The final campaigns in the West Indies 1808‐1810

This dissertation discusses British strategic policy in the West Indies and the conquest of Martinique and the Battle of Les Saintes

The MS Remyelinating Drug Bexarotene (an RXR Agonist) Promotes Induction of Human Tregs and Suppresses Th17 Differentiation <i>In Vitro</i>.

Funder: Biotechnology and Biological Sciences Research CouncilFunder: Wellcome TrustFunder: NIHR Cambridge Biomedical Research CentreThe retinoid X receptor agonist bexarotene promotes remyelination in patients with multiple sclerosis. Murine studies have also demonstrated that RXR agonists have anti-inflammatory effects by enhancing the ability of all-trans-retinoic acid (atRA) to promote T-regulatory cell (Treg) induction and reduce Th17 differentiation in vitro. By stimulating human naïve CD4 T-cells in the presence of Treg or Th17 skewing cytokines, we show that bexarotene also tips the human Treg/Th17 axis in favor of Treg induction, but unlike murine cells this occurs independently of atRA and retinoic acid receptor signaling. Tregs induced in the presence of bexarotene express canonical markers of T-regulation and are functionally suppressive in vitro. Circulating Treg numbers did not increase in the blood of trial patients receiving bexarotene; we believe this is because Treg induction is likely to occur within tissues. These findings lend support to developing RXR agonists as treatments of autoimmune diseases, in particular multiple sclerosis

Patient factors associated with non-attendance at colonoscopy after a positive screening faecal occult blood test

BACKGROUND: Screening participants with abnormal faecal occult blood test results who do not attend further testing are at high risk of colorectal cancer, yet little is known about their reasons for non-attendance. METHODS: We conducted a medical record review of 170 patients from two English Bowel Cancer Screening Programme centres who had abnormal guaiac faecal occult blood test screening tests between November 2011 and April 2013 but did not undergo colonoscopy. Using information from patient records, we coded and categorized reasons for non-attendance. RESULTS: Of the 170 patients, 82 were eligible for review, of whom 66 had at least one recorded reason for lack of colonoscopy follow-up. Reasons fell into seven main categories: (i) other commitments, (ii) unwillingness to have the test, (iii) a feeling that the faecal occult blood test result was a false positive, (iv) another health issue taking priority, (v) failing to complete bowel preparation, (vi) practical barriers (e.g. lack of transport), and (vii) having had or planning colonoscopy elsewhere. The most common single reasons were unwillingness to have a colonoscopy and being away. CONCLUSIONS: We identify a range of apparent reasons for colonoscopy non-attendance after a positive faecal occult blood test screening. Education regarding the interpretation of guaiac faecal occult blood test findings, offer of alternative confirmatory test options, and flexibility in the timing or location of subsequent testing might decrease non-attendance of diagnostic testing following positive faecal occult blood test

Stochastic search and joint fine-mapping increases accuracy and identifies previously unreported associations in immune-mediated diseases

Abstract: Thousands of genetic variants are associated with human disease risk, but linkage disequilibrium (LD) hinders fine-mapping the causal variants. Both lack of power, and joint tagging of two or more distinct causal variants by a single non-causal SNP, lead to inaccuracies in fine-mapping, with stochastic search more robust than stepwise. We develop a computationally efficient multinomial fine-mapping (MFM) approach that borrows information between diseases in a Bayesian framework. We show that MFM has greater accuracy than single disease analysis when shared causal variants exist, and negligible loss of precision otherwise. MFM analysis of six immune-mediated diseases reveals causal variants undetected in individual disease analysis, including in IL2RA where we confirm functional effects of multiple causal variants using allele-specific expression in sorted CD4+ T cells from genotype-selected individuals. MFM has the potential to increase fine-mapping resolution in related diseases enabling the identification of associated cellular and molecular phenotypes

Idd9.2 and Idd9.3 Protective Alleles Function in CD4+ T-Cells and Nonlymphoid Cells to Prevent Expansion of Pathogenic Islet-Specific CD8+ T-Cells

