Prevention of shoulder subluxation after stroke with electrical stimulation

BACKGROUND AND PURPOSE: Subluxation is a significant problem in poststroke hemiplegia, resulting in pain and loss of function. Current treatments are not proved and not considered effective. It has been demonstrated that cyclical electrical stimulation of the shoulder muscles can reduce existing subluxation. The purpose of this study was to determine whether electrical stimulation could prevent subluxation in both the short and long terms. METHODS: A prospective, randomized controlled study was used to determine the efficacy of electrical stimulation in preventing shoulder subluxation in patients after cerebrovascular accidents. Forty patients were selected and randomly assigned to a control or treatment group. They had their first assessment within 48 hours of their stroke, and those in the treatment group were immediately put on a regimen of electrical stimulation for 4 weeks. All patients were assessed at 4 weeks after stroke and then again at 12 weeks after stroke. Assessments were made of shoulder subluxation, pain, and motor control. RESULTS: The treatment group had significantly less subluxation and pain after the treatment period, but at the end of the follow-up period there were no significant differences between the 2 groups. CONCLUSIONS: Electrical stimulation can prevent shoulder subluxation, but this effect was not maintained after the withdrawal of treatment.     

Safety and tolerability of GV150526 (a glycine site antagonist at the N-methyl-D-aspartate receptor) in patients with acute stroke

BACKGROUND AND PURPOSE: GV150526 is a novel glycine site antagonist at the N-methyl-D-aspartate receptor complex. It is a potent neuroprotective agent in animal models of stroke, including permanent middle cerebral artery occlusion in the rat. Unlike antagonists at the glutamate ligand binding site, GV150526 appears to be free of hemodynamic and central nervous system adverse effects. The purpose of this study was to assess the safety, tolerability, and pharmacokinetics of loading and maintenance infusions of GV150526 in patients with acute stroke. METHODS: This was a randomized, placebo-controlled, parallel-group, ascending-dose study conducted in 2 phases. In part A of the study, loading doses of 50, 100, 200, 400, or 800 mg were administered. In part B, the maximum loading dose from part A was followed by maintenance infusions (5 infusions at 12-hour intervals), aiming to maintain neuroprotective levels. Safety data were collected throughout. The study was not designed to test efficacy, but outcome data (Barthel Index and National Institutes of Health Stroke Scale) were collected. RESULTS: Sixty-six patients were recruited to the study over 11 months; 18 patients received placebo. GV150526 was well tolerated by the 48 patients who received it. There was no excess of central nervous system or hemodynamic adverse events compared with placebo. Minor abnormalities in liver function tests were observed in association with the higher maintenance doses tested. Four of 7 patients receiving the 800-mg loading dose followed by 400 mg BID and 1 of 6 patients who received the 200-mg BID maintenance dose showed a small rise in bilirubin, and 3 patients had increases in transaminases; the mean values at 72 hours remained under twice the upper limit of normal. These changes were asymptomatic and resolved within 10 days. CONCLUSIONS: GV150526 is an emerging neuroprotective agent, with no apparent significant central nervous system or hemodynamic effects. Dose-limiting effects appear to be restricted to mild transient and asymptomatic rises in bilirubin and/or transaminases, primarily observed at high maintenance doses, and there were no findings that should preclude further clinical development.     

Inhibition of GABA-gated chloride channels by 12,14-dichlorodehydroabietic acid in mammalian brain

1. 12,14-dichlorodehydroabietic acid (12,14-Cl2DHA) reduced GABA-stimulated uptake of 36Cl- into mouse brain synaptoneurosomes suggesting inhibition of mammalian GABA(A) receptor function. 2. 12,14-Cl2DHA did not affect the binding of [3H]-muscimol to brain membranes but displaced specifically bound [3H]-EBOB. The inhibitory effect on [3H]-EBOB binding was not reversible. 12,14-Cl2DHA reduced the availability of [3H]-EBOB binding sites (Bmax) without changing the KD of the radioligand for remaining sites. 12,14-Cl2DHA did not affect the rate of association of [3H]-EBOB with its chloride channel receptor, but increased the initial rate of [3H]-EBOB dissociation. 3. 12,14-Cl2DHA enhanced the incidence of EPSCs when rapidly applied to cultured rat cortical neurones. Longer exposures produced block of IPSCs with marked increases in the frequency of EPSCs and min EPSCs. 12,14-Cl2DHA also irreversibly suppressed chloride currents evoked by pulses of exogenous GABA in these cells. 4. Ultimately, 12,14-Cl2DHA inhibited all synaptic traffic and action currents in current clamped cells indicating that, in contrast to picrotoxinin (which causes paroxysmal bursting), it is not fully selective for the GABA(A) receptor-chloride channel complex. 5. The depolarizing block seen with 12,14-Cl2DHA in amphotericin-perforated preparations implicates loss of Ca2+ buffering in the polarity change and this may account for inhibition of spontaneous action potentials. 6. Our investigation demonstrates that 12,14-Cl2DHA blocks GABA-dependent chloride entry in mammalian brain and operates as a non-competitive insurmountable GABA(A) antagonist. The mechanism likely involves either irreversible binding of 12,14-Cl2DHA to the trioxabicyclooctane recognition site or a site that is allosterically coupled to it. We cannot exclude, however, the possibility that 12,14-Cl2DHA causes localized proteolysis or more extensive conformational change within a critical subunit of the chloride channel.     

