Impaired fast-spiking, suppressed cortical inhibition and increased susceptibility to seizures in mice lacking Kv3.2 K+ channel proteins

Voltage-gated K+ channels of the Kv3 subfamily have unusual electrophysiological properties, including activation at very depolarized voltages (positive to −10 mV) and very fast deactivation rates, suggesting special roles in neuronal excitability. In the brain, Kv3 channels are prominently expressed in select neuronal populations, which include fast-spiking (FS) GABAergic interneurons of the neocortex, hippocampus, and caudate, as well as other high-frequency firing neurons. Although evidence points to a key role in high-frequency firing, a definitive understanding of the function of these channels has been hampered by a lack of selective pharmacological tools. We therefore generated mouse lines in which one of the Kv3 genes, Kv3.2, was disrupted by gene-targeting methods. Whole-cell electrophysiological recording showed that the ability to fire spikes at high frequencies was impaired in immunocytochemically identified FS interneurons of deep cortical layers (5-6) in which Kv3.2 proteins are normally prominent. No such impairment was found for FS neurons of superficial layers (2-4) in which Kv3.2 proteins are normally only weakly expressed. These data directly support the hypothesis that Kv3 channels are necessary for high-frequency firing. Moreover, we found that Kv3.2 −/− mice showed specific alterations in their cortical EEG patterns and an increased susceptibility to epileptic seizures consistent with an impairment of cortical inhibitory mechanisms. This implies that, rather than producing hyperexcitability of the inhibitory interneurons, Kv3.2 channel elimination suppresses their activity. These data suggest that normal cortical operations depend on the ability of inhibitory interneurons to generate high-frequency firing.

Vasopressin-dependent coupling between sodium transport and water flow in a mouse cortical collecting duct cell line.

Water balance is achieved through the ability of the kidney to control water reabsorption in the connecting tubule and the collecting duct. In a mouse cortical collecting duct cell line (mCCD(c11)), physiological concentrations of arginine vasopressin increased both electrogenic, amiloride-sensitive, epithelial sodium channel (ENaC)-mediated sodium transport measured by the short-circuit current (Isc) method and water flow (Jv apical to basal) measured by gravimetry with similar activation coefficient K(1/2) (6 and 12 pM, respectively). Jv increased linearly according to the osmotic gradient across the monolayer. A small but highly significant Jv was also measured under isoosmotic conditions. To test the coupling between sodium reabsorption and water flow, mCCD(c11) cells were treated for 24 h under isoosmotic condition with either diluent, amiloride, vasopressin or vasopressin and amiloride. Isc, Jv, and net chemical sodium fluxes were measured across the same monolayers. Around 30% of baseline and 50% of vasopressin-induced water flow is coupled to an amiloride-sensitive, ENaC-mediated, electrogenic sodium transport, whereas the remaining flow is coupled to an amiloride-insensitive, nonelectrogenic sodium transport mediated by an unknown electroneutral transporter. The mCCD(c11) cell line is a first example of a mammalian tight epithelium allowing quantitative study of the coupling between sodium and water transport. Our data are consistent with the 'near isoosmotic' fluid transport model.

Sleep deprivation effects on circadian clock gene expression in the cerebral cortex parallel electroencephalographic differences among mouse strains.

Sleep deprivation (SD) results in increased electroencephalographic (EEG) delta power during subsequent non-rapid eye movement sleep (NREMS) and is associated with changes in the expression of circadian clock-related genes in the cerebral cortex. The increase of NREMS delta power as a function of previous wake duration varies among inbred mouse strains. We sought to determine whether SD-dependent changes in circadian clock gene expression parallel this strain difference described previously at the EEG level. The effects of enforced wakefulness of incremental durations of up to 6 h on the expression of circadian clock genes (bmal1, clock, cry1, cry2, csnk1epsilon, npas2, per1, and per2) were assessed in AKR/J, C57BL/6J, and DBA/2J mice, three strains that exhibit distinct EEG responses to SD. Cortical expression of clock genes subsequent to SD was proportional to the increase in delta power that occurs in inbred strains: the strain that exhibits the most robust EEG response to SD (AKR/J) exhibited dramatic increases in expression of bmal1, clock, cry2, csnkIepsilon, and npas2, whereas the strain with the least robust response to SD (DBA/2) exhibited either no change or a decrease in expression of these genes and cry1. The effect of SD on circadian clock gene expression was maintained in mice in which both of the cryptochrome genes were genetically inactivated. cry1 and cry2 appear to be redundant in sleep regulation as elimination of either of these genes did not result in a significant deficit in sleep homeostasis. These data demonstrate transcriptional regulatory correlates to previously described strain differences at the EEG level and raise the possibility that genetic differences underlying circadian clock gene expression may drive the EEG differences among these strains.