OBJECTIVE - Multiple type 1 diabetes susceptibility genes have now been identified in both humans and mice, yet mechanistic understanding of how they impact disease pathogenesis is still minimal. We have sought to dissect the cellular basis for how the highly protective mouse Idd9 region limits the expansion of autoreactive CD8 T-cells, a key cell type in destruction of the islets. RESEARCH DESIGN AND METHODS - We assess the endogenous CD8 T-cell repertoire for reactivity to the islet antigen glucose-6-phosphatase-related protein (IGRP). Through the use of adoptively transferred T-cells, bone marrow chimeras, and reconstituted severe combined immunodeficient mice, we identify the protective cell types involved. RESULTS - IGRP-specific CD8 T-cells are present at low frequency in the insulitic lesions of Idd9 mice and could not be recalled in the periphery by viral expansion. We show that Idd9 genes act extrinsically to the CD8 T-cell to prevent the massive expansion of pathogenic effectors near the time of disease onset that occurs in NOD mice. The subregions Idd9.2 and Idd9.3 mediated this effect. Interestingly, the Idd9.1 region, which provides significant protection from disease, did not prevent the expansion of autoreactive CD8 T-cells. Expression of Idd9 genes was required by both CD4 T-cells and a nonlymphoid cell to induce optimal tolerance. CONCLUSIONS - Idd9 protective alleles are associated with reduced expansion of IGRP-specific CD8 T-cells. Intrinsic expression of protective Idd9 alleles in CD4 T-cells and nonlymphoid cells is required to achieve an optimal level of tolerance. Protective alleles in the Idd9.2 congenic subregion are required for the maximal reduction of islet-specific CD8 T-cells

Steady-state modulation of voltage-gated K+ channels in rat arterial smooth muscle by cyclic AMP-dependent protein kinase and protein phosphatase 2B

Voltage-gated potassium channels (Kv) are important regulators of membrane potential in vascular smooth muscle cells, which is integral to controlling intracellular Ca2+ concentration and regulating vascular tone. Previous work indicates that Kv channels can be modulated by receptor-driven alterations of cyclic AMP-dependent protein kinase (PKA) activity. Here, we demonstrate that Kv channel activity is maintained by tonic activity of PKA. Whole-cell recording was used to assess the effect of manipulating PKA signalling on Kv and ATP-dependent K+ channels of rat mesenteric artery smooth muscle cells. Application of PKA inhibitors, KT5720 or H89, caused a significant inhibition of Kv currents. Tonic PKA-mediated activation of Kv appears maximal as application of isoprenaline (a β-adrenoceptor agonist) or dibutyryl-cAMP failed to enhance Kv currents. We also show that this modulation of Kv by PKA can be reversed by protein phosphatase 2B/calcineurin (PP2B). PKA-dependent inhibition of Kv by KT5720 can be abrogated by pre-treatment with the PP2B inhibitor cyclosporin A, or inclusion of a PP2B auto-inhibitory peptide in the pipette solution. Finally, we demonstrate that tonic PKA-mediated modulation of Kv requires intact caveolae. Pre-treatment of the cells with methyl-β-cyclodextrin to deplete cellular cholesterol, or adding caveolin-scaffolding domain peptide to the pipette solution to disrupt caveolae-dependent signalling each attenuated PKA-mediated modulation of the Kv current. These findings highlight a novel, caveolae-dependent, tonic modulatory role of PKA on Kv channels providing new insight into mechanisms and the potential for pharmacological manipulation of vascular tone

Qigong Exercise Alleviates Fatigue, Anxiety, and Depressive Symptoms, Improves Sleep Quality, and Shortens Sleep Latency in Persons with Chronic Fatigue Syndrome-Like Illness

Objectives:. To evaluate the effectiveness of Baduanjin Qigong exercise on sleep, fatigue, anxiety, and depressive symptoms in chronic fatigue syndrome- (CFS-) like illness and to determine the dose-response relationship. Methods:. One hundred fifty participants with CFS-like illness (mean age = 39.0, SD = 7.9) were randomly assigned to Qigong and waitlist. Sixteen 1.5-hour Qigong lessons were arranged over 9 consecutive weeks. Pittsburgh Sleep Quality Index (PSQI), Chalder Fatigue Scale (ChFS), and Hospital Anxiety and Depression Scale (HADS) were assessed at baseline, immediate posttreatment, and 3-month posttreatment. The amount of Qigong self-practice was assessed by self-report. Results:. Repeated measures analyses of covariance showed a marginally nonsignificant (P = 0.064) group by time interaction in the PSQI total score, but it was significant for the “subjective sleep quality” and “sleep latency” items, favoring Qigong exercise. Improvement in “subjective sleep quality” was maintained at 3-month posttreatment. Significant group by time interaction was also detected for the ChFS and HADS anxiety and depression scores. The number of Qigong lessons attended and the amount of Qigong self-practice were significantly associated with sleep, fatigue, anxiety, and depressive symptom improvement. Conclusion:. Baduanjin Qigong was an efficacious and acceptable treatment for sleep disturbance in CFS-like illness. This trial is registered with Hong Kong Clinical Trial Register: HKCTR-1380