Hepatitis C virus-mediated mitochondrial dysfunctions are prevented and rescued by cyclophilin inhibition

Alisporivir (Debio-025) is an analogue of cyclosporine A andrepresents the prototype of a new class of non-immunosuppressivecyclophilin inhibitors. In vitro and in vivo studies have shownthat alisporivir inhibits hepatitis C virus (HCV) replication andongoing clinical trials are exploring its therapeutic potential inpatients with chronic hepatitis C. Recent data suggest that theantiviral effect is mediated by inhibition of cyclophilin A whichis an essential host factor in the HCV life cycle. However, alisporiviralso inhibits mitochondrial permeability transition by bindingto cyclophilin D. As HCV is known to affect mitochondrialfunction, we explored the effect of alisporivir on HCV proteinmediatedmitochondrial dysfunction. By the use of inducible celllines, which allow to investigate the effects of HCV polyproteinexpression independent from viral RNA replication and whichrecapitulate the major alterations of mitochondrial bioenergeticsobserved in infectious cell systems, we show that alisporivir preventsHCV protein-mediated cytochrome c redistribution,decrease of cell respiration, collapse of mitochondrial membranepotential, overproduction of reactive oxygen species and mitochondrialcalcium overload. Strikingly, some of the HCV-mediatedmitochondrial dysfunctions could even be rescued byalisporivir. These observations provide new insights into thepathogenesis of HCV-related liver disease and reveal an additionalmechanism of action of alisporivir that is likely beneficialin the treatment of chronic hepatitis C.

Cell differentiation to "mating bodies" induced by an integrating and conjugative element in free-living bacteria.

Lateral gene transfer (LGT) is one of the most important processes leading to prokaryotic genome innovation. LGT is typically associated with conjugative plasmids and bacteriophages, but recently, a new class of mobile DNA known as integrating and conjugative elements (ICE) was discovered, which is abundant and widespread among bacterial genomes. By studying at the single-cell level the behavior of a prevalent ICE type in the genus Pseudomonas, we uncover the remarkable way in which the ICE orchestrates host cell differentiation to ensure horizontal transmission. We find that the ICE induces a state of transfer competence (tc) in 3%-5% of cells in a population under nongrowing conditions. ICE factors control the development of tc cells into specific assemblies that we name "mating bodies." Interestingly, cells in mating bodies undergo fewer and slower division than non-tc cells and eventually lyse. Mutations in ICE genes disrupting mating-body formation lead to 5-fold decreased ICE transfer rates. Hence, by confining the tc state to a small proportion of the population, ICE horizontal transmission is achieved with little cost in terms of vertical transmission. Given the low transfer frequencies of most ICE, we anticipate regulation by subpopulation differentiation to be widespread.

Recovery of degraded pasture in Rondônia: macronutrients and productivity of brachiaria brizantha

Pasture is the main form of land use in Amazonia. Over time the pasture grass loses vigor and yields decrease, indicating a certain degree of degeneration. The main causes of degradation are lack of pasture maintenance and subsequent weed infestation, the choice of regionally unsuitable forage species and excessive grazing. The main purpose of this study was to evaluate the impact of different recovery managements on soil chemical properties and grass yield of a degraded pasture in Rondônia. For this purpose, an experiment was installed in October 2001, consisting of five treatments: C = control; HA = harrowing + NPK + micronutrients; HE = Herbicide + NK + micronutrients; R = No-tillage rice + NPK + micronutrients; and S = No-tillage soybean + PK + micronutrients. The following N, P and K sources were used: ammonium sulfate for N, calcined phosphate for P and potassium chloride for K. The experiment was arranged in a randomized block design with four replications. The shoot dry matter yield of the grass was analyzed as of the 35th month of experimentation, in a dry and a rainy period. Phosphorus fertilization resulted in significant increases in Ca2+ and Mg2+ and increasing trend of P in the topsoil in the initial months of the experiment in treatments HA and S and increases in Ca2+ and P (trend) in the treatment R. The cumulative production of Brachiaria brizantha, from Sep/2004 to Mar/2005, was 30,025, 28,267 and 27,735 kg ha-1 shoot dry matter in the treatments HA, R and S, respectively. These values differed significantly from treatments C and HE, with 17,040 and 17,057 kg ha-1, respectively. It was concluded that phosphorus fertilization associated to pasture reform was effective to raise the dry matter yield of Brachiaria brizantha. Rice or soybean under no-tillage is recommended as a practice of pasture recovery, due to the residual effect of fertilization.

