Heterologous expression of the Kv3.1 potassium channel eliminates spike broadening and the induction of a depolarizing afterpotential in the peptidergic bag cell neurons

The bag cell neurons of Aplysia are a cluster of cells that control egg laying behavior. After brief synaptic stimulation, they depolarize and fire spontaneously for up to 30 min. During the first few seconds of this afterdischarge, the action potentials of the bag cell neurons undergo pronounced broadening. Single bag cell neurons in culture also show spike broadening in response to repeated depolarizations. This broadening is frequency-dependent and associated with the induction of a depolarizing afterpotential lasting minutes. In some neurons the depolarizing afterpotential is sufficient to trigger spontaneous firing. To test the possibility that spike broadening during stimulation is required to trigger the depolarizing afterpotential, we eliminated frequency-dependent broadening by heterologous expression of the Kv3.1 potassium channel. This channel has rapid activation and deactivation kinetics and no use-dependent inactivation. Expression of Kv3.1 prevented spike broadening and also eliminated the depolarizing afterpotential. Measurements of the integral of calcium current during voltage commands, which simulated the action potentials of the control neurons and those expressing Kv3.1, indicate that spike broadening produces up to a fivefold increase in calcium entry. Manipulations that limit calcium entry during action potentials or chelation of intracellular calcium using BAPTA AM prevented the induction of the depolarizing afterpotential. We conclude that spike broadening is essential for the induction of the depolarizing afterpotential probably by regulating calcium influx and suggest that one of the physiological roles of spike broadening may be to regulate long-term changes in neuronal excitability.     

Religiosity and remission of depression in medically ill older patients

PURPOSE: The purpose of this study was to compare the fractional contributions of the three pathways of lactate transport (band 3 system, nonionic diffusion, and monocarboxylate pathway) into red blood cells (RBC) from trained and untrained humans. METHODS: Blood samples were obtained from 19 male subjects: 5 untrained, 5 aerobically-trained, 5 competitive collegiate cross-country runners, and 4 competitive collegiate sprinters. The influx of lactate into the RBC was measured by a radioactive tracer technique using [14C]lactate. Discrimination of each pathway of lactate transport was achieved by using PCMBS (1 mM) to block the monocarboxylate pathway and DIDS (0.2 mM) to block the band 3 system. Nonionic diffusion was calculated as the difference between total lactate influx and the sum of band 3 and monocarboxylate lactate influx. RESULTS: Total lactate influx into the RBC from the more aerobic individuals (trained subjects and cross-country runners) was significantly faster at 1.6 mM lactate concentration ([La]) as compared with the influx into RBC of the untrained subjects. Total influx of lactate was significantly higher (P < 0.05) in the RBC from the sprinters as compared with that in the RBC from the untrained subjects at 41 mM [La]. There were no significant differences among the four groups with regard to the total influx of lactate at 4.1, 8.1, and 20 mM [La]. In general, the percentage of total lactate influx accounted for by each of the three parallel pathways at 1.6, 8.1, and 41.0 mM [La] was not different among the four groups of subjects. CONCLUSIONS: Overall, the groups were more similar than different with regard to RBC lactate influx.     

Use of a prognostic treadmill score in identifying diagnostic coronary disease subgroups

BACKGROUND: Exercise testing is useful in the assessment of symptomatic patients for diagnosis of significant or extensive coronary disease and to predict their future risk of cardiac events. The Duke treadmill score (DTS) is a composite index that was designed to provide survival estimates based on results from the exercise test, including ST-segment depression, chest pain, and exercise duration. However, its usefulness for providing diagnostic estimates has yet to be determined. METHODS AND RESULTS: A logistic regression model was used to predict significant (>/=75% stenosis) and severe (3-vessel or left main) coronary artery disease, and a Cox regression analysis was used to predict cardiac survival. After adjustment for baseline clinical risk, the DTS was effectively diagnostic for significant (P<0.0001) and severe (P<0.0001) coronary artery disease. For low-risk patients (score >/=+5), 60% had no coronary stenosis >/=75% and 16% had single-vessel >/=75% stenosis. By comparison, 74% of high-risk patients (score <-11) had 3-vessel or left main coronary disease. Five-year mortality was 3%, 10%, and 35% for low-, moderate-, and high-risk DTS groups (P<0.0001). CONCLUSIONS: The composite DTS provides accurate diagnostic and prognostic information for the evaluation of symptomatic patients evaluated for clinically suspected ischemic heart disease.     

