Aortopathy in the 7q11.23 microduplication syndrome

The 7q11.23 microduplication syndrome, caused by the reciprocal duplication of the Williams-Beuren syndrome deletion region, is a genomic disorder with an emerging clinical phenotype. Dysmorphic features, congenital anomalies, hypotonia, developmental delay highlighted by variable speech delay, and autistic features are characteristic findings. Congenital heart defects, most commonly patent ductus arteriosus, have been reported in a minority of cases. Included in the duplicated region is elastin (), implicated as the cause of supravalvar aortic stenosis in patients with Williams–Beuren syndrome. Here we present a series of eight pediatric patients and one adult with 7q11.23 microduplication syndrome, all of whom had aortic dilation, the opposite vascular phenotype of the typical supravalvar aortic stenosis found in Williams–Beuren syndrome. The ascending aorta was most commonly involved, while dilation was less frequently identified at the aortic root and sinotubular junction. The findings in these patients support a recommendation for cardiovascular surveillance in patients with 7q11.23 microduplication syndrome. © 2014 Wiley Periodicals, Inc

Maternal Exposure to Criteria Air Pollutants and Congenital Heart Defects in Offspring: Results from the National Birth Defects Prevention Study

Background: Epidemiologic literature suggests that exposure to air pollutants is associated with fetal development

Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation

Purpose By incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS). Methods We used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups. Results We reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended. Conclusion The revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS

Neural mechanisms in the hemodynamic adjustment produced by pilocarpine in rats treated with adrenergic agonist and antagonist

A pilocarpina, uma droga classificada como um agonista colinergico muscarinico, age nas glandulas salivares, produzindo vasodilatacao e salivacao. Estudos recentes tem mostrado que grande parte da salivacao induzida pela pilocarpina depende de mecanismos cerebrais. A salivacao induzida pela pilocarpina pode ser inibida pela lesao de estruturas cerebrais anteriores, como a regiao anteroventral do terceiro ventriculo (AM), area septal (AS) ou hipotalamo lateral (HL). Um mecanismo inibitorio da salivacao induzida pela pilocarpina tambem muito estudado esta relacionado com receptores adrenergicos 2 e imidazolicos. A moxonidina, assim com a clonidina (agonistas adrenergicos 2 e imidazolicos), sao drogas anti-hipertensivas que quando administradas centralmente reduzem a salivacao induzida por pilocarpina. Alem de participarem do controle de mecanismos salivatorios, essas drogas tambem estao envolvidas na regulacao cardiovascular. Assim, foram objetivos deste trabalho: a) estudar as alteracoes hemodinamicas produzidas pela associacao de moxonidina (agonista de receptores adrenergicos 2 e imidazolicos) e -metil noradrenalina (agonista de receptores adrenergicos 2) injetada nos ventriculos cerebrais (ventriculo lateral - VL e quarto ventriculo - 4°V) sobre as respostas hemodinamicas produzidas pela pilocarpina (agonista colinergico) injetada no VL. b) investigar o papel dos receptores adrenergicos 2 nos efeitos hemodinamicos da associacao de moxonidina ou -metil noradrenalina injetada no VL ou 4° V seguido de pilocarpina no VL. Para tanto, foram utilizados ratos Wistar com canulas de aco inoxidavel implantadas nos ventriculos cerebrais: VL (volume de injecao 1 a 2 L) e/ou 4°V (volume de injecao 1 L). Os ratos foram anestesiados com uretana (1,2 g/kg, i.v.) e um cateter foi inserido na arteria femoral para registro de pressao arterial media (PAM) e frequencia cardiaca (FC). Sondas miniaturizadas foram posicionadas ao redor da arteria que irriga o complexo submandibular/sublingual, da arteria mesenterica superior, da arteria renal esquerda e da extremidade da aorta abdominal para registro de fluxo sanguineo pelo metodo da fluxometria Dopplera(au)BV UNIFESP: Teses e dissertaçõe

