HIV-1 specific and non-HIV-1 mAbs from an infected individual and analyzed the Ig gene usage. Green-fluorescence labeled virus-like particles (VLP) expressing HIV-1 envelope (Env) proteins of JRFL and BaL and control VLPs (without Env) were used to select single B cells for the production of 68 recombinant mAbs. Ten of these mAbs were HIV-1 Env specific with neutralizing activity against V3 and the CD4 binding site, as well as non-neutralizing mAbs to gp41. The remaining 58 mAbs were non-HIV-1 Env mAbs with undefined specificities. Analysis revealed that biased usage of Ig genes was restricted only to anti-HIV-1 but not to non-HIV-1 mAbs. The VH1 family genes were dominantly used, followed by VH3, VH4, and VH5 among anti-HIV-1 mAbs, while non-HIV-1 specific mAbs preferentially used VH3 family genes, followed by VH4, VH1 and VH5 families in a pattern identical to Abs derived from healthy individuals. This observation suggests that the biased usage of Ig genes by anti-HIV-1 mAbs is driven by structural requirements of the virus antigens rather than by compensation to any depletion of VH3 B cells due to autoreactive mechanisms, according to the gp120 superantigen hypothesis

Local Factors Determine Plant Community Structure on Closely Neighbored Islands

Despite the recent popularity of the metacommunity concept, ecologists have not evaluated the applicability of different metacommunity frameworks to insular organisms. We surveyed 50 closely spaced islands in the Thousand-Island Lake of China to examine the role of local (environmental) and regional (dispersal) factors in structuring woody plant assemblages (tree and shrub species) on these islands. By partitioning the variation in plant community structure into local and regional causes, we showed that local environmental conditions, specifically island morphometric characteristics, accounted for the majority of the variation in plant community structure among the studied islands. Spatial variables, representing the potential importance of species dispersal, explained little variation. We conclude that one metacommunity framework–species sorting–best characterizes these plant communities. This result reinforces the idea that the traditional approach of emphasizing the local perspective when studying ecological communities continues to hold its value

Uncharted waters: rare and unclassified cardiomyopathies characterized on cardiac magnetic resonance imaging

Cardiac magnetic resonance imaging (CMR) has undergone considerable technology advances in recent years, so that it is now entering into mainstream cardiac imaging practice. In particular, CMR is proving to be a valuable imaging tool in the detection, morphological assessment and functional assessment of cardiomyopathies. Although our understanding of this broad group of heart disorders continues to expand, it is an evolving group of entities, with the rarer cardiomyopathies remaining poorly understood or even unclassified. In this review, we describe the clinical and pathophysiological aspects of several of the rare/unclassified cardiomyopathies and their appearance on CMR

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P &lt; 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men