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The aim of this study was to evaluate the effect of haemophilia disease severity and potential intermediaries on body mass index (BMI) in patients with haemophilia. A secondary analysis of a cross‐sectional study of 88 adults with haemophilia was undertaken. On bivariate analysis, persons with severe haemophilia had 9.8% lower BMI (95% CI ?17.1, ?3.0) than persons with non‐severe haemophilia. The effect of haemophilia severity on BMI varied significantly by human immunodeficiency virus (HIV) status. Among HIV‐positive subjects, haemophilia severity was not associated with BMI (+5.0%, 95% CI ?22.4, 41.9). Among HIV‐negative subjects, severe haemophilia was associated with 15.1% lower BMI (95% CI, ?23.6, ?5.7). Older (>41 years) HIV‐negative subjects with severe haemophilia had a BMI that was 24.8% lower (95% CI ?39.1, ?7.0) than those with non‐severe haemophilia. No statistically significant association was detected between BMI and severe vs. non‐severe haemophilia for younger HIV‐negative subjects. Although joint disease, as measured by the World Federation of Hemophilia (WFH) joint score, did not influence the association between haemophilia disease severity and BMI, adjustment for the atrophy component of the WFH score reduced the association between haemophilia severity and BMI by 39.1–69.9%. This suggested that muscle atrophy mediated at least part of the relationship between haemophilia severity and BMI. Haemophilia disease severity is associated with BMI and appears to be mediated by muscle atrophy of surrounding joints. This association appears to be modified by HIV status and possibly age. 相似文献
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Lili Zhang Marianne Gallup Lorna Zlock Yu Ting Feeling Chen Walter E Finkbeiner Nancy A McNamara 《The Journal of pathology》2014,234(1):60-73
Cigarette smoke increases the risk of lung cancer by 20‐fold and accounts for 87% of lung cancer deaths. In the normal airway, heavily O‐glycosylated mucin‐1 (MUC1) and adherens junctions (AJs) establish a structural barrier that protects the airway from infectious, inflammatory and noxious stimuli. Smoke disrupts cell–cell adhesion via its damaging effects on the AJ protein epithelial cadherin (E‐cad). Loss of E‐cad is a major hallmark of epithelial–mesenchymal transition (EMT) and has been reported in lung cancer, where it is associated with invasion, metastasis and poor prognosis. Using organotypic cultures of primary human bronchial epithelial (HBE) cells treated with smoke‐concentrated medium (Smk), we have demonstrated that E‐cad loss is regulated through the aberrant interaction of its AJ binding partner, p120‐catenin (p120ctn), and the C‐terminus of MUC1 (MUC1‐C). Here, we reported that even before MUC1‐C became bound to p120ctn, smoke promoted the generation of a novel 400 kDa glycoform of MUC1's N‐terminus (MUC1‐N) differing from the 230 kDa and 150 kDa glycoforms in untreated control cells. The subsequent smoke‐induced, time‐dependent shedding of glycosylated MUC1‐N exposed MUC1‐C as a putative receptor for interactions with EGFR, Src and p120ctn. Smoke‐induced MUC1‐C glycosylation modulated MUC1‐C tyrosine phosphorylation (TyrP) that was essential for MUC1‐C/p120ctn interaction through dose‐dependent bridging of Src/MUC1‐C/galectin‐3/EGFR signalosomes. Chemical deglycosylation of MUC1 using a mixture of N‐glycosylation inhibitor tunicamycin and O‐glycosylation inhibitor benzyl‐α‐GalNAc disrupted the Src/MUC1‐C/galectin‐3/EGFR complexes and thereby abolished smoke‐induced MUC1‐C‐TyrP and MUC1‐C/p120ctn interaction. Similarly, inhibition of smoke‐induced MUC1‐N glycosylation using adenoviral shRNA directed against N‐acetyl‐galactosaminyl transferase‐6 (GALNT6, an enzyme that controls the initiating step of O‐glycosylation) successfully suppressed MUC1‐C/p120ctn interaction, prevented E‐cad degradation and maintained cellular polarity in response to smoke. Thus, GALNT6 shRNA represents a potential therapeutic modality to prevent the initiation of events associated with EMT in the smoker's airway. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. 相似文献
75.
