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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The signs of neurotoxicity observed in the cat and the rat following single or multiple doses of the phosphorous acid ester triphenyl phosphite (TPP) have been reported to differ from the syndrome known as organophosphorous compound induced delayed neuropathy (OPIDN) caused by some phosphoric acid esters. Since the hen is the test animal traditionally used to test compounds for OPIDN, we chose to study the neurotoxicity of single, subcutaneous doses of TPP using the hen. TPP (1000 mg/kg) produced progressive ataxia and paralysis which developed 5-10 days after dosing. The clinical signs were accompanied by axonal damage in the lateral columns of the spinal cord and peripheral nerve. Similar signs were observed following neurotoxic doses of the OPIDN-causing agents tri-o-cresyl phosphate (TOCP) or diisopropyl phosphorofluoridate (DFP). In addition, TPP caused damage to axons in the brain and gray matter of the spinal cord, and chromatolysis and neuronal necrosis were frequently observed in the spinal cord. These latter areas were not affected by TOCP or DFP. The minimum neurotoxic dose of TPP was found to be 500 mg/kg. Prior administration of phenylmethylsulfonyl fluoride (PMSF) reduced the incidence of damage to the peripheral nerve of animals dosed with TPP, but did not prevent toxic effects on the cell bodies in the spinal cord or the clinical effects. The results of this study indicate that TPP causes neuronal damage in addition to the axonal damage observed with OPIDN. Therefore, we conclude that two distinct mechanisms underlie the neurotoxicity of TPP.
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PMID:Histopathological assessment of triphenyl phosphite neurotoxicity in the hen. 320 32

The neuropathic syndrome resulting in the cat and the rat from single or multiple doses of the phosphorous acid ester tiphenyl phosphite (TPP) has been reported to differ from the syndrome caused by numerous phosphoric acid esters, which is known as organophosphorous compound-induced delayed neurotoxicity (OPIDN). Since the hen is used to test compounds for OPIDN, we chose to study the neurotoxicity of single subcutaneous doses of TPP using this animal model. TPP (1000 mg/kg) produced progressive ataxia and paralysis which began to develop 5-10 days after dosing. Similar signs were observed when subcutaneous doses of the OPIDN-causing agents tri-o-cresyl phosphate (TOCP) or diisopropyl phosphorofluoridate (DFP) were administered. The minimum neurotoxic dose of TPP was 500 mg/kg. Prior administration of phenylmethylsulfonyl fluoride (PMSF) prevented the development of a neuropathy induced by DFP, but did not fully protect the hens from TPP or TOCP. PMSF slowed, but did not prevent, the neuropathy caused by TOCP. PMSF reduced the neurotoxicity of 500 mg/kg TPP, but increased the neurotoxicity of 1000 mg/kg TPP. TPP was found to be a very potent inhibitor of neurotoxic esterase (NTE), the putative target site for OPIDN, in vitro, with a ki of about 2.1 x 10(5) M-1 min-1. Equimolar doses of either TPP (1000 mg/kg) and TOCP (1187 mg/kg) caused over 80% inhibition of neurotoxic esterase (NTE) in brain and sciatic nerve. This high level of NTE inhibition persisted for several weeks. This prolonged inhibition probably accounts for the inability of PMSF to block the neurotoxicity of TOCP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Triphenyl phosphite neurotoxicity in the hen: inhibition of neurotoxic esterase and of prophylaxis by phenylmethylsulfonyl fluoride. 324 48

Hens were repeatedly exposed to paraoxon (PO, phosphonothioic acid, diethyl paranitrophenyl ester), the chemical warfare agent VX/phosphorofluoridic acid, methyl-S-(2-[bis(1-methylethyl)amino/ethyl)O-ethyl ester], or the neuropathic DFP [phosphorofluoridic acid, bis(1-methylethyl)ester] as evidence was sought for nerve or other tissue damage following long-term treatments at high dose levels. Thirty-day and 90-d trials were performed in which each bird was injected 3 or 5 times per week with atropine as protection, weighed, their eggs collected, and their blood enzymes (cholinesterases creatine kinase, and lactic dehydrogenase) and locomotion periodically examined. Muscle and brain enzymes were assayed at the end of the experiments. Doses of PO and VX were at or above LD50 levels. DFP doses were lowered with each run to estimate a no-observable-effect level for organophosphate-induced delayed-neuropathy (OPIDN). No abnormalities attributable to repeated exposures to either PO or VX were found, even though acute, short-term symptoms of toxicity appeared after each injection. No evidence for OPIDN was obtained with repeated exposures to PO and VX under conditions where OPIDN was caused by DFP. Histological signs of OPIDN appeared in the spinal cord without gross symptoms of ataxia following repeated treatments of 25 mg/kg of DFP. The results of one experiment suggested that exposure to protective injections of atropine delays the appearance of the locomotor symptoms of the DFP-induced neuropathy.
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PMID:Toxicity of repeated doses of organophosphorus esters in the chicken. 333 56

