Ramipril sensitizes platelets to nitric oxide : implications for therapy in high-risk patients

Objectives
Using 2 sequential studies in HOPE (Heart Outcomes Prevention Evaluation) study–type patients, the aims of this study were: 1) to test the hypothesis that ramipril improves platelet nitric oxide (NO) responsiveness: and 2) to explore biochemical and physiological effects of ramipril in a cohort selected on the basis of platelet NO resistance.

Background
Ramipril prevents cardiovascular events, but the bases for these effects remain uncertain. NO resistance at both the platelet and vascular levels is present in a substantial proportion of patients with diabetes or ischemic heart disease and is an independent risk factor for cardiovascular events.

Methods
Study 1 was a double-blind, randomized comparison of ramipril (10 mg) with placebo in a cohort of patients (n = 119) with ischemic heart disease or diabetes plus additional coronary risk factor(s), in which effects on platelet responsiveness to NO were compared. Study 2 was a subsequent short-term evaluation of the effects of ramipril in a cohort of subjects (n = 19) with impaired platelet NO responsiveness in whom additional mechanistic data were sought.

Results
In study 1, ramipril therapy increased platelet responsiveness to NO relative to the extent of aggregation (p < 0.001), but this effect occurred primarily in patients with severely impaired baseline NO responsiveness (n = 41). In study 2, ramipril also improved platelet NO responsiveness (p < 0.01), and this improvement was correlated directly with increased NO-stimulated platelet generation of cyclic guanosine monophosphate (p < 0.02) but not with changes in plasma thrombospondin-1 levels.

Conclusions
Ramipril ameliorates platelet NO resistance in HOPE study–type patients, with associated increases in soluble guanylate cyclase responsiveness to NO. This effect is likely to contribute to treatment benefit and define patients in whom ramipril therapy is particularly effective.

Fish oil diet associated with acute reperfusion related hemorrhage, and with reduced stroke-related sickness behaviors and motor impairment

Ischemic stroke is associated with motor impairment and increased incidence of affective disorders such as anxiety/clinical depression. In non-stroke populations, successful management of such disorders and symptoms has been reported following diet supplementation with long chain omega-3-polyunsaturated-fatty-acids (PUFAs). However, the potential protective effects of PUFA supplementation on affective behaviors after experimentally induced stroke and sham surgery have not been examined previously. This study investigated the behavioral effects of PUFA supplementation over a 6-week period following either middle cerebral artery occlusion or sham surgery in the hooded-Wistar rat. The PUFA diet supplied during the acclimation period prior to surgery was found to be associated with an increased risk of acute hemorrhage following the reperfusion component of the surgery. In surviving animals, PUFA supplementation did not influence infarct size as determined 6 weeks after surgery, but did decrease omega-6-fatty-acid levels, moderate sickness behaviors, acute motor impairment, and longer-term locomotor hyperactivity and depression/anxiety-like behavior.

LC-REHAB : randomised trial assessing the effect of a new patient education method - learning and coping strategies - in cardiac rehabilitation

Due to improved treatments and ageing population, many countries now report increasing prevalence in rates of ischemic heart disease and heart failure. Cardiac rehabilitation has potential to reduce morbidity and mortality, but not all patients complete. In light of favourable effects of cardiac rehabilitation it is important to develop patient education methods which can enhance adherence to this effective program. The LC-REHAB study aims to compare the effect of a new patient education strategy in cardiac rehabilitation called 'learning and coping' to that of standard care. Further, this paper aims to describe the theoretical basis and details of this intervention.

Social competence following pediatric stroke: contributions of brain insult and family environment

Limited information is available regarding predictors of psychosocial difficulties in children following stroke. This study aimed to (i) compare social competence of children with arterial ischemic stroke (AIS) to those with chronic illness and healthy controls and (ii) investigate the contribution of stroke pathology, neurological outcome and environment. Thirty-six children with AIS > 12 months prior to recruitment were compared with children with chronic illness (asthma) (n = 15) and healthy controls (n = 43). Children underwent intellectual assessment, and children and parents completed questionnaires to assess social competence. Children with AIS underwent MRI scan and neurological evaluation. Child AIS was associated with poorer social adjustment and participation, and children with AIS were rated as having more social problems than controls. Lesion volume was not associated with social outcome, but subcortical stroke was linked to reduced social participation and younger stroke onset predicted better social interaction and higher self-esteem. Family function was the sole predictor of social adjustment. Findings highlight the risk of social impairment following pediatric stroke, with both stroke and environmental factors influencing children's social competence in the chronic stages of recovery. They indicate the potential for intervention targeting support at the family level.

