Elevated peritoneal expression and estrogen regulation of nociceptive ion channels in endometriosis

CONTEXT: Ovarian suppression is a common treatment for endometriosis-associated pelvic pain. Its exact mechanism of action is poorly understood, although it is assumed to reflect reduced production/action of estrogens. OBJECTIVE: The objective of the study was to measure the expression of mRNAs encoded by nociceptive genes in the peritoneum of women with chronic pelvic pain (CPP) with or without endometriosis and to investigate whether estrogens alter nociceptive gene expression in human sensory neurons. DESIGN: The study was performed using human tissue analysis and cell culture. SETTING: The study was conducted at a university research institute. PATIENTS: Peritoneal biopsies were obtained from women with CPP and endometriosis (n = 12), CPP and no endometriosis (n = 10), and no pain or endometriosis (n = 5). Endometriosis lesions were obtained from women with endometriosis (n = 18). MAIN OUTCOME MEASURES: mRNAs encoding ion channels (P2RX3, SCN9A, SCN11A, TRPA1, TRPV1) and the neurotransmitter TAC1 were measured in human tissue samples and in human embryonic stem cell-derived sensory neurons treated with estrogens. RESULTS: TRPV1, TRPA1, and SCN11A mRNAs were significantly higher in the peritoneum from women with endometriosis (P < .001, P < .01). TRPV1, SCN9A, and TAC1 were elevated in endometriosis lesions (P < .05). P2RX3 mRNA was increased in the peritoneum of women with CPP, with and without endometriosis (P < .05). Incubation of sensory neurons with 17β-estradiol increased TRPV1 mRNA (P < .01). The estrogen receptor-β-selective agonist 2,3-bis(4-hydroxy-phenyl)-propionitrile increased concentrations of TRPV1, P2RX3, SCN9A, and TAC1 mRNAs. CONCLUSIONS: Estrogen-dependent expression of TRPV1 in sensory neurons may explain why ovarian suppression can reduce endometriosis-associated pain. Strategies directly targeting ion channels may offer an alternative option for the management of CPP

Change in Cone Structure Over 24 Months in USH2A-Related Retinal Degeneration

Purpose: To describe cone structure changes using adaptive optics scanning laser ophthalmoscopy (AOSLO) in the Rate of Progression of USH2A-related Retinal Degeneration (RUSH2A) study. Design: Multicenter, longitudinal natural history study. Methods: AOSLO images were acquired at 4 centers, twice at baseline and annually for 24 months in this natural history study. For each eye, at least 10 regions of interest (ROIs) with ≥50 contiguous cones were analyzed by masked, independent graders. Cone spacing Z-scores, standard deviations from the normal mean at the measured location, were compared between graders and tests at baseline. The association of cone spacing with clinical characteristics was assessed using linear mixed effects regression models weighted by image quality score. Annual rates of change were calculated based on differences between visits. Results: Fourteen eyes of 14 participants were imaged, with 192 ROIs selected at baseline. There was variability among graders, which was greater in images with lower image quality score (P < .001). Cone spacing was significantly correlated with eccentricity, quality score, and disease duration (P < .02). On average, the cone spacing Z-score increased 0.14 annually (about 9%, P < .001). We observed no significant differences in rate of change between disease type (Usher syndrome or retinitis pigmentosa), imaging site, or grader. Conclusions: Using current methods, the analysis of quantitative measures of cone structure showed some challenges, yet showed promise that AOSLO images can be used to characterize progressive change over 24 months. Additional multicenter studies using AOSLO are needed to advance cone mosaic metrics as sensitive outcome measures for clinical trials

