Endogenous endothelin-1 limits exercise-induced vasodilation in hypertensive humans

Essential hypertension is a common disorder, associated with increased endothelin-l-mediated vasoconstrictor tone at rest. We hypothesized that increased vasoconstrictor activity of endothelin-1 might explain why the normal decrease in peripheral vascular resistance in response to exercise is attenuated in hypertensive patients. Therefore, we investigated the effect of endothelin A (ETA) receptor blockade on the vasodilator response to handgrip exercise. Forearm blood flow responses to handgrip exercise (15%, 30%, and 45% of maximum voluntary contraction) were assessed in hypertensive patients and matched normotensive subjects, before and after intra-arterial infusions of the ETA receptor antagonist BQ-123; a control dilator, hydralazine; and placebo (saline). Preinfusion (baseline) vasodilation in response to exercise was significantly attenuated at each workload in hypertensive patients compared with normotensive subjects. Intra-arterial infusions of hydralazine and saline did not increase the vasodilator response to exercise in either hypertensives or normotensives at any workload. The vasodilator response to exercise was markedly enhanced after BQ-123 at the 2 higher workloads in hypertensives (157 +/- 48%, P < 0.01; 203 &PLUSMN; 58%, P < 0.01) but not in normotensives. This suggests that the impaired vasodilator response to exercise in hypertensive patients is, at least in part, a functional limitation caused by endogenous ETA receptor-mediated vasoconstriction. Treatment with endothelin receptor antagonists may, therefore, increase exercise capacity in essential hypertension.

Jules Cotard (1840-1889) - His life and the unique syndrome which bears his name

Dr. Jules Cotard (1840-1889) was a Parisian neurologist who first described the delire des negations. Cotard's syndrome or Cotard's delusion comprises any one of a series of delusions ranging from the fixed and unshakable belief that one has lost organs, blood, or body parts to believing that one has lost one's soul or is dead. In its most profound form, the delusion takes the form of a professed belief that one does not exist. Encountered primarily in psychoses such as schizophrenia and bipolar disorder, Cotard's syndrome has also been described in organic lesions of the nondominant temporoparietal cortex as well as in migraine. Cotard's delusion is the only self-certifiable syndrome of delusional psychosis. Jules Cotard, a Parisian neurologist and psychiatrist and former military surgeon, was one of the first to induce cerebral atrophy by the experimental embolization of cerebral arteries in animals and a pioneer in studies of the clinicopathologic correlates of cerebral atrophy secondary to perinatal and postnatal pathologic changes. He was the first to record that unilateral cerebral atrophy in infancy does not necessarily lead to aphasia and was also the pioneer of studies of altered conscious states in diabetic hyperglycemia.

Characterization of the retinoid orphan-related receptor-alpha coactivator binding interface: A structural basis for ligand-independent transcription

The retinoid orphan-related receptor-alpha (RORalpha) is a member of the ROR subfamily of orphan receptors and acts as a constitutive activator of transcription in the absence of exogenous ligands. To understand the basis of this activity, we constructed a homology model of Rill using the closely related TRbeta as a template. Molecular modeling suggested that bulky hydrophobic side chains occupy the RORa ligand cavity leaving a small but distinct cavity that may be involved in receptor stabilization. This model was subject to docking simulation with a receptor-interacting peptide from the steroid receptor coactivator, GR-interacting protein-1, which delineated a coactivator binding surface consisting of the signature motif spanning helices 3-5 and helix 12 [activation function 2 (AF2)]. Probing this surface with scanning alanine mutagenesis showed structural and functional equivalence between homologous residues of RORalpha and TRbeta. This was surprising (given that Rill is a ligand-independent activator, whereas TRbeta has an absolute requirement for ligand) and prompted us to use molecular modeling to identify differences between Rill and TRbeta in the way that the All helix interacts with the rest of the receptor. Modeling highlighted a nonconserved amino acid in helix 11 of RORa (Phe491) and a short-length of 3.10 helix at the N terminus of AF2 which we suggest i) ensures that AF2 is locked permanently in the holoconformation described for other liganded receptors and thus 2) enables ligand-independent recruitment of coactivators. Consistent with this, mutation of RORa Phe491 to either methionine or alanine (methionine is the homologous residue in TRbeta), reduced and ablated transcriptional activation and recruitment of coactivators, respectively. Furthermore, we were able to reconstitute transcriptional activity for both a deletion mutant of Ill lacking All and Phe491 Met, by overexpression of a GAL-AF2 fusion protein, demonstrating ligand-independent recruitment of AF2 and a role for Phe491 in recruiting AF2.