Aspectos da produtividade do feijão correlacionados com atributos físicos do solo sob elevado nível tecnológico de manejo

No ano agrícola de 2006/07, no município de Selvíria (MS), foi analisada a produtividade do feijão em função de alguns atributos físicos de um Latossolo Vermelho distroférrico, cultivado nas condições de elevado nível tecnológico de manejo pelo sistema plantio direto irrigado com pivô central. O objetivo foi selecionar, entre os atributos pesquisados do solo, aquele com a melhor representatividade para explicar a variabilidade da produtividade agrícola. Foi instalada a malha geoestatística, para a coleta de dados do solo e da planta, com 117 pontos amostrais, numa área de 2.025 m² e declive homogêneo de 0,055 m m-1. Do ponto de vista linear e espacial, a produtividade de feijão foi explicada em função da densidade de partículas e da umidade gravimétrica do solo, respectivamente. Assim, os valores de densidade de partículas entre 1,95 e 2,20 kg dm-3 e de umidade gravimétrica entre 0,205 e 0,239 kg kg-1; ambas coletadas na camada intermediária, resultaram em sítios com as mais elevadas produtividades (2.200-2.600 kg ha-1). Entretanto, para as condições do elevado nível tecnológico de manejo empregado, a produtividade média do feijão não atingiu seu máximo potencial, uma vez que o agravado estado de compactação no qual o solo se encontrava proporcionou à produtividade redução de 26,6 %. Dessa forma, os valores médios da densidade do solo e da resistência do solo à penetração, respectivamente nas faixas de 1,36-1,41 kg dm-3 e de 1,56-3,24 MPa, típicos de solos argilosos compactados, atestaram a substancial queda da produtividade de grãos de feijão.