A mixed packing model for bone collagen

A wide variety of physical properties, including sonic velocity, dimensional changes between wet and dried stages, anisotropy of the tissue properties, density, X-ray diffraction, differential microcalorimetry, dielectric constant, and composition (water, mineral, organic content) for the mineralized and demineralized tissue was used to develop a model for the superlattice structure of bone collagen. A mixed model is suggested where the collagen molecules are in register as in SLS type of aggregation within the microfibril, and the microfibrils are staggered in D unit steps according to the Hodge-Petruska scheme. A square packing model with 4 or more molecules per microfibril best fits the HP scheme with the effective molecular diameter of the wet collagen molecule, and allows for the regular array of axial gap filling microcrystallites of 5 nm or larger diameter. It is concluded that: 1. Macroscopic dimensional changes of adult bovine bone matrix closely match molecular dimensional changes of collagen superlattice. 2. Effective molecular diameter of dry collagen is 1.09 nm and that of wet bone collagen is 1.42-1.45 nm. 3. Water layer of the wet bone collagen molecule is 0.16 nm thick. 4. Water in the bone collagen molecule is distributed in 5 regimes much like in the tendon collagen molecule. 5. "Hidden" water, 0.10 g water per dry collagen of regimes I and II, is within the triple helix. 6. "External" water incorporated in the collagen molecule provides transition between the highly structured collagen molecule and the intermolecular medium. 7. Water incorporated in the mineralized bone collagen molecule is less than in demineralized bone matrix. 8. For adult bovine cortical bone, 25% by volume is water, 32% dry organic, 43% mineral; 28% by volume of the mineral is axial gap filling, 58% radial intrafibrillar, and 14% radial extrafibrillar.     

Paroxysmal dystonic head tremor

Two patients with paroxysmal attacks of "no-no" direction head tremor and mild torticollis are described. One of them had the characteristic features of paroxysmal dystonic choreoathetosis and responded well to clonazepam.     

The effect of sleep on the dyskinetic movements of Parkinson's disease, Gilles de la Tourette syndrome, Huntington's disease, and torsion dystonia.

The effect of sleep on the involuntary movements or dyskinesias in Parkinson's disease, Huntington's disease, primary and secondary torsion dystonia, and Gilles de la Tourette syndrome was studied in a total of 52 patients and 10 normal subjects using video electroencephalographic telemetry. Movements typical of the wake pattern were seen occasionally during unequivocal sleep in all but two completed studies, and in each condition reappeared under similar circumstances. The movements were most likely to occur after awakenings or lightenings of sleep, or in stage one sleep. The movements were very rare during the deeper phases of sleep. Those movements that occurred during sleep without awakenings were usually preceded by arousal phenomena and, rarely, by sleep spindles or slow waves. The control group showed normal "semipurposeful" movements under the same conditions during sleep. The rare appearance of the different dyskinesias and normal movements under similar circumstances during sleep could be a result of common effects on the generator systems or changes in the excitability of the final common motor pathway.     

Phenylacetic acid in human body fluids: high correlation between plasma and cerebrospinal fluid concentration values.

In a group of six Parkinsonian patients and 13 "controls" with non-Parkinsonian neurological disease, there was a high correlation between both free and conjugated phenylacetic acid concentrations in plasma and cerebrospinal fluid taken at about the same time. This compound is the major metabolite of phenylethylamine, the production of which may be disturbed in a number of neuropsychiatric illnesses. Thus plasma measurements might be employed clinically to provide an estimate of central changes in phenylethylamine economy. A small but significantly higher proportion of conjugated phenylacetic acid was present in the plasma (but not cerebrospinal fluid) of Parkinsonians compared with controls.     

Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies

OBJECTIVE: To examine the association between patent foramen ovale (PFO) and atrial septal aneurysm (ASA) and stroke. METHOD: Data from case-control studies that examined the relative frequency of PFO, ASA, or both, in all patients with ischemic stroke, cryptogenic stroke, and known stroke cause as well as control subjects were included. Trials were categorized by age, clinical comparison, and abnormality. Combined OR were calculated using fixed effect (FE) and random effect (RE) methods. RESULTS: Comparing patients with ischemic stroke with control subjects using RE, OR for all ages was 1.83 (95% CI, 1.25 to 2.66) for PFO (15 studies), 2.35 (95% CI, 1.46 to 3.77) for ASA (nine studies), and 4.96 (95% CI, 2.37 to 10.39) for PFO plus ASA (four studies). Homogeneous results were found within the group younger than age 55: using FE, OR was 3.10 (95% CI, 2.29 to 4.21) for PFO, 6.14 (95% CI, 2.47 to 15.22) for ASA, and 15.59 (95% CI, 2.83 to 85.87) for PFO plus ASA. For patients older than age 55, using FE, OR was 1.27 (95% CI, 0.80 to 2.01) for PFO, 3.43 (95% CI, 1.89 to 6.22) for ASA, and 5.09 (95% CI, 1.25 to 20.74) for PFO plus ASA. Comparing cryptogenic stroke with known stroke cause, heterogeneous results were derived from total group examination using RE: OR was 3.16 (95% CI, 2.30 to 4.35) for PFO (22 studies), 3.65 (95% CI, 1.34 to 9.97) for ASA (five studies), and 23.26 (95% CI, 5.24 to 103.20) for PFO plus ASA (two studies). In patients younger than age 55, using FE the OR was 6.00 (95% CI, 3.72 to 9.68) for PFO; only one study examined ASA or PFO plus ASA. In patients aged 55 years or older, three studies produced heterogeneous results for PFO: using RE, OR was 2.26 (95% CI, 0.96 to 5.31); no data were available on ASA prevalence. CONCLUSIONS: PFO and ASA are significantly associated with ischemic stroke in patients younger than 55 years. Further studies are needed to establish whether an association exists between PFO and ischemic stroke in those older than 55.     

Low-dose olanzapine for levodopa induced dyskinesias

OBJECTIVE: To assess the usefulness of low-dose olanzapine (2.5 to 7. 5 mg/day) for Levodopa-induced-dyskinesias (LID) in patients with PD. METHODS: Ten patients with PD and LID took part in this randomized, placebo-controlled, double blind, crossover trial. Patients received a 2-week course of olanzapine or placebo in each treatment phase with 1-week washout in between. Dyskinesias were assessed at baseline and after each treatment period with an acute dopaminergic challenge and unified PD rating scale (UPDRS) questionnaires. Patients also kept on/off and dyskinesia diaries for the last 3 days prior to each assessment. RESULTS: There was a 41% difference in dyskinesia reduction on olanzapine compared to placebo, as measured by objective dyskinesia rating scales (mean percentage reduction abnormal involuntary movement score: 30% versus -11.2%, p < 0.02). Similar differences were demonstrated by patient diaries (mean reduction: 46% versus -2%, p < 0.02) and UPDRS items 32 and 33. Compared with placebo, treatment with olanzapine resulted in significant increases in 'off' time as measured by patient diaries (30% versus 2%) and reported adverse events (1.7 versus 0.1) including increased parkinsonism (1.1 versus 0.1) and a nonsignificant reported increase in drowsiness. CONCLUSIONS: Low-dose olanzapine is effective in reducing dyskinesias in PD, but even at very low doses can result in unacceptable increases in parkinsonism and 'off' time.     

Selfotel in acute ischemic stroke : possible neurotoxic effects of an NMDA antagonist

BACKGROUND AND PURPOSE: Based on neuroprotective efficacy in animal models, we evaluated the N-methyl D-aspartate antagonist Selfotel in patients with ischemic stroke, after doses up to 1.5 mg/kg were shown to be safe in phase 1 and phase 2a studies. METHODS: Two pivotal phase 3 ischemic stroke trials tested the hypothesis, by double-blind, randomized, placebo-controlled parallel design, that a single intravenous 1.5 mg/kg dose of Selfotel, administered within 6 hours of stroke onset, would improve functional outcome at 90 days, defined as the proportion of patients achieving a Barthel Index score of >/=60. The trials were performed in patients aged 40 to 85 years with acute ischemic hemispheric stroke and a motor deficit. RESULTS: The 2 trials were suspended on advice of the independent Data Safety Monitoring Board because of an imbalance in mortality after a total enrollment of 567 patients. The groups were well matched for initial stroke severity and time from stroke onset to therapy. There was no difference in the 90-day mortality rate, with 62 deaths (22%) in the Selfotel group and 49 (17%) in the placebo-treated group (RR=1.3; 95% CI 0.92 to 1.83; P=0.15). However, early mortality was higher in the Selfotel-treated patients (day 30: 54 of 280 versus 37 of 286; P=0.05). In patients with severe stroke, mortality imbalance was significant throughout the trial (P=0.05). CONCLUSIONS: Selfotel was not an effective treatment for acute ischemic stroke. Furthermore, a trend toward increased mortality, particularly within the first 30 days and in patients with severe stroke, suggests that the drug might have a neurotoxic effect in brain ischemia.