Conservation of the cardiostimulant effects of (-)-Norepinephrine across Ser49Gly and Gly389Arg Beta1-adrenergic receptor polymorphisms in human right atrium in vitro

OBJECTIVES The goal of this study was to determine whether the cardiostimulant effects of the endogenous beta(1)-adrenergic receptor (AR) agonist, (-)-norepinephrine are modified by polymorphic (Serine49Glycine [Ser49Gly], Glycine389Arginine [Gly389Arg]) variants of beta(1)-ARs in the nonfailing adult human heart. BACKGROUND Human heart beta(1)-ARs perform a crucial role in mediating the cardiostimulant effects of (-)-norepinephrine. An understanding of the significance of Ser49Gly and Gly389Arg polymorphisms in the human heart is beginning to emerge, but not as yet in adult patients who have coronary artery disease (CAD). METHODS The potency and maximal effects of (-)-norepinephrine at beta(1)-ARs (in the presence of beta(2)-AR blockade with 50 nM ICI 118,551 [erythro-DL-1(7-methylindan-4-yloxy)-3-isopropylamino-butan-2-ol]) for changes in contractile force and shortening of contractile cycle duration were determined in human right atrium in vitro from 87 patients undergoing coronary artery bypass grafting who were taking beta-blockers before surgery. A smaller sample of patients (n = 20) not taking beta-blockers was also investigated. Genotyping for two beta(1)-AR polymorphisms (Ser49Gly and Gly389Arg) was determined from a sample of blood taken at the time of surgery. RESULTS (-)-Norepinephrine caused concentration-dependent increases in contractile force and reductions in time to reach peak force and time to reach 50% relaxation. There were no differences in the potency or maximal effects of (-)-norepinephrine in the right atrium from patients with different Ser49Gly and Gly389Arg polymorphisms. CONCLUSIONS The cardiostimulant effects of (-)-norepinephrine at beta(1)-ARs were conserved across Ser49Gly and Gly389Arg polymorphisms in the right atrium of nonfailing hearts from patients with CAD managed with or without beta-blockers. (C) 2002 by the American College of Cardiology Foundation.

Long-term trends in sunshine duration and its association with schizophrenia birth rates and age at first registration - data from Australia and the Netherlands

Back ground. Based on the well-described excess of schizophrenia births in winter and spring, we hypothesised that individuals with schizophrenia (a) would be more likely to be born during periods of decreased perinatal sunshine, and (b) those born during periods of less sunshine would have an earlier age of first registration. Methods. We undertook an ecological analysis of long-term trends in perinatal sunshine duration and schizophrenia birth rates based on two mental health registers (Queensland. Australia n = 6630; The Netherlands n = 24, 474). For each of the 480 months between 1931 and 1970, the agreement between slopes of the trends in psychosis and long-term sunshine duration series were assessed. Age at first registration was assessed by quartiles of long-term trends in perinatal sunshine duration, Males and females were assessed separately. Results. Both the Dutch and Australian data showed a statistically significant association between falling long-term trends in sunshine duration around the time of birth and rising schizophrenia birth rates for males only. In both the Dutch and Australian data there were significant associations between earlier age of first registration and reduced long-term trends in sunshine duration around the time of birth for both males and females, Conclusions. A measure of long-term trends in perinatal sunshine duration was associated with two epidemiological features of schizophrenia in two separate data sets. Exposures related to sunshine duration warrant further consideration in schizophrenia research. (C) 2002 Elsevier Science B.V. All rights reserved.