Grupo de familiares na prática de ensino de graduação em enfermagem

Atualmente, os Centros de Atenção Psicossocial (CAPS) são dispositivos estratégicos para assistência em saúde mental no Brasil. Os enfermeiros são profissionais exigidos na equipe mínima deste dispositivo, que valoriza as atividades grupais na abordagem dos usuários. Relato de experiência de alunos do Curso de Graduação em Enfermagem da UFMT, na realização de grupo de sala de espera com familiares de usuários de um CAPS de Cuiabá-MT. Justifica-se em virtude das poucas oportunidades que alunos de enfermagem têm para desenvolver habilidades de abordagem grupal na sua formação, voltada prioritariamente para o cuidado clínico individual. O objetivo da experiência foi proporcionar aprendizado teórico-prático de todas as etapas do trabalho com grupos: reconhecimento da necessidade e possibilidade da atividade, planejamento, coordenação e avaliação do grupo. Os resultados confirmam a necessidade e possibilidade da realização de experiências grupais na assistência em saúde mental e no ensino de enfermagem.

Laqueadura tubária: caracterização de usuárias laqueadas de um serviço público

Objetivou-se traçar o perfil anticoncepcional pregresso de mulheres laqueadas e verificar associações entre variáveis educacionais, sexuais, obstétricas e a idade de realização da laqueadura tubária (LT). A pesquisa, de caráter documental retrospectiva, foi realizada no Centro de Parto Natural Lígia Barros Costa (CPN) em Fortaleza-CE, com 1423 prontuários, datados de 2005 a 2008, sendo 277 de mulheres laqueadas. Na análise aplicou-se cálculo de frequências, teste qui-quadrado de Pearson e correlação de Pearson/Spearman. As mulheres laqueadas revelaram perfil de baixa escolaridade, uniões maritais e escassa utilização pregressa de outros métodos, sendo a camisinha e o anticoncepcional oral os mais frequentes. Números de gestações e abortos se associaram com a idade de realização da LT, ao contrário das variáveis escolaridade e idade da coitarca. Sabedores dessa situação, os enfermeiros poderão aperfeiçoar seu olhar em relação às mulheres que almejam realizar a LT, fortalecendo estratégias educativas e promovendo maior diversidade contraceptiva à clientela.

New validated prognostic models and prognostic calculators in patients with low-grade gliomas diagnosed by central pathology review: a pooled analysis of EORTC/RTOG/NCCTG phase III clinical trials.

Background In a previous study, the European Organisation for Research and Treatment of Cancer (EORTC) reported a scoring system to predict survival of patients with low-grade gliomas (LGGs). A major issue in the diagnosis of brain tumors is the lack of agreement among pathologists. New models in patients with LGGs diagnosed by central pathology review are needed. Methods Data from 339 EORTC patients with LGGs diagnosed by central pathology review were used to develop new prognostic models for progression-free survival (PFS) and overall survival (OS). Data from 450 patients with centrally diagnosed LGGs recruited into 2 large studies conducted by North American cooperative groups were used to validate the models. Results Both PFS and OS were negatively influenced by the presence of baseline neurological deficits, a shorter time since first symptoms (<30 wk), an astrocytic tumor type, and tumors larger than 5 cm in diameter. Early irradiation improved PFS but not OS. Three risk groups have been identified (low, intermediate, and high) and validated. Conclusions We have developed new prognostic models in a more homogeneous LGG population diagnosed by central pathology review. This population better fits with modern practice, where patients are enrolled in clinical trials based on central or panel pathology review. We could validate the models in a large, external, and independent dataset. The models can divide LGG patients into 3 risk groups and provide reliable individual survival predictions. Inclusion of other clinical and molecular factors might still improve models' predictions.