Sleep disorders in boys with Duchenne muscular dystrophy

Introduction La dystrophie musculaire de Duchenne (DMD) est une myopathie progressive liée au chromosome X qui atteint environ un garçon sur 3500. Des troubles du sommeil (TDS) sont fréquemment rapportés par ces patients Les études effectuées à ce jour se sont essentiellement concentrées sur les troubles respiratoires liés au sommeil. Les TDS débutent toutefois fréquemment avant l'installation d'un trouble ventilatoire nocturne et de nombreux autres facteurs peuvent en être la cause. Objectif L'objectif de cette étude est d'évaluer la fréquence des TDS chez les garçons avec une DMD et d'en identifier les facteurs de risque. Méthode II s'agit d'une étude transversale effectuée par questionnaire postal adressé aux parents de tout garçon âgé de 4-18 ans avec une DMD, suivi dans deux centres tertiaires de réhabilitation pédiatrique (Lausanne et Dublin). Les TDS sont évalués à l'aide de la 'Sleep Disturbance Scale for Children' (SDSC), validée sur 1157 enfants sains. Elle permet d'obtenir un score total et des scores pour six facteurs représentant les TDS les plus fréquents (troubles de l'endormissement et du maintien du sommeil (TEMS), éveil nocturne-cauchemars, transition veille-sommeil, somnolence diurne excessive, troubles respiratoires associés au sommeil (TRS), hyperhidrose du sommeil). Un T- score supérieur à 70 (>2DS) est considéré comme pathologique. Les associations potentielles entre des scores pathologiques et des facteurs individuels (âge, mobilité diurne et nocturne, douleur), thérapeutiques (orthèses nocturnes, ventilation non-invasive, médication) et environnementaux (facteurs socio-familiaux) sont évaluées à l'aide d'analyses univariées (χ2) et de régressions logistiques ascendantes. Résultats Seize garçons sur 63, soit 25.4%, présentent un score total pathologique en comparaison au 3% attendus dans la population générale. Les TEMS (29.7%), les TRS (15.6%) et l'hyperhidrose du sommeil (14.3%) sont les TDS les plus prévalent. Le besoin d'être mobilisé la nuit par un tiers (OR=9.4; 95%CI: 2.2-40.7; p=0.003) et être l'enfant d'une famille monoparentale (OR=7.2; 95%CI: 1.5-35.1; p=0.015) sont des facteurs de risque indépendants pour un score total pathologique. Le besoin d'être mobilisé la nuit par un tiers (OR=18.0; 95%CI: 2.9¬110.6; p=0.002), le traitement par corticostéroïdes (OR=7.7; 95%CI: 1.4-44.0; p-0.021) et être l'enfant d'une famille monoparentale (OR=7.0; 95%CI: 1.3-38.4; p=0.025) sont des facteurs de risque indépendants pour un TEMS. Discussion Cette étude montre une prévalence élevée des TDS chez les garçons avec une DMD (25% contre 3% attendus dans la population générale). Le besoin d'être mobilisé la nuit par un tiers est identifié comme un facteur de risque important pour un score total pathologique et un TEMS. Il reflète vraisemblablement un degré d'atteinte motrice tel qu'il limite les mouvements spontanés et les adaptations posturales du sommeil, ayant pour conséquence une diminution importante de la qualité du sommeil. Les enfants vivant dans un foyer monoparental présentent plus fréquemment un score total pathologique et des TEMS, possiblement en lien avec un stress psychologique plus important dans ces familles. Le traitement par corticostéroïdes est identifié comme facteur de risque pour un TEMS. Une adaptation du schéma ou du dosage permet généralement de limiter cet effet secondaire. Si nécessaire, un traitement par Mélatonine peut être instauré. Aucune association n'a pu être mise en évidence entre les facteurs analysés et les TRS, possiblement en raison du petit nombre de garçons ayant rapporté de tels symptômes et du fait que certains symptômes d'hypoventilation nocturne ne sont pas évalués par la SDSC. Par ailleurs, la valeur prédictive de l'anamnèse, comme celle des fonctions pulmonaires diurnes, est connue pour être limitée, raison pour laquelle une oxy-capnométrie est effectuée de routine en dessous d'une capacité vitale forcée de 50%. Elle permet, si nécessaire, l'instauration précoce d'une ventilation non-invasive, limitant ainsi vraisemblablement l'impact de ('hypoventilation nocturne sur la qualité du sommeil dans notre population. Plusieurs limitations sont à évoquer. Le petit nombre de patients ne permet pas d'exclure d'autres associations potentielles. La nature transversale de l'étude augmente le risque de causalité inverse. Cette étude n'inclut pas de mesure quantitative du sommeil. Les questionnaires adressés aux parents ont toutefois pu être démontrés comme fiables hormis pour les TRS. Un biais de non-réponse ne peut pas être totalement exclu, bien que le taux de réponse soit élevé (86,5%) et qu'il n'y ait pas de différence significative entre les populations de répondeurs et non-répondeurs. Conclusion La prévalence des TDS est élevée chez les garçons avec une DMD et leurs causes sont multiples. Les facteurs de risques sont physiques (immobilité nocturne), pharmacologiques (corticothérapie) et environnementaux (famille monoparentale). Compte tenu de son impact sur la qualité de vie, l'évaluation du sommeil doit être systématique en consultation et ne pas se limiter aux seuls troubles ventilatoires nocturnes.

Complications après hystérectomie pour cancers gynécologiques : Laparoscopie vs Laparotomie.