Comorbid depression and health-related quality of life in patients with coronary artery disease.

This article reviews recent studies relating to the impact of depression and its treatment on the health-related quality of life (HRQOL) of patients with coronary artery disease (CAD).

Platelet supersensitivity to thrombin stimulation in depression: a possible mechanism for the association with cardiovascular mortality.

The mortality risk associated with cardiovascular disease is significantly increased in patients with major depression and panic disorder. The mechanism of this phenomenon is unclear. Thrombin is responsible for platelet aggregation and shape change, and it plays a significant role in the development of thromboembolic events. In this study, we examined the platelet second messenger intracellular calcium response to thrombin stimulation in patients with major depression (n = 13), major depression after response to electroconvulsive therapy (ECT; n = 13), subsyndromal depression (n = 16), schizophrenia (n = 15), and control subjects (n = 65). Patients with major depression had significantly higher intracellular calcium responses to thrombin stimulation than control subjects, patients with subsyndromal depression, and patients with schizophrenia (p < 0.05). Electroconvulsive therapy did not significantly change this supersensitivity. This suggests that the platelet response to activation in patients with major depression is supersensitive. This study suggests a possible mechanism for the increased risk of cardiovascular disease that is seen in these two psychiatric disorders. The lack of difference between the control and subsyndromal depression groups appears to validate current diagnostic thresholds in depression. The failure of nonpharmacologic treatment to alter this marker suggests that it may be a trait marker of depression.

Aortic intima-media thickness measured by trans-abdominal ultrasound as an early life marker of subclinical atherosclerosis

Atherosclerosis is a chronic inflammatory process that begins in early life. Improved identification of markers of early atherosclerosis via neonatal aortic intima-media thickness (aIMT) measurement may allow the development of interventions to prevent or reduce later cardiovascular disease.

Effects of systemic hypoxia on human muscular adaptations to resistance exercise training

Hypoxia is an important modulator of endurance exercise-induced oxidative adaptations in skeletal muscle. However, whether hypoxia affects resistance exercise-induced muscle adaptations remains unknown. Here, we determined the effect of resistance exercise training under systemic hypoxia on muscular adaptations known to occur following both resistance and endurance exercise training, including muscle cross-sectional area (CSA), one-repetition maximum (1RM), muscular endurance, and makers of mitochondrial biogenesis and angiogenesis, such as peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), citrate synthase (CS) activity, nitric oxide synthase (NOS), vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1 (HIF-1), and capillary-to-fiber ratio. Sixteen healthy male subjects were randomly assigned to either a normoxic resistance training group (NRT, n = 7) or a hypoxic (14.4% oxygen) resistance training group (HRT, n = 9) and performed 8 weeks of resistance training. Blood and muscle biopsy samples were obtained before and after training. After training muscle CSA of the femoral region, 1RM for bench-press and leg-press, muscular endurance, and skeletal muscle VEGF protein levels significantly increased in both groups. The increase in muscular endurance was significantly higher in the HRT group. Plasma VEGF concentration and skeletal muscle capillary-to-fiber ratio were significantly higher in the HRT group than the NRT group following training. Our results suggest that, in addition to increases in muscle size and strength, HRT may also lead to increased muscular endurance and the promotion of angiogenesis in skeletal muscle.

Using transcranial magnetic stimulation to quantify electrophysiological changes following concussive brain injury: a systematic review

Mild traumatic brain injury (mTBI) and sports concussion are a growing public health concern, with increasing demands for more rigorous methods to quantify changes in the brain post-injury. Electrophysiology, and in particular, transcranial magnetic stimulation (TMS), have been demonstrated to provide prognostic value in a range of neurological conditions; however, no review has quantified the efficacy of TMS in mTBI/concussion. In the present study, we present a systematic review and critical evaluation of the scientific literature from 1990 to 2014 that has used TMS to investigate corticomotor excitability responses at short-term (< 12 months), medium-term (1-5 years), and long-term (> 5 years) post-mTBI/concussion. Thirteen studies met the selection criteria, with six studies presenting short-term changes, five studies presenting medium-term changes, and two studies presenting long-term changes. Irrespective of time post-concussion, change in intracortical inhibition was the most reported observation. Other findings included increased stimulation threshold, and slowed neurological conduction time. Although currently limited, the data suggest that TMS has prognostic value in detecting neurophysiological changes post-mTBI/concussion.

