Use of focus groups to assess the educational needs of the primary care physician for the management of asthma.

OBJECTIVES: To determine the educational needs of primary care physicians, in the management of patients with asthma. DESIGN: Focus group discussions with physicians, pharmacists, respiratory therapists and patients. SETTING: Metropolitan Edmonton, Alberta, Canada. PARTICIPANTS: Out of an original mail request to 100 potential recruits, 52 people attended the focus group sessions. These included physicians, pharmacists, respiratory therapists, adult patients and paediatric patients accompanied by their parents. MAIN OUTCOME MEASURE: Consensus of the specific group being interviewed using facilitator-mediated responses, to identify problems in the care of asthma patients and appropriate educational methods to improve the situation. RESULTS: Both diagnostic and treatment concerns were identified by the primary care physicians and others in the study. Confusion with infection was the most common diagnostic problem. Major treatment problems involved confusion about aspects of management strategy and a lack of communication between physicians, patients and other members of the health care team. Poor patient compliance and patients changing doctors frequently were also of major concern. There were inconsistencies in the treatment of asthma between physicians. While most physicians felt that they were up-to-date in management, Asthma Control Guidelines were seldom followed. CONCLUSIONS: There is an urgent need for continuing medical education, not only in management but also in communication with patients and with other members of the health care team. The data permit the development of an ongoing educational programme which is practical and designed to deal with the issues identified in this survey.

Functional and histological characteristics of skeletal muscle and the effects of leptin in the genetically obese (ob/ob) mouse.

BACKGROUND: Skeletal muscle mass in genetically obese (ob/ob) mice displays a reduced mass compared with their normal lean counterpart mice. However, the functional capacity of the available skeletal muscle mass in these animals has not yet been determined. OBJECTIVE: To investigate the properties of skeletal muscle in ob/ob mice and determine the effects of leptin administration on skeletal muscle in these mice. METHODS: Following 4 weeks of i.p. leptin administration (or control treatment) anaesthetized ob/ob and lean mice had their extensor digitorum longus and soleus muscles removed, and standard measures of isometric contractile properties and fatigability were performed. Histochemistry was used to determine fibre type proportions and individual fibre areas of all muscles. RESULTS: Leptin had no effect on the morphology or function of ob/ob skeletal muscle despite reducing body mass in ob/ob mice. Force production was unaltered in obese mice. However, a significant prolongation of contraction and relaxation times were evident. Obese skeletal muscle was also more fatigue resistant. Fibre proportions displayed a more slow type profile in ob/ob skeletal muscle, and in conjunction with previous work a reduced ability to hypertrophy. CONCLUSION: Skeletal muscle from obese mice is morphologically and functionally different from lean mouse skeletal muscle. Obese muscle is very similar to skeletal muscle from aged mice, and the specific contractile properties examined appear to be determined by the fibre make-up of these muscles.

Effects of acute leptin administration on the differences in proton leak rate in liver mitochondria from ob/ob mice compared to lean controls.

In this investigation, the effects on proton leak of leptin administration to ob/ob mice was measured for liver mitochondria. We and others have shown that proton leak is approximately 3 times greater in liver mitochondria from ob/ob mice compared to lean controls at any given membrane potential. The results are consistent with obese mammals having higher lean mass-specific metabolic rates compared to lean controls. The increase in proton leak rate at any given membrane potential cannot be explained by the presence of free fatty acids associated with mitochondria isolated from the obese animals. The difference in proton leak must therefore represent a real difference in inner membrane permeability. Acute leptin (OB protein) administration restores the liver mitochondrial proton leak rate of ob/ob mice to that of lean controls. There was no effect on proton leak rate of liver mitochondria from sham-treated ob/ob mice. These novel results indicate a role for leptin, either directly or indirectly, in regulating the efficiency of oxidative phosphorylation.

Indirect measurement of mitochondrial proton leak and its application.

In mitochondria, ATP synthesis is coupled to oxygen consumption by the proton electrochemical gradient established across the mitochondrial inner membrane in a process termed oxidative phosphorylation. It has long been known from stoichiometric studies that ATP synthesis is not perfectly coupled to oxygen consumption. The major inefficiency in the system is leakage of protons across the mitochondrial inner membrane driven by the proton electrochemical gradient. The kinetics of the proton leak can be determined indirectly, by measuring the oxygen consumption of mitochondria under non-phosphorylating conditions (plus oligomycin) as a function of the proton electrochemical gradient. This experimental system provides a convenient means to investigate inner membrane permeability to protons and the effect of factors that may effect that permeability. In this paper we review some results from our laboratory of indirect measurement of mitochondrial proton leak and how it has been applied to investigate the effect of aging, obesity and thyroid status on proton leak. The results show that (i) proton leak in isolated liver mitochondria is not significantly different in a comparison of young and old rats, in contrast (ii) there is an apparent increase in proton leak in in situ mitochondria in hepatocytes from old rats when compared to those from young rats, (iii) proton leak in neuronal mitochondria in situ in synaptosomes is not significantly different in young and old rats, (iv) proton leak is greater in isolated liver mitochondria from ob/ob mice compared to lean controls, (v) acute leptin (OB protein) administration restores the increased leak rate in isolated liver mitochondria from ob/ob mice to that of lean controls, (vi) administration of thyroid hormone (T3) increases proton leak in rat muscle mitochondria, and (vii) proton leak in muscle mitochondria is insensitive to the presence of GDP. It is proposed that the experimental system described here for measuring proton leak, is an ideal functional assay for determining whether the novel uncoupling proteins increase inner membrane permeability to protons.

