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)

Four pharmacologic actions of intravenous ketamine (30 mg/kg) were studied in the rat. To elucidate the mechanism(s) terminating the pharmacologic effects, animals were pretreated with ketamine and agents anticipated to modify hepatic microsomal metabolism, including phenobarbital and SKF 525A. SKF 525A pretreatment markedly prolonged ataxia, analgesia and agitation, in addition to significantly elevating brain and plasma ketamine levels subsequent to the initial 10 minutes following injection; thus hepatic metabolism appeared to play a prominent role in the termination of the posthypnotic effects of the drug. While significantly shortening the durations of the three posthypnotic events, phenobarbital and ketamine pretreatments also lowered the brain and plasma levels of ketamine. With all pretreatments, brain ketamine levels were almost identical at the cessation of hypnosis (25 mug/g of tissue) and ataxia (8-10 mug/g of tissue). No pretreatment altered either the duration of loss of righting reflex (hypnosis) or brain and plasma ketamine levels during the initial 10 minutes after injection. Approximately 70% of the injected drug was recovered from four tissues, skeletal muscle, gut, skin and liver, at 10 minutes after injection; thus redistribution from brain to other tissues appeared to play a major role in the cessation of hypnosis. Ketamine pretreatment caused a 2-fold increase in the rate of its in vitro hepatic microsomal metabolism. Brain and plasma ketamine levels 30 minutes after injection were nearly identical in rats pretreated with ketamine and phenobarbital, although phenobarbital pretreatment resulted in a 4-fold increase in in vitro ketamine hepatic metabolism.
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PMID:Biodisposition of ketamine in the rat: self-induction of metabolism. 127 Dec 78

A case of neuronal intranuclear hyaline inclusion disease (NIHID) is described, and the literature on seven reported cases is briefly reviewed. The patient was a 24-year-old man who died of a chronic progressive neurologic disease starting at the age of 6 years. Clinically, the disease presented as Friedreichs's ataxia, and pathologically it was characterized by multisystem atrophy. An outstanding feature was the presence of widespread intranuclear hyaline inclusions in neurons of the brain, spinal cord, and myenteric plexus of the gut. The inclusions displayed yellow-green autofluorescence under ultraviolet (UV) light and were filamentous ultrastructurally. It seems that cases bearing such peculiar neuronal inclusions represent a distinct disease entity of unknown origin. The disease, which is sometimes familial, usually starts in childhood and affects both sexes. Clinically, it presents as multisystem degeneration with progressive ataxia as the prominent feature. Pathologically, it is characterized by neuronal loss, fiber tract atrophy, and intranuclear neuronal inclusions. In some cases such inclusions were found also in neurons of the myenteric plexus. Since these are accessible to biopsy it is recommended that rectal biopsy be made in every case of "atypical" system atrophy.
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PMID:Neuronal intranuclear hyaline inclusion disease presenting as Friedreich's ataxia. 257 19

The currently recognized toxic effects of quinine in humans are identified and the problems of management of overdosage of quinine are discussed. Quinine, available therapeutically as sulphate or hydrochloride salts, also is widely used in tonic water, and there are several case reports of allergic reactions to the drug when a patient has consumed the drug in this way. Another unintentional source of poisoning is its use as an adulterant in heroin for "street" use. This appears to be a problem in the US. Quinine, termed a "general protoplasmic poison" is toxic to many bacteria, yeasts, and trypanosomes, as well as to malarial plasmodia. Quinine has local anesthetic action but also is an irritant. The irritant effects may be responsible in part for the nausea associated with its clinical use. In addition it has a mild antipyretic effect. Several features are common to both an acute single overdose in self-poisoning and accumulation of quinine during therapy for malaria: together they are termed cinchonism. Auditory symptoms, gastrointestinal disturbances, vasodilatation, sweating, and headache occur with moderately elevated plasma quinine concentration. As these rise, increasingly severe visual disturbances and then cardiac and neurologic features occur. Mild nausea may be the only symptom, but with large overdoses profuse vomiting, abdominal pain, and diarrhea may occur. These result from a combination of the local irritant effect of quinine on the gut and the central effects of quinine on the chemoreceptor trigger zone. Vasodilatation and sweating are well recognized, and tinnitus is common. Visual symptoms usually are delayed, and blindness may not be discovered for a day or more. Aspirin-sensitive patients, and others, may develop angioedema by nonimmunological mechanisms in response to drugs, and quinine has been reported to produce pseudo-allergic reactions in aspirin-sensitive patients. Quinine also can cause drug-induced thrombocytopenia and purpura. In patients suffering with malaria due to "Plasmodium falciparum," anemia and acute intravascular hemolysis with renal failure are recognized complications. There appears to be little evidence in the literature in support of the folk tradition of quinine as an inducer of abortion. Quinine is known to cause deterioration in patients with myasthenia gravis and erythema multiforme, to stimulate insulin release in patients receiving treatment for falicparum malaria, and to be responsible at times for ataxia following moderate overdosage. Clinically, quinine poisoning is observed in 3 situations: self-poisoning; accidentally; and following use of quinine in excessive doses in the hope of achieving abortion. Treatment courses are reviewed.
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PMID:Quinine toxicity. 354 70

