Rapid desensitization of the acute stimulatory effects of nicotine on rat plasma adrenocorticotropin and prolactin

The dose of nicotine and the frequency of its administration appear to be essential determinants of its action on multiple systems including the neuroendocrine regulation of the adrenocorticotropin (ACTH)-corticosterone and prolactin (PRL) axes in the rat. Because desensitization to the acute depressive effects of nicotine has been observed after both acute and chronic administration, these investigations assessed whether desensitization to the stimulative effects of nicotine on ACTH and PRL secretion occurs with repetitive dosing. Extensive dose and time course experiments showed that nicotine rapidly elevates rat plasma ACTH and PRL levels with a threshold dose between 0.1 to 0.25 mg/kg b.wt. i.p. After the stimulation of PRL, levels became significantly depressed. Desensitization to the acute stimulatory effects of nicotine on both hormones was induced by a single dose of nicotine (0.5 mg/kg). One hour later nicotine (1.0 mg/kg) failed to significantly stimulate PRL levels and resulted in a modest increase of ACTH. Desensitization was maximal by 1 hr after the first dose and persisted for at least 6 hr. Adrenalectomy, performed to eliminate corticosterone-induced negative feedback, did not enhance PRL responsiveness to a second dose of nicotine but it partially restored the ACTH response. Pretreatment with corticosterone also failed to modify the PRL response to a single dose of nicotine whereas it partially suppressed the ACTH response. Rapid desensitization to the acute stimulatory effects of nicotine on plasma PRL is independent of glucocorticoid negative-feedback whereas desensitization of the ACTH response is modestly dependent.     

Effects of eight weeks of bicycle ergometer sprint training on human muscle buffer capacity

This investigation was undertaken to determine whether human skeletal muscle buffer capacity (BCm) is affected by training. Eight untrained males participated in 8 weeks of sprint training on bicycle ergometers. Muscle biopsy samples were taken from the vastus lateralis before and at several times following an incremental bicycle ergometer test (0 min, 5 min, 15 min). These subjects were tested before (PRE) and following (POST) the training period. Seven endurance-trained cyclists (ET) were also tested for the purpose of comparing the BCm of ET to that of PRE and POST. Biopsy samples were quick-frozen in liquid nitrogen and later analyzed for lactate concentration (HLam), homogenate pH (pHm), and creatine phosphate concentration. BCm was calculated from the change in HLam and pHm observed from rest to exhaustion and was expressed as mmol X kg-1 X pH-1 (Slykes). There was no significant difference in resting HLam or resting pHm among the groups. There was a significant difference in HLam at exhaustion between PRE (21.41 +/- 1.65 mmol X kg-1), POST (25.61 +/- 2.38 mmol X kg-1), and ET (11.16 +/- 0.31 mmol X kg-1) but no significant difference in pHm at exhaustion between PRE (6.65 +/- 0.03 pH units) and POST (6.69 +/- 0.06 pH units). pHm at exhaustion for the ET group was significantly higher than the others at 6.91 +/- 0.02 pH units. A significant difference between PRE and POST BCm was found (PRE: 44.68 +/- 3.03 S1; POST: 61.04 +/- 4.11 S1) while ET BCm (47.21 +/- 7.26 S1) was not significantly different from PRE. These data indicate that muscle buffer capacity is increased with highly intense sprint training but provide no evidence to suggest that muscle buffer capacity is affected by endurance training.     

