Background: Passive training of specific locomotor muscle groups by means of neuromuscular electrical stimulation (NMES) might be better tolerated than whole body exercise in patients with severe chronic obstructive pulmonary disease (COPD). It was hypothesised that this novel strategy would be particularly effective in improving functional impairment and the consequent disability which characterises patients with end stage COPD. Methods: Fifteen patients with advanced COPD (nine men) were randomly assigned to either a home based 6 week quadriceps femoris NMES training programme (group 1, n=9, FEV 1 =38.0 (9.6)% of predicted) or a 6 week control period before receiving NMES (group 2, n=6, FEV 1 =39.5 (13.3)% of predicted). Knee extensor strength and endurance, whole body exercise capacity, and health related quality of life (Chronic Respiratory Disease Questionnaire, CRDQ) were assessed. Results: All patients were able to complete the NMES training programme successfully, even in the presence of exacerbations (n=4). Training was associated with significant improvements in muscle function, maximal and endurance exercise tolerance, and the dyspnoea domain of the CRDQ (p<0.05). Improvements in muscle performance and exercise capacity after NMES correlated well with a reduction in perception of leg effort corrected for exercise intensity (p<0.01). Conclusions: For severely disabled COPD patients with incapacitating dyspnoea, short term electrical stimulation of selected lower limb muscles involved in ambulation can improve muscle strength and endurance, whole body exercise tolerance, and breathlessness during activities of daily living.

Tryptophan is metabolised primarily along the kynurenine pathway, of which two components are now known to have marked effects on neurons in the central nervous system. Quinolinic acid is an agonist at the population of glutamate receptors which are sensitive to N-methyl-D-aspartate (NMDA), and kynurenic acid is an antagonist at several glutamate receptors. Consequently quinolinic acid can act as a neurotoxin while kynurenic acid is neuroprotectant. A third kynurenine, 3-hydroxykynurenine, can generate free radicals and contribute to, or exacerbate, neuronal damage. Changes in the absolute or relative concentrations of these kynurenines have been implicated in a variety of central nervous system disorders such as the AIDS-dementia complex and Huntington's disease, raising the possibility that interference with their actions or synthesis could lead to new forms of pharmacotherapy for these conditions.

L Lo ow w i in nt te en ns si it ty y p pe er ri ip ph he er ra al l m mu us sc cl le e c co on nd di it ti io on ni in ng g i im mp pr ro ov ve es s e ex xe er rc ci is se e t to ol le er ra an nc ce e a an nd d b br re ea at th hl le es ss sn ne es ss s i in n C CO OP PD D ABSTRACT: This randomized, controlled study investigated the physiological effects of a specially designed 12 week programme of isolated conditioning of peripheral skeletal muscle groups. The programme required minimal infrastructure in order to allow continued rehabilitation at home after familiarization within hospital. Forty eight patients, aged 40-72 yrs with chronic obstructive pulmonary disease (COPD) (mean (SD) forced expiratory volume in one second (FEV1) 61 (27)% of predicted normal) were randomly allocated into training (n=32) and control (n=16) groups. Physiological assessments were performed before and after the 12 week study period, and included peripheral muscle endurance and strength, whole body endurance, maximal exercise capacity (maximum oxygen consumption (V ' 'O 2 ,max)) and lung function.The training group showed significant improvement in a variety of measures of upper and lower peripheral muscle performance, with no additional breathlessness. Whole body endurance measured by free arm treadmill walking increased by 6,372 (3,932-8,812) J (p<0.001). Symptom-limited maximal V ' 'O 2 was unchanged. However, the training group showed a reduction in ventilatory equivalents for oxygen and carbon dioxide, both at peak exercise and at equivalent work rate (Wmax).In summary, low intensity isolated peripheral muscle conditioning is well-tolerated, simple and easy to perform at home. The various physiological benefits should enable patients across the range of severity of chronic obstructive pulmonary disease to improve daily functioning.

The terminal stages of cortisol and aldosterone production in the human adrenal gland are catalysed by the enzymes 11 -hydroxylase and aldosterone synthase, which are encoded by the CYP11B1 and CYP11B2 genes respectively. Recent studies have suggested that aldosterone and cortisol are also made in other tissues such as the brain, heart and vascular system and may play a role in cardiovascular homeostasis. The aim of this study was to confirm the presence of these enzymes and localise them precisely in the rat brain.Reverse transcription-polymerase chain reaction (RT-PCR)/Southern blotting confirmed transcription of CYP11B1 and CYP11B2 in whole brain and hypothalamus minces from Wistar-Kyoto rats. 11 -Hydroxylase and aldosterone synthase were immunolocalised in paraffin-embedded rat adrenal and brain sections using mouse monoclonal antibodies. Negative controls utilised a mouse monoclonal antibody raised against a non-mammalian epitope. In the brain, 11 -hydroxylase and aldosterone synthase were detected in the cerebellum, especially the Purkinje cells, as well as the hippocampus. The specificities of the 11 -hydroxylase and aldosterone synthase antibodies were confirmed by positive immunostaining of the relevant regions of the adrenal cortex. This is the first direct evidence that steroid hydroxylases involved in the final stages of corticosteroid biosynthesis are present in specific regions of the central nervous system.