Renal and neurohormonal responses to increasing levels of lower body negative pressure in men.

BACKGROUND: The stimulation of efferent renal sympathetic nerve activity induces sequential changes in renin secretion, sodium excretion, and renal hemodynamics that are proportional to the magnitude of the stimulation of sympathetic nerves. This study in men investigated the sequence of the changes in proximal and distal renal sodium handling, renal and systemic hemodynamics, as well as the hormonal profile occurring during a sustained activation of the sympathetic nervous system induced by various levels of lower body negative pressure (LBNP). METHODS: Ten healthy subjects were submitted to three levels of LBNP ranging between 0 and -22.5 mm Hg for one hour according to a triple crossover design, with a minimum of five days between each level of LBNP. Systemic and renal hemodynamics, renal water and sodium handling (using the endogenous lithium clearance technique), and the neurohormonal profile were measured before, during, and after LBNP. RESULTS: LBNP (0 to -22.5 mm Hg) induced an important hormonal response characterized by a significant stimulation of the sympathetic nervous system and gradual activations of the vasopressin and the renin-angiotensin systems. LBNP also gradually reduced water excretion and increased urinary osmolality. A significant decrease in sodium excretion was apparent only at -22.5 mm Hg. It was independent of any change in the glomerular filtration rate and was mediated essentially by an increased sodium reabsorption in the proximal tubule (a significant decrease in lithium clearance, P < 0.05). No significant change in renal hemodynamics was found at the tested levels of LBNP. As observed experimentally, there appeared to be a clear sequence of responses to LBNP, the neurohormonal response occurring before the changes in water and sodium excretion, these latter preceding any change in renal hemodynamics. CONCLUSIONS: These data show that the renal sodium retention developing during LBNP, and thus sympathetic nervous stimulation, is due mainly to an increase in sodium reabsorption by the proximal segments of the nephron. Our results in humans also confirm that, depending on its magnitude, LBNP leads to a step-by-step activation of neurohormonal, renal tubular, and renal hemodynamic responses.

Revelação do diagnóstico de aids à criança na compreensão de familiares

Pesquisa fenomenológica que buscou compreender como a familiar cuidadora percebe a revelação do diagnóstico de aids à criança, fundamentado na filosofia de Martin Buber. Realizou-se em um hospital-escola de Porto Alegre com sete familiares de crianças com aids. A coleta das informações ocorreu por meio da entrevista fenomenológica e, para a interpretação, recorreu-se à hermenêutica. Os diálogos para a revelação do diagnóstico ao TU criança com aids demonstram que esta situação está presente no vivido por estas cuidadoras e interfere em sua existencialidade, ao estabelecer relações com o outro, no mundo. A revelação do diagnóstico de aids à criança é um fenômeno complexo e que gera diálogos relacionados às situações cotidianas compartilhadas pelas cuidadoras e crianças. Acredita-se na necessidade de outras pesquisas sobre esta temática, cada vez mais emergente nos serviços de saúde, e que considerem a dinamicidade e singularidade dos rumos tomados por esta epidemia no cenário brasileiro.

Once-yearly zoledronic acid and days of disability, bed rest, and back pain: randomized, controlled HORIZON Pivotal Fracture Trial.

