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)

Review of 20 patients with glucocorticoid deficiency (three cases also with salt loss) associated with absent tear secretion (19 cases) and achalasia of the cardia (15 cases) revealed neurological abnormalities in 17 including hyper-reflexia, muscle weakness, dysarthria, and ataxia together with impaired intelligence and abnormal autonomic function, particularly postural hypotension. These findings indicate that significant neurological problems are common in this multisystem disorder.
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PMID:Neurological and adrenal dysfunction in the adrenal insufficiency/alacrima/achalasia (3A) syndrome. 833 72

An 11-month-old female Vietnamese pot-bellied pig was examined for severe dehydration and neurologic signs including disorientation, ataxia, blindness, and involuntary twitching of the muscles of the neck and head. Biochemical analyses of serum revealed hypernatremia, hyperchloremia, hyperkalemia, azotemia, hyperphosphatemia, hyperalbuminemia, and high activities of aspartate transaminase and creatine kinase. A diagnosis of salt toxicosis/water deprivation was made. Medical management consisted of intravenous administration of a high-sodium crystalloid solution, anti-inflammatory drugs, and other supportive care. Sodium concentration of fluids administered intravenously was adjusted to be slightly less than the pig's serum sodium concentration so that the serum sodium concentration was reduced gradually over 48 hours. Resolution of clinical signs was rapid and the pig was discharged after 8 days of hospitalization. Fourteen days after the initial examination, the pig appeared healthy except for visual deficits. Historically, prognosis with conventional treatment of salt toxicosis/water deprivation is poor; however, this alternative approach to treating this condition appears promising.
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PMID:High-sodium crystalloid solution for treatment of hypernatremia in a Vietnamese pot-bellied pig. 883 48

We determined possible protective effects of benidipine hydrochloride (benidipine), a dihydropyridine calcium antagonist, on cerebrovascular lesions in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP). The animals were orally treated with benidipine at 1, 3 and 10 mg/kg daily for 7 weeks, and their neurological symptoms, body weight changes, systolic blood pressure and cerebrovascular lesions on magnetic resonance imaging (MRI) were determined at various time points of treatment. Moreover, the brains of the rats that showed cerebrovascular lesions on MRI in the course of treatment or completed 7-week treatment were examined histopathologically. Control rats presented such symptoms as sedation, ataxia and aggressiveness, while their MRI analysis revealed high signals over wide areas from the occipital to frontal cortex and from the corpus callosum to external capsule. These high signal areas corresponded in location to edematous or softening lesions revealed by the histopathological observation. Treatment with benidipine at 3 and 10 mg/kg ameliorated neurological symptoms, significantly suppressing cerebrovascular damages on MRI. Benidipine at 3 mg/kg significantly decreased blood pressure for the first four weeks but it did not thereafter. These findings demonstrate that benidipine can protect salt-loaded SHRSP from cerebrovascular injury as assessed by MRI.
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PMID:Effects of benidipine hydrochloride on cerebrovascular lesions in salt-loaded stroke-prone spontaneously hypertensive rats: evaluation by magnetic resonance imaging. 1104 54

An abridged prion protein (PrP) molecule of 106 amino acids, designated PrP106, is capable of forming infectious miniprions in transgenic mice (S. Supattapone, P. Bosque, T. Muramoto, H. Wille, C. Aagaard, D. Peretz, H.-O. B. Nguyen, C. Heinrich, M. Torchia, J. Safar, F. E. Cohen, S. J. DeArmond, S. B. Prusiner, and M. Scott, Cell 96:869-878, 1999). We removed additional sequences from PrP106 and identified a 61-residue peptide, designated PrP61, that spontaneously adopted a protease-resistant conformation in neuroblastoma cells. Synthetic PrP61 bearing a carboxy-terminal lipid moiety polymerized into protease-resistant, beta-sheet-enriched amyloid fibrils at a physiological salt concentration. Transgenic mice expressing low levels of PrP61 died spontaneously with ataxia. Neuropathological examination revealed accumulation of protease-resistant PrP61 within neuronal dendrites and cell bodies, apparently causing apoptosis. PrP61 may be a useful model for deciphering the mechanism by which PrP molecules acquire protease resistance and become neurotoxic.
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PMID:A protease-resistant 61-residue prion peptide causes neurodegeneration in transgenic mice. 1125 7

