Peri-partum cardiomyopathy (PPCM) is a frequently fatal disease that affects women near delivery, and occurs more frequently in women with pre-eclampsia and/or multiple gestation. The etiology of PPCM, or why it associates with pre-eclampsia, remains unknown. We show here that PPCM is associated with a systemic angiogenic imbalance, accentuated by pre-eclampsia. Mice that lack cardiac PGC-1α, a powerful regulator of angiogenesis, develop profound PPCM. Importantly, the PPCM is entirely rescued by pro-angiogenic therapies. In humans, the placenta in late gestation secretes VEGF inhibitors like soluble Flt1 (sFlt1), and this is accentuated by multiple gestation and pre-eclampsia. This anti-angiogenic environment is accompanied by sub-clinical cardiac dysfunction, the extent of which correlates with circulating levels of sFlt1. Exogenous sFlt1 alone caused diastolic dysfunction in wildtype mice, and profound systolic dysfunction in mice lacking cardiac PGC-1α. Finally, plasma samples from women with PPCM contained abnormally high levels of sFlt1. These data strongly suggest that PPCM is in large part a vascular disease, caused by excess anti-angiogenic signaling in the peri-partum period. The data also explain how late pregnancy poses a threat to cardiac homeostasis, and why pre-eclampsia and multiple gestation are important risk factors for the development of PPCM.

IMPORTANCE Firearm homicide is a leading cause of injury death in the United States, and there is considerable debate over the effectiveness of firearm policies. An analysis of the effectiveness of firearm laws on firearm homicide is important to understand optimal policies to decrease firearm homicide in the United States.OBJECTIVE To evaluate the association between firearm laws and preventing firearm homicides in the United States.EVIDENCE REVIEW We evaluated peer-reviewed articles from 1970 to 2016 focusing on the association between US firearm laws and firearm homicide. We searched PubMed, CINAHL, Lexis/Nexis, Sociological Abstracts, Academic Search Premier, the Index to Legal Periodicals and Books, and the references from the assembled articles. We divided laws into 5 categories: those that (1) curb gun trafficking, (2) strengthen background checks, (3) improve child safety, (4) ban military-style assault weapons, and (5) restrict firearms in public places and leniency in firearm carrying. The articles were assessed using the standardized Guide to Community Preventive Services data collection instrument and 5 additional quality metrics:(1) appropriate data source(s) and outcome measure(s) were used for the study, (2) the time frame studied was adequate, (3) appropriate statistical tests were used, (4) the analytic results were robust, and (5) the disaggregated results of control variables were consistent with the literature. FINDINGS In the aggregate, stronger gun policies were associated with decreased rates of firearm homicide, even after adjusting for demographic and sociologic factors. Laws that strengthen background checks and permit-to-purchase seemed to decrease firearm homicide rates. Specific laws directed at firearm trafficking, improving child safety, or the banning of military-style assault weapons were not associated with changes in firearm homicide rates. The evidence for laws restricting guns in public places and leniency in gun carrying was mixed. CONCLUSIONS AND RELEVANCEThe strength of firearm legislation in general, and laws related to strengthening background checks and permit-to-purchase in particular, is associated with decreased firearm homicide rates. High-quality research is important to further evaluate the effectiveness of these laws. Legislation is just 1 part of a multipronged approach that will be necessary to decrease firearm homicides in the United States.

Summary The transcriptional coactivators PGC-1α and PGC-1β are widely thought to be required for mitochondrial biogenesis and fiber typing in skeletal muscle. We show here that mice lacking both PGC-1s in myocytes do indeed have profoundly deficient mitochondrial respiration, but surprisingly have preserved mitochondrial content, isolated muscle contraction capacity, fiber type composition, in-cage ambulation, and voluntary running capacity. Most of these findings are recapitulated in cell culture, and thus cell-autonomous. Functional electron microscopy reveals normal cristae density with decreased cytochrome oxidase activity. These data lead to the following surprising conclusions: that PGC-1s are in fact dispensable for baseline muscle function, mitochondrial content, and fiber typing; that endurance fatigue at low workloads is not limited by muscle mitochondrial capacity; and that mitochondrial content and cristae density can be dissociated from respiratory capacity.