Pancreatic islets communicate with lymphoid tissues via exocytosis of insulin peptides.

Tissue-specific autoimmunity occurs when selected antigens presented by susceptible alleles of the major histocompatibility complex are recognized by T cells. However, the reason why certain specific self-antigens dominate the response and are indispensable for triggering autoreactivity is unclear. Spontaneous presentation of insulin is essential for initiating autoimmune type 1 diabetes in non-obese diabetic mice1,2. A major set of pathogenic CD4 T cells specifically recognizes the 12-20 segment of the insulin B-chain (B:12-20), an epitope that is generated from direct presentation of insulin peptides by antigen-presenting cells3,4. These T cells do not respond to antigen-presenting cells that have taken up insulin that, after processing, leads to presentation of a different segment representing a one-residue shift, B:13-214. CD4 T cells that recognize B:12-20 escape negative selection in the thymus and cause diabetes, whereas those that recognize B:13-21 have only a minor role in autoimmunity3-5. Although presentation of B:12-20 is evident in the islets3,6, insulin-specific germinal centres can be formed in various lymphoid tissues, suggesting that insulin presentation is widespread7,8. Here we use live imaging to document the distribution of insulin recognition by CD4 T cells throughout various lymph nodes. Furthermore, we identify catabolized insulin peptide fragments containing defined pathogenic epitopes in β-cell granules from mice and humans. Upon glucose challenge, these fragments are released into the circulation and are recognized by CD4 T cells, leading to an activation state that results in transcriptional reprogramming and enhanced diabetogenicity. Therefore, a tissue such as pancreatic islets, by releasing catabolized products, imposes a constant threat to self-tolerance. These findings reveal a self-recognition pathway underlying a primary autoantigen and provide a foundation for assessing antigenic targets that precipitate pathogenic outcomes by systemically sensitizing lymphoid tissues

Sex and Diffusion Tensor Imaging of White Matter in Schizophrenia: A Systematic Review Plus Meta-analysis of the Corpus Callosum

Sex is considered an understudied variable in health research. Schizophrenia is a brain disorder with known sex differences in epidemiology and clinical presentation. We systematically reviewed the literature for sex-based differences of diffusion properties of white matter tracts in schizophrenia. We then conducted a meta-analysis examining sex-based differences in the genu and splenium of the corpus callosum in schizophrenia. Medline and Embase were searched to identify relevant papers. Studies fulfilling the following criteria were included: (1) included individuals with a diagnosis of schizophrenia, (2) included a control group of healthy individuals, (3) included both sexes in the patient and the control groups, (4) used diffusion tensor imaging, and (5) involved analyzing metrics of white matter microstructural integrity. Fractional anisotropy (FA) was used as the measure of interest in the meta-analysis. Of 730 studies reviewed, 75 met the inclusion criteria. Most showed no effect of sex, however, those that did found either that females have lower FA than males, or that the effect of disease in females is larger than that in males. The findings of the meta-analysis in the corpus callosum supported this result. There is a recognized need for studies on schizophrenia with a sufficient sample of female patients. Lack of power undermines the ability to detect sex-based differences. Understanding the sex-specific impact of illness on neural circuits may help inform development of new treatments, and improvement of existing interventions

Speaking out about gender imbalance in invited speakers improves diversity.

Omissions of qualified women scientists from major meeting programs continue to occur despite a surge in articles indicating persistent gender-discriminatory practices in hiring and promotion, and calls for gender balance in conference organizing committees

Exploring the Quality of Life of People in North Eastern and Southern Thailand.

The assumption that development brings not only material prosperity but also a better overall quality of life lies at the heart of the development project. Against this, critics assert that development can undermine social cohesion and threaten cultural integrity. Rarely, however, is the impact of development on wellbeing rigourously analysed using empirical data. This is what the Wellbeing in Developing Countries Group at the University of Bath aims to do drawing on fieldwork carried out in four developing countries, which addresses the themes of resources, needs, agency and structure, and subjective Quality of life (QoL). The first phase of the QoL research in Thailand aimed to explore the categories and components of quality of life for people from different backgrounds and locations with the aim of developing methods for QoL assessment in the third phase of the WeD QoL research. The study presents data obtained from rural and peri-urban sites in Southern and Northeastern Thailand (two villages in Songkhla and three in Khon Kaen, Mukdaharn, and Roi-et). Participants were divided into six groups by gender and age, and were divided again by religion (Buddhist and Muslim) and wealth status in the South. Data collection was conducted between October and December 2004 using focus group discussions, semi-structured interviews, and the Person Generated Index. Content analysis was used for data analysis. The use of a qualitative approach enabled the gathering of empirical data that reflects the sources of difficulty and happiness in the lives of participants. Respondents identified 26 aspects to their quality of life, including family relations, health and longevity, income and having money, jobs, housing, education, debt, and so on. The results reveal clear similarities and differences in the role of traditions, religious beliefs, and values in the lives of people living in remote rural or peri-urban areas in Northeastern and Southern Thailand. These results, together with the findings from Peru, Ethiopia, and Bangladesh, will inform the rest of the WeD research and be used to develop measures to assess the quality of life of people living in developing countries

