Improved Parkinsons disease motor score in a single-arm open-label trial of febuxostat and inosine.

BACKGROUND: Cellular energetics play an important role in Parkinsons disease etiology, but no treatments directly address this deficiency. Our past research showed that treatment with febuxostat and inosine increased blood hypoxanthine and ATP in healthy adults, and a preliminary trial in 3 Parkinson's disease patients suggested some symptomatic improvements with no adverse effects. METHODS: To examine the efficacy on symptoms and safety in a larger group of Parkinsons disease patients, we conducted a single-arm, open-label trial at 5 Japanese neurology clinics and enrolled thirty patients (nmales = 11; nfemales = 19); 26 patients completed the study (nmales = 10; nfemales = 16). Each patient was administered febuxostat 20 mg and inosine 500 mg twice-per-day (after breakfast and dinner) for 8 weeks. The primary endpoint was the difference of MDS-UPDRS Part III score immediately before and after 57 days of treatment. RESULTS: Serum hypoxanthine concentrations were raised significantly after treatment (Pre = 11.4 µM; Post = 38.1 µM; P < .0001). MDS-UPDRS Part III score was significantly lower after treatment (Pre = 28.1 ±â€Š9.3; Post = 24.7 ±â€Š10.8; mean ±â€ŠSD; P = .0146). Sixteen adverse events occurred in 13/29 (44.8%) patients, including 1 serious adverse event (fracture of the second lumbar vertebra) that was considered not related to the treatment. CONCLUSIONS: The results of this study suggest that co-administration of febuxostat and inosine is relatively safe and effective for improving symptoms of Parkinsons disease patients. Further controlled trials need to be performed to confirm the symptomatic improvement and to examine the disease-modifying effect in long-term trials.

Identification of novel serum markers for the progression of coronary atherosclerosis in WHHLMI rabbits, an animal model of familial hypercholesterolemia.

BACKGROUND AND AIMS: The development of serum markers specific for coronary lesions is important to prevent coronary events. However, analyses of serum markers in humans are affected by environmental factors and non-target diseases. Using an appropriate model animal can reduce these effects. To identify specific markers for coronary atherosclerosis, we comprehensively analyzed the serum of WHHLMI rabbits, which spontaneously develop coronary atherosclerosis. METHODS: Female WHHLMI rabbits were fed standard chow. Serum and plasma were collected under fasting at intervals of 4 months from 4 months old, and a total of 313 lipid molecules, 59 metabolites, lipoprotein lipid levels, and various plasma biochemical parameters were analyzed. The severity of coronary lesions was evaluated with cross-sectional narrowing (CSN) corrected with a frequency of 75%-89% CSN and CSN> 90%. RESULTS: There was a large variation in the severity of coronary lesions in WHHLMI rabbits despite almost no differences in plasma biochemical parameters and aortic lesion area between rabbits with severe and mild coronary lesions. The metabolites and lipid molecules selected as serum markers for coronary atherosclerosis were lysophosphatidylcholine (LPC) 22:4 and diacylglycerol 18:0-18:0 at 4 months old, LPC 20:4 (sn-2), ceramide d18:1-18:2, citric acid plus isocitric acid, and pyroglutamic acid at 8 months old, and phosphatidylethanolamine plasminogen 16:1p-22:2 at 16 months old. CONCLUSIONS: These serum markers were coronary lesion-specific markers independent of cholesterol levels and aortic lesions and may be useful to detect patients who develop cardiovascular disease.

Tolerance of early pallidal stimulation in pediatric generalized dystonia.

