Developmental hypomyelination in Wolfram syndrome: New insights from neuroimaging and gene expression analyses

Wolfram syndrome is a rare multisystem disorder caused by mutations in WFS1 or CISD2 genes leading to brain structural abnormalities and neurological symptoms. These abnormalities appear in early stages of the disease. The pathogenesis of Wolfram syndrome involves abnormalities in the endoplasmic reticulum (ER) and mitochondrial dynamics, which are common features in several other neurodegenerative disorders. Mutations in WFS1 are responsible for the majority of Wolfram syndrome cases. WFS1 encodes for an endoplasmic reticulum (ER) protein, wolframin. It is proposed that wolframin deficiency triggers the unfolded protein response (UPR) pathway resulting in an increased ER stress-mediated neuronal loss. Recent neuroimaging studies showed marked alteration in early brain development, primarily characterized by abnormal white matter myelination. Interestingly, ER stress and the UPR pathway are implicated in the pathogenesis of some inherited myelin disorders like Pelizaeus-Merzbacher disease, and Vanishing White Matter disease. In addition, exploratory gene-expression network-based analyses suggest that WFS1 expression occurs preferentially in oligodendrocytes during early brain development. Therefore, we propose that Wolfram syndrome could belong to a category of neurodevelopmental disorders characterized by ER stress-mediated myelination impairment. Further studies of myelination and oligodendrocyte function in Wolfram syndrome could provide new insights into the underlying mechanisms of the Wolfram syndrome-associated brain changes and identify potential connections between neurodevelopmental disorders and neurodegeneration

Antipodean Intimacies: Medical Sex Advice for Women in the Australian colonies, 1857-1890

This article examines a genre of medical sex advice literature that emerged in colonial Australia at the close of the 19th century. While historians have examined medical discourse as a site for the production of raced bodies, this article points out that in the settler colonial context of Australia, what is notable is the systematic *absence* of Aboriginal people from this discourse

Fecal microbiota transplants: Emerging social representations in the English-language print media

open access articleThis study investigates how English-language news sources have represented fecal microbiota transplants (FMT). FMT involves transferring stool from a healthy donor to a recipient with a dysfunctional intestinal flora in order to repopulate their gut microbiome. FMT applications are increasingly moving into mainstream clinical care. We investigate press coverage of stool transplants, as well as broader themes associated with health and the gut microbiome, in order to uncover emerging social representations. Our findings show that print media focused in particular on creating novel, mainly hopeful, social representations of feces through wordplay and punning, side-lining issues of risk and fear. We also identify changing metaphorical framings of microbes and bacteria from ‘enemies’ to ‘friends’, and ways in which readers are familiarized with FMT through the depiction of the process as both mundane and highly medicalized

Intimate Partner Violence and Disabilities among Women Attending Family Practice Clinics

Purpose: To estimate the frequency and type of disabilities preventing work among those experiencing intimate partner violence (IPV) compared with those never experiencing IPV. Methods: We used a large cross-sectional survey of women, ages 18–65, attending family practice clinics from 1997 through 1998. Participation included a 5–10-minute in-clinic survey assessing IPV experience and a longer telephone survey assessing health status and chronic disabilities that prevented work outside the home or housework. Results: Of 1,152 eligible women surveyed, 54% experienced some type of IPV, and 24% were currently in a violent relationship. Women who had ever experienced IPV were more than twice as likely to report a disability (adjusted odds ratio [aOR] _ 2.2, 95% confidence interval [CI] 1.6, 3.0). The most commonly reported disabilities were those associated with heart or circulatory disease (4.9%), followed by back problems (3.5%), chronic pain (3.4%), arthritis (3.0%), nerve system damage (2.4%), asthma or another respiratory problem including emphysema (1.7%), and either depression (1.6%) or another mental illness (1.0%). Women ever experiencing IPV were more likely to report a disability due to generalized chronic pain (aOR _ 2.5, 95% CI 1.5, 4.3) and mental illness (aOR _ 4.5, 95% CI 1.5, 13.1). IPV-related injuries were associated in a dose-dependent manner with having any disability and with disability from chronic pain, asthma and other respiratory diseases, mental illness, and chronic diseases. Conclusions: Primary care-based efforts to screen for IPV and effectively intervene to reduce the impact of IPV on women’s lives must be a public health priority to reduce the shortterm and long-term health effects, including disabilities

A novel hypothesis-unbiased method for gene ontology enrichment based on transcriptome data