The present study examined the effects of a glucocorticoid and a mineralocorticoid on organophosphorus-induced delayed neuropathy (OPIDN) as previous investigations have indicated that an endogenous steroid with both properties could alter this syndrome in chickens. The glucocorticoid triamcinolone and the mineralocorticoid deoxycorticosterone were provided in the diet beginning 1 day before and continuing 10 days after triortho-tolyl phosphate (TOTP, 360 mg/kg po), phenyl saligenin phosphate (PSP, 2.5 mg/kg im), and diisopropyl phosphorofluoridate (DFP, 1 mg/kg sc). In a manner similar to that seen with corticosterone, a low concentration (0.1 ppm) of triamcinolone reduced and a high concentration (10 ppm) exacerbated clinical signs. Concentrations of deoxycorticosterone under 80 ppm also partially delayed or ameliorated ataxia induced by TOTP, PSP, and DFP, but a combination of 0.1 ppm triamcinolone and 80 ppm deoxycorticosterone was not more effective than triamcinolone alone. Peripheral nerve damage was noted in all chickens given organophosphorus compounds, whether or not they had been given corticoids. Both steroids induced hydroxylase activity, but effects on most other enzyme systems examined were unremarkable. High concentrations of triamcinolone (10 ppm) could, however, also reduce liver cytochrome P450 levels and liver cholinesterase activity. Exacerbation of OPIDN was most notable in chickens under highest stress, as indicated by elevated heterophil-to-lymphocyte ratios. The clinical, pathological, biochemical, and hematological indices of exposure to adrenocorticoids and agents inducing OPIDN in chickens were, therefore, similar for both a synthetic glucocorticoid and the endogenous steroid corticosterone.
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PMID:Types of adrenocorticoids and their effect on organophosphorus-induced delayed neuropathy in chickens. 334 Oct 34

There are several clinically distinct forms of neuronal ceroid lipofuscinosis whose presentation and pathology are usually homogeneous within families. Several atypical variants have also been reported. We have studied an inbred sibship in which neuronal ceroid lipofuscinosis appeared to present in two completely different ways. In the proband, the course was compatible with a somewhat atypical juvenile variant. Ataxia and spasticity started at 4.5 years, followed by blindness with optic atrophy, intractable seizures, dementia, and death at 14 years. Atypical features included areflexia, hypotonia, and ataxia. Electron microscopic studies of her skin and her rectal ganglion cells showed lucent, dense, and fingerprint inclusions that were also found in the central nervous system at autopsy. Her brother and sister developed difficulty walking at ages 8.5 and 10.5 years and are alive at 24 and 18 years. They presented with slowly progressive spinocerebellar degeneration with sensorimotor neuropathy without dementia, seizures, or visual impairment. Lysosomal enzymes and lipoprotein analysis were normal in all three siblings and their parents. Elevated dolichol in the urine and lucent, dense, and fingerprint inclusions in skin, cutaneous nerve, buffy coat lymphocytes in both siblings and in the sural nerve of the brother suggest that their disease may represent a novel phenotype of neuronal ceroid lipofuscinosis. While it is possible that two different recessive genes may be segregating in this consanguineous family, we cannot dismiss the possibility that variability of gene expression may account for the divergent phenotypes.
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PMID:Spino-cerebellar degeneration with polyneuropathy associated with ceroid lipofuscinosis in one family. 342 77

The clinical and histopathological features in sural nerve biopsies from 10 cases of dominantly inherited hypertrophic Charcot-Marie-Tooth disease (hereditary motor and sensory neuropathy (HMSN), type I) presenting in childhood are contrasted with those of 6 cases of Dejerine-Sottas disease (HMSN type III). There was a significantly greater incidence of ataxia, areflexia and clinical nerve enlargement in HMSN type III. In HMSN type III, there was also a significantly lower density of myelinated fibres 8 microns or more in diameter, a greater frequency of onion bulbs, more lamellae per onion bulb and, a higher ratio of mean axon diameter to fibre diameter. The functional severity of the HMSN type III cases was not markedly worse than those with HMSN type I. Using these parameters, it was possible to attempt classification of sporadic cases of hereditary motor and sensory neuropathy. Cerebrospinal fluid protein levels were unreliable in distinguishing the two types of neuropathy.
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PMID:The hypertrophic forms of hereditary motor and sensory neuropathy. A study of hypertrophic Charcot-Marie-Tooth disease (HMSN type I) and Dejerine-Sottas disease (HMSN type III) in childhood. 346 5

