Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Comparative studies were pursued to investigate the locomotor activity induced by phencyclidine hydrochloride in CD-1 male mice. Horizontal, vertical, and rotational activity counts were quantitated using an infrared beam animal activity monitor. Five doses (1.5, 2.5, 3.5, 5.0, and 10.0 mg/kg, i.p.) of phencyclidine were compared. At the 1.5 mg/kg dose, no locomotor activity changes were observed when compared to a saline control group. Increased activity was observed at the 2.5, 3.5, and 5.0 mg/kg doses. Decreased activity was observed at the 10.0 mg/kg dose when compared to the 5.0 mg/kg dose possibly due to ataxia. In addition, the locomotor activity produced by acute d-amphetamine and acute phencyclidine was compared at doses of 2.5 mg/kg and 5.0 mg/kg respectively. The overall locomotor activity levels produced by acute d-amphetamine and phencyclidine were not significantly different at p less than 0.05. The time to peak activities and peak level activities were also similar and occurred at 20-25 minutes and 1100-1300 inches respectively after i.p. administration. Administration of apomorphine after phencyclidine did not change overall locomotor activity. The data implies that phencyclidine may act primarily as a dopamine reuptake inhibitor rather than a dopamine release stimulator. Phencyclidine also affects other activity (unlike amphetamine) as seen by the severe depression of vertical activity.
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PMID:Comparison between locomotor activity changes produced by phencyclidine and D-amphetamine in CD-1 male mice. 402 8

We measured the activity of the thiamine pyrophosphate-dependent enzyme alpha-ketoglutarate dehydrogenase complex in postmortem brain of 12 patients with the spinocerebellar ataxia type 1 form of olivopontocerebellar atrophy. alpha-Ketoglutarate dehydrogenase complex activity measured in the absence of thiamine pyrophosphate was markedly reduced (-72%) in olivopontocerebellar atrophy cerebellar cortex. Decreased activity of this key rate-limiting Krebs cycle enzyme could compromise cerebellar energy metabolism and excitatory amino acid synthesis and thereby contribute to the brain dysfunction of olivopontocerebellar atrophy.
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PMID:Cerebellar alpha-ketoglutarate dehydrogenase activity is reduced in spinocerebellar ataxia type 1. 791 5

Pregnant CD-1 mice (30 per group) and female New Zealand White rabbits (15 per group) were exposed by inhalation to 0, 1000, 4000 and 8000 ppm methyl tertiary-butyl ether (MTBE) vapor for 6 h a day during gestational days (GD) 6-15 and 6-18, respectively. Maternal body weights, clinical observations and food consumption were recorded throughout gestation for both species. At scheduled euthanization (GD 18 for mice and GD 29 for rabbits), fetuses were weighed, sexed and examined for external, visceral (including craniofacial) and skeletal alterations. For both species, the pregnancy rate was high and equivalent across all groups; no pregnant animals died or aborted. There were no does that delivered early, but there were three mouse dams in the control group and two dams in the 4000 ppm group that delivered early and were removed from the study. In mice, maternal body weights, body weight gain, corrected maternal gestational weight change and food consumption were significantly reduced in mice at 8000 ppm. Hypoactivity and ataxia were observed in dams exposed to 4000 and 8000 ppm. Gestational parameters affected at 8000 ppm included post-implantation loss (due to increased late resorptions and dead fetuses) and altered sex ratio (decreased males); fetal body weights per litter were reduced at 4000 and 8000 ppm. There was a significantly increased incidence of cleft palate at 8000 ppm; this resulted in increased incidences of pooled external and visceral malformations and of total malformations at this exposure concentration. There were also treatment-related increases in the incidence of individual skeletal variations at 4000 and 8000 ppm. In rabbits, maternal weight gain and food consumption were significantly reduced at 4000 and 8000 ppm. Relative liver weights were also reduced at 8000 ppm. All gestational parameters were equivalent across all groups, including pre- and post-implantation loss, fetal sex ratios, litter size and fetal weights/litter. There was no evidence of treatment-related teratogenicity observed at any dose tested in rabbits. The no-observed-effect levels (NOELs) for maternal and developmental toxicity were both 1000 ppm in mice and 1000 ppm and at least 8000 ppm, respectively, in rabbits.
