Modulation of olfactory bulb neuron potassium current by tyrosine phosphorylation

Insulin causes a suppression of whole-cell voltage-dependent outward current in cultured neurons from the rat olfactory bulb. This suppression is time-dependent; it is mimicked by application of Src tyrosine kinase inside the cell via the whole-cell patch electrode or by treatment of the olfactory bulb neurons with the tyrosine phosphatase inhibitor pervanadate. The C-type inactivation properties of the outward current in olfactory bulb neurons resemble those of the cloned Kv1.3 potassium channel. In addition, at picomolar concentrations at which it is specific for Kv1.3, the scorpion toxin margatoxin blocks most of the olfactory bulb neuron outward current. Immunocytochemical analysis demonstrates that Kv1.3 is prominent in the cultured olfactory bulb neurons. To identify specific amino acid residues that might be important for potassium current modulation, we examined the effects of pervanadate and insulin on wild-type and mutant Kv1.3 channels expressed in human embryonic kidney (HEK 293) cells. As shown previously, treatment with either pervanadate or insulin suppresses Kv1.3 current in these cells. Mutational analysis demonstrates that at least two distinct tyrosine residues are required for current suppression by pervanadate. Insulin treatment stimulates the tyrosine phosphorylation of Kv1.3 in HEK 293 cells, and a different combination of tyrosine residues is required for the current suppression by insulin. The results suggest that complex patterns of phosphorylation may be involved in the modulation of neuronal potassium current by receptor and nonreceptor tyrosine kinases.     

Psychological distress and neuropsychological complications of HIV infection and AIDS.

AIDS, whether real or threatened, poses a radical challenge to the psychological, social, and practical adaptation of individuals at various stages of human immunodeficiency virus (HIV) disease. The challenge arises from multiple sources, including disease progression, social discrimination, bereavement, pressure for life-style change, and neurological impairment associated with HIV brain infection. The consequences of this challenge to people with HIV infection, AIDS-related complex, AIDS, and AIDS dementia complex are reviewed. The potential for both personal crisis and personal growth in response to this challenge is highlighted. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Spinal cord blood flow and evoked potential responses after treatment with nimodipine or methylprednisolone in spinal cord-injured rats

This study examined the effect of nimodipine or methylprednisolone on spinal cord blood flow (SCBF) and electrophysiological function after spinal cord injury in rats. Three groups of male rats (n = 10 per group) were injured by compression of the cord at T1 for 1 minute with a 52-g clip. The hydrogen clearance technique was used to measure SCBF at the T1 segment. Motor and somatosensory evoked potentials were recorded. SCBF and evoked potentials were measured before injury and again at approximately 1 and 2.5 hours after injury. The methylprednisolone group received a bolus of methylprednisolone (30 mg/kg) at 5 minutes after injury and then at 15 minutes after injury, the group received an infusion of methylprednisolone at 5.4 mg/kg per hour. The nimodipine group received placebo at 5 minutes and then received an infusion of nimodipine at 0.02 mg/kg per hour at 15 minutes. The placebo group received placebo at both times. Physiological parameters were closely monitored and maintained within the normal range. Albumin was administered after injury to maintain mean arterial blood pressure at or above 80 mm Hg. The infusions were continued for approximately 3 hours after spinal cord injury. SCBF was not significantly different between the experimental groups at either 1 or 2.5 hours postinjury (P = 0.16 and 0.71, respectively), and evoked potential responses did not return in any rat at any time after injury. Thus, this experiment failed to demonstrate an improvement in SCBF or electrophysiological function with either drug.(ABSTRACT TRUNCATED AT 250 WORDS)     

The routine use of radiography and arterial blood gases in the evaluation of blunt trauma in children