The objective of this study was to determine the effect of once-yearly zoledronic acid on the number of days of back pain and the number of days of disability (ie, limited activity and bed rest) owing to back pain or fracture in postmenopausal women with osteoporosis. This was a multicenter, randomized, double-blind, placebo-controlled trial in 240 clinical centers in 27 countries. Participants included 7736 postmenopausal women with osteoporosis. Patients were randomized to receive either a single 15-minute intravenous infusion of zoledronic acid (5 mg) or placebo at baseline, 12 months, and 24 months. The main outcome measures were self-reported number of days with back pain and the number of days of limited activity and bed rest owing to back pain or a fracture, and this was assessed every 3 months over a 3-year period. Our results show that although the incidence of back pain was high in both randomized groups, women randomized to zoledronic acid experienced, on average, 18 fewer days of back pain compared with placebo over the course of the trial (p = .0092). The back pain among women randomized to zoledronic acid versus placebo resulted in 11 fewer days of limited activity (p = .0017). In Cox proportional-hazards models, women randomized to zoledronic acid were about 6% less likely to experience 7 or more days of back pain [relative risk (RR) = 0.94, 95% confidence interval (CI) 0.90-0.99] or limited activity owing to back pain (RR = 0.94, 95% CI 0.87-1.00). Women randomized to zoledronic acid were significantly less likely to experience 7 or more bed-rest days owing to a fracture (RR = 0.58, 95% CI 0.47-0.72) and 7 or more limited-activity days owing to a fracture (RR = 0.67, 95% CI 0.58-0.78). Reductions in back pain with zoledronic acid were independent of incident fracture. Our conclusion is that in women with postmenopausal osteoporosis, a once-yearly infusion with zoledronic acid over a 3-year period significantly reduced the number of days that patients reported back pain, limited activity owing to back pain, and limited activity and bed rest owing to a fracture.

O referencial de vulnerabilidade ao HIV/AIDS aplicado às famílias: um exercício reflexivo

Objetiva-se realizar um exercício reflexivo acerca das vulnerabilidades que se apresentam no contexto das famílias que convivem com o Vírus da Imunodeficiência Humana/Síndrome da Imunodeficiência Adquirida (HIV/Aids), tendo como fundamentação a literatura pertinente. Para tanto, buscou-se tecer considerações em relação à pluralidade das famílias na contemporaneidade, bem como apresentar as compreensões e desdobramentos do referencial de vulnerabilidade à epidemia da Aids. Por fim, foram descritas aproximações e reflexões referentes às vulnerabilidades à infecção pelo HIV e/ou adoecimento por Aids a que estão expostas as famílias, em seus planos individual, social e programático. Conclui-se a enorme importância de se conhecer estas vulnerabilidades específicas vivenciadas pelas famílias, a fim de que se possa nortear e desenvolver as ações de cuidado em saúde.

Humanisme i traducció catalana durant la segona meitat del segle XV: Ferran Valentí, Arnau d'Alfarràs, Francesc Alegre i Aleix de Barcelona

Les traduccions al català de la segona meitat del segle XV se situen en un punt en què conflueixen les influències de traducció medievals, ad verbum o ad sensum, amb les noves influències humanístiques que, inspirant-se en els clàssics romans, postulen ja la traducció no només de les paraules i del sentit del text original sinó també la del seu estil. Les quatre traduccions d’aquest estudi mostren les influències modernes o humanístiques que poc a poc s’introdueixen des d’Itàlia en les traduccions catalanes del quatrecents, i els contactes d’aquests traductors amb els nous corrents de pensament.

La Crisi i el petit comerç alimentari : els queviures vs. els supermercats

Els queviures són petits comerços d’alimentació on el tractament personal amb els clients es la clau de l’èxit ja que això provoca una conscienciació per part d’aquests i així es mantenen fidels a aquest establiment. En canvi, el supermercats tracten de explotar al màxim la seva reducció dels costos sense tenir tant en compte el tracte amb el client i donant-li més importància al preu de producte. Com podem observar, són dos tipus de comerços molt diferenciats tot i que al cap i a la fi, són competidors directes.La idea d’aquest treball es veure com afecta la crisi actual en aquests petits comerços i comparar-los amb el grans supermercats per arribar a una sèrie de conclusions.Hem escollit aquest tema ja que ens ha semblat interessant tractar de demostrar com el queviures tradicionals segueixen sent un negoci de profit, tot i la forta expansió que han patit les grans superfícies comercials. Un exemple d’aquest fort creixement podrien ser les dades que ens ha facilitat l’Ajuntament de Barcelona on es reflexa que el consum d’aliments es solen donar en primer lloc al supermercat (47,3%), seguit pel mercat municipal (29,3%) i en tercer lloc en la botiga de barri (16,2%).Un dels grans problemes amb que es troben els queviures és el canvi en el ritme de vida de la societat actual, sempre amb presses i estressada, que busca més, la comoditat i l’estalvi, tant de temps com de diners, a l’hora d’anar a comprar. Peraquest motiu, hem volgut investigar sobre quin es el factor que facilita la supervivència dels queviures.Degut a que el tema dels comerços estrangers va ser un tema que va provocar molta controvèrsia a la presentació del nostre treball, hem cregut convenient estudiar-lo una mica més a fons, únicament a Poble Sec. Per fer-ho hem estudiat el punt de vista que tenen els comerços estrangers sobre els comerços nacionals i també la situació actual del nombre de queviures regentats per uns i altres a través de informació extreta de la associació de comerciants de Poble Sec.Per crear el nostre treball hem realitzar diferents enquestes i entrevistes, tant a consumidors com a propietaris, per poder extreure informació amb la qual poder treballar. En total hem realitzar 100 enquestes a clients, una enquesta a cadapropietari i dues entrevistes: una a un propietari estranger i una altra a Pedro de Diego ( fundador de la associació de comerciants del Poble Sec i primer tresorer del barri)Cal destacar que ens hem trobat amb moltes dificultats per trobar o aconseguir dades econòmiques i financeres sobre aquests establiments i per això hem realitzat una aproximació a la proporció de beneficis sobre ingressos per veure quina proporció dels ingressos es poden considerar beneficis.També hem recopilat diverses notícies de diaris que tracten sobre temes relacionats amb la crisi del petit comerç i sobre l’augment en el nombre de nous queviures regentats per gent estrangera, i a partir d’aquestes hem realitzat una breu crítica sobre la situació actual.

