Citations

AbstractIntroductionAfrican‐American (AA) individuals have a higher risk for late‐onset Alzheimer's disease (LOAD) than Americans of primarily European ancestry (EA). Recently, the largest genome‐wide association study in AAs to date confirmed that six of the Alzheimer's disease (AD)‐related genetic variants originally discovered in EA cohorts are also risk variants in AA; however, the risk attributable to many of the loci (e.g., APOE, ABCA7) differed substantially from previous studies in EA. There likely are risk variants of higher frequency in AAs that have not been discovered.MethodsWe performed a comprehensive analysis of genetically determined local and global ancestry in AAs with regard to LOAD status.ResultsCompared to controls, LOAD cases showed higher levels of African ancestry, both globally and at several LOAD relevant loci, which explained risk for AD beyond global differences.DiscussionExploratory post hoc analyses highlight regions with greatest differences in ancestry as potential candidate regions for future genetic analyses.

Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (POPH) are pulmonary vascular complications of portal hypertension with divergent clinicopathologic features and management. The presence of intrapulmonary vascular dilatations (IPVDs), detected by agitated saline contrast‐enhanced transthoracic echocardiography (cTTE), is an essential feature of HPS but is not typically characteristic of POPH. Although IPVDs have been reported rarely in POPH, the prevalence and significance of this finding have not been systematically studied. We conducted a retrospective chart review of 80 consecutive patients diagnosed with POPH from January 1, 2002 to June 30, 2014 with documentation of cTTE findings, pulmonary hemodynamics, oxygenation, and survival. A total of 34 of the 80 patients (42%) underwent cTTE during initial diagnosis of POPH. IPVDs were detected in 20/34 patients (59%); intracardiac shunting was detected in 9/34 patients (26%; 4 also had IPVDs); and 9 patients (26%) had negative cTTE with no evidence of IPVD or intracardiac shunting. Patients with IPVD had decreased survival as compared to those without IPVD (P = 0.003), a trend that persisted after exclusion of liver transplant recipients (P = 0.07). The IPVD group had a trend toward higher Model for End‐Stage Liver Disease score with and without incorporating sodium (MELD or MELD‐Na; P = 0.05 for both). The right ventricular index of myocardial performance (RIMP) was lower in the IPVD group (median, 0.4 versus 0.6; P = 0.006). Patients with moderate or large IPVDs (n = 6) had worse oxygenation parameters (partial pressure of arterial oxygen, diffusing capacity of the lung for carbon monoxide, and alveolar‐arterial oxygen gradient) as compared to the rest of the cohort. Unexpectedly, IPVDs were frequently documented in POPH and associated with decreased survival. To further understand this observation, we recommend screening for IVPD in all patients with POPH. Liver Transpl 21:1355‐1364, 2015. © 2015 AASLD.

Obesity and hypertension are major risk factors for cardiovascular diseases, and their growing coexistence accounts for an increase in adverse cardiac events, but the mechanisms are yet to be determined. We hypothesized that obesity exacerbates mitochondrial dysregulation imposed by hypertension and augments left ventricular dysfunction. Obesity-prone Ossabaw pigs were randomized to lean (standard diet) and obese (high-fat diet), without (Lean-sham and Obese-sham) or with renovascular hypertension (Lean-hypertension and Obese-hypertension), induced after 12 weeks of diet (n=7 each). Cardiac function, myocardial perfusion and oxygenation, and microvascular remodeling were assessed 4 weeks later. Mitochondrial biogenesis signals and structural proteins, respiratory chain complex activities, and mitochondrial self-degradation were examined, as was fibrosis. Obesity alone exerted no apparent effect on mitochondrial dynamics, but aggravated in hypertensive hearts the reduction of mitochondrial proteins, deoxyribonucleic acid content, and respiratory chain complex IV subunits activity, and amplified mitochondrial self-degradation. Synergistic interaction of obesity with hypertension also exacerbated myocardial fibrosis and left ventricular diastolic dysfunction. Mitochondrial content, respiratory chain complex IV subunits activity, and mitophagy were correlated with myocardial fibrosis. These findings suggest that obesity aggravates in renovascular hypertension cardiac mitochondrial aberrations. Mitochondrial function may regulate the progression of cardiac injury and functional deterioration in hypertension concomitant with obesity.

Purpose To determine long-term outcomes in a clinical trial evaluating the role of taxane type and schedule in operable breast cancer and evaluate the impact of obesity and black race on outcome. Patients and Methods A total of 4,954 eligible women with stage II to III breast cancer treated with four cycles of doxorubicin plus cyclophosphamide were randomly assigned to receive paclitaxel or docetaxel every 3 weeks for four doses or weekly for 12 doses using a 2 × 2 factorial design. The primary end point was disease-free survival (DFS). Results are expressed as hazard ratios (HRs) from Cox proportional hazards models. All P values are two sided. Results When compared with the standard every-3-week paclitaxel arm, after a median follow-up of 12.1 years, DFS significantly improved and overall survival (OS) marginally improved only for the weekly paclitaxel (HR, 0.84; P = .011 and HR, 0.87; P = .09, respectively) and every-3-week docetaxel arms (HR, 0.79; P = .001 and HR, 0.86; P = .054, respectively). Weekly paclitaxel improved DFS and OS (HR, 0.69; P = .010 and HR, 0.69; P = .019, respectively) in triple-negative breast cancer. For hormone receptor–positive, human epidermal growth factor receptor 2–nonoverexpressing disease, no experimental arm improved OS, and black race and obesity were associated with increased risk of breast cancer recurrence and death. Conclusion Improved outcomes initially observed for weekly paclitaxel were qualitatively similar but quantitatively less pronounced with longer follow-up, although exploratory analysis suggested substantial benefit in triple-negative disease. Further research is required to understand why obesity and race influence clinical outcome in hormone receptor–positive disease.