Holistic corpus-based dialectology

This paper is concerned with sketching future directions for corpus-based dialectology. We advocate a holistic approach to the study of geographically conditioned linguistic variability, and we present a suitable methodology, 'corpusbased dialectometry', in exactly this spirit. Specifically, we argue that in order to live up to the potential of the corpus-based method, practitioners need to (i) abandon their exclusive focus on individual linguistic features in favor of the study of feature aggregates, (ii) draw on computationally advanced multivariate analysis techniques (such as multidimensional scaling, cluster analysis, and principal component analysis), and (iii) aid interpretation of empirical results by marshalling state-of-the-art data visualization techniques. To exemplify this line of analysis, we present a case study which explores joint frequency variability of 57 morphosyntax features in 34 dialects all over Great Britain

Online Hate: From the Far-Right to the ‘Alt-Right’, and from the Margins to the Mainstream

In the 1990s and early 2000s, there was much discussion about the democratic and anti-democratic implications of the Internet. The latter particularly focused on the ways in which the far-right were using the Internet to spread hate and recruit members. Despite this common assumption, the American far-right did not harness the Internet quickly, effectively or widely. More recently, however, they have experienced a resurgence and mainstreaming, benefitting greatly from social media. This chapter examines the history of their use of the Internet with respect to: (1) how this developed in response to political changes and emerging technologies; (2) how it reflected and changed the status of such movements and their brand of hate; and (3) the relationship between online activity and traditional methods of communication

The translation, validity and reliability of the German version of the Fremantle Back Awareness Questionnaire

Background: The Fremantle Back Awareness Questionnaire (FreBAQ) claims to assess disrupted self-perception of the back. The aim of this study was to develop a German version of the Fre-BAQ (FreBAQ-G) and assess its test-retest reliability, its known-groups validity and its convergent validity with another purported measure of back perception. Methods: The FreBaQ-G was translated following international guidelines for the transcultural adaptation of questionnaires. Thirty-five patients with non-specific CLBP and 48 healthy participants were recruited. Assessor one administered the FreBAQ-G to each patient with CLBP on two separate days to quantify intra-observer reliability. Assessor two administered the FreBaQ-G to each patient on day 1. The scores were compared to those obtained by assessor one on day 1 to assess inter-observer reliability. Known-groups validity was quantified by comparing the FreBAQ-G score between patients and healthy controls. To assess convergent validity, patient\u27s FreBAQ-G scores were correlated to their two-point discrimination (TPD) scores. Results: Intra- and Inter-observer reliability were both moderate with ICC3.1 = 0.88 (95%CI: 0.77 to 0.94) and 0.89 (95%CI: 0.79 to 0.94), respectively. Intra- and inter-observer limits of agreement (LoA) were 6.2 (95%CI: 5.0±8.1) and 6.0 (4.8±7.8), respectively. The adjusted mean difference between patients and controls was 5.4 (95%CI: 3.0 to 7.8, p\u3c0.01). Patient\u27s FreBAQ-G scores were not associated with TPD thresholds (Pearson\u27s r = -0.05, p = 0.79). Conclusions: The FreBAQ-G demonstrated a degree of reliability and known-groups validity. Interpretation of patient level data should be performed with caution because the LoA were substantial. It did not demonstrate convergent validity against TPD. Floor effects of some items of the FreBAQ-G may have influenced the validity and reliability results. The clinimetric properties of the FreBAQ-G require further investigation as a simple measure of disrupted self-perception of the back before firm recommendations on its use can be made

Muscle dysmorphia: Could it be classified as an addiction to body image?

BACKGROUND: Muscle dysmorphia (MD) describes a condition characterised by a misconstrued body image in which individuals who interpret their body size as both small or weak even though they may look normal or highly muscular. MD has been conceptualized as a type of body dysmorphic disorder, an eating disorder, and obsessive–compulsive disorder symptomatology. METHOD AND AIM: Through a review of the most salient literature on MD, this paper proposes an alternative classification of MD – the ‘Addiction to Body Image’ (ABI) model – using Griffiths (2005) addiction components model as the framework in which to define MD as an addiction. RESULTS: It is argued the addictive activity in MD is the maintaining of body image via a number of different activities such as bodybuilding, exercise, eating certain foods, taking specific drugs (e.g., anabolic steroids), shopping for certain foods, food supplements, and the use or purchase of physical exercise accessories). In the ABI model, the perception of the positive effects on the self-body image is accounted for as a critical aspect of the MD condition (rather than addiction to exercise or certain types of eating disorder). CONCLUSIONS: Based on empirical evidence to date, it is proposed that MD could be re-classified as an addiction due to the individual continuing to engage in maintenance behaviours that may cause long-term harm

