Enhanced sensitivity of protein kinase B/Akt to insulin in hypoxia is independent of HIF1 alpha and promotes cell viability

Maintenance of oxygen homeostasis is a key requirement to ensure normal mammalian cell growth and differentiation. Hypoxia arises when oxygen demand exceeds supply, and is a feature of multiple human diseases including stroke, cancer and renal fibrosis. We have investigated the effect of hypoxia on kidney cells, and observed that insulin-induced cell viability is increased in hypoxia. We have characterized the role of protein kinase B (PKB/ Akt) in these cells as a potential mediator of this effect. PKB/Akt activity was increased by low oxygen concentrations in kidney cells, and insulin-stimulated activation of PKB/Akt was stronger, more rapid and more sustained in hypoxia. Reduction of HIF1 alpha levels using antimycin-A or siRNA targeting HlF1 alpha did not affect PKB/Akt activation in hypoxia. Pharmacologic stabilization of HIF1 alpha independent of hypoxia did not increase insulin-stimulated PKB/Akt activation. Although increased insulin-stimulated cell viability was observed in hypoxia, no differences in the degree of insulin-stimulated glucose uptake were observed in L6 muscle cells in hypoxia compared to normoxia. Thus, PKB/Akt may regulate specific cellular responses to growth factors such as insulin under adverse conditions such as hypoxia. alpha 2007 Elsevier GmbH. All rights reserved.

Bimanual coordination in chronic schizophrenia

Anomalies of movement are observed both clinically and experimentally in schizophrenia. While the basal ganglia have been implicated in its pathogenesis, the nature of such involvement is equivocal. The basal ganglia may be involved in bimanual coordination through their input to the supplementary motor area (SMA). While a neglected area of study in schizophrenia. a bimanual movement task may provide a means of assessing the functional integrity of the motor circuit. Twelve patients with chronic schizophrenia and 12 matched control participants performed a bimanual movement task on a set of vertically mounted cranks at different speeds (1 and 2 Hz) and phase relationships. Participants performed in-phase movements (hands separated by 0 degrees) and out-of-phase movements (hands separated by 180 degrees) at both speeds with an external cue on or off. All participants performed the in-phase movements well. irrespective of speed or cueing conditions. Patients with schizophrenia were unable to perform the out-of-phase movements, particularly at the faster speed, reverting instead to the in-phase movement. There was no effect of external cueing on any of the movement conditions. These results suggest a specific problem of bimanual coordination indicative of SMA dysfunction per se and/or faulty callosal integration. A disturbance in the ability to switch attention during the out-of-phase task may also be involved. (C) 2001 Academic Press.

Training-induced changes in the pattern of triceps to biceps activation during reaching tasks after chronic and severe stroke

This exploratory study was undertaken to investigate the mechanisms that contributed to improvements in upper limb function following a novel training program. Surface electromyography (EMG) was used to examine training-induced changes in the pattern of triceps and biceps activation during reaching tasks in stroke survivors with severe paresis in the chronic stage of recovery. The EMG data were obtained in the context of a single blind randomised clinical trial conducted with 42 stroke survivors with minimal upper limb muscle activity and who were more than 6 months post-stroke. Of the 33 participants who completed the study, 10 received training of reaching using a non-robotic upper limb training device, the SMART Arm, with EMG triggered functional electrical stimulation (EMG-stim), 13 received training of reaching using the SMART Arm alone, and 10 received no intervention. Each intervention group engaged in 12 1-h training sessions over a 4-week period. Clinical and laboratory measures of upper limb function were administered prior to training (0 weeks), at completion (4 weeks) and 2 months (12 weeks) after training. The primary outcome measure was 'upper arm function' which is Item 6 of the Motor Assessment Scale (MAS). Laboratory measures consisted of two multijoint reaching tasks to assess 'maximum isometric force' and 'maximum distance reached'. Surface EMG was used to monitor triceps brachii and biceps brachii during the two reaching tasks. To provide a comparison with normal values, seven healthy adults were tested on one of the reaching tasks according to the same procedure. Study findings demonstrated a statistically significant improvement in upper limb function for stroke participants in the two training groups compared to those who received no training however no difference was found between the two training groups. For the reaching tasks, all stroke participants, when compared to normal healthy adults, exhibited lower triceps and biceps activation and a lower ratio of triceps to biceps activation. Following training, stroke participants demonstrated increased triceps activation and an increased ratio of triceps to biceps activation for the task that was trained. Better performance was associated with greater triceps activation and a higher ratio of triceps to biceps activation. The findings suggest that increased activation of triceps as an agonist and an improved coordination between triceps and biceps could have mediated the observed changes in arm function. The changes in EMG activity were small relative to the changes in arm function indicating that factors, such as the contribution of other muscles of reaching, may also be implicated.

Increased cerebral output of free radicals during hypoxia: implications for acute mountain sickness?

Bailey DM, Taudorf S, Berg RMG, Lundby C, McEneny J, Young IS, Evans KA, James PE, Shore A, Hullin DA, McCord JM, Pedersen BK, Moller K. Increased cerebral output of free radicals during hypoxia: implications for acute mountain sickness? Am J Physiol Regul Integr Comp Physiol 297: R1283-R1292, 2009. First published September 2, 2009; doi: 10.1152/ajpregu.00366.2009.-This study examined whether hypoxia causes free radical-mediated disruption of the blood-brain barrier (BBB) and impaired cerebral oxidative metabolism and whether this has any bearing on neurological symptoms ascribed to acute mountain sickness (AMS). Ten men provided internal jugular vein and radial artery blood samples during normoxia and 9-h passive exposure to hypoxia (12.9% O-2). Cerebral blood flow was determined by the Kety-Schmidt technique with net exchange calculated by the Fick principle. AMS and headache were determined with clinically validated questionnaires. Electron paramagnetic resonance spectroscopy and ozone-based chemiluminescence were employed for direct detection of spin-trapped free radicals and nitric oxide metabolites. Neuron-specific enolase (NSE), S100 beta, and 3-nitrotyrosine (3-NT) were determined by ELISA. Hypoxia increased the arterio-jugular venous concentration difference (a-v(D)) and net cerebral output of lipid-derived alkoxyl-alkyl free radicals and lipid hydroperoxides (P

The Effects of Anti-Hypertensive Drugs Evaluated Using Markov Modelling for Northern Ireland Chronic Kidney Disease Patients

The aim of this paper is to use Markov modelling to
investigate survival for particular types of kidney patients
in relation to their exposure to anti-hypertensive treatment
drugs. In order to monitor kidney function an intuitive three
point assessment is proposed through the collection of blood
samples in relation to Chronic Kidney Disease for Northern
Ireland patients. A five state Markov Model was devised
using specific transition probabilities for males and
females over all age groups. These transition probabilities
were then adjusted appropriately using relative risk scores
for the event death for different subgroups of patients. The
model was built using TreeAge software package in order to
explore the effects of anti-hypertensive drugs on patients.