Calpain cleavage of collapsin response mediator proteins in ischemic mouse brain

Collapsin response mediator proteins (CRMPs) are important brain-specific proteins with distinct functions in modulating growth cone collapse and axonal guidance during brain development. Our previous studies have shown that calpain cleaves CRMP3 in the adult mouse brain during cerebral ischemia [S.T. Hou et al. (2006) J. Neurosci., 26, 2241-2249]. Here, the expression of all CRMP family members (1-5) was examined in mouse brains that were subjected to middle cerebral artery occlusion. Among the five CRMPs, the expressions of CRMP1, CRMP3 and CRMP5 were the most abundant in the cerebral cortex and all CRMPs were targeted for cleavage by ischemia-activated calpain. Sub-cellular fractionation analysis showed that cleavage of CRMPs by calpain occurred not only in the cytoplasm but also in the synaptosomes isolated from ischemic brains. Moreover, synaptosomal CRMPs appeared to be at least one-fold more sensitive to cleavage compared with those isolated from the cytosolic fraction in an in-vitro experiment, suggesting that synaptosomal CRMPs are critical targets during cerebral ischemia-induced neuronal injury. Finally, the expression of all CRMPs was colocalized with TUNEL-positive neurons in the ischemic mouse brain, which further supports the notion that CRMPs may play an important role in neuronal death following cerebral ischemia. Collectively, these studies demonstrated that CRMPs are targets of calpains during cerebral ischemia and they also highlighted an important potential role that CRMPs may play in modulating ischemic neuronal deathNRC publication: Ye

Preconditioning induces tolerance by suppressing glutamate release in neuron culture ischemia models

This study determined how preconditioned neurons responded to oxygen-glucose deprivation (OGD) to result in neuroprotection instead of neurotoxicity. Neurons preconditioned using chronically elevated synaptic activity displayed suppressed elevations in extracellular glutamate ([glutamateex]) and intracellular Ca\ub2+ (Ca\ub2+ in) during OGD. The glutamate uptake inhibitor TBOA induced neurotoxicity, but at a longer OGD duration for preconditioned cultures, suggestive of delayed up-regulation of transporter activity relative to non-preconditioned cultures. This delay was attributed to a critically attenuated release of glutamate, based on tolerance observed against insults mimicking key neurotoxic signaling during OGD (OGD-mimetics). Specifically, in the presence of TBOA, preconditioned neurons displayed potent protection to the OGD-mimetics: ouabain (a Na+/K+ ATPase inhibitor), high 55 mM KCl extracellular buffer (plasma membrane depolarization), veratridine (a Na+ ionophore), and paraquat (intracellular superoxide producer), which correlated with suppressed [glutamateex] elevations in the former two insults. Tolerance by preconditioning was reversed by manipulations that increased [glutamateex], such as by exposure to TBOA or GABAA receptor agonists during OGD, or by exposure to exogenous NMDA or glutamate. Pre-synaptic suppression of neuronal glutamate release by preconditioning, possibly via suppressed exocytic release, represents a key convergence point in neuroprotection during exposure to OGD and OGD-mimetics. \ua9 2012 National Research Council Canada. Journal of Neurochemistry \ua9 2012 International Society for Neurochemistry.Peer reviewed: YesNRC publication: Ye

Sustained Up-regulation of Semaphorin 3A, neuropilin1 and doublecortin expression in ischemic mouse brain during longterm recovery

NRC publication: Ye

Effect of synthetic cannabinoids on spontaneous neuronal activity: evaluation using Ca\ub2\u207a spiking and multi-electrode arrays

Activation of cannabinoid receptor 1 (CB\u2081) inhibits synaptic transmission in hippocampal neurons. The goal of this study was to evaluate the ability of benchmark and emerging synthetic cannabinoids to suppress neuronal activity in vitro using two complementary techniques, Ca\ub2\u207a spiking and multi-electrode arrays (MEAs). Neuron culture and fluorescence imaging conditions were extensively optimized to provide maximum sensitivity for detection of suppression of neural activity by cannabinoids. The neuronal Ca\ub2\u207a spiking frequency was significantly suppressed within 10 min by the prototypic aminoalkylindole cannabinoid, WIN 55,212-2 (10 \u3bcM). Suppression by WIN 55,212-2 was not improved by pharmacological intervention with signaling pathways known to interfere with CB\u2081 signaling. The naphthoylindole CB\u2081 agonist, JWH-018 suppressed Ca\ub2\u207a spiking at a lower concentration (2.5 \u3bcM), and the CB\u2081 antagonist rimonabant (5 \u3bcM), reversed this suppression. In the MEA assay, the ability of synthetic CB\u2081 agonists to suppress spontaneous electrical activity of hippocampal neurons was evaluated over 80 min sessions. All benchmark (WIN 55,212-2, HU-210, CP 55,940 and JWH-018) and emerging synthetic cannabinoids (XLR-11, JWH-250, 5F-PB-22, AB-PINACA and MAM-2201) suppressed neural activity at a concentration of 10 \u3bcM; furthermore, several of these compounds also significantly suppressed activity at 1 \u3bcM concentrations. Rimonabant partially reversed spiking suppression of 5F-PB-22 and, to a lesser extent, of MAM-2201, supporting CB\u2081- mediated involvement, although the inactive WIN 55,212-3 also partially suppressed activity. Taken together, synthetic cannabinoid CB\u2081-mediated suppression of neuronal activity was detected using Ca\ub2\u207a spiking and MEAs.Peer reviewed: YesNRC publication: Ye

