JNK/SAPK and p38 SAPK-2 mediate mechanical stretch-induced apoptosis via caspase-3 and -9 in NRK-52E renal epithelial cells

Background/Aims: In renal epithelial cells, mechanical forces produced from urinary obstruction serve as potential mediators of apoptosis by activating specific intracellular signaling pathways. In this study, we sought to further define the role of JNK and p38 SAPK-2 pathway and caspase activation in stretch-induced apoptosis. Methods: Immortalized cell lines derived from the various components of the nephron were subjected to cyclical stretch and their differential apoptotic response was assessed. Pharmacologic inhibitors and Western blot analysis were used to assess the involvement of the MAPK pathways. Caspases\u27 activity was assessed with ELISA and by Western blot analysis. Results: Stretch-induced apoptosis was dependent upon the cell phenotype and the degree of stretch. In NRK-52E cells, it was mediated through both JNK and p38 SAPK-2 pathways, and inhibition of either pathway reduced the degree of stretch-induced apoptosis. Stretched cells showed increased activity of caspase-3 and -9 but not -2 or -8. Stretch-induced apoptosis was modulated by inhibition of caspase-3 and to a lesser extent by caspase-9. Conclusion: These findings suggest that stretch induces apoptosis in renal epithelial cells through the specific activation of JNK/SAPK and p38 SAPK-2 pathways and is dependent on the activation of caspase-3 and -9. Copyright © 2006 S. Karger AG

Screening of human LPHN3 for variants with a potential impact on ADHD susceptibility

Attention deficit hyperactivity disorder (ADHD) is the most common behavioral disorder in childhood, and often has effects detectable into adulthood. Advances in genetic linkage and association analysis have begun to elucidate some of the genetic factor

Screening of human LPHN3 for variants with a potential impact on ADHD susceptibility

Attention deficit hyperactivity disorder (ADHD) is the most common behavioral disorder in childhood, and often has effects detectable into adulthood. Advances in genetic linkage and association analysis have begun to elucidate some of the genetic factors underlying this complex disorder. Recently, we identified LPHN3, a novel ADHD susceptibility gene harbored in 4q, and showed that a LPHN3 common haplotype confers susceptibility to ADHD and predicts effectiveness of stimulant medication. Here we present the mutational analysis of the entire coding region of LPHN3 in a cohort of 139 ADHD subjects and 52 controls from across the USA. We identified 21 variants, of which 14 have been reported and 7 are novel. These include 5 missense, 8 synonymous, and 8 intronic changes. Interestingly, neither susceptibility nor protective haplotype alleles are associated with obviously significant coding region changes, or canonical splice site alterations, suggesting that non-coding variations determining the quantity and/or quality of LPHN3 isoforms are the likely contributors to this common behavioral disorder.Fil: Domene, Sabina. National Institutes of Health; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Stanescu, Horia. National Institutes of Health; Estados UnidosFil: Wallis, Deeann. Texas A&M University; Estados UnidosFil: Tinloy, Bradford. National Institutes of Health; Estados UnidosFil: Pineda, Daniel E.. National Institutes of Health; Estados UnidosFil: Kleta, Robert. National Institutes of Health; Estados UnidosFil: Arcos Burgos, Mauricio. National Institutes of Health; Estados UnidosFil: Roessler, Erich. National Institutes of Health; Estados UnidosFil: Muenke, Maximilian. National Institutes of Health; Estados Unido

The future of value-based emergency care: Development of an emergency medicine MIPS value pathway framework

The Centers for Medicare & Medicaid Services (CMS) implemented the Merit-based Incentive Payment System (MIPS) to accelerate the transition of physician payment toward value-based care models and away from traditional fee-for-service payment programs. In recent years, CMS has sought to modify the program by developing a MIPS Value Pathway (MVP) framework intended to use existing and future physician quality and cost measures to reward value-based care delivery. This article describes the multi-step process of the MVP Task Force, convened by the American College of Emergency Physicians (ACEP) to develop an emergency medicine-specific MVP proposal informed by diverse stakeholder perceptions regarding: (1) which existing quality measures reflect high quality emergency care, and (2) the degree to which emergency clinicians can impact clinical outcomes and cost for the care domains captured by existing quality measures. The MVP Task Force synthesized stakeholder feedback and underwent a consensus-building approach to develop the Adopting Best Practices and Promoting Patient Safety within Emergency Medicine MVP, recently reviewed and approved by CMS for national implementation starting in 2023. Our process and findings have broad implications for clinicians, administrators, and policymakers navigating the continued transition to value-based care in conjunction with CMS\u27s implementation of the MVP framework

A novel missense mutation (G43S) in the switch I region of Rab27A causing Griscelli syndrome

The autosomal recessive Griscelli syndrome type II (GSII) is caused by mutations in the RAB27A gene. Typical clinical features include immunological impairment, silver-gray scalp hair, eyelashes and eyebrows, and hypomelanosis of the skin. Rabs help determine the specificity of membrane trafficking steps within cells. In melanocytes, the GTP-bound form of Rab27A associates with the membranes of mature fully-pigmented melanosomes through its geranylgeranyl group. Once attached, Rab27A recruits the downstream effector Melanophilin (Mlph) and the actin-dependent motor protein Myosin Va (MyoVa). The molecular Rab27A/Mlph/MyoVA tripartite complex, which links melanosomes to the peripheral actin network, is required to achieve melanosome transfer to surrounding keratinocytes in the epidermis. Here we report a novel homozygous missense mutation c.127G>A, p.G43S in exon 2 of the RAB27A gene of an Afghani GSII patient. Laser scanning confocal microscopy showed that the G43S mutation, which is located in the highly conserved switch I region of Rab27A, induces perinuclear localization of melanosomes in normal melanocytes, and fails to restore melanosomes to the actin-rich periphery in GSII melanocytes. Co-immunoprecipitation studies showed that Rab27A(G43S) fails to interact with its effector Melanophilin, indicating that the Switch I region functions in the recruitment of Rab effector proteins