The aims of this study were to determine whether combining features of a western lifestyle in mice with trans fats in a high-fat diet, high-fructose corn syrup in the water, and interventions designed to promote sedentary behavior would cause the hepatic histopathological and metabolic abnormalities that characterize nonalcoholic steatohepatitis (NASH). Male C57BL/6 mice fed ad libitum high-fat chow containing trans fats (partially hydrogenated vegetable oil) and relevant amounts of a high-fructose corn syrup (HFCS) equivalent for 1-16 wk were compared with mice fed standard chow or mice with trans fats or HFCS omitted. Cage racks were removed from western diet mice to promote sedentary behavior. By 16 wk, trans fat-fed mice became obese and developed severe hepatic steatosis with associated necroinflammatory changes. Plasma alanine aminotransferase levels increased, as did liver TNF-alpha and procollagen mRNA, indicating an inflammatory and profibrogenic response to injury. Glucose intolerance and impaired fasting glucose developed within 2 and 4 wk, respectively. Plasma insulin, resistin, and leptin levels increased in a profile similar to that seen in patients with NASH. The individual components of this diet contributed to the phenotype independently; isocaloric replacement of trans fats with lard established that trans fats played a major role in promoting hepatic steatosis and injury, whereas inclusion of HFCS promoted food consumption, obesity, and impaired insulin sensitivity. Combining risk factors for the metabolic syndrome by feeding mice trans fats and HFCS induced histological features of NASH in the context of a metabolic profile similar to patients with this disease. Because dietary trans fats promoted liver steatosis and injury, their role in the epidemic of NASH needs further evaluation.

Young adults born preterm demonstrate early pulmonary vascular disease, characterized by elevated pulmonary pressures, a stiffer pulmonary vascular bed, and right ventricular dysfunction, consistent with an increased risk of developing pulmonary hypertension.

Prematurity complicates 12% of births, and young adults with a history of prematurity are at risk to develop right ventricular (RV) hypertrophy and impairment. The long-term risk for pulmonary vascular disease, as well as mechanisms of RV dysfunction and ventricular-vascular uncoupling after prematurity, remain poorly defined. Using an established model of prematurity-related lung disease, pups from timed-pregnant Sprague Dawley rats were randomized to normoxia or hyperoxia (fraction of inspired oxygen, 0.85) exposure for the first 14 days of life. After aging to 1 year in standard conditions, rats underwent hemodynamic assessment followed by tissue harvest for biochemical and histological evaluation. Aged hyperoxia-exposed rats developed significantly greater RV hypertrophy, associated with a 40% increase in RV systolic pressures. Although cardiac index was similar, hyperoxia-exposed rats demonstrated a reduced RV ejection fraction and significant RV-pulmonary vascular uncoupling. Hyperoxia-exposed RV cardiomyocytes demonstrated evidence of mitochondrial dysregulation and mitochondrial DNA damage, suggesting potential mitochondrial dysfunction as a cause of RV dysfunction. Aged rats exposed to postnatal hyperoxia recapitulate many features of young adults born prematurely, including increased RV hypertrophy and decreased RV ejection fraction. Our data suggest that postnatal hyperoxia exposure results in mitochondrial dysregulation that persists into adulthood with eventual RV dysfunction. Further evaluation of long-term mitochondrial function is warranted in both animal models of premature lung disease and in human adults who were born preterm.Keywords: pulmonary hypertension; mitochondrial biogenesis; prematurity Clinical RelevanceThis study used a common rat model of chronic lung disease of prematurity aged to 1 year, similar to young adulthood in humans, to study the long-term effects on the right ventricle (RV) and pulmonary vasculature. These rats demonstrated significant RV hypertrophy and dysfunction, similar to human studies, and newly identified significant chronic pulmonary hypertension. In addition, there was evidence of mitochondrial dysregulation in the RV, which may provide new insight into the pathogenesis of RV dysfunction in human adults born prematurely.

Human MITF is, by convention, called the "microphthalmia-associated transcription factor" because of previously published seminal mouse genetic studies; however, mutations in MITF have never been associated with microphthalmia in humans. Here, we describe a syndrome that we term COMMAD, characterized by coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness. COMMAD is associated with biallelic MITF mutant alleles and hence suggests a role for MITF in regulating processes such as optic-fissure closure and bone development or homeostasis, which go beyond what is usually seen in individuals carrying monoallelic MITF mutations.

Purpose: The long-term implications of premature birth on autonomic nervous system (ANS) function are unclear. Heart rate recovery (HRR) following maximal exercise is a simple tool to evaluate ANS function and is a strong predictor of cardiovascular disease. Our objective was to determine whether HRR is impaired in young adults born preterm (PYA).Methods: Individuals born between 1989 and 1991 were recruited from the Newborn Lung Project, a prospectively followed cohort of subjects born preterm weighing <1500g with an average gestational age of 28 weeks. Age-matched term-born controls were recruited from the local population. HRR was measured for two minutes following maximal exercise testing on an upright cycle ergometer in normoxia and hypoxia, and maximal aerobic capacity (VO 2max ) was measured.Results: Preterms had lower VO 2max than controls (34.88±5.24 v 46.15±10.21 ml/kg/min respectively, p<0.05), and exhibited slower HRR compared to controls after one and two minutes of recovery in normoxia (absolute drop of 20±4 v 31±10 and 41±7 v 54±11 beats per minute (bpm), respectively, p<0.01) and hypoxia (19±5 v 26±8 and 39±7 v 49±13 bpm, respectively, p<0.05). After adjusting for VO 2max , HRR remained slower in preterms at one and two minutes of recovery in normoxia (21±2 v 30±2 and 42±3 v 52±3 bpm respectively, p<0.05), but not hypoxia (19±3 v 25±2 and 40±4 v 47±3 bpm, respectively, p>0.05). Conclusions:Autonomic dysfunction as seen in this study has been associated with increased rates of cardiovascular disease in non-preterm populations, suggesting further study ofthe mechanisms of autonomic dysfunction after preterm birth.