A molecular scheme for the reaction between γ-aminobutyric acid and the most abundant chloride channel on crayfish deep extensor abdominal muscle

Single-channel measurements were performed with the aim of constructing a detailed molecular scheme for the reaction between -aminobutyric acid (GABA) and a chloride channel of crayfish deep extensor abdominal muscle (DEAM). GABA was applied in pulses to outside-out patches of muscle membrane, and, based on the dose-response of the peak currents and of their rise times, a linear model with five binding steps has been proposed. Evaluation of the single-channel kinetics indicated at least three open states. Two of them originate most probably from the fully liganded receptor state and are grouped in mixed bursts due to their different life times. The third one appears independently, outside the bursts, and originates from a lower liganded receptor state. Simulations of the dose-responses and the open time distributions with this model led to a set of rate constants which generated relatively optimal fits.     

Physician attitudes toward computerized practice guidelines

Computerized information systems are gaining ground in quality improvement, and will become even more important as health plans implement, evaluate, and maintain clinical guidelines. PacifiCare of California explored physicians' attitudes toward applying computerized technologies to direct clinical guidelines. The results indicate not only physician acceptance factors, but illustrate the issues, such as information for medical decision making, that health plans must consider in developing computerized case management systems to manage the care of the chronically ill.     

Common carotid haemodynamic and metabolic effects of acutely administered nifedipine in human subarachnoid haemorrhage

Although the drugs known as "calcium antagonists" exert inhibitory actions on vascular smooth muscle, there are no quantitative data concerning the clinical use of these vasodilator agents in human subarachnoid haemorrhage. In the present clinical study, we have measured the effects of nifedipine (20 mg tablet) on common carotid artery diameter (D) blood flow velocity (V) common carotid blood flow (CCBF) as an index of cerebral blood flow, systolic (Qs) and diastolic (Qd) blood flow fractions using a pulsed Doppler apparatus and on carotid arterial pressure (CAP), heart rate (HR) and oxygen consumption (VO2). Eight patients with subarachnoid haemorrhage were studied during anaesthesia for cerebral angiography. Thirty minutes after sublingual nifedipine, diameter (P less than 0.05), blood flow velocity (P less than 0.001), CCBF (P less than 0.001), Qs (P less than 0.05), and Qd (P less than 0.05) increased with a decrease in Qs/Qd ratio (P less than 0.05). carotid vascular resistance (CVR) fell (P less than 0.02) and oxygen consumption of the brain increased (P less than 0.01). Systolic, diastolic, and mean carotid blood pressure, heart rate, and arteriovenous difference in oxygen were unchanged. The increase in CCBF was closely correlated with the vascular resistance in the control state (r = 0.928, P less than 0.001) and with oxygen consumption (r = 0.869, P less than 0.001). We conclude that in vivo, nifedipine exerts a preferential action on cerebral vessels, vasodilating large arteries and arterioles. This action is more powerful if the vessels are already vasoconstricted. Thus, the use of nifedipine could be fruitful in cerebral ischaemia that is secondary to subarachnoid haemorrhage.     

Reading, Demographic, Social and Psychological Factors Related to Pre-adolescent Smoking and Non-smoking Behaviors and Attitudes

The purpose of this study was to examine reading, demographic, social and psychological factors related to pre-adolescent smoking and non-smoking behaviors and attitudes. The school-home humanistic education program was implemented in a large, urban public school system. It stressed responsible decision-making, increased self-esteem and the inter-relationships among the acquisition of knowledge of the consequences of smoking, personal feelings, family relationships and behavior. The results showed that family involvement was necessary to affect smoking attitudes and behaviors. Of all the variables studied, reading had a most pervasive relationship. Peer influence and self-esteem also were related to smoking knowledge, smoking attitude, future smoking intentions and the "purchase" of cigarettes. Two of several conclusions drawn from the results are: 1. Family involvement is necessary to affect attitudes and behaviors. 2. Health education research that does not investigate the relationship between program outcomes and reading achievement may be misleading.     