Chronic intermittent hypoxia induces local inflammation of the rat carotid body via functional upregulation of proinflammatory cytokine pathways

Maladaptive changes in the carotid body (CB) induced by chronic intermittent hypoxia (IH) account for the pathogenesis of cardiovascular morbidity in patients with sleep-disordered breathing. We postulated that the proinflammatory cytokines, namely interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α, and cytokine receptors (IL-1r1, gp130 and TNFr1) locally expressed in the rat CB play a pathophysiological role in IH-induced CB inflammation. Results showed increased levels of oxidative stress (serum 8-isoprostane and nitrotyrosine in the CB) in rats with 7-day IH treatment resembling recurrent apneic conditions when compared with the normoxic control. Local inflammation shown by the amount of ED1-containing cells (macrophage infiltration) and the gene transcripts of NADPH oxidase subunits (gp91phox and p22phox) and chemokines (MCP-1, CCR2, MIP-1α, MIP-1β and ICAM-1) in the CB were significantly more in the hypoxic group than in the control. In addition, the cytokines and receptors were expressed in the lobules of chemosensitive glomus cells containing tyrosine hydroxylase and the levels of expressions were significantly increased in the hypoxic group. Exogenous cytokines elevated the intracellular calcium ([Ca2+]i) response to acute hypoxia in the dissociated glomus cells. The effect of cytokines on the [Ca2+]i response was significantly greater in the hypoxic than in the normoxic group. Moreover, daily treatment of IH rats with anti-inflammatory drugs (dexamethasone or ibuprofen) attenuated the levels of oxidative stress, gp91phox expression and macrophage infiltration in the CB. Collectively, these results suggest that the upregulated expression of proinflammatory cytokine pathways could mediate the local inflammation and functional alteration of the CB under chronic IH conditions

Albiglutide, a Long Lasting Glucagon-Like Peptide-1 Analog, Protects the Rat Heart against Ischemia/Reperfusion Injury: Evidence for Improving Cardiac Metabolic Efficiency

BACKGROUND: The cardioprotective effects of glucagon-like peptide-1 (GLP-1) and analogs have been previously reported. We tested the hypothesis that albiglutide, a novel long half-life analog of GLP-1, may protect the heart against I/R injury by increasing carbohydrate utilization and improving cardiac energetic efficiency. METHODS/PRINCIPAL FINDINGS: Sprague-Dawley rats were treated with albiglutide and subjected to 30 min myocardial ischemia followed by 24 h reperfusion. Left ventricle infarct size, hemodynamics, function and energetics were determined. In addition, cardiac glucose disposal, carbohydrate metabolism and metabolic gene expression were assessed. Albiglutide significantly reduced infarct size and concomitantly improved post-ischemic hemodynamics, cardiac function and energetic parameters. Albiglutide markedly increased both in vivo and ex vivo cardiac glucose uptake while reducing lactate efflux. Analysis of metabolic substrate utilization directly in the heart showed that albiglutide increased the relative carbohydrate versus fat oxidation which in part was due to an increase in both glucose and lactate oxidation. Metabolic gene expression analysis indicated upregulation of key glucose metabolism genes in the non-ischemic myocardium by albiglutide. CONCLUSION/SIGNIFICANCE: Albiglutide reduced myocardial infarct size and improved cardiac function and energetics following myocardial I/R injury. The observed benefits were associated with enhanced myocardial glucose uptake and a shift toward a more energetically favorable substrate metabolism by increasing both glucose and lactate oxidation. These findings suggest that albiglutide may have direct therapeutic potential for improving cardiac energetics and function