C57BL/6J mice infected with Plasmodium berghei ANKA develop neurological dysfunction and die within 7 days of infection. We show that treatment of infected mice with a kynurenine-3-hydroxylase inhibitor prevents them from developing neurological symptoms and extends their life span threefold until severe anemia develops.One possible cause of death associated with cerebral malaria is an imbalance in the production of neurotoxic and neuroprotective factors brought about by parasite-triggered cerebral inflammation (7,13,14). A candidate mechanism in this process is the kynurenine pathway from tryptophan, which is activated in macrophages and microglia by inflammatory stimuli and which generates excitotoxic and neuroprotectant metabolites (1, 8). The compound 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulfonamide (Ro-61-8048; synthesized by F. Hoffmann-La Roche Ltd.) has been developed as a highaffinity inhibitor of kynurenine-3-hydroxylase (16) (Fig. 1). It has been shown to reduce the formation of quinolinic acid (5), a known excitant and neurotoxin acting through N-methyl-Daspartate (NMDA) receptors (19), and increase the formation of the neuroprotective glutamate antagonist kynurenic acid (5,19) in the brains of mice immune stimulated with pokeweed mitogen. In order to assess the importance of kynurenines in the morbidity and mortality associated with cerebral malaria, we tested the effect of Ro-61-8048 treatment in a well-characterized murine model of this condition. It has been commented that in mice, mononuclear leukocytes are the predominant cell type sequestered in the cerebral microvasculature, and in humans, parasitized red blood cells are prominent (10). However, recent work has shown that leukocytes are seen clearly in brain vessels in human cerebral malaria in adults and parasitized red blood cells are sequestered in the brain in the murine disease (10). Also, cerebral malaria is a syndrome in which the same altered cell (the endothelial cell) plays a pivotal role in both human and experimental lesions (10).C57BL/6J mice infected with asexual blood stages of Plasmodium berghei ANKA have been shown to develop neurological behavioral changes such as ataxia, convulsions, and coma at approximately day 5 after infection and usually die between days 6 and 8 postinfection (15). Similarly, in our study, all 10 mice infected with P. berghei ANKA (6) and receiving only the solvent in which Ro-61-8048 was dissolved (vehicle, 0.9% NaCl-60 mM NaOH, pH adjusted to 7.5) exhibited signs of cerebral involvement on day 6 postinfection, with reduced locomotion and marked ataxia. All the mice in this group died or were euthanized to avoid unnecessary suffering between days 7 and 9 postinfection. In contrast, none of nine infected mice treated intraperitoneally with 200 mg/kg Ro-61-8048 (days 1, 2, 3, 4, 6, 8, 10, and 12 postinfection) showed any signs of cerebral dysfunction throughout the duration of the experiment, and all were surviving on day 21 postinfection (P ϭ 0.0002, Fisher's exact test), when the expe...

This study poses two questions: 1) is there an abnormality in isokinetic skeletal muscle strength and endurance in mild chronic obstructive pulmonary disease (COPD)? and 2) what is the effect of a randomized, controlled, 12 week hospital outpatient weight training programme in terms of skeletal muscle function and exercise tolerance?Upper and lower limb isokinetic maximum and sustained muscle function were compared in 43 COPD patients (age 4911 yrs), mean forced expiratory volume in one second (FEV1) 7723% pred and 52 healthy, sedentary subjects (age 51 (10) yrs), mean FEV1 10916% pred. The 43 COPD patients were randomly allocated into training (n=26) and control (n=17) groups. Isokinetic and isotonic muscle function, whole body endurance, maximal exercise capacity and lung function were measured.The COPD patients had reduced isokinetic muscle function (with the exception of sustained upper limb strength) as compared with healthy sedentary subjects. Muscle function improved after weight training in the COPD patients. Whole body endurance during treadmill walking also improved with no change in maximal oxygen consumption.A deficit in skeletal muscle function can be identified in patients with mild chronic obstructive pulmonary disease which cannot be explained by factors such as hypoxaemia and malnutrition. Intervention with weight training is effective in countering this deficit which the authors conclude is probably due to muscle deconditioning. Eur Respir J 2000; 15: 92±97.

Chances of treatment success were improved if patients received the model-predicted treatment. Using the model's prediction system may enable personalized, evidence-based epilepsy care, accelerating the match between patients and their ideal therapy, thereby delivering significantly better health outcomes for patients and providing health-care savings by applying resources more efficiently. Our goal will be to strengthen the predictive power of the model by integrating diverse data sets and potentially moving to prospective data collection.

There is some evidence for improved blood pressure outcomes with nurse-led interventions for hypertension in people with diabetes compared with doctor-led care. Nurse-based interventions require an algorithm to structure care and there is some preliminary evidence for better outcomes with nurse prescribing. Further work is needed to elucidate which nurse-led interventions are most effective.