Estrogen treatment decreases matrix metalloproteinase (MMP)-9 in autoimmune demyelinating disease through estrogen receptor alpha (ERalpha).

Matrix metalloproteinases (MMPs) have a crucial function in migration of inflammatory cells into the central nervous system (CNS). Levels of MMP-9 are elevated in multiple sclerosis (MS) and predict the occurrence of new active lesions on magnetic resonance imaging (MRI). This translational study aims to determine whether in vivo treatment with the pregnancy hormone estriol affects MMP-9 levels from immune cells in patients with MS and mice with experimental autoimmune encephalomyelitis (EAE). Peripheral blood mononuclear cells (PBMCs) collected from three female MS patients treated with estriol and splenocytes from EAE mice treated with estriol, estrogen receptor (ER) alpha ligand, ERbeta ligand or vehicle were stimulated ex vivo and analyzed for levels of MMP-9. Markers of CNS infiltration were assessed using MRI in patients and immunohistochemistry in mice. Supernatants from PBMCs obtained during estriol treatment in female MS patients showed significantly decreased MMP-9 compared with pretreatment. Decreases in MMP-9 coincided with a decrease in enhancing lesion volume on MRI. Estriol treatment of mice with EAE reduced MMP-9 in supernatants from autoantigen-stimulated splenocytes, coinciding with decreased CNS infiltration by T cells and monocytes. Experiments with selective ER ligands showed that this effect was mediated through ERalpha. In conclusion, estriol acting through ERalpha to reduce MMP-9 from immune cells is one mechanism potentially underlying the estriol-mediated reduction in enhancing lesions in MS and inflammatory lesions in EAE

Strengths and coping strategies in the life narratives of sexual minority women

This study explored self-described strengths and strategies for coping with stress among sexual minority women (SMW), drawing on qualitative narratives of sexual minority and heterosexual women who were recruited from a population-based sample. In-depth follow-up qualitative telephone interviews were conducted with 48 women who had participated in the National Alcohol Survey, a U.S. population-based survey. Participants included 25 SMW and 16 matched exclusively heterosexual women. Narrative data were analyzed using inductive thematic analysis and constant comparison to explore the study aim, with an emphasis on themes that diverged or that were particularly salient for SMW relative to heterosexual women. Strengths and coping strategies that were especially meaningful in the narratives of sexual minority women emerged in two areas. First, participants described development of intrapersonal strengths through nurturing an authentic sense of self and embracing multifaceted identity. Second, participants described multiple strategies for cultivation of interpersonal resources: navigating distance and closeness with family of origin, cultivating supportive friends and chosen family, connecting to community, finding solace and joy with animals, and engaging in collective action. Findings underscore the importance of considering protective factors that are salient to SMW in developing or refining prevention and intervention efforts

Purkinje cell loss in experimental autoimmune encephalomyelitis

Gray matter atrophy observed by brain MRI is an important correlate to clinical disability and disease duration in multiple sclerosis. The objective of this study was to link brain atrophy visualized by neuroimaging to its underlying neuropathology using the MS model, experimental autoimmune encephalomyelitis (EAE). Volumetric changes in brains of EAE mice, as well as matched healthy normal controls, were quantified by collecting post-mortem high-resolution T2-weighted magnetic resonance microscopy and actively stained magnetic resonance histology images. Anatomical delineations demonstrated a significant decrease in the volume of the whole cerebellum, cerebellar cortex, and molecular layer of the cerebellar cortex in EAE as compared to normal controls. The pro-apoptotic marker caspase-3 was detected in Purkinje cells and a significant decrease in Purkinje cell number was found in EAE. Cross modality and temporal correlations revealed a significant association between Purkinje cell loss on neuropathology and atrophy of the molecular layer of the cerebellar cortex by neuroimaging. These results demonstrate the power of using combined population atlasing and neuropathology approaches to discern novel insights underlying gray matter atrophy in animal models of neurodegenerative disease

Rapid-onset dystonia-Parkinsonism phenotype consistency for a novel variant of ATP1A3 in patients across 3 global populations

info:eu-repo/semantics/publishedVersio

Application of behavior change techniques in a personalized nutrition Electronic Health intervention study: protocol for the web-based Food4Me randomized controlled trial