A metropolitan experience with infrainguinal revascularization. Operative risk and late results in northeastern Ohio

Despite being of fundamental importance, the late results of major arterial reconstruction rarely have been documented throughout a large metropolitan area. In this study of 932 patients entered into the computer registry of the Cleveland Vascular Society, 19 surgeons representing 13 community hospitals and referral centers in Cleveland and Akron report the intermediate-term outcome during a mean interval of 35 months after infrainguinal lower extremity revascularization performed in northeastern Ohio from 1978 through 1982. Operative risk (5%), the early amputation rate (7%), and actuarial 5-year survival (48% to 55%) for patients with rest pain or tissue necrosis were significantly worse (p less than 0.05) than comparable figures (0.6%, 0%, and 77%, respectively) for others who underwent procedures for disabling claudication. Although both materials had similar success above the knee, the cumulative 3-year patency rate of autogenous vein bypass to the distal popliteal (69% to 88%; p less than 0.05) and tibioperoneal arteries (43%; 0.05 less than p less than 0.1) was superior to the results of polytetrafluoroethylene grafts (32% to 50% and 19%, respectively). Moreover, polytetrafluoroethylene grafts required reoperations at three times the rate of vein grafts to maintain limb salvage.     

Breast screening: a subject for debate.

The National Health Service Breast Screening Programme was instituted in 1988 following the recommendations of the Forrest report in 1986. From the beginning it has been controversial. Is breast cancer screening efficacious? Can the efficacy produced in trials be reproduced nationwide in the UK? Do the benefits of screening outweigh the adverse effects? Answers to all these questions are not yet available but in the light of current evidence, breast screening does appear to offer a realistic opportunity to reduce the mortality from a disease which constitutes a major public health problem in the UK. The role of the general practitioner and the primary care team is considered in the light of the experience gained in the first phase of the screening programme.     

Regional cerebral glucose transport in insulin-dependent diabetic patients studied using [11C]3-O-methyl-D-glucose and positron emission tomography

Regional cerebral [11C]3-O-methyl-D-glucose ([11C]MeG) uptake kinetics have been measured in five insulin-dependent diabetic patients and four normal controls using positron emission tomography (PET). Concomitant measurement of regional cerebral blood volume and CBF enabled corrections for the presence of intravascular [11C]MeG signal in cerebral regions of interest to be carried out, and regional cerebral [11C]MeG unidirectional extraction fractions to be computed. Four of the five diabetic subjects were studied with their fasting plasma glucose level clamped at a normoglycaemic level (4 mM), and four were studied at hyperglycaemic plasma glucose levels (mean 13 mM). The four diabetic subjects whose fasting plasma glucose levels were clamped at a normoglycaemic level of 4 mM had mean fasting whole-brain, cortical, and white matter [11C]MeG extraction fractions of 15, 15, and 16%, respectively, values similar to those found for the four normal controls (whole brain, 14%; cortex, 13%; white matter, 17%). Mean regional cerebral [11C]MeG extraction fractions were significantly reduced in diabetic subjects during hyperglycaemia whether their plasma insulin levels were undetectable or whether they were raised by continuous intravenous insulin infusion. Such a reduction in [11C]MeG extraction under hyperglycaemic conditions can be explained entirely in terms of increased competition between [11C]MeG and D-glucose for the passive facilitated transport carrier system for hexoses across the blood-brain barrier (BBB). It is concluded that the number and affinity of D-glucose carriers present in the BBB are within normal limits in treated insulin-dependent diabetic subjects. In addition, insulin appears to have no effect on the transport of D-glucose across the BBB.     

Positive genetic selection for gene disruption in mammalian cells by homologous recombination.

Efficient modification of genes in mammalian cells by homologous recombination has not been possible because of the high frequency of nonhomologous recombination. An efficient method for targeted gene disruption has been developed. Cells with substitution of exogenous sequences into a chromosomal locus were enriched, by a factor of 100, using a positive genetic selection that specifically selects for homologous recombination at the targeted site. The selection is based on the conditional expression of a dominant selectable marker by virtue of in-frame gene fusion with the target gene. The dominant selectable marker was derived by modification of the Escherichia coli neo gene so that it retains significant activity in mammalian cells after in-frame fusion with heterologous coding sequences. In the example presented here, homologous recombinants were efficiently recovered from a pool in which the targeted gene was disrupted in 1 per 10,000 cells incorporating exogenous DNA.