An 8-year-old boy with a short gut had six episodes of metabolic acidosis and neurological dysfunction over a 1 month period. The neurological features consisted of a depressed conscious state, confusion, aggressive behaviour, slurred speech and ataxia. The organic acid profile of urine demonstrated increased amounts of lactic, 3-hydroxypropionic, 3-hydroxyisobutyric, 2-hydroxyisocaproic, phenyllactic, 4-hydroxyphenylacetic and 4-hydroxyphenyllactic acids. Of the lactic acid 99% was D-lactic acid. The anaerobic gut flora consisted almost entirely of Lactobacilli in unusually large numbers. A course of vancomycin prevented further episodes. A urinary organic acid profile may be diagnostic when a person with a short gut develops metabolic acidosis or an unusual encephalopathy and bacterial metabolites should be considered in other patients with unusual combinations of organic acids in the urine.
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PMID:Severe illness caused by the products of bacterial metabolism in a child with a short gut. 401 4

Pyrrolizidine alkaloids are among the most significant plant chemicals causing disease in animals and humans. After absorption from the gut, the compounds are converted to electrophilic pyrroles in the liver which, apart from causing damage to this organ, may escape to cause injury to extraheptic tissues such as the lungs, heart, and kidneys. A group of compounds more recently found to be associated with neurotoxicity are various polyhydroxyalkaloids which are able to interfere with polysaccharide metabolism. They are able to inhibit lysosomal monosaccharidases by virtue of their structural resemblance to the transition state of particular sugar molecules. The resulting lysosomal storage diseases have pathology identical to that of the respective congenital and heritable lysosomal storage diseases which occur in animals and humans. Consumption of cycad plants by cattle may cause a neurotoxicity characterised mainly by a posterior sensory ataxia. In recent years, cycads are considered to be a risk factor for a spectrum of progressive neuro degenerative diseases of humans in the Western Pacific region. The known toxins in the plant are the methylazoxymethanol glycosides which are hepatotoxic and carcinogenic, and the neurotoxic non-protein amino acid beta-methylaminoalanine. A plant carcinogen which can be of great abundance in the nutritional environment is the illudine norsesquiterpene glucoside ptaquiloside which is found in bracken fern. This is the only plant carcinogen which causes natural outbreaks of bladder and/or intestinal cancer in livestock. Many legumes contain phytooestrogens, notably isoflavones. Consumption of these compounds at high levels by sheep can cause extensive lesions of the genitalia of females and castrated males.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Directly toxic effects of plant chemicals which may occur in human and animal foods. 758 21