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PMID:Developmental toxicity evaluation of methyl tertiary-butyl ether (MTBE) by inhalation in mice and rabbits. 917 24

The authors present a case of adult GM2 gangliosidosis, B1 enzymatic type. The main clinical features found were cerebellar ataxia, proximal lower limb weakness and myokymia. The neurological examination, and the biochemical, electrophysiologic and imaging studies are all described. Decreased activity of the enzyme beta-hexosaminidase A in the metabolism of the sulfate substrate 4-MU-NAGS was found in serum. Global cerebellar atrophy was observed in a cranial nuclear magnetic resonance. The electrophysiologic study showed continuous spontaneous activity integrated by myokymia and neuromyotonic discharges in addition to signs of acute and chronic denervation. Disappearance of the myokymia and improvement in the ataxia were attained with the use of the GABAergic drugs gabapentin and tiagabine. The authors try to explain the clinical improvement obtained with the drugs by relating their mechanisms of action to the central nervous system neurotransmitter alterations proposed for this disease.
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PMID:[Adult GM2 gangliosidosis: improvement of ataxia with GABAergic drugs]. 1192 6

Acetonitrile is used primarily as a solvent in extractive distillation and crystallization of pharmaceutical and agricultural products and as a catalyst in chemical reactions. It was nominated for testing by the National Cancer Institute due to its presence in drinking water supplies and the environment, due to lack of information on the carcinogenicity of alkyl cyanides, and because of widespread worker exposure. Male and female F344/N rats and B6C3F1 mice were exposed to acetonitrile (at least 99% pure) by inhalation for 13 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and peripheral blood of B6C3F1 mice exposed to acetonitrile for 13 weeks. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were exposed to 0, 100, 200, 400, 800, or 1,600 ppm (equivalent to 0, 168, 335, 670, 1,340, or 2,681 mg/m(3)) acetonitrile by inhalation for 6 hours per day, 5 days per week for 13 weeks. Six male and three female rats that received 1,600 ppm and one male that received 800 ppm died during the study. At exposure concentrations up to and including 800 ppm, the final mean body weights and body weight gains were generally similar to those of the controls. At 1,600 ppm, body weight gain was lower and the final mean body weights of both males and females were significantly lower than those of the controls. Hypoactivity and ruffled fur were observed during the first week of the study in males receiving 800 ppm and males and females receiving 1,600 ppm. Additional clinical findings in 1,600 ppm males that died during week 1 were ataxia, abnormal posture, and clonic convulsions. Clinical pathology findings included nonresponsive, normocytic, normochromic anemia in 1,600 ppm males and females and in 800 ppm females, and decreased triiodothyronine (T3) concentrations in 1,600 ppm females. Absolute and relative thymus weights were significantly lower than those of the controls in the 800 and 1,600 ppm males and females. Females exposed to 1,600 ppm had significantly greater absolute and relative heart, kidney, and liver weights than those of the controls. There were no clear exposure-related histopathologic effects, although pulmonary congestion and edema and hemorrhage in the lung and brain were seen in some rats that died early. These lesions are consistent with cyanide-induced anoxia. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were exposed to 0, 100, 200, 400, 800, or 1,600 ppm (equivalent to 0, 168, 335, 670, 1,340, or 2,681 mg/m(3)) acetonitrile by inhalation for 6 hours per day, 5 days per week for 13 weeks. All mice exposed to 1,600 ppm died during the first 3 weeks of the study. In addition, one 400 ppm female and one male and four females from the 800 ppm groups also died before the end of the study. Body weight gains were similar to those of controls for all surviving groups of mice except the 800 ppm males, for which the final mean body weight was slightly lower than that of the controls. Clinical findings observed during the first week in 800 and 1,600 ppm mice were hypoactivity and a hunched, rigid posture. In males that received 200 ppm and above, absolute liver weights were greater than that of the controls and relative liver weights were greater in all exposed groups. In 800 ppm females, the absolute liver weight was greater than that of the controls and relative liver weights of females that received 400 ppm and above were greater than that of the controls. Lesions clearly associated with acetonitrile exposure were observed in the stomach, predominantly the forestomach, of males that received 400 ppm and above and of females that received 200 ppm and above. Histologically, these focal or multifocal pale to dark raised lesions consisted of areas of focal epithelial hyperplasia and ulceration, sometimes associated with hemosiderin deposition. An increased incidence of cytoplasmic vacuolation occurred in the liver of males and females exposed to 400 or 800 ppm. A lack of fatty degenerative change was observed inrved in the X-zone of the adrenal cortex of 800 and 1,600 ppm female mice. 2-YEAR STUDY IN RATS: The doses selected for the 2-year study of acetonitrile were based on