Objectif : Comparer les hystérectomies réalisées par laparoscopie à celles accomplies par laparotomie pour des pathologies gynécologiques malignes. Méthode : Etude basée sur 169 hystérectomies effectuées pour cancer de l'endomètre, du col ou de l'ovaire, pratiquées dans le service de gynécologie de la Maternité du CHUV de janvier 2002 à décembre 2009 sur des femmes âgées de 28 à 91 ans. Le but est de comparer deux différentes voies d'abord chirurgicales qui sont la laparotomie et la laparoscopie en terme de durée d'hospitalisation, d'indications, de complications per et post opératoires mineures et majeures et de nécessité de reprise ou d'une ré-hospitalisation. Résultats: Cette étude compte 169 patientes, dont 126 hystérectomies réalisées par laparotomie et 43 accomplies par laparoscopie. Les deux groupes sont similaires en terme d'âge (âge moyen : 63ans), d'indice de masse corporelle (26 vs 25) et de parité (1.5 enfants). Le temps opératoire est semblable entre les deux groupes (211 vs 219 minutes). Des hémorragies (pertes sanguines de plus de 1000ml) surviennent dans 24.6% des hystérectomies par laparotomie et dans 11.63% des hystérectomies par laparoscopie. Il existe une différence statistiquement significative entre la nécessité d'une transfusion peropératoire et les deux différentes voie d'abord (p=0.045). Une transfusion peropératoire a été nécessaire dans 13.22% des laparotomies contre seulement 2.33% des laparoscopies. La durée d'hospitalisation est significativement plus longue pour les patientes ayant subi une hystérectomie par laparotomie (12 vs 6 jours; p<0.001). Les complications peropératoires et postopératoires mineures dépendent de manière significative de la voie d'abord (p=0.01 ; p= 0.025). On observe des complications peropératoires dans 31.75% des laparotomies et dans 11.63% des laparoscopies. Les complications postopératoires mineures sont observées dans 28.57% des laparotomies et dans 11.63% des laparoscopies. Dans 7.14% des laparotomies on observe une complications postopératoire majeure et aucune de sont apparues lors d'hystérectomie par laparoscopie. La nécessité de reprise, de ré-opération ou de ré-hospitalisation n'est statistiquement pas différente entre la laparoscopie et la laparotomie. Conclusion : On observe un avantage significatif en faveur de l'hystérectomie par laparoscopie avec une réduction de la durée d'hospitalisation, ainsi que des complications peropératoires et postopératoires mineures et majeures, moins importantes.

Agregação e frações físicas da matéria orgânica de um argissolo vermelho sob sistemas de uso no bioma Pampa

O emprego de sistemas agrossilvipastoris tem sido importante estratégia de uso de solos, principalmente arenosos pertencentes ao bioma Pampa. Objetivou-se, neste estudo, avaliar a agregação, o teor de C orgânico total (COT) e de N total (NT), o teor de C nas frações físicas e o grau de humificação da MO em um Argissolo Vermelho eutrófico arênico submetido a diferentes sistemas de uso no município de Alegrete, RS. As avaliações foram desenvolvidas em uma floresta homogênea de eucalipto (FH), na entrelinha do sistema agrossilvipastoril sob pastagem (SA) e em campo nativo (CN), nas camadas de 0,000-0,025 m; 0,025-0,075 m; 0,075-0,125 m; e de 0,125-0,225 m. Foram coletadas amostras deformadas de solo para a avaliação de agregados estáveis em água (AEA, %) e dos teores de COT e de NT. Foi realizado o fracionamento físico granulométrico e densimétrico da MO, sendo as frações leve livre (FLL) e fração leve oclusa (FLO) da camada superficial submetidas às análises de Infravermelho com Transformada de Fourier (FTIR) e Ressonância Paramagnética Eletrônica (EPR). Os AEA em todas as camadas e o diâmetro médio ponderado na camada de 0,025-0,075 m indicaram maior degradação estrutural do solo na entrelinha do SA. Teores mais elevados de COT, NT, C da fração grosseira (CFG), C associado aos minerais (CAM), FLL e FLO na camada superficial foram observados na FH. Entre os usos do solo, os espectros de FTIR foram semelhantes, contudo a FLL apresentou bandas mais intensas na região de 1.072 cm-1, sugerindo maiores quantidades de polissacarídeos em relação à FLO. As densidades de spins obtidas por EPR na FLO foram maiores em relação à FLL, indicando maior humificação desta fração.

