Establishing a Canadian registry of patients with amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating cause of progressive weakness, respiratory failure and death. To date there is no effective therapy to meaningfully extend survival but continuously emerging targets and putative treatments are studied in clinical trials. Canadian epidemiological data on ALS is scarce and the socioeconomic impact of ALS on Canadian society is unclear. The Canadian Neuromuscular Disease Registry (CNDR) is a national clinic-based registry of patients with neuromuscular diseases with the goal of facilitating the design and execution of clinical research. METHODS: We conducted a national stakeholder survey to assess interest for a Canadian ALS registry and an assessment of expected case ascertainment. A dataset derivation meeting was held to establish the registry medical dataset. RESULTS: We report the results of the national stakeholder survey, case ascertainment assessment, and the derived dataset that have resulted in the current implementation of a Canadian registry of patients with ALS. CONCLUSIONS: The development of this long sought-after resource is a significant step forward for the Canadian ALS patient and research communities that will result in more efficient clinical trial recruitment and advancements in our understanding of ALS in Canada.

Association of paraoxonase gene cluster polymorphisms with ALS in France, Quebec, and Sweden.

BACKGROUND: The paraoxonase gene cluster on chromosome 7 comprising the PON1-3 genes is an attractive candidate for association in amyotrophic lateral sclerosis (ALS) given the role of paraoxonase genes during the response to oxidative stress and their contribution to the enzymatic break down of nerve toxins. Oxidative stress is considered one of the mechanisms involved in ALS pathogenesis. Evidence for this includes the fact that mutations of SOD1, which normally reduce the production of toxic superoxide anion, account for 12% to 23% of familial cases in ALS. In addition, PON variants were shown to be associated with susceptibility to ALS in several North American and European populations. METHODS: We extended this analysis to examine 20 single nucleotide polymorphisms (SNPs) across the PON gene cluster in a set of patients from France (480 cases, 475 controls), Quebec (159 cases, 95 controls), and Sweden (558 cases, 506 controls). RESULTS: Although individual SNPs were not considered associated on their own, a haplotype of SNPs at the C-terminal portion of PON2 that includes the PON2 C311S amino acid change was significant in the French (p value 0.0075) and Quebec (p value 0.026) populations as well as all three populations combined (p value 1.69 x 10(-6)). Stratification of the samples showed that this variation was pertinent to ALS susceptibility as a whole, and not to a particular subset of patients. CONCLUSIONS: These findings contribute to the increasing weight of evidence that genetic variants in the paraoxonase gene cluster are associated with amyotrophic lateral sclerosis.

Reduced sensory and motor nerve conduction velocities in moderate drinkers.

The mechanism responsible for peripheral nerve dysfunction in chronic alcoholism has not been fully elucidated either in terms of its relationship to the quantity of alcohol consumed or to nutritional status. As part of a series of studies to address these issues, the effects of moderate drinking (60-90 g ethanol per day) or heavy drinking (> 100 g ethanol per day) on peripheral nervous function and thiamine status was measured in 73 patients admitted to a detoxification unit. Electromyographic evaluation revealed significant reductions in median and ulnar sensory and motor nerve conduction velocities in both moderate drinkers (n = 30) and heavy drinkers (n = 43) compared to age-matched controls. Twelve moderate drinkers and 25 heavy drinkers manifested clinical neurological signs of peripheral neuropathy. Thiamine deficiency, as revealed by erythrocyte transketolase activation assay, was detected in two moderate drinkers and seven heavy drinkers but was not significantly correlated with electromyographic alterations with the exception of ulnar nerves. These findings provide evidence for significant early peripheral nerve dysfunction in moderate drinkers and a possible contributory role of thiamine deficiency to the ulnar nerve conduction deficits. Whether deficits in other water-soluble vitamins or a direct neurotoxic effect of ethanol are implicated in alcoholic peripheral neuropathy awaits further studies.

Effects of subchronic exposure of monochloramine in drinking water on male rats.

