Neuroendocrine function following traumatic brain injury and subsequent intensive care treatment: A prospective longitudinal evaluation

Neuroendocrine dysfunction following traumatic brain injury (TBI) has been described extensively. However, few studies are longitudinal and most lack subtle radiological, clinical, and repetitive endocrine assessment in the acute phase. Accordingly, we prospectively assessed neuroendocrine function in 71 patients after TBI. Injury was documented by a computed tomography (CT). During the first week, critical clinical data (Glasgow Coma Score, APACHE score), treatment variables such as duration of analgosedation for mechanical ventilation, were related to basal pituitary function. More than 2 years later, a subgroup of patients was re-evaluated using dynamic testing with ACTH and GHRH-arginine tests. The Pearson's correlation analysis and Mann-Whitney rank sum test for group differences were used for statistical analysis. None of the CT findings predicted neuroendocrine dysfunction following TBI. The adaptive response to critical illness with significantly elevated cortisol levels on admission and decreased levels thereafter in patients ventilated for more than 24 h (p < 0.05) was attenuated following severe TBI (p < 0.05). However, the coincidence of low serum cortisol and increased urinary excretion of glucocorticoid metabolites in about 80% of patients challenges the relevance of basal hormone measurements. In ventilated patients, total T3 and free T4 were decreased (p < 0.05), TSH was low on day 3 (p < 0.05), and a gonadotropic insufficiency was present (p < 0.05). The thyrotropic and gonadotropic system recovered completely within the follow-up period. With regard to the somatotropic system, neither brain injury severity nor mechanical ventilation was associated with an insufficiency during the acute phase post-injury. However, initially low GH levels predicted a persistent deficiency (r = 0.731, p < 0.001). We conclude that both severe TBI and prolonged mechanical ventilation result in hormonal disturbances early after injury, suggesting a pathophysiological response to brain injury and subsequent intensive care treatment rather than morphological damage

Expression of the kcnk3 potassium channel gene lessens the injury from cerebral ischemia, most likely by a general influence on blood pressure

7 p., 3 figures, 2 tables and references.We examined the possible protective effect of TASK-1 (TWIK-related acid-sensitive potassium channel-1, kcnk3) and -3 potassium channels during stroke. TASK-1 and TASK-3, members of the two pore domain (K2P or kcnk) potassium channel family, form hetero or homodimers and help set the resting membrane potential. We used male TASK-1 and TASK-3 knockout mice in a model of focal cerebral ischemia, permanent middle cerebral artery occlusion (pMCAO). Infarct volume was measured 48 h after pMCAO. The TASK-1 knockout brains had larger infarct volumes (P=0.004), and those in TASK-3 knockouts were unchanged. As the TASK-1 gene is expressed in adrenal gland, heart and possibly blood vessels, the higher infarct volumes in the TASK-1 knockout mice could be due to TASK-1 regulating blood vessel tone and hence blood pressure or influencing blood vessel microarchitecture and blood flow rate. Indeed, we found that male TASK-1 knockout mice had reduced blood pressure, likely explaining the increased brain injury seen after pMCAO. Thus to make precise conclusions about how TASK-1 protects neurons, neural- or organ-specific deletions of the gene will be needed. Nevertheless, a consequence of having TASK-1 channels expressed (in various non-neuronal tissues and organs) is that neuronal damage is lessened when stroke occurs.Peer reviewe

Selective and protracted effect of nifedipine on fear memory extinction correlates with induced stress response

Memory extinction, defined as a decrease of a conditioned response as a function of a non-reinforced conditioned stimulus presentation, has high biological and clinical relevance. Extinction is not a passive reversing or erasing of the plasticity associated with acquisition, but a novel, active learning process. Nifedipine blocks L-type voltage gated calcium channels (LVGCC) and has been shown previously to selectively interfere with the extinction, but not the acquisition, of fear memory. We studied here the effect of retrograde and anterograde shifts of nifedipine application, with respect to an extinction training, on the extinction of fear conditioning. Subcutaneous injection of 30 mg/kg nifedipine, at least up to 4 h before the extinction session, significantly impaired extinction, as did intraperitoneal injection of 15 mg/kg nifedipine, at least up to 2 h before extinction training. However, the injection of nifedipine also induced a strong and protracted stress response. The pharmacokinetics of nifedipine suggest that it was mainly this stress response that triggered the specific inhibition of extinction, not the blockade of LVGCC in the brain. Our results support recent findings that stress selectively interferes with the extinction, but not the acquisition, of fear memory. They also indicate that a pharmacological approach is not sufficient to study the role of brain LVGCC in learning and memory. Further research using specific genetically modified animals is necessary to delineate the role of LVGCC in fear memory extinction