Conteúdo de carbono orgânico em planossolo háplico sob sistemas de manejo do arroz irrigado

Nos solos de várzea da região Sul do Rio Grande do Sul, onde um milhão de hectares são cultivados com arroz irrigado por alagamento em diferentes sistemas de manejo, a influência da condição de má drenagem e alternância entre ciclos de oxidação e redução sobre o conteúdo de C orgânico do solo (COS) é pouco conhecida. Este estudo foi realizado em um experimento de longa duração (21 anos), localizado no município do Capão do Leão, RS, com o objetivo de avaliar o efeito de sistemas de manejo do arroz irrigado sobre os estoques de COS e das frações físicas da matéria orgânica em um Planossolo Háplico. O fracionamento físico da matéria orgânica do solo foi realizado pelo método densimétrico, em amostras de solo coletadas das camadas de 0-0,025; 0,025-0,05; 0,05-0,10; e 0,10-0,20 m, nos tratamentos: ST- Sistema tradicional de cultivo um ano com arroz (preparo convencional) e dois anos com pousio; APC- Sistema de cultivo contínuo de arroz (preparo convencional) e controle de invasoras com herbicida; APD- Sucessão azevém/arroz (plantio direto); e SN- Solo mantido com vegetação natural (campo nativo). O sistema com arroz/azevém em plantio direto APD foi mais eficiente em manter os estoques de COS e da fração leve livre até 0,05 m de profundidade, em comparação com o ST e APC. A fração leve oclusa não se mostrou sensível aos efeitos dos diferentes sistemas de manejo, sugerindo para o solo de várzea baixa eficiência da proteção física da MOS por oclusão em agregados, o que pode estar relacionado aos efeitos da condição de má drenagem no processo de agregação. A umidade excessiva no inverno e o alagamento durante os cultivos de arroz estariam proporcionando agregação transitória entre cultivos. A quantidade de CO nesse Planossolo, tanto entre os sistemas de cultivo quanto em profundidade, deve-se principalmente à fração pesada, que é a fração mais estável e mais difícil de ser degradada.

Intervalo hídrico ótimo como indicador de melhoria da qualidade estrutural de latossolo degradado

As pastagens de gramíneas, quando bem formadas e manejadas, representam um componente ambiental importante em razão do papel que exercem na cobertura dos solos, na formação e estabilização dos agregados e na redução do adensamento ou da compactação. Os objetivos deste estudo foram quantificar o intervalo hídrico ótimo (IHO), para um Latossolo Vermelho-Amarelo degradado fisicamente e cultivado com Coastcross (Cynodon spp.), e utilizar o IHO como indicador de alteração da estrutura desse solo. Amostras indeformadas foram coletadas em anéis volumétricos de 0,025 m de altura e 0,065 m de diâmetro, nas profundidades de 0-0,05 e 0,20-0,25 m e no horizonte Bw (0,80-0,85 m), na ausência de tráfego de máquinas agrícolas, durante a estação chuvosa de 2008/2009, nos meses de novembro de 2008, março de 2009 e maio de 2009. Essas amostras foram utilizadas para determinar a curva de retenção de água, a curva de resistência à penetração, a densidade, o IHO e a densidade crítica do solo (Dsc). O IHO revelou-se um adequado indicador da alteração da estrutura de Latossolo. O Coastcross apresenta potencial para melhoria da estrutura, sendo sugerida sua utilização como alternativa ao uso de implementos agrícolas nesse contexto. A Dsc de 1,24 Mg m-3 é limitante ao adequado crescimento e desenvolvimento da forrageira no solo em estudo.

Effects of neuropeptide Y on the blood pressure response to various vasoconstrictor agents.

Neuropeptide Y (NPY) is known to potentiate the pressor effect of norepinephrine. In the present work, we evaluated in unanesthetized normotensive rats the effect of NPY on blood pressure responsiveness not only to norepinephrine, but also to tyramine, a sympathomimetic agent acting indirectly to B-HT933, a selective alpha-2 adrenoceptor stimulant, to angiotensin II and vasopressin. Dose-response curves to the various pressor agents were established starting at the 45th min of an i.v. infusion with either NPY (0.025 and 0.1 microgram/min) or its vehicle. The two doses of NPY increased blood pressure by an average of approximately 6 mm Hg, which was not significantly different from the vehicle-induced blood pressure changes. NPY significantly enhanced the pressor effect of norepinephrine, tyramine and angiotensin II, but not that of B-HT933 and vasopressin. We also tested whether NPY inhibits the enzyme activity of Na, K-adenosine triphosphatase using a purified toad kidney preparation. Concentrations of NPY from 10(-14) M up to 10(-6) M had no effect on the enzyme activity. It appears therefore that the blood pressure potentiating effect of NPY is not restricted to alpha adrenoceptor stimulation with norepinephrine, but involves also the vasoconstrictor hormone angiotensin II. This NPY-induced potentiation does not seem to depend upon stimulation of alpha-2 adrenoceptors or inhibition of Na,K-adenosine triphosphatase.