Borna disease is an immunopathological virus-induced encephalopathy comprising severe inflammation and degenerative brain cell lesions which results in organ atrophy and chronic debility in rats. CD4+ and CD8+ T cells have been reported to be involved in the development of this disease of the central nervous system. A virus-specific homogeneous T-cell line, established in vitro after immunization of rats with the recombinant 24-kDa virus-specific protein, showed antigen-specific proliferation in the presence of the 24-kDa but not the 38-kDa Borna disease virus-specific protein, another major virus-specific antigen. This T-cell line, P205, was found to exhibit characteristics of a T-helper cell: CD4+ CD8- IL-2- IL-4- IFN-gamma+ IL-6+ IL-10+. Furthermore, this T-cell line expressed the alpha/beta T-cell receptor and the alpha 4 integrin (VLA-4). Adoptive transfer of this helper cell resulted in an increase of antibody titers and two different types of disease in virus-infected rats after cyclophosphamide-induced immunosuppression. (i) Rats receiving T cells between 10 and 18 days after treatment with cyclophosphamide showed an acute lymphoproliferative disease in the gut and lungs within 9 days after adoptive transfer and died. (ii) Passive transfer within the first 5 days after immunosuppressive treatment resulted in typical Borna disease associated with neurological symptoms such as ataxia and paresis starting 14 to 16 days after transfer. Immunohistological analysis of the brains of rats with Borna disease uniformly revealed the presence of CD8+ T cells in encephalitic lesions in addition to CD4+ cells that were found in the brains of recipients of the virus-specific CD4+ T-cell line, irrespective of whether neurological symptoms developed or not. However, recipient rats treated with antibodies against CD8+ T cells developed neither encephalitis nor disease. Therefore, CD4+ T cells appear to accumulate in the brain and cause perivascular inflammatory lesions which alone obviously do not cause disease. In contrast, the presence of CD8+ cells apparently directly correlates with the development of neurological symptoms.
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PMID:Immunopathogenic role of T-cell subsets in Borna disease virus-induced progressive encephalitis. 781 58

Since the discovery of the biologically active platinum complexes 30 years ago, 2 agents have become widely established in clinical oncology practice. Both cisplatin and carboplatin are platinum(II) complexes with 2 ammonia groups in the cis- position. However, they differ in their solubility, chemical reactivity, dichloride or alicyclic oxygenated leaving groups, pharmacokinetics and toxicology. Cisplatin causes severe renal tubular damage and reduces glomerular filtration, and requires concurrent saline hydration and mannitol diuresis to eliminate potentially lethal and unacceptable damage to the kidneys. Carboplatin, at conventional doses, causes no decrease in glomerular filtration and only minor transient elevations in urinary enzymes. Cisplatin is the most emetic cancer drug in common use, while nausea and vomiting associated with carboplatin are moderately severe. Serotonin release from enterochromaffin gut mucosal cells and stimulation of serotonin 5-HT3-receptors mediates acute emesis. Selective inhibitors of the 5-HT3-receptor protect against cisplatin- and carboplatin-induced nausea and vomiting. Peripheral neurotoxicity is the most dose-limiting problem associated with cisplatin. Loss of vibration sense, paraesthesia and sensory ataxia comes on after several treatment cycles. Carboplatin, however, is relatively free from peripheral neurotoxicity. Audiometry shows cisplatin-induced ototoxicity in 75 to 100% of patients, which may be associated with tinnitus and hearing loss. Ototoxicity is rare with conventional dose carboplatin therapy. Monitoring hearing with audiograms may identify early signs before significant impairment occurs. Cisplatin causes mild haematological toxicity to all 3 blood lineages. Haematological toxicity is dose-limiting for carboplatin, with thrombocytopenia being a greater problem than leucopenia. Although carboplatin is not toxic to the kidney, renal function markedly affects the severity of carboplatin-induced thrombocytopenia. The major clearance mechanism of cisplatin is irreversible binding in plasma and tissues, while carboplatin is cleared by glomerular filtration. Metabolism of cisplatin to aqua, amino acid and protein species is extensive, whereas carboplatin exists mainly as the free unchanged form. Strong relationships between carboplatin renal clearance, glomerular filtration rate, area under the plasma concentration-time curve (AUC) of filterable platinum and severity of thrombocytopenia have prompted dose adjustment according to renal function. New analogues such as JM216 offer the potential advantages of oral administration and few nonhaematological toxicities. Analogues based on the diaminocyclohexane ligand have encountered problematic neurotoxicity.
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PMID:Comparative adverse effect profiles of platinum drugs. 857 96