The relation of physical activity to cardiovascular disease risk factors in Mauritians. Mauritius Noncommunicable Disease Study Group

The authors investigated the relation between physical activity and cardiovascular disease risk factors in a random sample of 4,658 Asian Indian, Creole, and Chinese adults aged 25-74 years from the island nation of Mauritius. Subjects known to have diabetes were excluded from analyses. Subjects were divided into "active" and "inactive" groups on the basis of a combined leisure and occupational physical activity score determined at interview (April 1987). Two-hour plasma glucose concentration and fasting and 2-hour serum insulin concentrations were significantly lower and high density lipoprotein (HDL) cholesterol was significantly higher in active subjects of both sexes. Plasma uric acid and fasting triglyceride levels were also lower among active subjects, but significantly so only in females. Systolic and diastolic blood pressure levels, body mass index (weight (kg)/height (m)2), and waist:hip ratio varied little between the two activity groups. In multiple linear regression analyses, physical activity made an independent negative contribution to the models for 2-hour glucose and insulin in both males and females, as well as for fasting insulin in males. When glucose and insulin were not included, physical activity also made an independent contribution to the models for plasma triglycerides (inversely) in females and HDL cholesterol and HDL cholesterol as a proportion of total cholesterol (positively) in males. The authors have demonstrated improved cardiovascular disease profiles associated with physical activity in Mauritians. The data suggest that much of the effect is modulated via an effect on insulin-glucose metabolism. Promotion of exercise should become an important strategy in the prevention of cardiovascular disease and glucose intolerance in this population.     

Association of two resistance mechanisms in a clinical isolate of Enterobacter cloacae with high-level resistance to imipenem.

Carbapenem resistance was studied in a clinical isolate of Enterobacter cloacae, strain 201 (MIC of imipenem and meropenem, 16 micrograms/ml). This strain was analyzed comparatively with the carbapenem-susceptible parent strain 200, an equally susceptible revertant, 201-Rev, and in vitro-selected mutants with different levels of carbapenem resistance. All strains produced similarly high amounts of the same cephalosporinase (pIapp = 8.8). Strain 201 apparently lacked two major outer membrane proteins of ca. 37 and 38 kDa, while 201-Rev produced only the 37-kDa protein. The permeability coefficient, determined with cephaloridine, was reduced up to ninefold in the resistant strains which also showed a substantial reduction in the uptake of [14C]meropenem. The introduction of the plasmid-borne ampD gene (whose product decreases the expression of ampC) resulted in almost complete cessation of cephalosporinase production in all strains and a substantial decrease in the MICs of the carbapenems which remained, however, 8- to 16-fold higher than those determined for the susceptible strains containing the ampD gene. This "residual" resistance was attributed to reduced outer membrane permeability. The contribution of cephalosporinase production was verified in a reverse experiment, in which the introduction of ampC into a low-level cephalosporinase producer resulted in a fourfold increase in the carbapenem MICs. From these results, we infer that reduced outer membrane permeability and high-level cephalosporinase production can operate in conjunction in clinical isolates of E. cloacae to confer imipenem resistance.     

Influence of dietary soy isoflavones on the accessory sex organs of the Wistar rat.

We evaluated the effects of three rodent diets differing in soybean meal content on the response of the seminal vesicles, prostate and bulbocavernosus/levator ani (BC/LA) muscle to androgens and anti-androgenic compounds in the Hershberger assay. The diets tested were (1) L5, a semi-synthetic phytoestrogen-free diet, (2) DO4, 8.5% (w/w) vegetable protein and (3) DO3, 22.5% (w/w) vegetable protein. We determined the effects of dietary soy isoflavones after ten days of exposure and in animals fed L5 and DO3 diets throughout their lifetime (including the period of treatment with androgenic or anti-androgenic compounds). After ten days of exposure, we observed no effect of diet on the accessory sex organs of male Wistar rats. In contrast, diet affected the androgenic response to testosterone propionate in seminal vesicles and prostate. Seminal vesicles were the most sensitive organs. Vinclozolin caused a dose-dependent decrease in the relative weights of seminal vesicles, prostate and BC/LA regardless of diet. As vegetable proteins may contain high proportions of genistein and daidzein, two well-known oestrogenic endocrine disrupters that may alter the results of reproductive studies, we recommend the use of a standardised open-formula diet without soy isoflavones, such as L5, if the Hershberger assay is to be performed.     

Inactivation of adenosine A2A receptors selectively attenuates amphetamine-induced behavioral sensitization.