reduced survival of 800 ppm males and 1,600 ppm males and females in the 13-week study. Groups of up to 56 male and 56 female rats were exposed to 0, 100, 200, or 400 ppm (equivalent to 0, 168, 335, or 670 mg/m(3)) acetonitrile by inhalation for 6 hours per day, 5 days per week for 2 years. Eight male and eight female rats from each exposure group were evaluated at 15 months for histopathology and hematology parameters. Survival, Body Weights, Clinical Findings, and Hematology: Two-year survival, mean body weights, organ weights, behavior, general health, and appearance of exposed male and female rats were similar to those of the controls. The hematologic effects observed were minor and of no biological significance. Pathology Findings: The incidences of hepatocellular adenoma (3/48), hepatocellular carcinoma (3/48), and hepatocellular adenoma or carcinoma (combined; 5/48) were greater in male rats exposed to 400 ppm than in the controls (one carcinoma). The incidences of hepatocellular adenoma and hepatocellular carcinoma were within the range of historical controls. However, the incidence of hepatocellular adenoma or carcinoma (combined) slightly exceeded the range of historical controls (2%-8%). In addition, the incidences of basophilic, eosinophilic, and mixed cell foci in 400 ppm males were marginally greater than in controls, suggesting hepatotoxicity of acetonitrile. There were no exposure-related liver lesions in female rats. 2-YEAR STUDY IN MICE: The exposure concentrations selected for the 2-year study were based on reduced survival and gross and histopathologic lesions in 400, 800, and 1,600 ppm groups of male and female mice in the 13-week study. Groups of 60 male and 60 female mice were exposed to 0, 50, 100, or 200 ppm (equivalent to 0, 84, 168, or 335 mg/m(3)) acetonitrile by inhalation for 6 hours per day, 5 days per week for 2 years. Ten male and 10 female mice from each exposure group were evaluated at 15 months for histopathology. Survival, Body Weights, and Clinical Findings: Two-year survival of exposed male and female mice was similar to that of the controls, except that the survival of male mice in the 200 ppm group was significantly greater than that of the controls. Mean body weights and organ weights of exposed groups of male and female mice were similar to those of the controls, and no clinical observations in any group were clearly related to acetonitrile exposure. Pathology Findings: There were no increases in the incidences of neoplasms that were considered related to acetonitrile exposure in mice. The incidence of squamous hyperplasia of the epithelium of the forestomach was significantly increased at 15 months in 200 ppm females. At 2 years, the increased incidence of this lesion was dose related in all exposed groups of males and females. GENETIC TOXICOLOGY: Acetonitrile was not mutagenic in Salmonella typhimurium strain TA97, TA98, TA100, TA1535, or TA1537, with or without S9 metabolic activation. In cultured Chinese hamster ovary cells, acetonitrile produced a weakly positive response in the sister chromatid exchange test without, but not with, S9. A small increase in chromosomal aberrations was observed in cultured Chinese hamster ovary cells treated with acetonitrile in the presence, but not in the absence, of S9. A significant increase in micronucleated normochromatic erythrocytes was observed in peripheral blood samples from male mice treated with acetonitrile for 13 weeks; the frequency of micronucleated erythrocytes in female mice was not affected by exposure to acetonitrile. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was equivocal evidence of carcinogenic activity of acetonitrile in male F344/N rats based on marginally increased incidences of hepatocellular adenoma and carcinoma. There was no evidence of carcinogenic activity of acetonitrile in female F344/N rats exposed to 100, 200, or 400 ppm. There was no evidence of carcinogenic activity of acetonitrile in male or female B6C3F1 mice exposed to 50, 100, or 200 ppm. Exposure to acetonitrile by inhalation resulted in increased incidences of hepatic basophilic foci in male rats and of squamous hyperplasia of the forestomach in male and female mice. Synonyms: Cyanomethane, ethanenitrile, ethyl nitrile, methanecarbonitrile, methyl cyanide, nitrile of acetic acid
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PMID:NTP Toxicology and Carcinogenesis Studies of Acetonitrile (CAS No. 75-05-8) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). 1259 28

Monochloroacetic acid, a colorless crystalline material, is used as a postemergence contact herbicide and as an intermediate in the synthesis of other organic compounds. Toxicology and carcinogenicity studies were conducted by administering monochloroacetic acid (99% pure) in deionized water by gavage to groups of F344/N rats and B6C3F1 mice of each sex once daily, 5 days per week for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse lymphoma L5178Y cells, Chinese hamster ovary cells, and Drosophila melanogaster. 16-Day Studies: Groups of five rats of each sex received 0, 7.5, 15, 30, 60, or 120 mg monochloroacetic acid/kg body weight. Doses administered to mice were 0, 15, 30, 60, 120, or 240 mg/kg to groups of five males and 0, 30, 60, 120, 240, or 480 mg/kg to groups of five females. One of five male rats given 120 mg/kg died during the studies. Clear nasal discharge, lacrimation, or both, were observed in all groups of male and female rats receiving monochloroacetic acid. No compound-related gross lesions were observed in rats. All male mice given 240 mg/kg and all females given 240 or 480 mg/kg died during the studies. Hypoactivity, piloerection, ataxia, and lacrimation were observed in mice given 240 or 480 mg/kg. No compound-related gross lesions were observed in mice at necropsy. 