Determination of Transmembrane Water Fluxes in Neurons Elicited by Glutamate Ionotropic Receptors and by the Cotransporters KCC2 and NKCC1: A Digital Holographic Microscopy Study.

Digital holographic microscopy (DHM) is a noninvasive optical imaging technique that provides quantitative phase images of living cells. In a recent study, we showed that the quantitative monitoring of the phase signal by DHM was a simple label-free method to study the effects of glutamate on neuronal optical responses (Pavillon et al., 2010). Here, we refine these observations and show that glutamate produces the following three distinct optical responses in mouse primary cortical neurons in culture, predominantly mediated by NMDA receptors: biphasic, reversible decrease (RD) and irreversible decrease (ID) responses. The shape and amplitude of the optical signal were not associated with a particular cellular phenotype but reflected the physiopathological status of neurons linked to the degree of NMDA activity. Thus, the biphasic, RD, and ID responses indicated, respectively, a low-level, a high-level, and an "excitotoxic" level of NMDA activation. Moreover, furosemide and bumetanide, two inhibitors of sodium-coupled and/or potassium-coupled chloride movement strongly modified the phase shift, suggesting an involvement of two neuronal cotransporters, NKCC1 (Na-K-Cl) and KCC2 (K-Cl) in the genesis of the optical signal. This observation is of particular interest since it shows that DHM is the first imaging technique able to monitor dynamically and in situ the activity of these cotransporters during physiological and/or pathological neuronal conditions.

Androgenetic alopecia: identification of four genetic risk loci and evidence for the contribution of WNT signaling to its etiology.

The pathogenesis of androgenetic alopecia (AGA, male-pattern baldness) is driven by androgens, and genetic predisposition is the major prerequisite. Candidate gene and genome-wide association studies have reported that single-nucleotide polymorphisms (SNPs) at eight different genomic loci are associated with AGA development. However, a significant fraction of the overall heritable risk still awaits identification. Furthermore, the understanding of the pathophysiology of AGA is incomplete, and each newly associated locus may provide novel insights into contributing biological pathways. The aim of this study was to identify unknown AGA risk loci by replicating SNPs at the 12 genomic loci that showed suggestive association (5 × 10(-8)<P<10(-5)) with AGA in a recent meta-analysis. We analyzed a replication set comprising 2,759 cases and 2,661 controls of European descent to confirm the association with AGA at these loci. Combined analysis of the replication and the meta-analysis data identified four genome-wide significant risk loci for AGA on chromosomes 2q35, 3q25.1, 5q33.3, and 12p12.1. The strongest association signal was obtained for rs7349332 (P=3.55 × 10(-15)) on chr2q35, which is located intronically in WNT10A. Expression studies in human hair follicle tissue suggest that WNT10A has a functional role in AGA etiology. Thus, our study provides genetic evidence supporting an involvement of WNT signaling in AGA development.