MAP4K4 Inhibition Promotes Survival of Human Stem Cell-Derived Cardiomyocytes and Reduces Infarct Size In Vivo

Heart disease is a paramount cause of global death and disability. Although cardiomyocyte death plays a causal role and its suppression would be logical, no clinical counter-measures target the responsible intracellular pathways. Therapeutic progress has been hampered by lack of preclinical human validation. Mitogen-activated protein kinase kinase kinase kinase-4 (MAP4K4) is activated in failing human hearts and relevant rodent models. Using human induced-pluripotent-stem-cell-derived cardiomyocytes (hiPSC-CMs) and MAP4K4 gene silencing, we demonstrate that death induced by oxidative stress requires MAP4K4. Consequently, we devised a small-molecule inhibitor, DMX-5804, that rescues cell survival, mitochondrial function, and calcium cycling in hiPSC-CMs. As proof of principle that drug discovery in hiPSC-CMs may predict efficacy in vivo, DMX-5804 reduces ischemia-reperfusion injury in mice by more than 50%. We implicate MAP4K4 as a well-posed target toward suppressing human cardiac cell death and highlight the utility of hiPSC-CMs in drug discovery to enhance cardiomyocyte survival

Hypernatremia in the geriatric population

Maulin K Shah,1 Biruh Workeneh,1,2 George E Taffet1,3 1Department of Internal Medicine, 2Department of Nephrology, 3Huffington Center on Aging, Baylor College of Medicine, Houston, TX, USA Abstract: Hypernatremia in the geriatric population is a common disorder associated with significant morbidity and mortality. Older people are predisposed to developing hypernatremia because of age-related physiologic changes such as decreased thirst drive, impaired urinary concentrating ability, and reduced total body water. Medications may exacerbate this predisposition. Hypernatremia and dehydration occurring in nursing homes are considered indicators of neglect that warrant reporting, but there are other nonavoidable causes of hypernatremia, and consideration at time of presentation is essential to prevent delay in diagnosis and management. We describe a case illustrating the importance of the consideration of alternate explanations for hypernatremia in a nursing home resident, followed by a review of hypernatremia in the elderly population, to underscore that neglect is the etiology of exclusion after alternatives have been considered. Keywords: geriatric, hypernatremia, sodiu

Considerations for managing chronic obstructive pulmonary disease in the elderly

George E Taffet,1 James F Donohue,2 Pablo R Altman31Geriatrics Section, Geriatrics and Cardiovascular Sciences, Baylor College of Medicine, The Methodist Hospital, Houston, TX, 2Pulmonary Diseases and Critical Care Medicine, University of North Carolina, Chapel Hill, NC, 3Medical Affairs, Mylan Specialty L.P., Basking Ridge, NJ, USAAbstract: Chronic obstructive pulmonary disease (COPD) is common in older people, with an estimated prevalence of 10% in the US population aged ≥75 years. Inhaled medications are the cornerstone of treatment for COPD and are typically administered by one of three types of devices, ie, pressurized metered dose inhalers, dry powder inhalers, and nebulizers. However, age-related pulmonary changes may negatively influence the delivery of inhaled medications to the small airways. In addition, physical and cognitive impairment, which are common in elderly patients with COPD, pose special challenges to the use of handheld inhalers in the elderly. Health care providers must take time to train patients to use handheld inhalers and must also check that patients are using them correctly on a regular basis. Nebulizers should be considered for patients unable to use handheld inhalers properly. What follows is a review of issues associated with COPD and its treatment in the elderly patient.Keywords: chronic obstructive pulmonary disease, inhaler, device, cognition, disability, comorbidities, maintenance therap

MAP4K4 inhibition promotes survival of human stem cell derived cardiomyocyte and reduces infarct size in vivo

Heart disease is a paramount cause of global death and disability. Although cardiomyocyte death plays a causal role and its suppression would be logical, no clinical counter-measures target the responsible intracellular pathways. Therapeutic progress has been hampered by lack of preclinical human validation. Mitogen-activated protein kinase kinase kinase kinase-4 (MAP4K4) is activated in failing human hearts and relevant rodent models. Using human induced-pluripotent-stem-cell-derived cardiomyocytes (hiPSC-CMs) and MAP4K4 gene silencing, we demonstrate that death induced by oxidative stress requires MAP4K4. Consequently, we devised a small-molecule inhibitor, DMX-5804, that rescues cell survival, mitochondrial function, and calcium cycling in hiPSC-CMs. As proof of principle that drug discovery in hiPSC-CMs may predict efficacy in vivo, DMX-5804 reduces ischemia-reperfusion injury in mice by more than 50%. We implicate MAP4K4 as a well-posed target toward suppressing human cardiac cell death and highlight the utility of hiPSC-CMs in drug discovery to enhance cardiomyocyte survival