The CTFA Evaluation of Alternatives Program: an evaluation of in vitro alternatives to the Draize primary eye irritation test. (Phase III) surfactant-based formulations

The CTFA Evaluation of Alternatives Program is an evaluation of the relationship between data from the Draize primary eye irritation test and comparable data from a selection of promising in vitro eye irritation tests. In Phase III, data from the Draize test and 41 in vitro endpoints on 25 representative surfactant-based personal care formulations were compared. As in Phase I and Phase II, regression modelling of the relationship between maximum average Draize score (MAS) and in vitro endpoint was the primary approach adopted for evaluating in vitro assay performance. The degree of confidence in prediction of MAS for a given in vitro endpoint is quantified in terms of the relative widths of prediction intervals constructed about the fitted regression curve. Prediction intervals reflect not only the error attributed to the model but also the material-specific components of variation in both the Draize and the in vitro assays. Among the in vitro assays selected for regression modeling in Phase III, the relationship between MAS and in vitro score was relatively well defined. The prediction bounds on MAS were most narrow for materials at the lower or upper end of the effective irritation range (MAS = 0-45), where variability in MAS was smallest. This, the confidence with which the MAS of surfactant-based formulations is predicted is greatest when MAS approaches zero or when MAS approaches 45 (no comment is made on prediction of MAS > 45 since extrapolation beyond the range of observed data is not possible). No single in vitro endpoint was found to exhibit relative superiority with regard to prediction of MAS. Variability associated with Draize test outcome (e.g. in MAS values) must be considered in any future comparisons of in vivo and in vitro test results if the purpose is to predict in vivo response using in vitro data.     

Longitudinal trends and gender differences in physical fitness and lifestyle factors in career U.S. Navy personnel (1983-1994)

This study examines long-term health and physical readiness trends in the U.S. Navy. We mailed lifestyle questionnaires to all participants in baseline studies between 1983 and 1989 who were still on active duty in 1994. Commands provided body composition and physical readiness test scores for the participants. Two longitudinal cohorts were created: an 8-year sample (N = 640) with matched data from 1986, 1989, and 1994; and an 11-year sample (N = 1,576), with data from 1983 and 1994. Analyses of both cohorts revealed significant improvements in cardiovascular fitness, muscle strength, exercise, lean body mass, dietary habits, and sleep, as well as significant decreases in tobacco and alcohol use and job stress. However, hypertension rates, percentage of body fat, and body mass index increased over time. Women's scores were significantly better than men's on a number of factors. Overall, these findings suggest that the Navy's health promotion efforts have had a significant positive effect on the fitness and health behaviors of career Navy men and women.     

Emergency admissions of older people to hospital: a link with material deprivation

Nonproductive cough is a frequent and distressing symptom in patients with lung cancer, and it is not even relieved by palliative chemotherapy. A double-blind, randomized clinical trial regarding the treatment of nonproductive cough was performed in 140 adults with primary lung cancer or metastatic cancer of the lungs. The therapeutic efficacy and the tolerability of a 7-day treatment with levodropropizine drops (75 mg t.i.d.) were evaluated in comparison with dihydrocodeine drops (10 mg t.i.d.; 7 days). Efficacy was assessed on the basis of cough severity scores, number of night awakenings due to cough, and overall estimate of antitussive efficacy. Tolerability was evaluated by laboratory results, vital signs and any adverse event occurring during the clinical trial, including presence or absence of somnolence. Subjective cough severity was significantly reduced during treatment with either levodropropizine and dihydrocodeine, the antitussive effect and its time-profile being similar for both drugs. Also, according to the investigator's evaluation, both levodropropizine and dihydrocodeine produced a significant decrease in cough severity. Concurrently with the relief of cough, the number of night awakenings was decreased significantly by both drugs, with no difference between the two treatments. No change in laboratory test values was considered clinically relevant, and vital signs were not clinically affected. The number of patients reporting adverse events was similar in the levodropropizine (n=6) and dihydrocodeine (n=4) group. However, the percentage of patients experiencing somnolence in the group receiving levodropropizine (8%) was significantly lower as compared with that of the dihydrocodeine group (22%). These results confirm the antitussive effectiveness of levodropropizine and suggest a more favourable benefit/risk profile when compared to dihydrocodeine.