No abstract

Normal blood vessel tone is maintained by a balance of vasoconstrictors and vasodilators produced by endothelial cells in the vasculature. Nitric oxide (NO) is a potent vasodilator that causes vascular smooth muscle cell relaxation by elevating intracellular guanosine 3',5'-cyclic monophosphate (cGMP) levels. The physiological mechanisms regulating NO production in the vasculature are not completely understood. We report here that production of this vasodilator by vascular endothelial cells can be significantly suppressed by hypoxia. Exposing human endothelial cells to low PO2 results in 40-60% reduction in the steady-state mRNA levels of endothelial constitutive NO synthase (eNOS), the major enzyme responsible for NO production in these cells. The lower levels of eNOS mRNA result from decreased transcription of the gene as well as reduced message stability. In endothelial-smooth muscle cell co-culture experiments, hypoxic endothelial cells stimulated significantly less cGMP production by smooth muscle cells than the corresponding normoxic controls. This inhibitory effect of hypoxia on NOS production by endothelial cells occurs after 24 h of hypoxia and persists for at least 48 h. These new findings suggest that hypoxia might cause changes in blood vessel tone through compound mechanisms: by increasing the production of endothelium-derived vasoconstrictors and, as shown here, by suppressing the production of vasodilators like NO.

Objective: To investigate the feasibility, acceptability, and safety of a supervised video game exercise program administered via Dance Dance Revolution in individuals with Huntington's disease. Design: A cross-over, controlled, single-blinded, six-week trial. Setting: Home-based. Participants: Eighteen ambulatory individuals with Huntington's disease (seven male, mean age 50.7 SD 14.7). Interventions: Participants played the Dance Dance Revolution game with supervision and the handheld game without supervision for 45 minutes, two days per week for six weeks. Outcome measures: Game play performance and adherence, participant perceptions of the game, safety (vital signs, adverse health changes), spatiotemporal gait measures, Four-Square Step Test, Tinetti Mobility Test, Activities-Specific Balance Confidence Scale, and World Health Organization Quality of Life -Bref, before and after each intervention. Results: Most participants improved on game play, enjoyed playing the game, and wanted to continue playing after study completion. After playing Dance Dance Revolution, participants showed significant reductions in double support percentage (adjusted mean difference (95% confidence intervals): -2.54% (-4.75, -0.34) for forward walking and -4.18 (-6.89, -0.48) for backward walking) and those with less severe motor symptoms had reductions in heel-to-heel base of support during forward walking. The remaining measures were not significantly impacted by the intervention. Conclusion:Dance Dance Revolution appears to be a feasible, motivating, and safe exercise intervention for individuals with Huntington's disease.

The TMT is a reliable and valid tool for assessing the mobility status of and fall risk for individuals with PD.

A Randomized Clinical Trial of High-Dosage Coenzyme Q10 in Early Parkinson Disease No Evidence of Benefit The Parkinson Study Group QE3 Investigators IMPORTANCE Coenzyme Q10 (CoQ10), an antioxidant that supports mitochondrial function, has been shown in preclinical Parkinson disease (PD) models to reduce the loss of dopamine neurons, and was safe and well tolerated in early-phase human studies. A previous phase II study suggested possible clinical benefit. OBJECTIVE To examine whether CoQ10 could slow disease progression in early PD. DESIGN, SETTING, AND PARTICIPANTS A phase III randomized, placebo-controlled, double-blind clinical trial at 67 North American sites consisting of participants 30 years of age or older who received a diagnosis of PD within 5 years and who had the following inclusion criteria: the presence of a rest tremor, bradykinesia, and rigidity; a modified Hoehn and Yahr stage of 2.5 or less; and no anticipated need for dopaminergic therapy within 3 months. Exclusion criteria included the use of any PD medication within 60 days, the use of any symptomatic PD medication for more than 90 days, atypical or drug-induced parkinsonism, a Unified Parkinson's Disease Rating Scale (UPDRS) rest tremor score of 3 or greater for any limb, a Mini-Mental State Examination score of 25 or less, a history of stroke, the use of certain supplements, and substantial recent exposure to CoQ10. Of 696 participants screened, 78 were found to be ineligible, and 18 declined participation. INTERVENTIONS The remaining 600 participants were randomly assigned to receive placebo, 1200 mg/d of CoQ10, or 2400 mg/d of CoQ10; all participants received 1200 IU/d of vitamin E. MAIN OUTCOMES AND MEASURES Participants were observed for 16 months or until a disability requiring dopaminergic treatment. The prospectively defined primary outcome measure was the change in total UPDRS score (Parts I-III) from baseline to final visit. The study was powered to detect a 3-point difference between an active treatment and placebo. RESULTS The baseline characteristics of the participants were well balanced, the mean age was 62.5 years, 66% of participants were male, and the mean baseline total UPDRS score was 22.7. A total of 267 participants required treatment (94 received placebo, 87 received 1200 mg/d of CoQ10, and 86 received 2400 mg/d of CoQ10), and 65 participants (29 who received placebo, 19 who received 1200 mg/d of CoQ10, and 17 who received 2400 mg/d of CoQ10) withdrew prematurely. Treatments were well tolerated with no safety concerns. The study was terminated after a prespecified futility criterion was reached. At study termination, both active treatment groups showed slight adverse trends relative to placebo. Adjusted mean changes (worsening) in total UPDRS scores from baseline to final visit were 6.9 points (placebo), 7.5 points (1200 mg/d of CoQ10; P = .49 relative to placebo), and 8.0 points (2400 mg/d of CoQ10; P = .21 relative to placebo). CONCLUSIONS AND RELEVANCE Coenzyme Q10 was safe and well tolerated in this population, bu...