Systemic injection of diisopropyl phosphorofluoridate (DFP; 1 mg/kg, sc) causes delayed neuropathy in hens. This effect is associated with a high level of organophosphorylation of neuropathy target esterase (NTE) followed by an intramolecular rearrangement called "aging." Phenylmethanesulfonyl fluoride (PMSF) also attacks the active center of NTE but "aging" cannot occur. This compound does not cause neuropathy and protects against a subsequent challenge systemic dose of DFP. Intraarterial injection of DFP (0.185 mg/kg) into only one leg of hens caused a high NTE inhibition (greater than 80%) in the sciatic nerve of the injected leg, but not in other parts of the nervous system (37% average). A unilateral neuropathy with typical histopathological lesions developed in the injected leg. PMSF (0.55 mg/kg) injected into each sciatic artery caused 47% inhibition of sciatic nerve NTE but only 17-22% inhibition of NTE elsewhere; it did not produce clinical or histopathological lesions. When these hens were challenged with DFP (1 mg/kg, sc), high inhibition of residual-free NTE (greater than 85%) occurred throughout the nervous system and clinical signs of a syndrome different from the classical delayed neuropathy developed: this spinal cord type of ataxia was associated with histopathological lesions in the spinal cord but not in peripheral nerve. PMSF (1 mg/kg) injected into only one sciatic artery caused selective protective inhibition of sciatic nerve NTE of that leg. After systemic challenge by DFP, clinical effects expressed were a combination of spinal cord ataxia plus unilateral peripheral neuropathy. The challenge dose of DFP (1 mg/kg, sc) was insufficient to produce clear histopathological lesions in unprotected peripheral nerves although spinal lesions were found in these hens. Thus clinical evaluation of the peripheral nervous system by means of walking tests and a simple test of "leg retraction" reflexes was more sensitive and specific in diagnosis of peripheral neuropathy than was the histopathology.
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PMID:Central-peripheral delayed neuropathy caused by diisopropyl phosphorofluoridate (DFP): segregation of peripheral nerve and spinal cord effects using biochemical, clinical, and morphological criteria. 356 33

Hens were given a single oral dose (0.235 mg/kg) of tri-o-cresylphosphate (TOCP) during chronic n-hexane treatment (200 mg/kg daily, 5 days/week). They were compared with other animals treated only with n-hexane or only with TOCP. Animals treated with a higher TOCP dose (1 ml/kg) were used as positive controls. The animals treated with both n-hexane and TOCP showed rapid development of severe ataxia. The rate of the ataxia development was similar to that of the positive controls but with earlier onset of the first signs and with less loss of body weight. However, animals treated only with n-hexane, under the same conditions, showed only reversible weakness and sedative effects, and those treated only with TOCP showed slow and slight ataxia development. The n-hexane- and TOCP-treated hens showed axonal swelling with myelin retraction associated with Ranvier's nodes, which is characteristic of long hexacarbon exposure. Some internodal swellings were also observed but less frequently than the paranodal swellings. The time course of the ataxia development was similar to an organophosphorus-induced delayed neuropathy (OPIDN); however, the light microscopy observation more closely resembled hexacarbon neuropathy. The results suggest a potentiation effect of n-hexane and TOCP neurotoxicities which could be related to some human occupational neuropathies.
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PMID:Sensitivity to tri-o-cresylphosphate neurotoxicity on n-hexane exposed hens as a model of simultaneous hexacarbon solvent and organophosphorus occupational intoxication. 357 94

Chick embryos were treated during late embryonic development with tri-ortho-cresyl phosphate (TOCP), an organophosphate compound that causes delayed neurotoxicity in humans and some other species. Embryos were treated on incubation d 14 with either 62 or 250 microliters TOCP/kg egg. The higher dose reduced the number hatched, and signs of cholinergic toxicity were apparent in the newly hatched chick. All chicks that survived this dose were unable to stand. Recovery from the cholinergic effects occurred within a few days after hatching, but the chicks remained severely ataxic through 3 wk of observation. The mortality of embryos treated with 62 microliters TOCP/kg egg was not higher than that of controls, and young chicks showed no overt signs of cholinergic toxicity or ataxia. Motor impairment was detected by measuring gait parameters. These chicks had a short stride and walked with a more open angle of foot placement. These are adjustments in gait that provide a more steady base of support. The change in gait developed over a 3-wk period after hatching. The hindlimb motor impairment detected at both doses is consistent with neuropathy such as is seen in the adult chicken. The value of gait analysis is the ability to quantify effects that are not apparent by simple observation.
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PMID:Gait analysis of chicks following treatment with tri-ortho-cresyl phosphate in ovo. 359 89

Giant axonal neuropathy (GAN) is a disease characterized by a slowly progressive neuropathy and signs of central involvement, manifested by visual impairment, corticospinal tract dysfunction, ataxia, and dementia. Pathological hallmarks of the disease include axonal swellings packed with neurofilaments in both peripheral and central nervous systems, and accumulations of intermediate filaments in Schwann cells, fibroblasts, melanocytes, endothelial, and Langerhans cells. Rosenthal fibers, sometimes appearing in masses and mimicking Alexander's disease, emerge as a conspicuous characteristic in longstanding GAN.
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PMID:Giant axonal neuropathy. A neuropathological study. 360 81


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