Modulating exercise-induced hormesis: does less equal more?

Hormesis encompasses the notion that low levels of stress stimulate or upregulate existing cellular and molecular pathways that improve the capacity of cells and organisms to withstand greater stress. This notion underlies much of what we know about how exercise conditions the body and induces long-term adaptations. During exercise, the body is exposed to various forms of stress, including thermal, metabolic, hypoxic, oxidative, and mechanical stress. These stressors activate biochemical messengers, which in turn activate various signaling pathways that regulate gene expression and adaptive responses. Historically, antioxidant supplements, nonsteroidal anti-inflammatory drugs, and cryotherapy have been favored to attenuate or counteract exercise-induced oxidative stress and inflammation. However, reactive oxygen species and inflammatory mediators are key signaling molecules in muscle, and such strategies may mitigate adaptations to exercise. Conversely, withholding dietary carbohydrate and restricting muscle blood flow during exercise may augment adaptations to exercise. In this review article, we combine, integrate, and apply knowledge about the fundamental mechanisms of exercise adaptation. We also critically evaluate the rationale for using interventions that target these mechanisms under the overarching concept of hormesis. There is currently insufficient evidence to establish whether these treatments exert dose-dependent effects on muscle adaptation. However, there appears to be some dissociation between the biochemical/molecular effects and functional/performance outcomes of some of these treatments. Although several of these treatments influence common kinases, transcription factors, and proteins, it remains to be determined if these interventions complement or negate each other, and whether such effects are strong enough to influence adaptations to exercise.

Nearshore-offshore-basin species diversity and body size variation patterns in Late Permian (Changhsingian) brachiopods

 B.V. Body size is a fundamental and defining character of an organism, and its variation in space and time is generally considered to be a function of its biology and interactions with its living environment. A great deal of body size related ecological and evolutionary research has been undertaken, mostly in relation to extant animals. Among the many body size-related hypotheses proposed and tested, the size-bathymetry relationship is probably the least studied. In this study, we compiled a global body size dataset of Changhsingian (Late Permian, ca. 254. Ma-252. Ma) brachiopod species from low-latitude areas (30°S-30°N) and analyzed their species diversity and body size distribution patterns in relation to the nearshore-offshore-basin bathymetric gradient. The dataset contained 1768 brachiopod specimens in 435 species referred to 159 genera and 9 orders, from 135 occurrences (localities) of 18 different palaeogeographic regions. Treating the whole of the Changhsingian Stage as a single time slice, we divided the nearshore-offshore-basin bathymetric gradient into three broad depth-related environments: nearshore, offshore and basinal environments, and compared how the species diversity and body size varied along this large-scale bathymetric gradient.Here, we report an array of complex patterns. First, we found a clear overall inverse correlation between species diversity and water depth along the nearshore-offshore-basin gradient, with most species concentrating in the nearshore environment. Second, when the median sizes of all low-latitude brachiopod species from the three environments were compared, we found that there was no significant size difference between the nearshore and offshore environments, suggesting that neither the wave base nor the hydrostatic pressure exerts a critical influence on the body size of brachiopods. On the other hand, the median sizes of brachiopods from the nearshore environment and, to a lesser extent, the offshore environment were found to be significantly larger than that of basinal brachiopods. This trend of significant size reduction in basinal brachiopods mirrors the relative low species diversity in the basinal environment, and neither can be easily explained by the tendency of decreasing food availability towards deeper sea environments. Rather, both trends are consistent with the hypothesis of an expanding Oxygen Minimum Zone (OMZ) in the bathyal (slope to deepsea) environments, where hypoxic to anoxic conditions are considered to have severely restricted the diversification of benthos and favored the relative proliferation of small-sized brachiopods. Finally, a significant difference was also found between eurybathic and stenobathic species in their body size response to the nearshore-offshore-basin gradient, in that eurybathic species (species found in all three environments) did not tend to change their body size significantly according to depth, whereas stenobathic forms (species restricted to a single environment) exhibit a decline in body size towards the basinal environment. This pattern is interpreted to suggest that bathymetrically more tolerant species are less sensitive to depth control with respect to their body size change dynamics, in contrast to stenobathic species which tend to grow larger in shallower water depths.