Misregulated E-Cadherin Expression Associated with an Aggressive Brain Tumor Phenotype

BACKGROUND: Cadherins are essential components of the adherens junction complexes that mediate cell-cell adhesion and regulate cell motility. During tissue morphogenesis, changes in cadherin expression (known as cadherin switching) are a common mechanism for altering cell fate. Cadherin switching is also common during epithelial tumor progression, where it is thought to promote tumor invasion and metastasis. E-cadherin is the predominant cadherin expressed in epithelial tissues, but its expression is very limited in normal brain. METHODOLOGY/PRINCIPAL FINDINGS: We identified E-cadherin expression in a retrospective series of glioblastomas exhibiting epithelial or pseudoepithelial differentiation. Unlike in epithelial tissues, E-cadherin expression in gliomas correlated with an unfavorable clinical outcome. Western blotting of two panels of human GBM cell lines propagated either as xenografts in nude mice or grown under conventional cell culture conditions confirmed that E-cadherin expression is rare. However, a small number of xenograft lines did express E-cadherin, its expression correlating with increased invasiveness when the cells were implanted orthotopically in mouse brain. In the conventionally cultured SF767 glioma cell line, E-cadherin expression was localized throughout the plasma membrane rather than being restricted to areas of cell-cell contact. ShRNA knockdown of E-cadherin in these cells resulted in decreased proliferation and migration in vitro. CONCLUSIONS/SIGNIFICANCE: Our data shows an unexpected correlation between the abnormal expression of E-cadherin in a subset of GBM tumor cells and the growth and migration of this aggressive brain tumor subtype

Recruitment and Retention of Underrepresented Populations in Alzheimer’s Disease Research: A Systematic Review

Introduction: Alzheimer’s disease and related dementias (ADRD) disproportionately impact racial and ethnic minority and socioeconomically disadvantaged adults. Yet, these populations are significantly underrepresented in research. Methods: We systematically reviewed the literature for published reports describing recruitment and retention of individuals from underrepresented backgrounds in ADRD research or underrepresented participants’ perspectives regarding ADRD research participation. Relevant evidence was synthesized and evaluated for quality. Results: We identified 22 eligible studies. Seven studies focused on recruitment/retention approaches, all of which included multifaceted efforts and at least one community outreach component. There was considerable heterogeneity in approaches used, specific activities and strategies, outcome measurement, and conclusions regarding effectiveness. Despite limited use of prospective evaluation strategies, most authors reported improvements in diverse representation in ADRD cohorts. Studies evaluating participant views focused largely on predetermined explanations of participation including attitudes, barriers/facilitators, education, trust, and religiosity. Across all studies, the strength of evidence was low. Discussion: Overall, the quantity and quality of available evidence to inform best practices in recruitment, retention, and inclusion of underrepresented populations in ADRD research are low. Further efforts to systematically evaluate the success of existing and emergent approaches will require improved methodological standards and uniform measures for evaluating recruitment, participation, and inclusivity

The “Hypertension Approaches in the Elderly: a Lifestyle study” multicenter, randomized trial (HAEL Study): rationale and methodological protocol

Background: Hypertension is a clinical condition highly prevalent in the elderly, imposing great risks to cardiovascular diseases and loss of quality of life. Current guidelines emphasize the importance of nonpharmacological strategies as a first-line approach to lower blood pressure. Exercise is an efficient lifestyle tool that can benefit a myriad of health-related outcomes, including blood pressure control, in older adults. We herein report the protocol of the HAEL Study, which aims to evaluate the efficacy of a pragmatic combined exercise training compared with a health education program on ambulatory blood pressure and other health-related outcomes in older individuals. Methods: Randomized, single-blinded, multicenter, two-arm, parallel, superiority trial. A total of 184 subjects (92/center), ≥60 years of age, with no recent history of cardiovascular events, will be randomized on a 1:1 ratio to 12-week interventions consisting either of a combined exercise (aerobic and strength) training, three times per week, or an active-control group receiving health education intervention, once a week. Ambulatory (primary outcome) and office blood pressures, cardiorespiratory fitness and endothelial function, together with quality of life, functional fitness and autonomic control will be measured in before and after intervention. Discussion: Our conceptual hypothesis is that combined training intervention will reduce ambulatory blood pressure in comparison with health education group. Using a superiority framework, analysis plan prespecifies an intention-to-treat approach, per protocol criteria, subgroups analysis, and handling of missing data. The trial is recruiting since September 2017. Finally, this study was designed to adhere to data sharing practices. Trial registration: NCT03264443. Registered on 29 August, 2017

Racial and Ethnic Differences in the Delivery of the Resources for Enhancing Alzheimer's Caregiver Health II Intervention

Previous analyses of the Resources for Enhancing Alzheimer’s Caregiver Health (REACH II) intervention have found that it was less effective for African American than for Hispanic or White caregivers. We examined whether there were race/ethnicity group differences in REACH II intervention delivery