Spermine modulation of the glutamate(NMDA) receptor is differentially responsive to conantokins in normal and Alzheimer's disease human cerebral cortex

The pharmacology of the N -methyl-d-aspartate (NMDA) receptor site was examined in pathologically affected and relatively spared regions of cerebral cortex tissue obtained at autopsy from Alzheimer's disease cases and matched controls. The affinity and density of the [H-3]MK-801 binding site were delineated along with the enhancement of [H-3]MK-801 binding by glutamate and spermine. Maximal enhancement induced by either ligand was regionally variable; glutamate-mediated maximal enhancement was higher in controls than in Alzheimer's cases in pathologically spared regions, whereas spermine-mediated maximal enhancement was higher in controls in areas susceptible to pathological damage. These and other data suggest that the subunit composition of NMDA receptors may be locally variable. Studies with modified conantokin-G (con-G) peptides showed that Ala(7)-con-G had higher affinity than Lys(7)-con-G, and also defined two distinct binding sites in controls. Nevertheless, the affinity for Lys(7)-con-G was higher overall in Alzheimer's brain than in control brain, whereas the reverse was true for Ala(7)-con-G. Over-excitation mediated by specific NMDA receptors might contribute to localized brain damage in Alzheimer's disease. Modified conantokins are useful for identifying the NMDA receptors involved, and may have potential as protective agents.

Distribution of two splice variants of the glutamate transporter GLT-1 in rat brain and pituitary

We have performed immunocytochemistry on rat brains using a highly specific antiserum directed against the originally described form of the glutamate transporter GLT-1 (referred to hereafter as GLT-1alpha), and another against a C-terminal splice variant of this protein, GLT-1B. Both forms of GLT-1 were abundant in rat brain, especially in regions such as the hippocampus and cerebral cortex, and macroscopic examination of sections suggested that both forms were generally regionally coexistent. However, disparities were evident; GLT-1alpha was present in the intermediate lobe of the pituitary gland, whereas GLT-1B was absent. Similar marked disparities were also noted in the external capsule, where GLT1A labeling was abundant but GLT-1B was only occasionally encountered. Conversely, GLT-1B was more extensively distributed, relative to GLT-1alpha, in areas such as the deep cerebellar nuclei. In most regions, such as the olfactory bulbs, both splice variants were present but differences were evident in their distribution. In cerebral cortex, patches were evident where GLT-1B was absent, whereas no such patches were evident for GLT-1alpha. At high resolution, other discrepancies were evident; double-labeling of areas such as hippocampus indicated that the. two splice variants may either be differentially expressed by closely apposed glial elements or that the two splice variants may be differentially targeted to distinct membrane domains of individual glial cells. (C) 2002 Wiley-Liss, Inc.

ATP-dependent K+ channels in renal ischemia reperfusion injury

ATP-dependent K+ channels (K-ATP) account for most of the recycling of K+ which enters the proximal tubules cell via Na, K-ATPase. In the mitochondrial membrane, opening of these channels preserves mitochondrial viability and matrix volume during ischemia. We examined KATP channel modulation in renal ischemia-reperfusion injury (IRI), using an isolated perfused rat kidney (IPRK) model, in control, IRI, IRI + 200 muM diazoxide (a K-ATP opener), IRI + 10 muM glibenclamide (a K-ATP blocker) and IRI + 200 muM diazoxide + 10 muM glibenclamide groups. IRI was induced by 2 periods of warm ischemia, followed by 45 min of reperfusion. IRI significantly decreased glomerular filtration rate (GFR) and increased fractional excretion of sodium (FENa) (p < 0.01). Neither diazoxide nor glibenclamide had an effect on control kidney function other than an increase in renal vascular resistance produced by glibenclamide. Pretreatment with 200 muM diazoxide reduced the postischemic increase in FENa (p < 0.05). Adding 10 muM glibenclamide inhibited the diazoxide effect on postischemic FENa (p < 0.01). Histology showed that kidneys pretreated with glibenclamide demonstrated an increase in injure in the thick ascending limb of outer medulla (p < 0.05). Glibenclamide significantly decreased post ischemic renal vascular resistance (p < 0.05). but had no significant effect on other renal function parameters. Our results suggest that sodium reabsorption is improved by K-ATP activation and blockade of K-ATP channels during IRI has an injury enhancing effect on renal epithelial function and histology. This may be mediated through K-ATP modulation in cell and or mitochondrial inner membrane.

