Objective To use genetic variants as unconfounded proxies of C reactive protein concentration to study its causal role in coronary heart disease. Design Mendelian randomisation meta-analysis of individual participant data from 47 epidemiological studies in 15 countries. Participants 194 418 participants, including 46 557 patients with prevalent or incident coronary heart disease. Information was available on four CRP gene tagging single nucleotide polymorphisms (rs3093077, rs1205, rs1130864, rs1800947), concentration of C reactive protein, and levels of other risk factors. Main outcome measures Risk ratios for coronary heart disease associated with genetically raised C reactive protein versus risk ratios with equivalent differences in C reactive protein concentration itself, adjusted for conventional risk factors and variability in risk factor levels within individuals. Results CRP variants were each associated with up to 30% per allele difference in concentration of C reactive protein (P<10 −34) and were unrelated to other risk factors. Risk ratios for coronary heart disease per additional copy of an allele associated with raised C reactive protein were 0.93 (95% confidence interval 0.87 to 1.00) for rs3093077; 1.00 (0.98 to 1.02) for rs1205; 0.98 (0.96 to 1.00) for rs1130864; and 0.99 (0.94 to 1.03) for rs1800947. In a combined analysis, the risk ratio for coronary heart disease was 1.00 (0.90 to 1.13) per 1 SD higher genetically raised natural log (ln) concentration of C reactive protein. The genetic findings were discordant with the risk ratio observed for coronary heart disease of 1.33 (1.23 to 1.43) per 1 SD higher circulating ln concentration of C reactive protein in prospective studies (P=0.001 for difference). Conclusion Human genetic data indicate that C reactive protein concentration itself is unlikely to be even a modest causal factor in coronary heart disease.
Rationale: The Scleroderma Lung Study II (SLS II) demonstrated significant improvements in pulmonary function and dyspnea at 24 months compared with baseline when patients with symptomatic scleroderma-related interstitial lung disease (SSc-ILD) were treated with either cyclophosphamide for 1 year (followed for another year on placebo) or mycophenolate mofetil for 2 years in a randomized, double-blind clinical trial. Physiologic and clinical outcomes of SLS II have been published previously. Objectives: The aim of the study was to assess changes from baseline in the extent of SSc-ILD on high-resolution computed tomography (HRCT) measured in the SLS II participants using quantitative image analysis after 2 years and to determine whether these HRCT changes were correlated with the changes in physiologic and clinical measures over the same time interval. Methods: Ninety-seven of the 142 randomized subjects (cyclophosphamide group, 47 subjects; mycophenolate mofetil group, 50 subjects) participating in SLS II underwent thoracic volumetric thin-section HRCT at both baseline and 24 months. Quantitative computer-aided diagnosis scores using volumetric HRCT scans were obtained using a previously developed computeraided system. The scores were quantitative lung fibrosis, quantitative ground glass, quantitative honeycomb, and quantitative interstitial lung disease (QILD), the latter representing the sum of quantitative lung fibrosis, quantitative ground glass, and quantitative honeycomb. These scores were obtained both for the whole lung and for individual lobes. Paired t tests were used for the combined (pooled) cyclophosphamide and mycophenolate mofetil groups to compare 24-month changes from baseline in both the whole lung and the lobe of maximal involvement as determined at baseline (worst lobe). Results: At the end of the 24-month trial, QILD in the whole lung was significantly reduced by a mean of 2.51% in the pooled groups (adjusted 95% confidence interval, 24.00 to 21.03%; P = 0.001). There was no significant difference in the QILD score improvement between the cyclophosphamide (22.66%) and mycophenolate (22.38%) groups when assessed separately (P = 0.88). For the pooled group, the 24-month changes in QILD scores in the whole lung correlated significantly with other outcomes, including 24-month changes in forced vital capacity (r = 20.37), single-breath diffusing capacity of the lung for carbon monoxide (r = 20.22), and breathlessness as measured by the Transition Dyspnea Index (r = 20.26). Conclusions: Treatment of SSc-ILD with either cyclophosphamide for 1 year, followed by placebo for a second year, or mycophenolate for 2 years was associated with a significant reduction (improvement) in the extent of HRCT SSc-ILD assessed by computer-aided diagnosis scores, which correlated well with one or more other measures of treatment response. These findings demonstrate that actual changes in lung structure accompany improvements in physiologic and/or symptomatic measures in SSc-ILD.
The heat shock response of a fish which inhabits a highly stressful environment (Poeciliopsis lucida, a minnow from river systems of the Sonoran desert in northwestern Mexico) was investigated. Cells derived from this fish exhibited a typical heat shock response when exposed to elevated temperature, synthesizing high levels of 90 kDa, 70 kDa, and 30 kDa heat shock proteins (Hsp90, Hsp70, and Hsp30), as well as lower amounts of other heat shock proteins. Additional small heat shock proteins (sHSPs), including Hsp27, were induced after a prolonged heat shock at a time when synthesis of Hsp70 and Hsp30 was decreasing. Characterization of cDNA clones for hsp27 and hsp30 revealed that both are members of the alpha-crystallin/sHSP superfamily but belong to separate lineages within this gene family. The multiple isoforms of P. lucida Hsp30 appear to be members of a multigene family and are most closely related to salmon and Xenopus Hsp30s. In contrast, Hsp27 is highly similar to mammalian and avian sHSPs; it was synthesized as three isoforms which represented differentially phosphorylated forms of a single polypeptide. In Poeciliopsis, the various sHSPs may each perform a subset of the roles attributed to mammalian sHSPs. The conservation of phosphorylation sites in Hsp27 may indicate an involvement in signal transduction to the actin cytoskeleton. The hsp30 genes appear to have diverged more rapidly than the corresponding hsp27 genes; the various members of the Hsp30 family may function as molecular chaperones and, in this role, may be less evolutionarily constrained. Finally, the presence of these two classes of sHSP in a single taxon indicates that these two lineages arose by gene duplication early in the evolution of vertebrates and raises questions about the fate of homologs of Hsp30 in mammals and of Hsp27 in Xenopus.
Introduction Among individuals with schizophrenia, those who have persistent and clinically significant negative symptoms (PNS) have the poorest functional outcomes and quality of life. The NIMH-MATRICS Consensus Statement indicated that these symptoms represent an unmet therapeutic need for large numbers of individuals with schizophrenia. No psychosocial treatment model addresses the entire constellation of PNS. Method 51 patients with PNS were randomized into one of two groups for a period of 9 months: 1) MOtiVation and Engagement (MOVE) or 2) Treatment as usual. MOVE is a home based, manual-driven, multi-modal treatment that employs a number of cognitive and behavioral principles to address the broad range of factors contributing to PNS and their functional consequences. Components of MOVE include: Environmental supports to prompt initiation and persistence, in-vivo skills training to ameliorate deficits and encourage interaction, cognitive behavioral techniques to address self-defeating attitudes, in-vivo training in emotional processing to address affective blunting and problems in identifying emotions, and specific techniques to address the deficits in anticipatory pleasure. Patients were assessed at baseline and each 3 months with multiple measures of negative symptoms. Results Repeated measures analyses of variance for mixed models indicated significant Group by Time effects for the Negative Symptom Assessment (NSA; p<.02) and the Clinical Assessment Interview for Negative Symptoms (CAINS p<.04). Group differences were not significant until 9 months of treatment and were not significant for the Brief Negative Symptom Scale (BNSS). Conclusion Further investigation of a comprehensive treatment for PNS, such as MOVE, is warranted.
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