A subchronic rat study with paired-water control was conducted to resolve the question of whether monochloramine at 200 ppm in drinking water can cause reduced body weight gain and other changes observed in earlier investigations. Male Sprague-Dawley rats (93 +/- 5 g) were divided into three groups of 10 rats each: the treatment group was fed drinking water containing 200 ppm monochloramine, the control group was fed bicarbonate-buffered water ad libitum, and the paired-water control rats were given a daily volume of bicarbonate-buffered water equal to that consumed by the monochloramine treatment group. Compared to the control group, rats in the treatment group consumed an average of 42% less fluid and 16% less food over the 13-week treatment period and had 15-20% lower final body weight gain. Similar degrees of reduction in food consumption and body weight gain were observed in the paired-water rats. A decreased liver to body weight ratio occurred in the treatment and paired-water groups. Increased inorganic phosphate, albumin, total protein, and urea nitrogen were detected in sera from both the treatment group and the paired-water groups. The paired-water animals had lower levels of white blood cells and lymphocytes, while the paired-water and monochloramine-treated groups had reduced monocyte counts. Except for a slightly increased response to Con A observed in splenic lymphocytes of the monochloramine-treated rats (versus the paired-water), no significant changes were found in mitogen responsiveness to T cell, B cell, and B plus T cell mitogens or in splenic natural killer (NK) cell activities. There were no significant changes in serum levels of IgG, IgA, and IgM. The following biochemical parameters showed no significant variations among the three groups: serum thyroxin, liver phase I (PROD, EROD, and MROD) and phase II (UDPGT and GST) drug-metabolizing enzyme activities; serum and liver thiobarbituric acid-reactive substances (TBARS); bronchoalveolar lavage fluid protein and N-acetylgluosaminidase (NAGA) activity; and urinary ascorbic acid, protein, and NAGA activity. Histopathological examination revealed minimal to mild adaptive changes in the liver of the paired-water and monochloramine-treated rats and in the thyroid of the monochloramine-treated animals. No treatment-related cytological changes were found in red cells and bone marrow. The results indicate that the reduced body weight gain and the minor biochemical, hematological, immunological, and histopathological changes associated with subchronic exposure to 200 ppm monochloramine in drinking water (equivalent to an intake of 21.6 mg/kg/day) were largely related to the reduced water intake and food consumption and not caused by monochloramine.

Flumazenil in cirrhotic patients in hepatic coma: a randomized double-blind placebo-controlled crossover trial.

Previous reports have suggested that "endogenous" benzodiazepines could contribute to neural inhibition in hepatic encephalopathy. RO 15-1788 (flumazenil), a specific antagonist of brain benzodiazepine receptors, could thus reverse the neurological symptoms of hepatic encephalopathy. To test this possibility, we conducted a double-blind, placebo-controlled crossover trial of the efficacy of flumazenil in cirrhotic patients in hepatic coma. Seventy-seven cirrhotic patients in hepatic coma were evaluated. Fifty-six were excluded from the trial because of multiorgan failure or because coma was precipitated by prior use of benzodiazepines, and 21 patients were randomly assigned to the flumazenil group (11 patients) or the placebo group (10 patients). Treatment was administered intravenously as a 20-ml solution (placebo or 2 mg flumazenil); seven patients were crossed over. Clinical status was assessed blindly by two observers, using a modified Glasgow scale, every 15 min for 6 hr. Electroencephalogram tracings obtained before and after drug administration were evaluated blindly by two independent observers. Serum concentrations of benzodiazepines before treatment were measured by means of a fluorescence polarization immunoassay. Improvement in neurological symptoms was observed in six patients treated with flumazenil, whereas none in the placebo group showed improvement (p < 0.05; Fisher's exact test). Improvements in electroencephalogram tracings were demonstrated in four patients treated with flumazenil, compared with two patients in the placebo group (p = NS). Benzodiazepines were found in the serum of four patients treated with flumazenil (two responders and two nonresponders); all of these patients had received pharmaceutical benzodiazepines 4 to 6 days before the trial.(ABSTRACT TRUNCATED AT 250 WORDS)

Sex-related difference in hepatic glutathione conjugation of hexachlorobenzene in the rat.