Industrial and urban organic wastes increase soil microbial activity and biomass

Microbial processes have been used as indicators of soil quality, due to the high sensitivity to small changes in management to evaluate, e.g., the impact of applying organic residues to the soil. In an experiment in a completely randomized factorial design 6 x 13 + 4, (pot without soil and residue or absolute control) the effect of following organic wastes was evaluated: pulp mill sludge, petrochemical complex sludge, municipal sewage sludge, dairy factory sewage sludge, waste from pulp industry and control (soil without organic waste) after 2, 4, 6, 12, 14, 20, 28, 36, 44, 60, 74, 86, and 98 days of incubation on some soil microbial properties, with four replications. The soil microbial activity was highly sensitive to the carbon/nitrogen ratio of the organic wastes. The amount of mineralized carbon was proportional to the quantity of soil-applied carbon. The average carbon dioxide emanating from the soil with pulp mill sludge, corresponding to soil basal respiration, was 0.141 mg C-CO2 100 g-1 soil h-1. This value is 6.4 times higher than in the control, resulting in a significant increase in the metabolic quotient from 0.005 in the control to 0.025 mg C-CO2 g-1 Cmic h-1 in the soil with pulp mill sludge. The metabolic quotient in the other treatments did not differ from the control (p < 0.01), demonstrating that these organic wastes cause no disturbance in the microbial community.

The cyclophilin inhibitor alisporivir prevents hepatitis C virus-mediated mitochondrial dysfunction.

Alisporivir (Debio-025) is an analogue of cyclosporine A and represents the prototype of a new class of non-immunosuppressive cyclophilin inhibitors. In vitro and in vivo studies have shown that alisporivir inhibits hepatitis C virus (HCV) replication, and ongoing clinical trials are exploring its therapeutic potential in patients with chronic hepatitis C. Recent data suggest that the antiviral effect is mediated by inhibition of cyclophilin A, which is an essential host factor in the HCV life cycle. However, alisporivir also inhibits mitochondrial permeability transition by binding to cyclophilin D. Because HCV is known to affect mitochondrial function, we explored the effect of alisporivir on HCV protein-mediated mitochondrial dysfunction. Through the use of inducible cell lines, which allow to investigate the effects of HCV polyprotein expression independent from viral RNA replication and which recapitulate the major alterations of mitochondrial bioenergetics observed in infectious cell systems, we show that alisporivir prevents HCV protein-mediated decrease of cell respiration, collapse of mitochondrial membrane potential, overproduction of reactive oxygen species and mitochondrial calcium overload. Strikingly, some of the HCV-mediated mitochondrial dysfunctions could even be rescued by alisporivir. Conclusion: These observations provide new insights into the pathogenesis of HCV-related liver disease and reveal an additional mechanism of action of alisporivir that is likely beneficial in the treatment of chronic hepatitis C. (HEPATOLOGY 2012).