Gene Ontology (GO) classification of statistically significantly differentially expressed genes is commonly used to interpret transcriptomics data as a part of functional genomic analysis. In this approach, all significantly expressed genes contribute equally to the final GO classification regardless of their actual expression levels. Gene expression levels can significantly affect protein production and hence should be reflected in GO term enrichment. Genes with low expression levels can also participate in GO term enrichment through cumulative effects. In this report, we have introduced a new GO enrichment method that is suitable for multiple samples and time series experiments that uses a statistical outlier test to detect GO categories with special patterns of variation that can potentially identify candidate biological mechanisms. To demonstrate the value of our approach, we have performed two case studies. Whole transcriptome expression profiles of Salmonella enteritidis and Alzheimer's disease (AD) were analysed in order to determine GO term enrichment across the entire transcriptome instead of a subset of differentially expressed genes used in traditional GO analysis. Our result highlights the key role of inflammation related functional groups in AD pathology as granulocyte colony-stimulating factor receptor binding, neuromedin U binding, and interleukin were remarkably upregulated in AD brain when all using all of the gene expression data in the transcriptome. Mitochondrial components and the molybdopterin synthase complex were identified as potential key cellular components involved in AD pathology.Mario Fruzangohar, Esmaeil Ebrahimie, David L. Adelso

Caspase-1 causes truncation and aggregation of the Parkinson's disease-associated protein α-synuclein

The aggregation of α-synuclein (aSyn) leading to the formation of Lewy bodies is the defining pathological hallmark of Parkinson's disease (PD). Rare familial PD-associated mutations in aSyn render it aggregation-prone; however, PD patients carrying wild type (WT) aSyn also have aggregated aSyn in Lewy bodies. The mechanisms by which WT aSyn aggregates are unclear. Here, we report that inflammation can play a role in causing the aggregation of WT aSyn. We show that activation of the inflammasome with known stimuli results in the aggregation of aSyn in a neuronal cell model of PD. The insoluble aggregates are enriched with truncated aSyn as found in Lewy bodies of the PD brain. Inhibition of the inflammasome enzyme caspase-1 by chemical inhibition or genetic knockdown with shRNA abated aSyn truncation. In vitro characterization confirmed that caspase-1 directly cleaves aSyn, generating a highly aggregation-prone species. The truncation-induced aggregation of aSyn is toxic to neuronal culture, and inhibition of caspase-1 by shRNA or a specific chemical inhibitor improved the survival of a neuronal PD cell model. This study provides a molecular link for the role of inflammation in aSyn aggregation, and perhaps in the pathogenesis of sporadic PD as well

Exploration of candidate serum biomarkers potentially related to the chronic pain condition in Medication-overuse headache

Background Medication Overuse Headache (MOH) is a prevalent and disabling disorder resulting from the overuse of analgesic drugs, triptans or other acute headache medications. In previous proteomic studies, several proteins have been found at high concentrations in the urine of MOH patients and in the serum of rats with neuropathic pain. The aim of this study was to compare the serum levels of lipocalin-type Prostaglandin D2 synthase (L-PGDS), Vitamin D-binding protein (VDBP), apolipoprotein E (APOE) and apolipoprotein A1 (APOA1) in MOH patients and healthy individuals, further exploring their relationship with cutaneous pain thresholds (CPTs) in the territories innervated by the trigeminal nerve. Methods 69 MOH patients and 42 age- and sex-matched healthy volunteers were enrolled in the study. Von Frey-like filaments were applied to the skin territories innervated by the trigeminal nerve, to determine the CPTs. L-PGDS, VDBP, APOE and APOA1 were quantified in the serum by Enzyme-linked Immunosorbent Assay (ELISA). Clinical and laboratory data were collected. Comparisons between MOH patients and healthy individuals were performed using independent t test or χ2 test. To correlate serum proteins with CPTs, Pearson correlation coefficient or Spearman's rank correlation coefficient were used. Results CPTs were lower among MOH patients. L-PGDS, VDBP and APOE had significantly different serum concentrations between groups (p < 0.01), but no correlation was found with CPTs. APOA1 serum concentrations did not differ between patients and healthy individuals. Conclusions L-PGDS, VDBP and APOE had abnormal serum levels in MOH patients, confirming their alteration in some conditions of chronic headache and neuropathic pain. The in-depth study of target proteins represents a promising approach for a better understanding of MOH, as well as the detection of candidate biomarkers for chronic headache or the risks associated with overuse medications

Panel criteria and working methods

"This document sets out the assessment criteria and working methods of the main and sub-panels for the 2014 Research Excellence Framework. The deadline for submissions is 29 November 2013" -- front cover

University College London/University of Gothenburg PhD course "Biomarkers in neurodegenerative diseases" 2019—course organisation

Biomarkers are increasingly employed for effective research into neurodegenerative diseases. They have become essential for reaching an accurate clinical diagnosis, monitoring disease, and refining entry criteria for participation in clinical treatment trials, and will be key in measuring target engagement and treatment outcome in disease-modifying therapies. Emerging techniques and research combining different biomarker modalities continue to strengthen our understanding of the underlying pathology and the sequence of pathogenic events. Given recent advances, we are now at a pivotal stage in biomarker research. PhD students working in the field of neurodegenerative disease require a working knowledge of a range of biomarkers available and their limitations, to correctly interpret scientific literature and to design and conduct successful research studies themselves. Here, we outline the University College London/University of Gothenburg “Biomarkers in neurodegenerative diseases course”, the first initiative of its kind aimed to bring together both experts and PhD students from all areas within the field of neurodegeneration, to provide comprehensive knowledge of biomarker research for the next generation of scientists