Paul S. Gunning Ted J. Vaughan Laoise M. McNamara 《Annals of biomedical engineering》2014,42(9):1989-2001
Self expanding Transcatheter Aortic Valve Replacements (TAVR) can conform to the geometry of the aortic annulus and the calcified leaflet complex, which may result in leaflet distortion and altered leaflet kinematics, but such changes have not yet been characterized. In this study we developed a computational model to investigate the deployment of a self expanding TAVR in a realistic aortic root model derived from multi-slice computed tomography (MSCT) images. We simulated TAVR crimping/deployment in realistic and idealized aortic root models, followed by diastolic loading of the TAVR leaflets in its final deployed configuration. The TAVR deployed in a realistic aortic root had increased peak loading in the commissural region of the leaflets compared to TAVRs under idealized circular deployment conditions (2.97 vs. 1.52 MPa). Furthermore, orientation of the TAVR in the asymmetric aortic annulus such that the commissures of the TAVR are aligned with the native valve commissures minimized the effect of TAVR stent distortion on peak stresses in the TAVR leaflets (2.97 vs. 2.35 MPa). We propose that preoperative planning of the orientation of the TAVR in the aortic root annulus might minimize the impact of potential stent distortion on leaflet function and may in turn increase long term leaflet durability. 相似文献
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Monitoring respiratory status in cystic fibrosis (CF) is challenging, particularly in young children. We aimed to test whether the Liverpool Respiratory Symptom Questionnaire (LRSQ) could distinguish well, pre-school and older children with and without CF, whether it could distinguish well and unwell children with CF and, finally, whether LRSQ scores in older children with CF correlated with established measures of disease severity. 20 stable pre-school children with CF had significantly higher total LRSQ scores than 51 pre-school controls, and higher scores in two out of eight domains. Similarly, 21 stable 6- to 12-yr-old children with CF had higher total scores than 97 6- to 12-yr-old controls, and higher scores in seven out of eight domains. In older children with CF, LRSQ scores correlated negatively with Shwachman score and forced expiratory volume in 1 s (r = -0.58, p < 0.001, n = 31; and r = -0.46, p < 0.010, n = 34, respectively). Within the CF group, patients who cultured Pseudomonas aeruginosa, who used more "back-up" antibiotics or whose school attendance was lower also had higher LRSQ scores. The LRSQ differentiates well children from those with CF in both pre-school and the 6- to 12-yr-old age group, even at a point of stability. It also differentiates stable from unwell children with CF, and scores correlate with other measures of respiratory disease, highlighting its potential as a clinical monitoring tool in paediatric CF. 相似文献
80.
Rollman BL Herbeck Belnap B Mazumdar S Houck PR He F Alvarez RJ Schulberg HC Reynolds CF McNamara DM 《Journal of cardiac failure》2012,18(3):238-245
BackgroundGiven the association of depression with poorer cardiac outcomes, an American Heart Association Science Advisory has advocated routine screening of cardiac patients for depression using the 2-item Patient Health Questionnaire (PHQ-2) “at a minimum.” However, the prognostic value of the PHQ-2 among HF patients is unknown.Methods and ResultsWe screened hospitalized HF patients (ejection fraction [EF] <40%) that staff suspected may be depressed with the PHQ-2, and then determined vital status at up to 12-months follow-up. At baseline, PHQ-2 depression screen–positive patients (PHQ-2+; n = 371), compared with PHQ-2 screen–negative patients (PHQ-2?; n = 100), were younger (65 vs 70 years) and more likely to report New York Heart Association (NYHA) functional class III/IV than class II symptoms (67% vs. 39%) and lower levels of physical and mental health–related quality of life (all P ≤ .002); they were similar in other characteristics (65% male, 26% mean EF). At 12 months, 20% of PHQ-2+ versus 8% of PHQ-2? patients had died (P = .007) and PHQ-2 status remained associated with both all-cause (hazard ratio [HR] 3.1, 95% confidence interval [CI] 1.4–6.7; P = .003) and cardiovascular (HR 2.7, 95% CI 1.1–6.6; P = .03) mortality even after adjustment for age, gender, EF, NYHA functional class, and a variety of other covariates.ConclusionsAmong hospitalized HF patients, a positive PHQ-2 depression screen is associated with an elevated 12-month mortality risk. 相似文献