Variação diurno-noturna do potencial mátrico e gradiente de potencial total da água no solo

O potencial mátrico em solos não saturados é um importante componente do potencial total e, portanto, deve ser medido da melhor forma possível. Este trabalho teve por objetivo avaliar a influência da temperatura do solo sobre o potencial mátrico e o gradiente de potencial total, durante a redistribuição da água num Latossolo Vermelho-Amarelo, em Piracicaba, SP, a partir de dados coletados por tensiometria. Em uma parcela circular de 3 m de diâmetro, foram instalados 10 tensiômetros com transdutor de tensão, modelo SWT3 da Delta-T, nas profundidades de 0,10; 0,15; 0,20; 0,25; 0,30; 0,35; 0,40; 0,45; 0,50; e 0,55 m, com os quais foram obtidos os potenciais mátricos para essas profundidades e o gradiente de potencial total, (ΔΦm/Δz)+1, para a profundidade de 0,25 m, com Δz de 0,1; 0,2; e 0,3 m, utilizando os tensiômetros instalados nas profundidades de 0,20 e 0,30; 0,15 e 0,35; e 0,10 e 0,40 m para ΔΦm, respectivamente. Na mesma parcela, foram também instalados termopares tipo T na superfície e nas profundidades 0,025; 0,050; e 0,075 m de solo. Ambas as leituras dos tensiômetros e termopares foram armazenadas em um Datalogger, Modelo DL2, da Delta-T, a idênticos intervalos de tempo. As avaliações detectaram oscilações na leitura do potencial mátrico da água no solo ao longo do dia e nos efeitos diferenciados nos tensiômetros instalados em profundidades diferentes, ocasionando oscilações também no gradiente de potencial total da água no solo. Os melhores horários para a realização das leituras dos tensiômetros são nas primeiras sete horas do dia ou após às 18 h.

Relationship of CYP2D6, CYP3A, POR, and ABCB1 Genotypes With Galantamine Plasma Concentrations.

BACKGROUND:: The frequently prescribed antidementia drug galantamine is extensively metabolized by the enzymes cytochrome P450 (CYP) 2D6 and CYP3A and is a substrate of the P-glycoprotein. We aimed to study the relationship between genetic variants influencing the activity of these enzymes and transporters with galantamine steady state plasma concentrations. METHODS:: In this naturalistic cross-sectional study, 27 older patients treated with galantamine were included. The patients were genotyped for common polymorphisms in CYP2D6, CYP3A4/5, POR, and ABCB1, and galantamine steady state plasma concentrations were determined. RESULTS:: The CYP2D6 genotype seemed to be an important determinant of galantamine pharmacokinetics, with CYP2D6 poor metabolizers presenting 45% and 61% higher dose-adjusted galantamine plasma concentrations than heterozygous and homozygous CYP2D6 extensive metabolizers (median 2.9 versus 2.0 ng/mL·mg, P = 0.025, and 1.8 ng/mL·mg, P = 0.004), respectively. CONCLUSIONS:: The CYP2D6 genotype significantly influenced galantamine plasma concentrations. The influence of CYP2D6 polymorphisms on the treatment efficacy and tolerability should be further investigated.

Usefulness of heart rate to predict cardiac events in treated patients with high-risk systemic hypertension.

A high heart rate (HR) predicts future cardiovascular events. We explored the predictive value of HR in patients with high-risk hypertension and examined whether blood pressure reduction modifies this association. The participants were 15,193 patients with hypertension enrolled in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial and followed up for 5 years. The HR was assessed from electrocardiographic recordings obtained annually throughout the study period. The primary end point was the interval to cardiac events. After adjustment for confounders, the hazard ratio of the composite cardiac primary end point for a 10-beats/min of the baseline HR increment was 1.16 (95% confidence interval 1.12 to 1.20). Compared to the lowest HR quintile, the adjusted hazard ratio in the highest quintile was 1.73 (95% confidence interval 1.46 to 2.04). Compared to the pooled lower quintiles of baseline HR, the annual incidence of primary end point in the top baseline quintile was greater in each of the 5 study years (all p <0.05). The adjusted hazard ratio for the primary end point in the highest in-trial HR heart rate quintile versus the lowest quintile was 1.53 (95% confidence interval 1.26 to 1.85). The incidence of primary end points in the highest in-trial HR group compared to the pooled 4 lower quintiles was 53% greater in patients with well-controlled blood pressure (p <0.001) and 34% greater in those with uncontrolled blood pressure (p = 0.002). In conclusion, an increased HR is a long-term predictor of cardiovascular events in patients with high-risk hypertension. This effect was not modified by good blood pressure control. It is not yet known whether a therapeutic reduction of HR would improve cardiovascular prognosis.