The objective of the present study was to characterise the neuroprotective activity of the novel glycineB site NMDA (N-methyl-D-aspartate) receptor antagonist MRZ 2/576 (8-chloro-4-hydroxy-l-oxo- 1,2-dihydropyridazino[4,5-b]quinolin-5-oxide choline salt, CAS 202807-80-5) in a rodent model of focal cerebral ischaemia. Since the solubility of MRZ 2/576 at a physiological pH, is minimal and adequate concentrations can be achieved only at relatively high basic pH the in vivo use of the substance is substantially limited. Therefore, a special nanoparticle formulation was developed to provide means for lengthy i.v. administration of experimentally relevant doses within the physiological range of pH. Focal ischaemia of 75 min duration was induced in rats by a reversible occlusion of the middle cerebral artery (MCAo). MRZ 2/576 (18 mg/kg over 10 min followed by 18 mg/kg/h over 6 h) or placebo treatment was initiated immediately after onset of MCAo. Neurological deficit was evaluated daily for 3 consecutive days and then brain infarct analysis was performed. MRZ 2/576 significantly improved the neurological score at 24 h and 72 h post stroke (p < 0.05 vs. placebo). It also produced a 53.0% reduction of total infarct size, 60.4% of cortical and 42.3% of striatal infarction (p < 0.05 vs. placebo). Temporary drug-induced hypothermia and ataxia were observed during infusions. This leads to the conclusion that prolonged administration of the glycineB site antagonist MRZ 2/576 in form of the nanoparticle suspension ameliorates ischaemic damage induced by the transient MCAo in rats. The results suggest that nanoparticles hold promise as an effective strategy e.g. for substances with physico-chemical characteristics that otherwise would preclude them from pre-clinical development and/or clinical application.
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PMID:Neuroprotective activity of a nanoparticulate formulation of the glycineB site antagonist MRZ 2/576 in transient focal ischaemia in rats. 1196 43

ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride salt] is a selective neuronal nicotinic receptor (NNR) modulator with cognitive enhancing properties in animal models of cognitive functioning. Amongst NNR subtypes, ABT-089 shows selectivity for the cytisine binding site on the alpha4beta2 receptor subtype as compared to the alpha-bungarotoxin (alpha-BgT) binding sites on the alpha7 and alpha1beta1deltagamma receptor subtypes. In functional in vitro electrophysiological and cation flux assays, ABT-089 displays differential activity including agonism, partial agonism and antagonism depending upon the NNR subtype and assay. ABT-089 is as potent and efficacious as (-)-nicotine at evoking acetylcholine (ACh) release from hippocampal synaptosomes. Furthermore, ABT-089 is neuroprotective against excitotoxic glutamate insults, with even greater potency seen after chronic treatment. Similarly, ABT-089 is effective in models of cognitive functioning, including enhancement of baseline functioning as well as improvement of impaired cognitive functioning seen following septal lesioning and natural aging. In neuroprotective assays the compound is most potent by chronic administration. In stark contrast to the positive effects in the cognitive models, ABT-089 shows little propensity to induce adverse effects such as ataxia, hypothermia, seizures, cardiovascular or gastrointestinal side effects. Together these data suggest that ABT-089 is a NNR modulator with the potential for treating cognitive disorders with markedly limited adverse cardiovascular and gastrointestinal side effects.
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PMID:ABT-089: pharmacological properties of a neuronal nicotinic acetylcholine receptor agonist for the potential treatment of cognitive disorders. 1517 45

Kearns-Sayre syndrome, first described by Kearns and Sayre in 1958, is a rare disorder consisting of ptosis, limited movement of both eyes and atypical retinal pigmentary change (salt-pepper like appearance). Most cases have shown an increase in the concentration of mitochondria and ragged-red fiber under Gomori-trichrome staining on muscle biopsy. Occasionally, it is combined with other neurologic and endocrinologic symptoms such as ataxia, dementia, diabetes, and hyperaldosteronism. We recently experienced three cases of male teenaged patients who expressed the clinical features of Kearns-Sayre syndrome.
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PMID:Kearns-Sayre syndrome -3 case reports and review of clinical feature. 1534 17

gamma-Hydroxybutyrate (GHB), a therapeutic for narcolepsy and a drug of abuse, has several mechanisms of action that involve GHB and GABA(B) receptors, metabolism to GABA, and modulation of dopaminergic signaling. The aim of these studies was to examine the role of GHB and GABA(B) receptors in the behavioral effects of GHB. Three approaches were used to synthesize GHB analogs that bind selectively to GHB receptors and are not metabolized to GABA-active compounds. Radioligand binding assays identified UMB86 (4-hydroxy-4-napthylbutanoic acid, sodium salt), UMB72 [4-(3-phenylpropyloxy)butyric acid, sodium salt], UMB73 (4-benzyloxybutyric acid, sodium salt), 2-hydroxyphenylacetic acid, 3-hydroxyphenylacetic acid (3-HPA), and 4-hydroxy-4-phenylbutyric acid as compounds that displace [(3)H]NCS-382 [5-[(3)H]-(2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7] annulen-6-ylidene) ethanoic acid] from GHB receptors at concentrations that do not markedly affect [(3)H]GABA binding to GABA(B) receptors. In rats and pigeons, GHB discriminative stimulus effects were not mimicked or attenuated by UMB86, UMB72, or 3-HPA up to doses that decreased responding. In mice, GHB, GHB precursors (gamma-butyrolactone and 1,4-butanediol) and GABA(B) receptor agonists [SKF97541 [3-aminopropyl(methyl)phosphinic acid hydrochloride] and baclofen] dose-dependently produced hypolocomotion, catalepsy, ataxia, and loss of righting. The GABA(B) receptor antagonist CGP35348 (3-aminopropyl(diethoxymethyl)phosphinic acid) attenuated catalepsy and ataxia that was observed after GHB and GABA(B) receptor agonists SKF97541 and baclofen. UMB86, UMB72, UMB73, and 3-HPA, like GHB, produced hypolocomotion, ataxia, and loss of righting; however, catalepsy was never observed with these compounds, which is consistent with the cataleptic effects of GHB being mediated by GABA(B) receptors. Ataxia that was observed with UMB86, UMB72, UMB73, and 3-HPA was not antagonized by CGP35348, suggesting that ataxia induced by these analogs is not mediated by GABA(B) receptors and might involve GHB receptors.
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PMID:Novel gamma-hydroxybutyric acid (GHB) analogs share some, but not all, of the behavioral effects of GHB and GABAB receptor agonists. 1576 68

