4 research outputs found

    Role of Platelet-Activating Factor and Hypoxia in Persistent Pulmonary Hypertension of the Newborn — Studies with Perinatal Pulmonary Vascular Smooth Muscle Cells

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    Platelet-activating factor (PAF) plays an important physiological role of maintaining a high vasomotor tone in fetal pulmonary circulation. At birth, endogenous vasodilators such as nitric oxide and prostacyclin are released and facilitate pulmonary vasodilation via cAMP-dependent protein kinase (cAMP/PKA) and cGMP-dependent protein kinase (cGMP/PKG) pathways. Interaction between the cyclic nucleotides and PAF receptor (PAFR)-mediated responses in pulmonary arterial smooth muscle is not well understood. To further understand the interactions of PAF-PAFR pathway and the cyclic nucleotides in ovine fetal pulmonary arterial smooth muscle cells (FPASMC), effects of cAMP and cGMP on PAFR-mediated responses in pulmonary arterial smooth muscle cells (PASMC) were studied. Ovine FPASMC were incubated with 10μM cAMP or cGMP in normoxia (5% CO2 in air, pO2~100 Torr) or hypoxia (2% O2, 5% CO2, pO2~30-40 Torr). Proteins were prepared and subjected to Western blotting. Effect of cell permeable cAMP and cGMP on PAFR binding was also studied and effect of cAMP on cell proliferation was also studied by RNAi to PKA-Cα. cAMP and cGMP significantly decreased PAFR binding and protein expression in normoxia and hypoxia, more so in hypoxia, when PAFR expression was usually high. PKA-Cα siRNA demonstrated that inhibition of PAFR-mediated responses by the cyclic nucleotides occurred through PKA. These data suggest that the normally high levels of cyclic nucleotides in the normoxic newborn pulmonary circulation assist in the downregulation of postnatal PAFR-mediated responses and that under hypoxic conditions, increasing the levels of cyclic nucleotides will abrogate PAF-mediated vasoconstriction thereby ameliorating PAF-induced persistent pulmonary hypertension of the newborn

    A case of autism with an interstitial deletion on 4q leading to hemizygosity for genes encoding for glutamine and glycine neurotransmitter receptor sub-units (AMPA 2, GLRA3, GLRB) and neuropeptide receptors NPY1R, NPY5R

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    BACKGROUND: Autism is a pervasive developmental disorder characterized by a triad of deficits: qualitative impairments in social interactions, communication deficits, and repetitive and stereotyped patterns of behavior. Although autism is etiologically heterogeneous, family and twin studies have established a definite genetic basis. The inheritance of idiopathic autism is presumed to be complex, with many genes involved; environmental factors are also possibly contributory. The analysis of chromosome abnormalities associated with autism contributes greatly to the identification of autism candidate genes. CASE PRESENTATION: We describe a child with autistic disorder and an interstitial deletion on chromosome 4q. This child first presented at 12 months of age with developmental delay and minor dysmorphic features. At 4 years of age a diagnosis of Pervasive Developmental Disorder was made. At 11 years of age he met diagnostic criteria for autism. Cytogenetic studies revealed a chromosome 4q deletion. The karyotype was 46, XY del 4 (q31.3-q33). Here we report the clinical phenotype of the child and the molecular characterization of the deletion using molecular cytogenetic techniques and analysis of polymorphic markers. These studies revealed a 19 megabase deletion spanning 4q32 to 4q34. Analysis of existing polymorphic markers and new markers developed in this study revealed that the deletion arose on a paternally derived chromosome. To date 33 genes of known or inferred function are deleted as a consequence of the deletion. Among these are the AMPA 2 gene that encodes the glutamate receptor GluR2 sub-unit, GLRA3 and GLRB genes that encode glycine receptor subunits and neuropeptide Y receptor genes NPY1R and NPY5R. CONCLUSIONS: The deletion in this autistic subject serves to highlight specific autism candidate genes. He is hemizygous for AMPA 2, GLRA3, GLRB, NPY1R and NPY5R. GluR2 is the major determinant of AMPA receptor structure. Glutamate receptors maintain structural and functional plasticity of synapses. Neuropeptide Y and its receptors NPY1R and NPY5R play a role in hippocampal learning and memory. Glycine receptors are expressed in very early cortical development. Molecular cytogenetic studies and DNA sequence analysis in other patients with autism will be necessary to confirm that these genes are involved in autism
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