Utilização da frutose-1, 6-Bisfosfato como um protetor celular na preservação de fígados para transplante

A solução de preservação da Universidade de Wisconsin (UW) é considerada a solução padrão para preservação de fígados, rins e pâncreas. A frutose-1,6-bisfosfato (FBP) é uma substância que apresenta efeito protetor do fígado contra injúrias provocadas por agentes químicos e ocorridas durante o período de isquemia-reperfusão. O objetivo deste estudo foi avaliar os efeitos da FBP na composição de soluções para preservação de fígados para transplante. Neste estudo experimental, a perfusão e a preservação dos fígados foram realizadas em cada grupo com as soluções de UW, UW contendo 10 mmol/L de FBP (UWM) e FBP 10 mmol/L (FBPS), respectivamente. Os fígados foram armazenados em um recipiente plástico contendo solução de preservação a 4oC por 24 horas. As mensurações bioquímicas de AST, ALT, LDH e TBARS foram realizadas em amostras das soluções de preservação nos tempos de 0, 12, 18 e 24 horas. A análise histológica foi realizada em fígados preservados por 24 horas. O grau de preservação observado com as soluções de UW e FBPS foi similar até 18 horas de armazenamento. A adição de 10 mmol/L de FBP à solução de UW provocou um aumento das injúrias ocorridas e uma pior preservação quando comparado ao grupo armazenado em UW. A FBP protegeu os fígados contra danos causados pelos radicais livres por tempos de preservação inferiores a 18 horas. Não houve diferença significativa entre os grupos na análise histológica dos fígados preservados no tempo de 24 horas. A FBP utilizada em solução foi eficaz na preservação de fígados, podendo ser um importante constituinte para outras formulações.

Estudo comparativo da viabilidade miocárdica em áreas dissinérgicas ao ecocardiograma basal : cintilografia tomográfica com Tecnécio 99m-mibi sob baixa dose de Dobutamina versus Tálio em repouso-redistribuição

A cintilografia com radioisótopos em repouso tem despertado muito interesse nos últimos anos para pesquisa da viabilidade miocárdica na disfunção isquêmica avançada do VE, porque esta pode ser reversível e porque há melhora prognóstica neste contexto. O objetivo desse trabalho é buscar identificar a acurácia da cintilografia tomográfica Tc-99m-Sestamibi, sob a infusão de dobutamina em baixa dose. Foram protocolados trinta pacientes que sofreram um infarto do miocárdio com padrão “Q”, com dissinergia ao ecocardiograma, e submetidos a estudos perfusionais em dias diferentes, com Tc-99m-Sestamibi − dobutamina e Tl-201 em repouso-redistribuição 4 horas, usado como padrão ouro. Não ocorreram complicações com nenhum paciente submetido ao protocolo do estudo. Os resultados revelaram: sensibilidade = 85%, especificidade = 87%, valor preditivo positivo = 96%, valor preditivo negativo = 65 % e acurácia de = 85,2%. A razão de probabilidade positiva foi de 6,68 e a razão de probabilidade negativa de 0,17. Confrontando-se nossos dados com uma metanálise de resultados para o Tc-99m-Sestamibi em repouso, a sensibilidade no presente estudo foi 85% vs. 81% e a especificidade de 87% vs. 60%. Em relação aos dados da literatura para Tl-201: 85% vs. 90% e 87% vs. 54%, sensibilidade e especificidade, respectivamente. Em conclusão, o Tc-99m-Sestamibi sob a infusão de dobutamina parece ser um método promissor para detectar viabilidade superior a esta modalidade de cintilografia em repouso, com valores preditivos comparáveis à literatura disponível para esse mesmo método: 85,2% vs. 87%, 96% vs. 90% e 65% vs. 83%, para acurácia, valor preditivo positivo e valor preditivo negativo, respectivamente.

Contribuição ao estudo das hepatectomias parciais com oclusão do fluxo sanguíneo aferente