Repetitive brief ischemia: Intermittent reperfusion during ischemia ameliorates the extent of injury in the perfused kidney

Acute renal failure commonly follows reduced renal perfusion or ischemia. Reperfusion is essential for recovery but can itself cause functional and structural injury to the kidney. The separate contributions of ischemia and of reperfusion were examined in the isolated perfused rat kidney. Three groups were studied: brief (5 min) ischemia, 20 min ischemia, and repetitive brief ischemia (4 periods of 5 min) with repetitive intervening reperfusion of 5 min. A control group had no intervention, the three ischemia groups were given a baseline perfusion of 30 min before intervention and all groups were perfused for a total of 80 min. In addition, the effects of exogenous (NO)-N-. from sodium nitroprusside and xanthine oxidase inhibition by allopurinol were assessed in the repetitive brief ischemia-reperfusion model. Brief ischemia produced minimal morphological injury with near normal functional recovery. Repetitive brief ischemia reperfusion caused less functional and morphological injury than an equivalent single period of ischemia (20 min) suggesting that intermittent reperfusion is less injurious than ischemia alone over the time course of study. Pretreatment with allopurinol improved renal function after repetitive brief ischemia-reperfusion compared with the allopurinol-untreated repetitive brief ischemia-reperfusion group. Similarly, sodium nitroprusside reduced renal vascular resistance but did not improve the glomerular filtration rate or sodium reabsorption in the repetitive brief ischemia-reperfusion model. Thus, these studies show that the duration of uninterrupted ischemia is more critical than reperfusion in determining the extent of renal ischemia-reperfusion injury and that allopurinol, in particular, counteracts the oxidative stress of reperfusion.

A randomized trial of aggressive lipid reduction for improvement of myocardial ischemia, symptom status, and vascular function in patients with coronary artery disease not amenable to intervention

PURPOSE: To determine the effects of aggressive lipid lowering on markers of ischemia, resistance vessel function, atherosclerotic burden, and Symptom status in patients with symptomatic coronary artery disease. METHODS: Sixty consecutive patients with coronary artery disease that was unsuitable for revascularization were assigned randomly to either usual therapy of lipids for patients with a low-density lipoprotein (LDL) cholesterol target level <116 mg/dL, or to a, more aggressive lipid-lowering strategy involving up to 80 mg/d of atorvastatin, with a target LDL cholesterol level <77 mg/dL. The extent and severity of inducible ischemia (by dobutamine echocardiography), vascular function.(brachial artery reactivity), atheroma burden (carotid intima-media thickness), and symptom status were evaluated blindly at baseline and after 12 weeks of treatment. RESULTS: After 12 weeks of treatment, patients in the aggressive therapy group had a significantly greater decrease in mean (+/- SD) LDL cholesterol level than those in the usual care group (29 +/- 38 mg/dL vs. 7 +/- 24 mg/dL, P = 0.03). Patients in the aggressive therapy group had a reduction in the number of ischemic wall segments (mean between-group difference of 1.3; 95% confidence interval: 0.1 to 2.0; P = 0.04), flow-mediated dilatation (mean between-group difference of 5.9%; 95% confidence interval: 2.5% to 9.4%; P = 0.001), and angina score after 12 weeks. There were no significant changes in atherosclerotic burden in either group. CONCLUSION: Patients with symptomatic coronary artery disease who are treated with aggressive lipid lowering have improvement of symptom status and ischemia that appears to reflect improved vascular function but not atheroma burden. Am J Med. 2003;114:445-453. (C) 2003 by Excerpta Medica Inc.

Abnormal left ventricular filling with increasing age reflects abnormal myocardial characteristics independent of ischemia or hypertrophy

Abnormal left ventricular (IV) filling may occur with increasing age despite apparently normal IV size and function, and is usually attributed to IV hypertrophy and coronary artery disease. The purpose of this study was to determine whether myocardial abnormalities could be identified in 67 such patients (36 men, mean age 57 +/- 9 years) whose IV hypertrophy and coronary artery disease were excluded by dobutamine echocardiography. All patients underwent gray scale and color tissue Doppler imaging from 3 apical views, which were stored and analyzed off line. Disturbances in structure and function were assessed by averaging the cyclic variation of integrated backscatter, strain rate, and peak systolic strain from each myocardial segment. Calibrated integrated backscatter (corrected for pericardial backscatter intensity) was measured in the septum and posterior wall from the parasternal long-axis view. Abnormal IV filling was present in 36 subjects (54%). Subjects with and without abnormal IV filling had similar IV mass, but differed in age (p <0.01), cyclic variation (p = 0.001), strain rate (p <0.01), and peak systolic strain (p <0.001). Multivariate logistic regression analysis demonstrated that age (p = 0.016) and cyclic variation (p = 0.042) were the most important determinants of abnormal IV filling in these apparently normal subjects. (C) 2003 by Excerpta Medica, Inc.

