Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C-deficient mice

Laminopathies are a group of disorders caused by mutations in the LMNA gene that encodes the nuclear lamina proteins, lamin A and lamin C; their pathophysiological basis is unknown. We report that lamin A/C-deficient (Lmna(-/-)) mice develop rapidly progressive dilated cardiomyopathy (DCM) characterized by left ventricular (LV) dilation and reduced systolic contraction. Isolated Lmna(-/-) myocytes show reduced shortening with normal baseline and peak amplitude of Ca(2+) transients. Lmna(-/-) LV myocyte nuclei have marked alterations of shape and size with central displacement and fragmentation of heterochromatin; these changes are present but less severe in left atrial nuclei. Electron microscopy of Lmna(-/-) cardiomyocytes shows disorganization and detachment of desmin filaments from the nuclear surface with progressive disruption of the cytoskeletal desmin network. Alterations in nuclear architecture are associated with defective nuclear function evidenced by decreased SREBP1 import, reduced PPARgamma expression, and a lack of hypertrophic gene activation. These findings suggest a model in which the primary pathophysiological mechanism in Lmna(-/-) mice is defective force transmission resulting from disruption of lamin interactions with the muscle-specific desmin network and loss of cytoskeletal tension. Despite severe DCM, defects in nuclear function prevent Lmna(-/-) cardiomyocytes from developing compensatory hypertrophy and accelerate disease progression.     

Marijuana and Alcohol Use and Attempted Smoking Cessation in Adolescent Boys and Girls

ABSTRACT. Background: This study sought to determine the relationship between the frequency of current marijuana and alcohol use and cigarette quit attempts in male and female adolescent smokers. Methods: Data from a cross-sectional survey of health behaviors in high-school-aged adolescents were analyzed. Current cigarette smokers (n = 804) who reported use of at least 1 cigarette in the past month were divided into those with and without a history of at least 1 quit attempt (a self-reported episode of trying to “stop smoking”). Logistic regression models were fit to describe the association between the frequency of marijuana/alcohol use and a history of cigarette quit attempts. Results: Among the total sample, higher-frequency marijuana use (more than 6 times in the past 30 days) and frequent binge drinking (more than 5 days of binge drinking in the past 30 days) decreased the odds of having a past cigarette quit attempt (higher-frequency marijuana: adjusted odds ratio [AOR] = 0.56, 95% confidence interval [CI] = 0.36–0.86; frequent binge drinking: AOR = 0.49, 95% CI = 0.29–0.83). A significant gender interaction was observed for the relationship between higher-frequency marijuana use and a history of cigarette quit attempts (P = .03), with decreased odds in boys (AOR = 0.41, 95% CI = 0.22–0.77) but not in girls (AOR = 0.71, 95% CI = 0.37–1.33). Conclusions: Adolescent smokers who report higher-frequency marijuana use or frequent binge drinking have a decreased likelihood of a history of a cigarette quit attempt. The gender-related association between higher-frequency marijuana use and a history of quit attempts suggests that boys with greater substance use may need particularly intensive support to initiate quit attempts.     

Revealing the microscale spatial signature of dengue transmission and immunity in an urban population

It is well-known that the distribution of immunity in a population dictates the future incidence of infectious disease, but this process is generally understood at individual or macroscales. For example, herd immunity to multiple pathogens has been observed at national and city levels. However, the effects of population immunity have not previously been shown at scales smaller than the city (e.g., neighborhoods). In particular, no study has shown long-term effects of population immunity at scales consistent with the spatial scale of person-to-person transmission. Here, we use the location of dengue patients' homes in Bangkok with the serotype of the infecting pathogen to investigate the spatiotemporal distribution of disease risk at small spatial scales over a 5-y period. We find evidence for localized transmission at distances of under 1 km. We also observe patterns of spatiotemporal dependence consistent with the expected impacts of homotypic immunity, heterotypic immunity, and immune enhancement of disease at these distances. Our observations indicate that immunological memory of dengue serotypes occurs at the neighborhood level in this large urban setting. These methods have broad applications to studying the spatiotemporal structure of disease risk where pathogen serotype or genetic information is known.