Present and future pharmacotherapy for benign prostatic hyperplasia

Around 50% of men 51-60 years of age have pathological benign prostatic hyperplasia (BPH). Pharmacotherapy for BPH includes the 5alpha-reductase inhibitor finasteride, and alpha(1)-adrenoceptor antagonists. Finasteride reduces prostate volume and symptom scores, while increasing peak urinary flow rates. The main problem with finasteride treatment is that it increases the incidence of ejaculation disorders. All of the alpha(1)-adrenoceptor antagonists have been shown to reduce symptom scores and increase peak urinary flow rates in BPH. The nonselective alpha(1)-adrenoceptor antagonists (prazosin, terazosin and doxazosin) were developed as antihypertensives, and hypotensive-related side effects are the main problem with these agents in BPH. These side effects can be diminished by reducing peak concentrations of the drugs, as with once-daily alfuzosin, or by using the uroselective antagonist tamsulosin. Phytopharmaceuticals are commonly used in the treatment of BPH, such as saw palmetto berry which has been shown to improve the symptoms and peak urinary flow rate. Androgen receptor antagonists are not used in BPH because of their adverse effects. Newer drugs under development for the treatment of BPH include alpha(1)-adrenoceptor antagonists that show more selectivity for alpha(1A)-adrenoceptors than tamsulosin, combined 5alpha-reductase/alpha(1)-adrenoceptor inhibitors and combined type 1/type 2 5alpha-reductase inhibitors. New targets for the drug treatment of BPH include indothelin, growth factors, estrogens and the phosphodiesterase isoenzymes.

Elucidating the molecular mechanisms that underlie the target control of motoneuron death

Approximately half of the motoneurons generated during normal embryonic development undergo programmed cell death. Most of this death occurs during the time when synaptic connections are being formed between motoneurons and their target, skeletal muscle. Subsequent muscle activity stemming from this connection helps determine the final number of surviving motoneurons. These observations have given rise to the idea that motoneuron survival is dependent upon access to muscle derived trophic factors, presumably through intact neuromuscular synapses. However, it is not yet understood how the muscle regulates the supply of such trophic factors, or if there are additional mechanisms operating to control the fate of the innervating motoneuron. Recent observations have highlighted target independent mechanisms that also operate to support the survival of motoneurons, such as early trophic-independent periods of motoneuron death, trophic factors derived from Schwann cells and selection of motoneurons during pathfinding. Here we review recent investigations into motoneuron cell death when the molecular signalling between motoneurons and muscle has been genetically disrupted. From these studies, we suggest that in addition to trophic factors from muscle and/or Schwann cells, specific adhesive interactions between motoneurons and muscle are needed to regulate motoneuron survival. Such interactions, along with intact synaptic basal lamina, may help to regulate the supply and presentation of trophic factors to motoneurons.

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.

Proteasomal targeting of a viral oncogene abrogates oncogenic phenotype and enhances immunogenicity

The ability of viral or mutated cellular oncogenes to initiate neoplastic events and their poor immunogenicity have considerably undermined their potential use as immunotherapeutic tools for the treatment of human cancers. Using an EpsteinBarr virus-encoded oncogene, latent membrane protein 1 (LMP1), as a model, we report a novel strategy that both deactivates cellular signaling pathways associated with the oncogenic phenotype and reverses poor immunogenicity. We show that cotranslational ubiquitination combined with Wend rule targeting of LMP1 enhanced the intracellular degradation of LMP1 and total blockade of LMP1-mediated nuclear factor-kappaB (NF-kappaB) and signal transducer and activator of transcription (STAT) activation in human cells. In addition, although murine cells expressing LMP1 were uniformly tumorigenic, this oncogenicity was completely abrogated by covalent linkage of LMP1 with ubiquitin, while an enhanced CD8(+) T cell response to a model epitope fused to the C-terminus of LMP1 was observed following immunization with ubiquitinated LMP1. These observations suggest that proteasomal targeting of tumor-associated oncogenes could be exploited therapeutically by either gene therapy or vaccination.