Changes in cytochrome oxidase activity in brown adipose tissue during oestrous cycle in the rat.

Cold-acclimated female Wistar rats were killed at a known phase of the oestrous cycle to investigate whether natural fluctuations of female sex steroids during the cycle are mirrored by changes in brown adipose tissue (BAT) activity. Four phases: proestrus, oestrus, dioestrus I and dioestrus II, were identified by the cells types appearing in vaginal smears. BAT was removed and analysed for composition and specific indicators of BAT activity. No changes in BAT mass, protein or mitochondrial content were detected during the cycle. Thermogenesis was also unchanged as judged by both lipid multilocularity and mitochondrial GDP-binding. However, cytochrome c oxidase (COX) activity did cycle with a minimum at proestrus and a maximum at dioestrus I. The involvement of oestradiol in such a cycle is suggested by the fact that oestradiol treatment decreased COX activity to values similar to those found in proestrus. The physiological function of a cyclic oxidative capacity remains to be elucidated.

Interleukin-1 beta inhibits glutamate release in hippocampus of young, but not aged, rats.

The proinflammatory cytokine, interleukin-1, is synthesized in neuronal and glial cells and is released in response to stress/injury. IL-1 exerts profound effects on the central nervous system, which include an inhibitory effect on synaptic activity in hippocampus, a brain area expressing a high density of IL-1 receptors. We report that IL-1 beta has an inhibitory effect on KCl-stimulated release of glutamate and KC1-stimulated [45Ca] influx in synaptosomes prepared from hippocampus of 4-month-old rats. These effects were inhibited by the endogenous receptor antagonist, IL-1ra, and by the phospholipase A2 (PLA2) inhibitor, quinacrine, suggesting that IL-1 receptor activation is coupled to PLA2. An inhibitory effect of IL-1 beta on protein kinase C activity was also observed. KC1-induced calcium-dependent release and calcium influx, and protein kinase C activity were significantly decreased in hippocampal synaptosomes prepared from 22-month-old compared to 4-month-old animals. In contrast to the inhibitory effect of IL-1 beta in synaptosomes prepared from young adult animals, no effect was observed on release, calcium influx, or protein kinase C activity in synaptosomes prepared from aged animals. We report that there is an age-related increase in expression of IL-1 beta in hippocampus and propose that this change may underlie the attenuated responses to IL-1 beta in hippocampus of aged animals.

Stress ulceration and gastric mucosal cell kinetics: the influence of prophylaxis against acute stress ulceration.

Acute gastric stress ulceration occurs frequently in severely ill patients. Mucosal ischemia is central to the etiology of stress ulceration. The ability of the mucosa to restore continuity when damaged is one of the most important of the local defence mechanisms against injury. The aims of this study were to investigate this restitutive process during stress ulcer formation and to determine the effect of prophylaxis against stress ulceration on gastric mucosal cell kinetics. Nuclear DNA was radiolabeled in vivo with tritiated thymidine, and after autoradiography the position and number of labeled cells along the gastric mucosal gland were determined. Wistar rats were studied immediately and 48 hr after cold restraint stress. The labeling index in the proliferative zone of the gastric mucosa was significantly suppressed immediately after stress (12.58% vs 16.81% for unstressed controls, P < 0.001). This effect persisted for 48 hr after stress (9.89% vs 16.35% for unstressed controls, P < 0.001). Prophylaxis against stress ulceration with cimetidine or allopurinol prevented this suppression of gastric mucosal cell kinetics and promoted early migration of labeled cells towards the surface of the mucosal gland. Allopurinol prophylaxis was associated with migration of mucosal cells immediately following stress greater than that following cimetidine prophylaxis (14.0% vs 9.3% surface layer labeling index, P < 0.01). Allopurinol, a xanthine oxidase inhibitor, reduces oxygen free radical production during ischemia reperfusion injury. These results emphasise the importance of the gastric mucosal defence mechanisms in protection against injury and indicate the role of ischemia in the aetiology of acute gastric stress ulceration.

Stimulus properties of antidepressants in the rat.

Various doses of bupropion HCl (Wellbatrin) (5, 10, and 20 mg/kg), a new phenylaminoketone antidepressant, were employed as cues in a two-lever operant discrimination from saline control injections in rats on an FR10 schedule of food reinforcement. Subjects reached and maintained a high level of discrimination in the O vs 20 mg/kg bupropion stimulus condition but not at the lower doses. In generalization testing, the following compounds produced dose-related responding on the bupropion lever: viloxazine, nomifensine, caffeine, d-amphetamine, cocaine, methylphenidate, and benzylpiperazine. Drugs that failed to show dose-related generalization included phenethylamine, thyrotropin-releasing hormone, imipramine, nortriptyline, amitriptyline, desipramine, mianserin, chlordiazepoxide, diazepam, scopolamine, phenobarbital, and morphine. With the important exception of viloxazine, the generalization profile of bupropion seems to reflect its previously reported locomotor stimulant effects in the rat rather than its antidepressant activity and suggests that species differences exist between man and rat with regard to the pharmacologic activity of this new antidepressant.