Repeated treatment with the psychostimulant amphetamine produces behavioral sensitization that may represent the neural adaptations underlying some features of psychosis and addiction in humans. In the present study we investigated the role of adenosine A(2A) receptors in psychostimulant-induced locomotor sensitization using an A(2A) receptor knockout (A(2A) KO) model. Daily treatment with amphetamine for 1 week resulted in an enhanced motor response on day 8 (by two-fold compared to that on day 1), and remained enhanced at day 24 upon rechallenge with amphetamine. By contrast, locomotor sensitization to daily amphetamine did not develop in A(2A) KO mice on day 8 or 24, and this absence was not the result of a nonspecific threshold effect. The absence of behavioral sensitization was selective for amphetamine since daily treatment with the D(1) agonist SKF81297 (2.5 mg/kg) or the D(2) agonist quinpirole (1.0 mg/kg) produced similar behavioral sensitization in both WT and A(2A) KO mice. Furthermore, coinjection of SKF81297 and quinpirole also resulted in indistinguishable locomotor sensitization in A(2A) KO and WT mice, suggesting normal D(1) and D(2) receptor responsiveness. Finally, at the cellular level A(2A) receptor inactivation abolished the increase in striatal dynorphin mRNA induced by repeated amphetamine administration. The selective absence of amphetamine-induced behavioral sensitization in A(2A) KO mice suggests a critical role of the A(2A) receptor in the development of psychostimulant-induced behavioral sensitization, and supports the pharmacological potential of A(2A) adenosinergic agents to modulate adaptive responses to repeated psychostimulant exposure.     

Quantified relationship between cellular radiosensitivity, DNA repair defects and chromatin relaxation: a study of 19 human tumour cell lines from different origin.

BACKGROUND AND PURPOSE: There is still confusion in the choice of the molecular assays to predict the radiation response of human cells. The case of tumours appears to be particularly complex, may be because of their instability and heterogeneity. The aim of this study was to investigate quantitatively the relationships between DNA double-strand breaks (DSB) repair, chromatin relaxation and cellular radiosensitivity. Nineteen human tumour cell lines, representing a large spectrum of radiation responses and tissues, were examined. MATERIALS AND METHODS: Intrinsic radiosensitivity was quantified with surviving fraction at 2 Gy (SF2) as an endpoint. Standard and modified pulsed-field gel electrophoresis techniques were employed to assess DSB repair rate and chromatin relaxation. A cell-free assay was chosen to estimate DSB repair activity, independently of chromatin impairment. RESULTS AND CONCLUSIONS: Surviving fraction at 2 Gy (SF2) decreases linearly with the amount of unrepaired DSB and the extent of chromatin relaxation: one additional unrepaired DSB per cell or 1% chromatin decondensation produce a loss of about 1.5% surviving fraction. However, all the cell lines did not obey both correlations, suggesting that DSB repair and chromatin impairments contribute separately to increase the severity of DNA damage involved in cell lethality. Four cell lines groups showing different DSB repair and/or chromatin impairments were defined. Cell lines exhibiting both DSB repair defect and chromatin relaxation are the most radiosensitive.     

Serious adverse effects of amifostine during radiotherapy in head and neck cancer patients

Background and purpose: Amifostine has been shown to protect against xerostomia induced by radiotherapy for head and neck cancer, but its impact on the therapeutic index is unknown. This is the first report focusing on amifostine related adverse effects leading to discontinuation of amifostine treatment.

Patients and methods: Thirty-nine patients from two centers irradiated for head and neck cancer received i.v.-infusions of amifostine prior to each radiation fraction. In a phase III study, two daily amifostine doses, 200 mg/m² (n=21) and 340 mg/m² (n=18), were compared for protection against radiation induced toxicity. Total radiation dose was 60–70 Gy (2 Gy per fraction), nine patients received concurrent chemotherapy with cisplatin/5-FU. amifostine was usually discontinued after >1 episode of serious toxicity during subsequent treatment sessions.

Results: In 16/39 patients (41%) amifostine was discontinued due to severe adverse effects, which led to discontinuation of the phase III study. In four of 16 patients radiotherapy was delayed due to amifostine related adverse effects for 1–3 days. Discontinuation occurred more often in patients receiving chemotherapy. The results led to a literature review for amifostine treatment during radiotherapy in head and neck cancer patients. Regarding our series and published series using an amifostine schedule comparable to ours, total discontinuation rate was 27% (57/214). Discontinuation was significantly influenced by chemotherapy (P=0.007), but not by amifostine dose (P=0.156).

Conclusion: Daily i.v. administration of amifostine during radiotherapy in head and neck cancer is associated with a high rate of serious adverse effects leading to discontinuation of amifostine treatment and sometimes delay of radiotherapy.