Background: In order to determine the efficacy of behavior change techniques (BCT) applied in dietary and physical activity intervention studies, it is first necessary to record and describe techniques which have been used during such interventions. Published frameworks used in dietary and smoking cessation interventions undergo continuous development and most are not adapted for online delivery. The Food4Me study (N=1607) provided the opportunity to use existing frameworks to describe standardized online techniques employed in a large-scale internet-based intervention to change dietary behaviour and physical activity. Objectives: To describe techniques embedded in the Food4Me study design and explain the selection rationale. To demonstrate the use of behaviour change technique taxonomies, develop standard operating procedures for training, and identify strengths and limitations of the Food4Me framework that will inform its use in future studies. Methods: The 6-month randomized controlled trial took place simultaneously in 7 European countries, with participants receiving one of 4 levels of personalized advice (generalized, intake-based, intake+phenotype-based and intake+phenotype+gene-based). A 3-phase approach was taken: (I), existing taxonomies were reviewed and techniques were identified a priori for possible inclusion in the Food4Me study; (II) a standard operating procedure was developed to maintain consistency in the use of methods and techniques across research centers; (III) the Food4Me BCT framework was reviewed and updated post intervention. An analysis of excluded techniques was also conducted. Results: Of 46 techniques identified a priori as being applicable to Food4Me, 17 were embedded in the intervention design. Eleven were from a dietary taxonomy and 6 from a smoking cessation taxonomy. In addition, the 4-category smoking cessation framework structure was adopted for clarity of communication. Smoking cessation texts were adapted for dietary use where necessary. A posteriori, a further 9 techniques were included. Examination of excluded items highlighted the distinction between techniques considered appropriate for face-to-face vs internet-based delivery. Conclusions: The use of existing taxonomies facilitated the description and standardization of techniques used in Food4Me. We recommend that for complex studies of this nature, technique analysis should be conducted a priori to develop standardized procedures and training, and reviewed a posteriori to audit the techniques actually adopted. The present framework description makes a valuable contribution to future systematic reviews and meta-analyses which explore technique efficacy and underlying psychological constructs. This was a novel application of the behavior change taxonomies, and was the first internet-based personalized nutrition intervention to use such a framework remotely

Estrogen treatment prevents gray matter atrophy in experimental autoimmune encephalomyelitis

Gray matter atrophy is an important correlate to clinical disability in multiple sclerosis (MS), and many treatment trials include atrophy as an outcome measure. Atrophy has been shown to occur in experimental autoimmune encephalomyelitis (EAE), the most commonly used animal model of MS. The clinical severity of EAE is reduced in estrogen-reated mice, but it remains unknown whether estrogen treatment can reduce gray matter atrophy in EAE. In this study, mice with EAE were treated with either estrogen receptor (ER)-α ligand or ER-β ligand, and diffusion tensor images (DTI) were collected and neuropathology was performed. DTI showed atrophy in the cerebellar gray matter of vehicle-treated EAE mice compared with healthy controls but not in ER-α or ER-β ligand-treated EAE mice. Neuropathology demonstrated that Purkinje cell numbers were decreased in vehicle-treated EAE mice, whereas neither ER ligand-treated EAE groups showed a decrease. This is the first report of a neuroprotective therapy in EAE that unambiguously prevents gray matter atrophy while sparing a major neuronal cell type. Fractional anisotropy (FA) in the cerebellar white matter was decreased in vehicle- and ER-β ligand-treated but not in ER-α ligand-treated EAE mice. Inflammatory cell infiltration was increased in vehicle- and ER-β ligand-treated but not in ER-α ligand-treated EAE mice. Myelin staining was decreased in vehicle-treated EAE mice and was spared in both ER ligand-treated groups. This is consistent with decreased FA as a potential biomarker for inflammation rather than myelination or axonal damage in the cerebellum in EAE

Evaluation of 22 genetic variants with Crohn's Disease risk in the Ashkenazi Jewish population: a case-control study

<p>Abstract</p> <p>Background</p> <p>Crohn's disease (CD) has the highest prevalence among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Caucasian populations (NJ). We evaluated a set of well-established CD-susceptibility variants to determine if they can explain the increased CD risk in the AJ population.</p> <p>Methods</p> <p>We recruited 369 AJ CD patients and 503 AJ controls, genotyped 22 single nucleotide polymorphisms (SNPs) at or near 10 CD-associated genes, <it>NOD2</it>, <it>IL23R</it>, <it>IRGM</it>, <it>ATG16L1</it>, <it>PTGER4</it>, <it>NKX2-3</it>, <it>IL12B</it>, <it>PTPN2</it>, <it>TNFSF15 </it>and <it>STAT3</it>, and assessed their association with CD status. We generated genetic scores based on the risk allele count alone and the risk allele count weighed by the effect size, and evaluated their predictive value.</p> <p>Results</p> <p>Three <it>NOD2 </it>SNPs, two <it>IL23R </it>SNPs, and one SNP each at <it>IRGM </it>and <it>PTGER4 </it>were independently associated with CD risk. Carriage of 7 or more copies of these risk alleles or the weighted genetic risk score of 7 or greater correctly classified 92% (allelic count score) and 83% (weighted score) of the controls; however, only 29% and 47% of the cases were identified as having the disease, respectively. This cutoff was associated with a >4-fold increased disease risk (p < 10e-16).</p> <p>Conclusions</p> <p>CD-associated genetic risks were similar to those reported in NJ population and are unlikely to explain the excess prevalence of the disease in AJ individuals. These results support the existence of novel, yet unidentified, genetic variants unique to this population. Understanding of ethnic and racial differences in disease susceptibility may help unravel the pathogenesis of CD leading to new personalized diagnostic and therapeutic approaches.</p