Hexachlorobenzene (HCB) induces hepatic porphyria and liver cancer in female rats, whereas toxicity is minimal in male rats. HCB is biotransformed to sulfur-containing metabolites originating from conjugation to glutathione (GSH). This study aimed to assess differences in GSH conjugation of HCB between male and female rats. Sprague-Dawley rats of both sexes were given (po, 10 ml/kg in corn oil) five consecutive doses of 100 mg/kg HCB [2 bid (7:30, 15:30) + 1 sid (7:30)]. This cumulative dose produced porphyria in female but not male rats after a delay period of 6 weeks. Animals were killed 0, 6, 12, 18, or 24 hr after the last dose. Hepatic GSH level showed a diurnal cycle in rats of both sexes, but it was more pronounced in males; the minimum level was observed at 12 hr after dosing. The GSH level in HCB-treated male rats was significantly lower than control at 6, 18, and 24 hr, whereas no significant differences were observed for HCB-treated female rats. Biliary excretion of pentachlorothiophenol, a metabolite originating from GSH conjugation of HCB, was higher in male than female rats. Liver cytosolic GSH transferase activity toward 3,4-dichloronitrobenzene was significantly higher than control level in male but not female rats given HCB. GSH transferase activity toward 1,2-epoxy-3-(p-nitrophenoxy)propane in male and female rats was not increased by HCB treatment. The liver HCB concentration at 24 hr after dosing was higher in male rats than in female rats but decreased faster thereafter. These results suggest that hepatic GSH conjugation of HCB is more important in male than in female rats. This may be related to the reduced liver porphyria observed in HCB-treated male rats compared to female rats.

Abnormalities of peripheral nerve conduction in relation to thiamine status in alcoholic patients.

Thiamine status was evaluated using the erythrocyte transketolase activation assay in 20 alcoholic patients admitted on a voluntary basis to a Detoxification Unit. Electromyographic evaluation revealed significant reductions of motor and sensory conduction velocities in the alcoholic group. 38% of alcoholic patients showed significant erythrocyte transketolase activation deficits indicative of severe thiamine deficiency. In the case of peroneal nerve, reduced conduction velocities were negatively correlated with abnormal transketolase parameters. These findings are consistent with a contributory (but not exclusive) role of thiamine deficiency in the pathogenesis of alcoholic peripheral neuropathy. Deficiencies of other vitamins as well as direct neurotoxic effects of alcohol could also be involved in this phenomenon.

Peripheral neurological complications of aortoiliac vascular disease.

Six patients with an aortoiliac vascular disease and a peripheral neurological deficit are presented. Clinical and electromyographic findings revealed lumbosacral plexus, sciatic and femoral nerve lesions. A correlation is made between the level of the vascular lesion (aortic, aortoiliac or distally) and the type of peripheral nerve deficit observed. In a patient complaining of pain, weakness, or numbness in a leg, the differential diagnosis should include aortoiliac vascular disease. The peripheral neurological symptoms may be the initial manifestation of the vascular disease or may appear in the early post-operative period.

Electromyographic study of bulbocavernosus muscle in 15 patients with postmicturition dribbling.

Fifteen patients with postmicturition dribbling were studied with cystourethroscopy and electromyography of the bulbocavernosus muscle. In all patients the bulbocavernosus reflex and activity of the muscle during and after micturition were normal. No abnormality was found to explain the clinical symptoms.

Sensory nerve conduction in chronic uremic patients during the first six months of hemodialysis.

In an attempt to find the best electrophysiological indicator of improvement for the neuropathy present in patients with chronic renal failure undergoing hemodialysis, several types of nerve conduction were studied at the beginning of dialysis and six months later. Sural nerve conduction and late response latencies were recorded in addition to conventional motor and sensory nerve conductions. After six months of hemodialysis, sensory nerve conduction velocities in the median, ulnar and sural nerves were improved. These values appear to be the most sensitive indices of the beneficial effect of hemodialysis on the neuropathy.

The importance of studying sural nerve conduction and late responses in the evaluation of alcoholic subjects.

Motor conduction velocities of median, ulnar, peroneal, and tibial nerves and sensory conduction velocities of median and ulnar nerves were studied in 30 alcoholic subjects and a similar group of control subjects. The results were compared to sural nerve conduction velocities and late response latencies (H reflex, F response). The latter two techniques improved the diagnostic yield by 20%: Whereas 73% of our patients showed an abnormality of conduction with conventional techniques, 93% had an abnormality of sural nerve conduction, late response latencies, or both. Abnormalities of motor and sensory conduction, which were more prominent in the lower limbs than the arms, could be documented in patients who did not have any clinical evidence of peripheral neuropathy. The electrophysiologic studies performed in the present study suggest that "axonal degeneration" is the underlying pathologic process in alcoholic peripheral nerve disease.