STUDY OBJECTIVE: To evaluate the usefulness of routine radiographs and arterial blood gases in children with blunt trauma. DESIGN: Retrospective chart review. TYPE OF PARTICIPANTS: Ninety patients who met triage criteria for our trauma team evaluation and who were less than 15 years old were evaluated. Patients with a Glasgow Coma Scale score (GCS) of 15 (lie, mild to moderately injured children) were the focus of this study. METHODS: Children seen from May 1991 through August 1992 had charts reviewed systematically and within 24 hours of emergency department evaluation. Standard radiologic evaluation, including cervical-spine, chest, and pelvic radiographs, as well as arterial blood gas analysis, were obtained. The severity of injury was graded according to the Modified Injury Severity Scale. RESULTS: The mean age of patients was 6.4 years, and the injuries observed were exclusively extremity fractures. The correlation between physical examination findings and radiologic evaluation was assessed. Forty-three patients had an abnormal physical examination (ie, gross deformity, limitation of motion, or pain), and 26 had a fracture identified on radiograph. Forty-seven patients had a normal physical examination and none had a fracture identified on radiograph (P < .001; sensitivity of positive signs and symptoms, 100%; false-negative findings, 0%). Four patients with abnormal blood gases are described. No patient had any vascular or solid organ injury identified. CONCLUSION: In children with a GCS score of 15, selected radiologic and laboratory tests based on clinical findings are recommended. Careful observation and repeat examinations by trained clinicians can select a group of children at low risk for occult injury.     

Correlation between pharmacokinetic parameters of rifampicin and its biologically active metabolite as related to estimation of the relative bioavailability of the antibiotic

In the bioavailability studies with drugs biotransformed to biologically active metabolities only the concentrations of the parent drug (PD) are usually taken into account even when the pharmacokinetic data on the metabolite(s) (M) are available. However, such data may be useful as an alternative source for the bioavailability determination. Moreover, the clinical outcomes often depend on both the PD and M concentrations. The aim of the study performed with two rifampicin formulations, tablets and dragee, was to correlate the pharmacokinetic parameters of the PD and 25-O-deacetylrifampicin, a microbiologically active M of rifampicin, and to examine whether the bioavailability parameters based on the PD and M concentrations were compatible. The serum concentrations of the PD and M were determined in 8 healthy volunteers by HPLC. Despite different patterns of the PD and M pharmacokinetic profiles the PD peak concentration (Cmax) and especially the AUC correlated with Cmax or the AUC of the M (r = 0.76 and 0.92 respectively). Moreover, the extent of the absorption expressed as the AUC ratio for the PD correlated with the AUC ratio for the M (r = 0.86). However, neither the time to reach the maximum (tmax), nor the Cmax/AUC ratio, a measure of the absorption rate, based on the PD pharmacokinetic data correlated with the respective parameters calculated with using the M concentrations. Thus, only the estimates of the extent of the absorption and not of the absorption rate based on the PD and M data may be considered as compatible.     

Comparison of pH-stat and alpha-stat cardiopulmonary bypass on cerebral oxygenation and blood flow in relation to hypothermic circulatory arrest in piglets

Melagatran, a new, competitive and rapid inhibitor of thrombin with a molecular mass of 429 Da is described. Melagatran is well tolerated when administered in very high doses, and the oral bioavailability in the dog is relatively high. The aim of the study was to determine, in the preclinical setting, the degree of selectivity against the fibrinolytic system required for entering the clinical development phase. Melagatran was compared with two structurally similar thrombin inhibitors, inogatran and H 317/86. The potent inhibition of thrombin by melagatran was demonstrated by a low inhibition constant (Ki) for thrombin (0.002 micromol/l) and prolongation of clotting time to twice the control value in coagulation assays at low concentrations (0.010, 0.59 and 2.2 micromol/l for thrombin time, activated partial thromboplastin time and prothrombin time, respectively). Furthermore, thrombin-induced platelet aggregation was inhibited at the same concentration (IC50-value 0.002 micromol/l) as the Ki-value for thrombin. In two assays of global fibrinolysis, inhibition was observed at a concentration of 1.1 micromol/l in a euglobulin plasma fraction model, while no inhibition was observed at a concentration of < or = 10 micromol/l in a plasma model. In an in vivo model of endogenous fibrinolysis in the rat, inhibition of fibrinolysis was observed at > or = 1.0 micromol/l. In all assays, except the Ki-ratio determinations, the compounds could be graded with regard to selectivity against the fibrinolytic system: inogatran > melagatran > H 317/86. For melagatran, inhibition of fibrinolysis was not observed at concentrations below the upper limit of the proposed therapeutic plasma concentration interval (< 0.5 micromol/l). Thus, melagatran seems to have a sufficient selectivity against the fibrinolytic system, while H 317/86 was considered to be insufficient for clinical development.