Independent contribution of plaque complexity to myocardial ischemia during Dobutamine stress echocardiography

The influence of complex plaque morphology on the extent of demand-induced ischemia in unselected patients is not well defined. We sought to investigate the functional significance of lesion morphology in patients who underwent coronary angiography and dobutamine stress echocardiography (DSE).,Angiography and DSE were performed within a 6-month period (mean 1 +/- 1 month) in 196 patients. Angiographic assessments involved quantification of stenosis severity, assessment of the extent of jeopardized myocardium, and categorization of plaque morphology according to the Ambrose classification. DSE was interpreted by separate investigators with respect to wall motion score index (WMSI) and number of coronary territories involved. A general linear model was constructed to assess,the independent contribution of patient characteristics and angiographic and DSE results with respect to extent of ischemic myocardium. Complex lesion morphology was seen in 62 patients (32%). Patients with complex lesions were more likely to have had prior myocardial infarction (p < 0.001) and be current smokers (p = 0.03). During angiography, they exhibited a trend toward a greater number of diseased vessels, had a greater coronary jeopardy score (p < 0.001) and more frequent collateral flow (p = 0.03). During echocardiography, patients had a higher stress WMSI (p < 0.001) and were more likely to show ischemia in all 3 arterial territories (p < 0.01). On multivariate regression, the coronary artery jeopardy score and the presence of complex plaque morphology were independent predictors of the extent of ischemic myocardium (R 2 = 34%, p < 0.001). Thus, patients with complex plaque morphology are older, more likely to smoke, and more likely to have had prior myocardial. infarction. They exhibit more extensive disease with higher coronary jeopardy scores and a higher resting and peak stress WMSI. Despite these differences, complex plaque morphology remains an independent predictor of the extent of ischemia during stress. (C) 2003 by Excerpta Medica, Inc.

Cerebral impedance and neurological outcome following a mild or severe hypoxic/ischemic episode in neonatal piglets

Multi-frequency bio-impedance has the potential to identify infants at risk of poor neurodevelopmental outcome following hypoxia by detecting cerebral edema. This study investigated the relationship between the severity of an hypoxic/ischemic episode, neurological outcome following the hypoxia and non-invasively measured cerebral bioelectrical impedance in piglets. One-day-old piglets were anaesthetised and ventilated. Hypoxia was induced by reducing the inspired oxygen concentration to 3-5%. Severe hypoxia was defined as hypoxia resulting in at least 30 min of low amplitude EEG (

Alunos com paralisia cerebral na escola : linguagem, comunicação alternativa e processos de comunicativos

O estudo assume como problema de investigação analisar as contribuições da Comunicação Alternativa e Ampliada (CAA) aos processos comunicativos de alunos sem fala articulada no contexto da escola, destacando nesses processos o papel potencializador dos interlocutores. Fundamenta-se na abordagem de linguagem e na noção de enunciado discutidas por Bakhtin e nas contribuições de Vigotski sobre a relação entre desenvolvimento e aprendizagem, postulando que a aquisição e o desenvolvimento da linguagem ocorrem no curso das aprendizagens, ao longo da vida. As análises e reflexões empreendidas evidenciam uma discussão acerca da linguagem que se desloca da dimensão orgânica para a dimensão da constituição do sujeito como humano. Sob essa visão, outros conceitos, como os de língua, fala, interação verbal, dialogia, enunciação, aprendizagem e desenvolvimento são problematizados e também considerados como elementos fundantes e presentes nas relações comunicativas entre os sujeitos sem fala articulada e seus interlocutores. Na primeira etapa, o estudo busca conhecer as formas organizativo-pedagógicas de cinco Secretarias Municipais de Educação da Região Metropolitana de Vitória e da Secretaria de Estado da Educação no que diz respeito à identificação dos alunos com Paralisia Cerebral, sem fala articulada, ao acompanhamento técnico-pedagógico e à formação de professores que atuam na Educação Especial. Na segunda etapa, objetiva conhecer a processualidade da organização do trabalho pedagógico instituída nos contextos escolares e investiga os processos comunicativos em/com dois alunos com severos comprometimentos motores e de fala em duas escolas de Ensino Fundamental, localizadas no município de Serra e de Vitória. Nesta etapa, opta pela pesquisa- ação colaborativo-crítica por contribuir, teórica e metodologicamente, para sustentar os fazeres individuais e coletivos nos lócus de investigação. Os resultados revelam que, institucionalmente, ainda não se conhece quem são e quantos são os alunos com Paralisia Cerebral sem fala articulada no contexto de suas reais necessidades. Esse desconhecimento é atribuído pelas gestoras das Secretarias Municipais de Educação investigadas ao considerarem que, via de regra, são tomadas apenas as informações do Educacenso-INEP. As identificações pontuais, quando ocorrem, são decorrentes de estratégias internas adotadas, sendo uma delas o assessoramento pedagógico das equipes às escolas. No que tange ao ensino, à aprendizagem e à avaliação, o estudo constata que são atravessados por concepções equivocadas sobre os sujeitos com Paralisia Cerebral sustentadas, sobretudo, pela baixa expectativa e pelo pouco “esforço” quanto à sua escolarização. Constata também que o uso dos recursos de CAA potencializa os processos comunicativos dos alunos investigados e, movimentados pela linguagem, possibilita-lhes enunciar e fixar posições, opiniões e decisões, assegurando-lhes mais autonomia e fluidez do processo comunicacional. As formas de mediação dos interlocutores assim como as dinâmicas dialógicas por eles utilizadas com os alunos se constituem como elementos importantes nos processos de comunicação e interação. A espera do outro, o apoio e o incentivo à reformulação daquilo que se quer expressar, as modificações e alterações no jogo dialógico são exemplos dessa mediação. Quanto às ações de reorganização do trabalho pedagógico, o estudo registra maior articulação e colaboração entre professores da classe, professora da Educação Especial e estagiária no planejamento das aulas, dos conteúdos, com a inserção no notebook para um dos alunos; o uso das pranchas de comunicação, por ambos os alunos e seus interlocutores, como ação inovadora nos contextos escolares; a realização de atividades pelos alunos, com gradativa autonomia, a partir da disponibilização de recursos de TA/CAA (pasta de conteúdos temáticos, figuras imantadas, quadro metálico, ponteira, plano inclinado, notebook); a proposição de ações intencionais de alfabetização, a partir da reorganização de espaços-tempos no cotidiano da escola. Conclui que as discussões teóricas e práticas das questões relacionadas com a linguagem, com os processos cognitivos e com o uso de recursos de TA/CAA alavancam mudanças na concepção dos profissionais das escolas pesquisadas que, ainda, sob uma visão reducionista quanto às formas de comunicação e de interação verbal, “impõem” limites à escolarização dos alunos com deficiência.