(-)-CGP 12177 increases contractile force and hastens relaxation of human myocardial preparations through a propranolol-resistant state of the beta1-adrenoceptor

Two forms of the activated beta(1)-adrenoceptor exist, one that is stabilized by (-)-noradrenaline and is sensitive to blockade by (-)-propranolol and another which is stabilized by partial agonists such as (-)-pindolol and (-)-CGP 12177 but is relatively insensitive to (-)-propranolol. We investigated the effects of stimulation of the propranolol-resistant PI-adrenoceptor in the human heart. Myocardium from non-failing and failing human hearts were set up to contract at 1 Hz. In right atrium from non-ailing hearts in the presence of 200 nM (-)-propranolol, (-)-CGP 12177 caused concentration-dependent increases in contractile force (-logEC(50)[M] 7.3+/-0.1, E-max 23+/-1% relative to maximal (-)-isoprenaline stimulation of beta(1)- and beta(2)-adrenoceptors, n=86 patients), shortening of the time to reach peak force (-logEC(50)[M] 7.4+/-0.1, E-max 37+/-5%, n=61 patients) and shortening of the time to reach 50% relaxation (t(50%), -logEC(50)[M] 7.3+/-0.1, E-max 33+/-2%, n=61 patients). The potency and maxima of the positive inotropic effects were independent of Ser49Gly- and Gly389Arg-beta(1)-adrenoceptor polymorphisms but were potentiated by the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (-logEC(50)[M] 7.7+/-0.1, E-max 68+/-6%, n=6 patients, P

Complicações perinatais no Hospital Universitário Cassiano Antonio de Moraes: uma questão de idade?

A população brasileira vem passando por uma transição demográfica e epidemiológica, caracterizadas por aumento na expectativa de vida, diminuições nas taxas de mortalidade, natalidade e fecundidade, aumento da escolaridade, diminuição do desemprego, aumento das enfermidades crônico-degenerativas e diminuição das enfermidades infectocontagiosas. Tais transições vêm afetando também a perinatologia, com aumento proporcional e absoluto das gestações tardias tanto no Espírito Santo quanto no Brasil. Este estudo realizou uma análise retrospectiva das gestações tardias no HUCAM, comparando as mesmas com as gestações de mulheres adolescentes e adultas jovens quanto aos seguintes desfechos perinatais: anomalia fetal, hipóxia no primeiro e quinto minuto de vida, duração da gestação, peso ao nascer e tipo de parto. As variáveis foram analisadas categoricamente, e comparadas através de análise bivariada, utilizando-se o Teste Exato de Fisher, e através de regressão logística. Na análise bivariada, foi encontrada apenas associação entre a idade materna e o tipo de parto, mas esta associação não foi confirmada na regressão logística. Analisando outros fatores relativos à gestação, restou evidenciado uma associação positiva entre um menor número de consultas pré-natais e uma maior frequência de hipóxia no recém-nascido e de prematuridade (odds ratio de 2,9 e 5,7, respectivamente). Ao final deste trabalho são elaboradas propostas para aprimoramento da coleta e do armazenamento de dados acerca da gestação no HUCAM, e para otimização da assistência pré-natal das gestantes atendidas pelo hospital, visando melhorar os desfechos perinatais encontrados.

A importância da associação obesidade e gravidez

Foram estudados dois grupos de gestantes, sendo um de grávidas normais e outro de obesas, com a finalidade de reconhecer algumas características da evolução da gravidez, em mulheres obesas, e suas repercussões sobre o concepto. Foram relacionadas as seguintes variáveis: status sócio-econômico familiar, idade, altura, perímetro braquial, peso habitual, número de gestações anteriores, paridade materna, ganho de peso durante a gestação, idade gestacional, intercorrências durante a gestação, peso ao nascer e vitalidade do recém-nascido. Pelos resultados concluiu-se que as gestantes obesas são diferentes das normais e apresentam maior incidência de complicações obstétricas. Os recém-nascidos, filhos de obesas, registraram índice maior de mortalidade, principalmente no período perinatal. Houve maior incidência de prematuridade e de fetos macrossômicos, sendo a curva de distribuição de peso ao nascer diferente da dos recém-nascidos das gestantes normais. A média de peso ao nascer das crianças das gestantes obesas é maior que o das normais. Concluiu-se ainda que toda vez que a gestante obesa sofre restrição alimentar, com ganho de peso inadequado, o crescimento intra-uterino é afetado; não sendo, portanto, a época da gravidez a melhor para a obesa perder peso, mas, ao contrário, ela deveria receber uma orientação alimentar adequada. A obesidade é pois um fator de aumento do risco gravídico, que pode afetar tanto a mãe como o concepto.

