Congenital generalized lipodystrophy (CGL) and pulmonary arterial hypertension (PAH) have recently been associated with mutations in the caveolin-1 (CAV1) gene, which encodes the primary structural protein of caveolae. However, little is currently known about how these CAV1 mutations impact caveolae formation or contribute to the development of disease. Here, we identify a heterozygous F160X CAV1 mutation predicted to generate a C-terminally truncated mutant protein in a patient with both PAH and CGL using whole exome sequencing, and characterize the properties of CAV1, caveolae-associated proteins and caveolae in skin fibroblasts isolated from the patient. We show that morphologically defined caveolae are present in patient fibroblasts and that they function in mechanoprotection. However, they exhibited several notable defects, including enhanced accessibility of the C-terminus of wild-type CAV1 in caveolae, reduced colocalization of cavin-1 with CAV1 and decreased stability of both 8S and 70S oligomeric CAV1 complexes that are necessary for caveolae formation. These results were verified independently in reconstituted CAV1−/− mouse embryonic fibroblasts. These findings identify defects in caveolae that may serve as contributing factors to the development of PAH and CGL and broaden our knowledge of CAV1 mutations associated with human disease.
Background
Serum albumin concentration has been recognized as a marker of nutrition, severity of inflammation, and hepatic function in patients with various chronic diseases. The purpose of this study was to investigate the impact of pretransplant serum albumin concentration on post-transplant outcome in heart transplant recipients.
Methods and Results
Preoperative laboratory variables, including albumin concentration and donor-related information, were obtained from 822 consecutive patients undergoing heart transplant at Columbia University Medical Center between 1999 and 2010. The association between pretransplant albumin concentration and post-transplant 1-year survival was analyzed. Available data from the United Network for Organ Sharing (n=13 671) were also analyzed to evaluate the impact of preoperative albumin levels on post-transplant outcome. In our cohort, multivariable analysis revealed that preoperative albumin (mg/dL; hazard ratio, 0.46; P<0.0001) and preoperative total bilirubin (mg/dL; hazard ratio, 1.26; P=0.0002) were associated with post-transplant 1-year mortality. This implied that for every 1 mg/dL increase in albumin concentration, the post-transplant 1-year mortality rate decreased by 54%. The Kaplan–Meier analysis based on our patients cohort and the United Network for Organ Sharing dataset showed lower survival rate at 1-year post-transplant in patients with albumin levels ≤3.5 mg/dL compared with those with >3.5 mg/dL (our patients, 91.3 versus 72.4%; P<0.0001; United Network for Organ Sharing, 88.4 versus 84.8%; P<0.0001).
Conclusions
Pretransplant serum albumin concentration is a strong prognostic marker for post-transplant survival in heart transplant recipients.
ObjectivesTo investigate temporal trends in incidence and severity of COVID-19 among patients with systemic autoimmune rheumatic diseases (SARDs) from the first wave through the initial Omicron wave.MethodsWe conducted a retrospective cohort study investigating COVID-19 outcomes among patientswith SARD systematically identified to have confirmed COVID-19 from 1 March 2020 to 31 January 2022 at Mass General Brigham. We tabulated COVID-19 counts of total and severe cases (hospitalisations or deaths) and compared the proportion with severe COVID-19 by calendar period and by vaccination status. We used logistic regression to estimate the ORs for severe COVID-19 for each period compared with the early COVID-19 period (reference group).ResultsWe identified 1449 patients with SARD with COVID-19 (mean age 58.4 years, 75.2% female, 33.9% rheumatoid arthritis). There were 399 (28%) cases of severe COVID-19. The proportion of severe COVID-19 outcomes declined over calendar time (p for trend <0.001); 46% of cases were severe in the early COVID-19 period (1 March 2020–30 June 2020) vs 15% in the initial Omicron wave (17 December 2021–31 January 2022; adjusted OR 0.29, 95% CI 0.19 to 0.43). A higher proportion of those unvaccinated were severe compared with not severe cases (78% vs 60%).ConclusionsThe proportion of patients with SARD with severe COVID-19 has diminished since early in the pandemic, particularly during the most recent time periods, including the initial Omicron wave. Advances in prevention, diagnosis and treatment of COVID-19 may have improved outcomes among patients with SARD.
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