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Objectives: Stroke, frequently a consequence of hypertension, is one of the leading causes of death and neurological disabilities worldwide. In the ischemic brain, levels of endothelin-1, one of the most potent vasoconstrictors, are raised. Anti-inflammatory and neuroprotective effects of endothelin antagonists after stroke have been described in literature. Based on these findings, we investigated the protective effect of the endothelin converting enzyme/neutral endopeptidase blocker, SLV 338, in salt-loaded, stroke-prone, spontaneously hypertensive rats.
Methods: Male, 8-week-old spontaneously hypertensive stroke-prone rats were put on a high salt diet and treated with either 30 mg/kg or 100 mg/kg SLV 338 or vehicle for 27 weeks. Blood pressure, neurological outcome, body weight, and mortality were investigated throughout treatment. In weeks 1 and 9, animals were housed in metabolic cages for collection of urinary and blood samples and assessment of salt water and food intake. In weeks 22 and 27, additional blood samples were taken. At the end of the study, all brains were analyzed using magnetic resonance imaging.
Results: SLV 338 was well tolerated in all animals. Neurological outcome and infarct size were similar in all groups. Albuminuria was considerably delayed and the incidence of stroke significantly lowered in treated animals. In spontaneously hypertensive stroke-prone rats, treatment with SLV 338 significantly (P=0.01) improved survival in comparison to the vehicle treated group in a blood pressure-independent manner.
Discussion: Our data in spontaneously hypertensive stroke-prone rats demonstrate that combined endothelin converting enzyme/neutral endopeptidase inhibition could offer a new therapeutic approach for primary stroke prevention and improvement of mortality. The mechanism seems to be blood pressure-independent.
Many agrammatic aphasics have a specific syntactic comprehension deficit involving processing syntactic transformations. It has been proposed that this deficit is due to a dysfunction of Broca's area, an area that is thought to be critical for comprehension of complex transformed sentences. The goal of this study was to investigate the role of Broca's area in processing canonical and non-canonical sentences in healthy subjects. The sentences were presented auditorily and were controlled for task difficulty. Subjects were asked to judge the grammaticality of the sentences while their brain activity was monitored using event-related functional magnetic resonance imaging. Processing both kinds of sentences resulted in activation of language-related brain regions. Comparison of non-canonical and canonical sentences showed greater activation in bilateral temporal regions; a greater activation of Broca's area in processing antecedent-gap relations was not found. Moreover, the posterior part of Broca's area was conjointly activated by both sentence conditions. Broca's area is thus involved in general syntactic processing as required by grammaticality judgments and does not seem to have a specific role in processing syntactic transformations. (C) 2004 Wiley-Liss, Inc
People differ with regard to how they perceive, experience, and express negative affect. While trait negative affect reflects a stable, sustained personality trait, state negative affect represents a stimulus limited and temporally acute emotion. So far, little is known about the neural systems mediating the relationship between negative affect and acute emotion processing. To address this issue we investigated in a healthy female sample how individual differences in state negative affect are reflected in changes in blood oxygen level-dependent responses during passive viewing of emotional stimuli. To assess autonomic arousal we simultaneously recorded changes in skin conductance level. At the psychophysiological level we found increased skin conductance level in response to aversive relative to neutral pictures. However, there was no association of state negative affect with skin conductance level. At the neural level we found that high state negative affect was associated with increased left insular activity during passive viewing of aversive stimuli. The insula has been implicated in interoceptive processes and in the integration of sensory, visceral, and affective information thus contributing to subjective emotional experience. Greater recruitment of the insula in response to aversive relative to neutral stimuli in subjects with high state negative affect may represent increased processing of salient aversive stimuli.
Normal aging is associated with a decline in different cognitive domains and local structural atrophy as well as decreases in dopamine concentration and receptor density. To date, it is largely unknown how these reductions in dopaminergic neurotransmission affect human brain regions responsible for reward-based decision making in older adults. Using a learning criterion in a probabilistic object reversal task, we found a learning stage by age interaction in the dorsolateral prefrontal cortex (dIPFC) during decision making. While young adults recruited the dlPFC in an early stage of learning reward associations, older adults recruited the dlPFC when reward associations had already been learned. Furthermore, we found a reduced change in ventral striatal BOLD signal in older as compared to younger adults in response to high probability rewards. Our data are in line with behavioral evidence that older adults show altered stimulus-reward learning and support the view of an altered fronto-striatal interaction during reward-based decision making in old age, which contributes to prolonged learning of reward associations.