Referências anatômicas na cirurgia do implante auditivo de tronco cerebral

O implante auditivo de tronco cerebral é uma opção os pacientes surdos que não têm a integridade das vias auditivas preservada. A cirurgia, por sua complexidade anatômica e funcional, requer treinamento específico em laboratório de anatomia por parte do cirurgião. OBJETIVOS: Estudar a anatomia cirúrgica da cirurgia do implante auditivo de tronco cerebral. FORMA DE ESTUDO: Estudo anatômico. MATERIAL E MÉTODO: Neste estudo dissecamos cadáver fresco preparado com solução corante injetada nas artérias e veias intra-cranianas. O local de inserção do eletrodo do implante auditivo de tronco cerebral foi estudado através do acesso translabiríntico. RESULTADOS: A técnica cirúrgica utilizada para a implantação do eletrodo de tronco cerebral é semelhante à utilizada na remoção do shwannoma vestibular. O complexo de núcleo coclear, composto pelo núcleo coclear ventral e dorsal, é o local para a colocação do eletrodo. O núcleo coclear ventral é o principal núcleo de transmissão de impulsos neurais do VIII par e seus axônios formam a principal via ascendente do nervo coclear. Tanto o núcleo ventral como o dorsal não são visíveis durante a cirurgia e sua localização depende de identificação de estruturas anatômicas adjacentes. CONCLUSÃO: A região de implantação do eletrodo do implante auditivo de tronco cerebral apresenta referências anatômicas que permitem sua fácil identificação durante a cirurgia.

Implante auditivo de tronco cerebral: técnica cirúrgica e resultados auditivos precoces em pacientes com neurofibromatose tipo 2

O implante auditivo de tronco cerebral foi desenvolvido para restaurar alguma audição útil em pacientes que apresentam ausência de nervo coclear bilateralmente. OBJETIVOS: Discutir a indicação, cirurgia e resultados em quatro pacientes submetidos à cirurgia para colocação de implante auditivo de tronco cerebral. CASUÍSTICA E MÉTODOS: Quatro pacientes com diagnóstico de schwannomas vestibulares bilaterais foram submetidos à cirurgia para colocação de Implante Auditivo de Tronco Cerebral durante o mesmo ato cirúrgico utilizado para a exérese de um dos tumores. Aspectos clínicos e técnicos e as referências anatômicas da cirurgia e os resultados auditivos foram analisados. RESULTADOS: Em todos os casos foram identificados as referências anatômicas ao forame de Luschka. As complicações cirúrgicas se resumiram à fístula liquórica em dois pacientes. Os eletrodos foram bem posicionados e a sensação auditiva foi suficiente para reconhecimento de sons e auxílio à leitura labial. CONCLUSÃO: Os resultados auditivos de nossos pacientes abrem uma perspectiva importante aos pacientes com surdez profunda bilateral sem integridade anatômica das vias auditivas centrais.