Risco de morrer no primeiro ano de vida entre favelados e não favelados no município de Porto Alegre, RS (Brasil), em 1980

Foram apresentados o risco relativo (RR) e o risco atribuível percentual (RAP) ao fator favelado de morrer, no primeiro ano de vida, em quatro setores de Porto Alegre, RS (Brasil), em 1980. O risco relativo médio de morrer no primeiro ano de vida foi de 2,4 a 3,62 vezes maior para o favelado, considerado um intervalo de confiança de 95%. O RAP ao favelado de morrer no primeiro ano de vida variou de 23,2% a 33,0% considerado um intervalo de confiança de 95%. O estudo dos cinco principais grupos de causas revelou que com exceção dos óbitos por anomalias congênitas, o risco relativo por essas causas foi sempre superior para o favelado; 1,8 vezes maior para afecções perinatais, 5,9 para a doença infecciosa intestinal, 6,1 para pneumonia e gripe e 8,0 para septicemia. Houve setores, como o intermediário sul, em que o risco relativo de morrer por septicemia foi 18,2 vezes maior para o favelado. Quanto ao risco atribuível, verificou-se que em média 28% da mortalidade infantil é atribuível a 18% de favelados. Considerados os principais grupos de causas, o RAP ao fator favelado foi de 12,8% para a mortalidade perinatal, 47,7% para doença infecciosa intestinal, 48,7% para pneumonia e gripe e 56,7% para septicemia. Mesmo levando em conta que o problema social e econômico é o principal determinante do fato de um indivíduo ser favelado, recomenda-se verificar a qualidade da assistência à saúde prestada às populações faveladas, pois é possível obter-se redução de morbi-mortalidade por aquelas causas, através da aplicação de cuidados médicos adequados, dirigidos prioritariamente às populações em piores condições de vida.

Mortalidade infantil por causas no Estado de São Paulo (Brasil) em 1983: análise sob a perspectiva das causas múltiplas de morte

Objetivou-se apresentar a mortalidade infantil por causas no Estado de São Paulo, Brasil, com base nos dados de 1983 obtidos a partir da classificação por causas múltiplas de morte, disponíveis desde a implantação do Sistema de Classificação Automática de Causas de Morte. Detectaram-se dois tipos de casos bem definidos: os óbitos ocorridos predominantemente no período neonatal, e cujo processo mórbido envolve quase que exclusivamente as afecções pertencentes ao Capítulo das Perinatais da Classificação Internacional de Doenças; e os óbitos ocorridos principalmente no período pós-neonatal, em cujo processo mórbido aparecem mencionadas significativamente as infecções intestinais, a septicemia, a desnutrição, a desidratação e a broncopneumonia. O estudo da associação entre as principais causas de morte mostrou, por um lado, a imaturidade e a prematuridade fortemente relacionadas com as afecções respiratórias do recém-nascido e com as infecções específicas do período perinatal; e por outro lado, um complexo inter-relacionamento entre as outras cinco causas mencionadas.

Mortalidade infantil nos Estados Unidos, Suécia e Estado de São Paulo

São apresentados dados de mortalidade infantil, neonatal precoce, neonatal, pós-neonatal e perinatal, para Estados Unidos e Suécia e o Estado de São Paulo em uma série temporal de 1950 a 1982. A Suécia, consistentemente, apresenta os menores coeficientes, sendo que aqueles para o Estado de São Paulo podem ser considerados ainda bastante elevados, pois no início da década de 80 apresentava uma mortalidade infantil igual a daquele país meio século antes e a mortalidade de menores de 1 dia foi maior que a mortalidade para todo o primeiro ano de vida na Suécia. Para as três populações existe declínio de todos os coeficientes, porém, para a Suécia e os Estados Unidos, ainda que com números já bastante baixos em relação ao Estado de São Paulo no início do período estudado, o declínio tem sido maior.