The Nijmegen breakage syndrome (NBS; MIM 251260), is an autosomal recessive disease characterized by microcephaly, growth retardation, immuno-deficiency and cancer predisposition. NBS cells show spontaneous chromosomal instability and hypersensitivity to ionizing radiation in combination with radioresistant DNA synthesis. At the cellular level, NBS has some features in common with ataxia teleangiectasia. In this study the murine Nbs1 gene was used for an expression study in mouse embryos at different developmental stages as well as in adult mice. A low level of expression is observed in all tissues. Highly specific expression was observed in organs with physiologic DNA double strand breakage (DSB), such as testis, thymus and spleen. Enhanced expression is also found at sites of high proliferative activity. These are the subventricular layer of the telencephalon and the diencephalon, the liver, lung, kidney and gut, as well as striated and smooth muscle cells in various organs. In the adult cerebellum the postmitotic Purkinje cells are marked specifically. These expression patterns suggest that in addition to the role of the Nbs1 gene product as part of a DNA DSB repair complex, the Nbs1 gene product may serve further functions during development.
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PMID:Expression pattern of the Nijmegen breakage syndrome gene, Nbs1, during murine development. 1091 61

The gastrointestinal (GI) tract plays a central role in the pathogenesis of transmissible spongiform encephalopathies. These are human and animal diseases that include bovine spongiform encephalopathy, scrapie and Creutzfeldt-Jakob disease. They are uniformly fatal neurological diseases, which are characterized by ataxia and vacuolation in the central nervous system. Although they are known to be caused by the conversion of normal cellular prion protein to its infectious conformational isoform (PrPsc) the process by which this isoform is propagated and transported to the brain remains poorly understood. M cells, dendritic cells and possibly enteroendocrine cells are important in the movement of infectious prions across the GI epithelium. From there, PrPsc propagation requires B lymphocytes, dendritic cells and follicular dendritic cells of Peyer's patches. The early accumulation of the disease-causing agent in the plexuses of the enteric nervous system supports the contention that the autonomic nervous system is important in disease transmission. This is further supported by the presence of PrPsc in the ganglia of the parasympathetic and sympathetic nerves that innervate the GI tract. Additionally, the lymphoreticular system has been implicated as the route of transmission from the gut to the brain. Although normal cellular prion protein is found in the enteric nervous system, its role has not been characterized. Further research is required to understand how the cellular components of the gut wall interact to propagate and transmit infectious prions to develop potential therapies that may prevent the progression of transmissible spongiform encephalopathies.
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PMID:Prion diseases and the gastrointestinal tract. 1643 55

Alpha-, beta-, gamma- and delta-tocopherol are present in many foods and are, in the absence of fat malabsorption, well absorbed from the gut. Their anti-oxidant property is well known and protects arteries and capillaries as well as blood lipids and nervous tissue against oxidative stress. In contrast to beta-, gamma- and delta-tocopherol, alpha-tocopherol is preferentially conserved by the discriminating action of the liver alpha-tocopherol transfer protein, which also maintains plasma alpha-tocopherol concentration within a range of 20 to 40 microM. In the circulation, alpha-tocopherol, in association with the transfer-protein, is assembled into the very low-density lipoprotein and low-density lipoprotein particles and released for use by the peripheral tissues. Recent data suggest that alpha-tocopherol is not only an anti-oxidant but also a regulator of gene expression through its binding to nuclear receptors. The precise mechanism of regulating gene expression, however, is still unknown. The four tocopherols are ultimately degraded by omega-oxidation and subsequent beta-oxidations followed by the elimination of the metabolites in the bile and in the urine. Patients with a defect of the alpha-tocopherol transfer protein are unable to maintain their alpha-tocopherol reserves and progressively lose tendon reflexes and have signs and symptoms of spinocerebellar ataxia while plasma vitamin E level drops below 2 microg/ml.
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PMID:Recent advances in vitamin E metabolism and deficiency. 1649 83


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