Sodium chloride (NaCl) is widely used as a deicing agent on roadways. There are numerous anecdotal reports of poisoning of passerine birds by road salt in the United States and Canada, but little is known about the toxicity of NaCl to songbirds. The objectives of this study were to determine the lethal dose range for NaCl in a representative passerine species (house sparrow [Passer domesticus]); to determine the clinical, physiologic, and pathologic effects of sublethal and lethal oral NaCl exposure; and to assess the potential for recovery after exposure to granular salt or highly concentrated salt solutions. The up-and-down method was used in a pilot study to estimate the lethal oral dose of granular NaCl in wild caught house sparrows. The toxicity of highly concentrated NaCl solution also was investigated. This was followed by an acute dose response study in which house sparrows were dosed orally with granular NaCl at 0, 500, 1,500, 2,500, or 3,500 mg/kg. Sparrows were deprived of water for 6 hr postexposure (PE) in an attempt to mimic specific winter conditions. Groups of three birds at each dose were euthanized at 1, 3, 6, and 12 hr PE, and samples were collected for histopathology and brain and plasma electrolyte analyses. Results indicated an approximate mean lethal dose (LD50) of 3,000-3,500 mg/kg in water-deprived birds, which is similar to mammalian values. House sparrows dosed with a concentrated solution of NaCl generally died at doses of 8,000 mg/kg. Clinical signs observed at >or=1,500 mg/kg included rapid onset (<30 min) of depression (indicated by reduced activity and reduced response to visual and auditory stimuli), ataxia, inability to fly or perch, and death in as little as 45 min. Birds that survived for 6 hr usually recovered. Plasma Na concentrations >200 mmol/l were consistently associated with clinical signs. Pathologic lesions consisted of edema and distension of the caudoventral thin muscled region of the gizzard and were observed 1 hr PE in most birds dosed with >or=500 mg/kg. Brain Na concentrations in clinically ill sparrows and those that died of NaCl toxicity ranged from 1,297 to 1,615 (mean=1,450; SD=115) ppm wet weight or 5,603 to 6,958 (mean=6,367; SD=454) ppm dry weight, which differed significantly from control birds. No histologic lesions were observed in brain sections of exposed birds, likely reflecting the acute nature of the exposure. However, fluid accumulation beneath the koilin layer of the gizzard was observed in the majority of birds at high dosage levels. These results indicate that passerines ingesting relatively small numbers of road salt granules or small quantities of highly concentrated NaCl solutions are at risk of sodium poisoning.
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PMID:Toxicity of sodium chloride to house sparrows (Passer domesticus). 1610 71

We describe members of 4 kindreds with a previously unrecognized syndrome characterized by seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (hypokalemia, metabolic alkalosis, and hypomagnesemia). By analysis of linkage we localize the putative causative gene to a 2.5-Mb segment of chromosome 1q23.2-23.3. Direct DNA sequencing of KCNJ10, which encodes an inwardly rectifying K(+) channel, identifies previously unidentified missense or nonsense mutations on both alleles in all affected subjects. These mutations alter highly conserved amino acids and are absent among control chromosomes. Many of these mutations have been shown to cause loss of function in related K(+) channels. These findings demonstrate that loss-of-function mutations in KCNJ10 cause this syndrome, which we name SeSAME. KCNJ10 is expressed in glia in the brain and spinal cord, where it is believed to take up K(+) released by neuronal repolarization, in cochlea, where it is involved in the generation of endolymph, and on the basolateral membrane in the distal nephron. We propose that KCNJ10 is required in the kidney for normal salt reabsorption in the distal convoluted tubule because of the need for K(+) recycling across the basolateral membrane to enable normal activity of the Na(+)-K(+)-ATPase; loss of this function accounts for the observed electrolyte defects. Mice deficient for KCNJ10 show a related phenotype with seizures, ataxia, and hearing loss, further supporting KCNJ10's role in this syndrome. These findings define a unique human syndrome, and establish the essential role of basolateral K(+) channels in renal electrolyte homeostasis.
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PMID:Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10. 1928 23


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