Filamin-A as a Balance between Erk/Smad Activities During Cardiac Valve Development

Mitral valve prolapse (MVP) affects 2.4% of the population and has poorly understood etiology. Recent genetic studies have begun to unravel the complexities of MVP and through these efforts, mutations in the FLNA (Filamin-A) gene were identified as disease causing. Our in vivo and in vitro studies have validated these genetic findings and have revealed FLNA as a central regulator of valve morphogenesis. The mechanisms by which FLNA mutations result in myxomatous mitral valve disease are currently unknown, but may involve proteins previously associated with mutated regions of the FLNA protein, such as the small GTPase signaling protein, R-Ras. Herein, we report that Filamin-A is required for R-Ras expression and activation of the Ras–Mek–Erk pathway. Loss of the Ras/Erk pathway correlated with hyperactivation of pSmad2/3, increased extracellular matrix (ECM) production and enlarged mitral valves. Analyses of integrin receptors in the mitral valve revealed that Filamin-A was required for β1-integrin expression and provided a potential mechanism for impaired ECM compaction and valve enlargement. Our data support Filamin-A as a protein that regulates the balance between Erk and Smad activation and an inability of Filamin-A deficient valve interstitial cells to effectively remodel the increased ECM production through a β1-integrin mechanism. As a consequence, loss of Filamin-A function results in increased ECM production and generation of a myxomatous phenotype characterized by improperly compacted mitral valve tissue. Anat Rec, 302:117–124, 2019. © 2018 Wiley Periodicals, Inc.     

Public Health Consequences of Terrorism on Maternal–Child Health in New York City and Madrid

Past research provides evidence for trajectories of health and wellness among individuals following disasters that follow specific pathways of resilience, resistance, recovery, or continued dysfunction. These individual responses are influenced by event type and pre-event capacities. This study was designed to utilize the trajectories of health model to determine if it translates to population health. We identified terrorist attacks that could potentially impact population health rather than only selected individuals within the areas of the attacks. We chose to examine a time series of population birth outcomes before and after the terrorist events of the New York City (NYC) World Trade Center (WTC) attacks of 2001 and the Madrid, Spain train bombings of 2004 to determine if the events affected maternal–child health of those cities and, if so, for how long. For percentages of low birth weight (LBW) and preterm births, we found no significant effects from the WTC attacks in NYC and transient but significant effects on rates of LBW and preterm births following the bombings in Madrid. We did find a significant positive and sustained effect on infant mortality rate in NYC following the WTC attacks but no similar effect in Madrid. There were no effects on any of the indicator variables in the comparison regions of New York state and the remainder of Spain. Thus, population maternal–health in New York and Madrid showed unique adverse effects after the terrorist attacks in those cities. Short-term effects on LBW and preterm birth rates in Madrid and long-term effects on infant mortality rates in NYC were found when quarterly data were analyzed from 1990 through 2008/2009. These findings raise questions about chronic changes in the population’s quality of life following catastrophic terrorist attacks. Public health should be monitored and interventions designed to address chronic stress, environmental, and socioeconomic threats beyond the acute aftermath of events.     

Physiological,pharmacological and toxicological considerations of drug-induced structural cardiac injury

The incidence of drug-induced structural cardiotoxicity, which may lead to heart failure, has been recognized in association with the use of anthracycline anti-cancer drugs for many years, but has also been shown to occur following treatment with the new generation of targeted anti-cancer agents that inhibit one or more receptor or non-receptor tyrosine kinases, serine/threonine kinases as well as several classes of non-oncology agents. A workshop organized by the Medical Research Council Centre for Drug Safety Science (University of Liverpool) on 5 September 2013 and attended by industry, academia and regulatory representatives, was designed to gain a better understanding of the gaps in the field of structural cardiotoxicity that can be addressed through collaborative efforts. Specific recommendations from the workshop for future collaborative activities included: greater efforts to identify predictive (i) preclinical; and (ii) clinical biomarkers of early cardiovascular injury; (iii) improved understanding of comparative physiology/pathophysiology and the clinical predictivity of current preclinical in vivo models; (iv) the identification and use of a set of cardiotoxic reference compounds for comparative profiling in improved animal and human cellular models; (v) more sharing of data (through publication/consortia arrangements) on target-related toxicities; (vi) strategies to develop cardio-protective agents; and (vii) closer interactions between preclinical scientists and clinicians to help ensure best translational efforts.