O tratamento cirúrgico dos tumores hepáticos tem sido um grande desafio na história evolutiva da cirurgia. No passado, as altas taxas de morbidade e mortalidade limitavam sua aplicação como opção terapêutica. O refinamento da técnica de ressecção hepática está associado a menores índices de mortalidade e morbidade peri-operatória e, embora, a mortalidade tenha sido reduzida a menos de 10% nos serviços especializados, a morbidade ainda é bastante significativa, sendo que a hemorragia grave e a embolia aérea permanecem como complicações graves das hepatectomias. O controle da perda sanguínea é o objetivo primordial durante este tipo de cirurgia. As técnicas descritas, com a finalidade de conter a hemorragia transoperatória, são aquelas associadas à redução do fluxo sanguíneo ao fígado, seja através da oclusão vascular aferente ou manobra de Pringle por clampeamento do pedículo hepático, seja por exclusão vascular total do órgão. Hepatectomias parciais podem ser realizadas com pequeno sangramento e, mesmo quando associadas a períodos prolongados de isquemia tecidual, não foram identificadas lesões parenquimatosas ou falência hepática persistente. A redução na necessidade de reposição de sangue, no período peri-operatório, está associada a menor morbidade e à diminuição significativa na incidência de sepse abdominal. O objetivo deste estudo foi o de avaliar uma série de hepatectomias parciais com oclusão do fluxo sanguíneo aferente, em pacientes portadores de patologias benignas e neoplasias malignas. Foram analisadas 60 hepatectomias em 59 pacientes com oclusão do fluxo sanguíneo aferente quanto a possíveis fatores de risco para morbidade e mortalidade, bem como a relação entre o tempo de isquemia hepática e a variação das transaminases, tempo de protrombina e bilirrubinas, e destes, com a evolução pós-operatória. A prevalência de complicações pós-operatórias foi de 43,3% e a mortalidade de 6,7%. O fator de risco significativo para mortalidade foi tempo cirúrgico mais prolongado, quando comparado com os pacientes que não foram a óbito. Para a morbidade pós-operatória, foram identificados como fatores de risco a idade acima de 60 anos, cirurgia por neoplasia maligna, parênquima hepático anormal, ou seja, presença de cirrose, esteatose ou colestase, perda sanguínea necessitando reposição de mais de uma unidade de sangue e outros procedimentos cirúrgicos concomitantes. Na análise multivariada por regressão logística, estes fatores de risco foram reduzidos, apenas, para presença de cirrose, esteatose ou colestase. O tempo de isquemia não apresentou relação com a morbi-mortalidade pós-operatória. A variação das transaminases foram mais acentuadas nos casos com maior tempo de isquemia, porém, retornaram aos níveis pré-operatórios em, aproximadamente, uma semana. Não houve variação de tempo de protrombina e bilirrubinas quanto ao tempo de isquemia. A variação de AST e ALT não foram diferentes entre os pacientes com e sem morbidade pós-operatória.

Estudo da incidência de complicações da anastomose brônquica em pacientes submetidos à transplante de pulmão em um período de 10 anos

Uma das complicações cirúrgicas que mais afeta o resultado do transplante pulmonar é a complicação da anastomose brônquica. Esta pode apresentar-se com um espectro que vai desde a isquemia transitória da anastomose sem outras alterações até a deiscência total com mediastinite e sépsis. Embora a sua ocorrência tenha diminuído nos últimos anos, continua sendo uma das complicações mais frequentes no pós-operatório. Em nosso trabalho, foi analisada a ocorrência de complicações de anastomose brônquica que necessitaram algum tipo de intervenção cirúrgica na população de pacientes transplantados de pulmão durante um período de dez anos (1989-1999). Este grupo representa a quase totalidade dos transplantes pulmonares realizados no Brasil neste período. Pacientes e Métodos: Foram avaliados todos os transplantes de pulmão realizados em um período de 10 anos (1989-1999) no Pavilhão Pereira Filho, Santa Casa de Misericórdia, Porto Alegre, RS, Brasil, para a ocorrência de complicação da anastomose brônquica e possíveis fatores de risco. Resultados: Em um total de 76 pacientes e 81 anastomoses com o risco de complicação, ocorreram 12 complicações (15,79%). Entre os fatores analisados para risco possivelmente associado à complicação, não houve diferença estatisticamente significativa para o tempo de isquemia superior ou inferior a quatro horas (Teste de Fischer com p=1,00), entre um ou mais de um episódio de rejeição (Teste de Fischer com p=0,756), um ou mais de um pulsos de metilprednisolona (p=0,58), a ocorrência de infecção por citomegalovírus ou não ( teste de Fischer com p=0,169), e nem houve maior número de complicações brônquicas nos pacientes que tiveram maior número de episódios de infecção. Houve diferença estatisticamente entre a técnica de anastomose brônquica término-terminal e a telescopagem brônquica, sendo a ocorrência de complicações bem menor no segundo grupo (teste de Fischer com p=0,005), e também ocorreu diferença estatisticamente significativa entre dois períodos de transplante, de 1989 a 1993 e de 1994 a 1999, sendo a ocorrência menor no segundo grupo (teste exato de Fischer com p=0,037). Conclusões: A técnica de telescopagem brônquica apresentou menor número de complicações da anastomose brônquica, e a maior experiência da equipe de transplantes também contribuiu para a redução das complicações da anastomose.