The authors report on 2 cases of pediatric generalized dystonia with a DYT1 mutation; the patients, an 11-year-old girl and a 9-year-old boy, underwent chronic, pallidal deep brain stimulation (DBS) of the globus pallidus internus (GPi). The dystonic postures in both cases showed dramatic improvements with pallidal DBS, but each patient's symptoms gradually recurred within a year, irrespective of exhaustive readjustments of the stimulation settings. After the recurrence of the dystonic symptoms, the DBS leads were replaced within the GPi in one patient (Case 1) and additional DBS leads were implanted into the bilateral subthalamic nuclei in the other patient (Case 2). Neither measure produced any further clinical benefit, and the patient in Case 2 died of status dystonicus 2 days after reoperation. These findings suggest that early pallidal DBS for pediatric dystonia is indeed effective, although there are some cases in which its therapeutic effect is lost. One possible reason may be the ability of the preadolescent brain to tolerate chronic electrical stimuli during the active maturation process.

Direct localization of subthalamic nucleus supplemented by single-track electrophysiological guidance in deep brain stimulation lead implantation: techniques and clinical results.

BACKGROUND/AIMS: In subthalamic nucleus (STN) deep brain stimulation (DBS) lead implantation, it is still controversial whether it is more appropriate to employ indirect or direct methods in magnetic resonance imaging (MRI)-based tentative targeting and to select single- or multiple-track recording in electrophysiological definitive targeting. The efficacy of single-track electrophysiological recording through direct targeting was compared with the conventional indirect targeting methods in light of the identified STN thickness and clinical results. METHODS: The identified mean STN thickness, pre- and 6-month postoperative Unified Parkinson's Disease Rating Scale (UPDRS), dose change of L-dopa and dopaminergic agonists were compared in indirect (midcommissural point-based, 44 procedures) and direct (image-based, 44 procedures) targeting methods. RESULTS: The identified mean STN thickness was significantly greater in the group employing direct methods. For evaluation of the UPDRS, a significant scale improvement was noted in part 2 OFF for both groups. Significant scale improvements occurred in parts 3 and 4 in the group employing the direct method. Both groups revealed significant L-dopa dose reduction with the tendency towards a greater reduction in the group employing the direct method. CONCLUSION: MRI-based direct targeting supplemented by single-track recording could be justified as a standard for DBS lead implantation to achieve better clinical results.

International Space Station medical standards and certification for space flight participants.

INTRODUCTION: The medical community of the International Space Station (ISS) has developed joint medical standards and evaluation requirements for Space Flight Participants ("space tourists") which are used by the ISS medical certification board to determine medical eligibility of individuals other than professional astronauts (cosmonauts) for short-duration space flight to the ISS. These individuals are generally fare-paying passengers without operational responsibilities. MATERIAL AND CONTEXT: By means of this publication, the medical standards and evaluation requirements for the ISS Space Flight Participants are offered to the aerospace medicine and commercial spaceflight communities for reference purposes. It is emphasized that the criteria applied to the ISS spaceflight participant candidates are substantially less stringent than those for professional astronauts and/or crewmembers of visiting and long-duration missions to the ISS. CONCLUSIONS: These medical standards are released by the government space agencies to facilitate the development of robust medical screening and medical risk assessment approaches in the context of the evolving commercial human spaceflight industry.

Effects of HZE particle on the nigrostriatal dopaminergic system in a future Mars mission.

Because of long duration travel outside the Earth's magnetic field, the effect of iron-rich high charge and energy (HZE) particles in Galactic Cosmic Rays on human body is the major concern in radiation protection. Recently attention has been directed to effects on the central nervous system in addition to mutagenic effects. In particular, a reduction in striatal dopamine content on nigrostriatal dopaminergic system has been reported by investigators using accelerated iron ions in ground-based mammalian studies. In addition, studies of the pathophysiology of Parkinson's disease demonstrated that excess iron cause a reduction in the dopamine content in the substantia nigra. This suggests an intriguing possibility to explain the selective detrimental effects of HZE particles on the dopaminergic system. Should these particles have biochemical effects, possible options for countermeasures are: (1) nutritional prevention, (2) medication, and (3) surgical placement of a stimulator electrode at a specific anatomic site in the basal ganglia.