Semaphorin3A elevates vascular permeability and contributes to cerebral ischemia-induced brain damage

Semaphorin 3A (Sema3A) increased significantly in mouse brain following cerebral ischemia. However, the role of Sema3A in stroke brain remains unknown. Our aim was to determine wether Sema3A functions as a vascular permeability factor and contributes to ischemic brain damage. Recombinant Sema3A injected intradermally to mouse skin, or stereotactically into the cerebral cortex, caused dose-and time-dependent increases in vascular permeability, with a degree comparable to that caused by injection of a known vascular permeability factor vascular endothelial growth factor receptors (VEGF). Application of Sema3A to cultured endothelial cells caused disorganization of F-actin stress fibre bundles and increased endothelial monolayer permeability, confirming Sema3A as a permeability factor. Sema3A-mediated F-actin changes in endothelial cells were through binding to the neuropilin2/VEGFR1 receptor complex, which in turn directly activates Mical2, a F-actin modulator. Down-regulation of Mical2, using specific siRNA, alleviated Sema3A-induced F-actin disorganization, cellular morphology changes and endothelial permeability. Importantly, ablation of Sema3A expression, cerebrovascular permeability and brain damage were significantly reduced in response to transient middle cerebral artery occlusion (tMCAO) and in a mouse model of cerebral ischemia/haemorrhagic transformation. Together, these studies demonstrated that Sema3A is a key mediator of cerebrovascular permeability and contributes to brain damage caused by cerebral ischemia.Peer reviewed: YesNRC publication: Ye

Maternal Exposure to Criteria Air Pollutants and Congenital Heart Defects in Offspring: Results from the National Birth Defects Prevention Study

Background: Epidemiologic literature suggests that exposure to air pollutants is associated with fetal development. Objectives: We investigated maternal exposures to air pollutants during weeks 2–8 of pregnancy and their associations with congenital heart defects. Methods: Mothers from the National Birth Defects Prevention Study, a nine-state case–control study, were assigned 1-week and 7-week averages of daily maximum concentrations of carbon monoxide, nitrogen dioxide, ozone, and sulfur dioxide and 24-hr measurements of fine and coarse particulate matter using the closest air monitor within 50 km to their residence during early pregnancy. Depending on the pollutant, a maximum of 4,632 live-birth controls and 3,328 live-birth, fetal-death, or electively terminated cases had exposure data. Hierarchical regression models, adjusted for maternal demographics and tobacco and alcohol use, were constructed. Principal component analysis was used to assess these relationships in a multipollutant context. Results: Positive associations were observed between exposure to nitrogen dioxide and coarctation of the aorta and pulmonary valve stenosis. Exposure to fine particulate matter was positively associated with hypoplastic left heart syndrome but inversely associated with atrial septal defects. Examining individual exposure-weeks suggested associations between pollutants and defects that were not observed using the 7-week average. Associations between left ventricular outflow tract obstructions and nitrogen dioxide and between hypoplastic left heart syndrome and particulate matter were supported by findings from the multipollutant analyses, although estimates were attenuated at the highest exposure levels. Conclusions: Using daily maximum pollutant levels and exploring individual exposure-weeks revealed some positive associations between certain pollutants and defects and suggested potential windows of susceptibility during pregnancy. Citation: Stingone JA, Luben TJ, Daniels JL, Fuentes M, Richardson DB, Aylsworth AS, Herring AH, Anderka M, Botto L, Correa A, Gilboa SM, Langlois PH, Mosley B, Shaw GM, Siffel C, Olshan AF, National Birth Defects Prevention Study. 2014. Maternal exposure to criteria air pollutants and congenital heart defects in offspring: results from the National Birth Defects Prevention Study. Environ Health Perspect 122:863–872; http://dx.doi.org/10.1289/ehp.130728