13-Week Studies: Groups of 20 rats of each sex received 0, 30, 60, 90, 120, or 150 mg/kg monochloroacetic acid, and groups of 20 mice of each sex received doses of 0, 25, 50, 100, 150, or 200 mg/kg. Three to five animals in each dose group were killed at weeks 4 and 8 for the evaluation of hematology parameters. Compound-related deaths occurred in rats in the three highest dose groups (all males given 120 or 150 mg/kg, 9/10 males given 90 mg/kg, and all females given 90 to 150 mg/kg) and in mice given 200 mg/kg (all males and 2/10 females). Final mean body weights of surviving rats and mice receiving monochloroacetic acid were similar to those of controls. In rats, dose-related increases in blood urea nitrogen, alanine aminotransferase, and aspartate aminotransferase levels were observed, and relative liver and kidney weights were elevated. There were no compound-related changes in the various hematologic or clinical pathology parameters in mice. A dose-related increase in the incidence and severity of cardiomyopathy was observed in male and female rats receiving monochloroacetic acid, and hepatocellular cytoplasmic vacuolization was observed in the high-dose mice that died during the studies. 2-Year Studies: Based on the mortality and compound-related histopathologic lesions observed in the 13-week studies, doses selected for the 2-year studies of monochloroacetic acid were 0, 15, or 30 mg/kg, administered to groups of 70 rats of each sex, and 0, 50, or 100 mg/kg, administered to groups of 60 mice of each sex. Interim evaluations were conducted on 10 rats per dose group after 6 months of treatment with monochloroacetic acid and on seven rats per dose group after 15 months of treatment. Body Weight and Survival in the 2-Year Studies: Mean body weights of low- and high-dose female and low-dose male rats receiving monochloroacetic acid were within 10% of those of controls throughout the studies; however, after week 30, the mean body weights of high-dose male rats were 4% to 8% less than those of controls. In mice, the mean body weights of dosed males were similar to controls, but those of low- and high-dose females were 6% to 10% less than control values after week 52. Survival of high-dose male and dosed female rats and high-dose male mice was significantly lower than that of controls (male rats: control, 27/53; low-dose, 21/53; high-dose, 16/53; female rats: 37/53; 19/53; 26/53; male mice: 46/60; 39/60; 21/60; female mice: 42/60; 40/60; 44/60). Neoplasms and Nonneoplastic Lesions in the 2-Year Studies: There was no compound-related increase in the incidence of neoplasms or nonneoplastic lesions in rats given monochloroacetic acid for 2 years. The incidence of uterine stromal polypss. The incidence of uterine stromal polyps in low- and high-dose female rats was slightly higher than that in controls (2/60; 7/57; 10/60). However, the incidence in the controls was unusually low, and those in the dosed groups were well within the range for NTP historical controls (mean: 21%, range: 10%-38%). Further, because the only malignant stromal neoplasm occurred in a control animal, the polyps were not considered to be related to the administration of monochloroacetic acid. Similarly, there was no monochloroacetic acid-related increase in the incidence of neoplasms in male or female mice, and malignant lymphoma occurred with a significant negative trend in dosed female mice. Increases in the incidence of inflammation of the mucosa of the nasal passages, respiratory epithelial metaplasia of the olfactory epithelium of the nose, and focal squamous cell hyperplasia of the forestomach occurred in dosed male and female mice. Genetic Toxicology: Monochloroacetic acid was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, or TA98, with or without exogenous metabolic activation (S9). It induced trifluorothymidine resistance in L5178Y cells in the absence of S9 and induced sister chromatid exchanges without S9 in Chinese hamster ovary cells. Monochloroacetic acid did not induce a significant increase in chromosomal aberrations in Chinese hamster ovary cells, with or without S9. Monochloroacetic acid administered in feed was negative for the induction of sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster; however, when it was administered by injection, the results were equivocal. Conclusions: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity for monochloroacetic acid in male or female F344/N rats given 15 or 30 mg/kg. There was no evidence of carcinogenic activity for monochloroacetic acid in male or female B6C3F1 mice given 50 or 100 mg/kg. Monochloroacetic acid administration was associated with inflammatory lesions of the nasal mucosa, metaplasia of the olfactory epithelium, and squamous cell hyperplasia of the forestomach in male and female mice. Synonyms: Chloroacetic acid, a-chloroacetic acid, chloroethanoic acid
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PMID:NTP Toxicology and Carcinogenesis Studies of Monochloroacetic Acid (CAS No. 79-11-8) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1263 63