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)

The purpose of the study was to evaluate the clinical significance of Actinobacillus minor, Actinobacillus porcinus and Actinobacillus indolicus strains in gnotobiotic piglets. Twenty-two 6-h-old Caesarean-delivered and colostrum-deprived piglets were intranasally and orally inoculated with 2 x 10(6) colony-forming units of an A. minor (group 2; n = 9), A. indolicus (group 3; n = 5), or A. porcinus (group 4; n = 8) strain. Six other piglets were inoculated in the same way with phosphate-buffered saline solution and used as controls (group 1). All pigs were observed for clinical signs and rectal temperatures were taken until euthanasia 7 days after inoculation. At necropsy, conchae, tonsils, lungs, brains, liver, spleen and kidneys were macroscopically examined for lesions and samples were taken for bacteriology. None of the pigs developed fever. Mild ataxia was observed in one pig from group 3 for 2 days. Clinical signs were not observed in the other animals. In none of the animals were macroscopic lesions detected at necropsy. NAD-dependent Pasteurellaceae were not isolated from control animals (group 1). The A. minor, A. indolicus and A. porcinus strains were isolated from the tonsils of one, two and one pigs, respectively. Actinobacillus porcinus was isolated from the brains of the pig with central nervous symptoms and from the conchae of another pig. The inoculation strains were not demonstrated in the other samples. It was concluded that, using these inoculation routes and dose, the A. minor, A. indolicus and A. porcinus strains had low capacity to colonize the upper respiratory tract of gnotobiotic piglets and demonstrated low or no pathogenicity in such animals.
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PMID:Pathogenicity of Actinobacillus minor, Actinobacillus indolicus and Actinobacillus porcinus strains for gnotobiotic piglets. 1131 22

Congenital disorders of glycosylation (CDG) are caused by autosomal recessive mutations in genes affecting N-glycan biosynthesis. Mutations in the PMM2 gene, which encodes the enzyme phosphomannomutase (mannose 6-phosphate <--> mannose 1-phosphate), give rise to the most common form: CDG-Ia. These patients typically present with dysmorphic features and neurological abnormalities, cerebellar hypoplasia, ataxia, hypotonia, and coagulopathy, in addition to feeding problems. However, the clinical symptoms vary greatly. The great majority of known CDG-Ia patients are of European descent where the most common mutant alleles originated. This ethnic bias can also be explained by lack of global awareness of the disorder. Here we report an Asian patient with prominent systemic features that we diagnosed with CDG-Ia resulting from two new mutations in the PMM2 gene (310C --> G resulting in L104V and an intronic mutation IVS1-1G --> A). The latter mutation seems to result in lower mRNA levels, and the L104V has been functionally analyzed in a yeast expression system together with known mutations. The Filipino and Cambodian origins of the parents show that CDG-Ia mutations occur in these ethnic groups as well as in Caucasians.
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PMID:Functional analysis of novel mutations in a congenital disorder of glycosylation Ia patient with mixed Asian ancestry. 1135 Jan 85

HIT (histidine triad) proteins, named for a motif related to the sequence HphiHphiHphiphi (phi, a hydrophobic amino acid), are a superfamily of nucleotide hydrolases and transferases, which act on the alpha-phosphate of ribonucleotides, and contain a approximately 30 kDa domain that is typically either a homodimer of approximately 15 kDa polypeptides with two active-sites or an internally, imperfectly repeated polypeptide that retains a single HIT active site. On the basis of sequence, substrate specificity, structure, evolution, and mechanism, HIT proteins can be classified into the Hint branch, which consists of adenosine 5'-monophosphoramide hydrolases, the Fhit branch, which consists of diadenosine polyphosphate hydrolases, and the GalT branch, which consists of specific nucleoside monophosphate transferases, including galactose-1-phosphate uridylyltransferase, diadenosine tetraphosphate phosphorylase, and adenylyl sulfate:phosphate adenylytransferase. At least one human representative of each branch is lost in human diseases. Aprataxin, a Hint branch hydrolase, is mutated in ataxia-oculomotor apraxia syndrome. Fhit is lost early in the development of many epithelially derived tumors. GalT is deficient in galactosemia. Additionally, ASW is an avian Hint family member that has evolved to have unusual gene expression properties and the complete loss of its nucleotide binding site. The potential roles of ASW and Hint in avian sexual development are discussed elsewhere. Here we review what is known about biological activities of HIT proteins, the structural and biochemical bases for their functions, and propose a new enzyme mechanism for Hint and Fhit that may account for the differences between HIT hydrolases and transferases.
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PMID:Hint, Fhit, and GalT: function, structure, evolution, and mechanism of three branches of the histidine triad superfamily of nucleotide hydrolases and transferases. 1211 13

A clinical and neuropathological comparison was made between chickens poisoned with tri-o-cresyl phosphate and those treated with the major cyclic phosphate metabolite of tri-o-cresyl phosphate. Ataxia was evident with both materials, and the degree of peripheral neuropathy increased with higher doses of these agents. Morphological changes were evident with the onset of symptoms and increased in number as the neurological signs progressed. Demyelination of the spinal cord following administration of the metabolite occurred at doses considerably below those necessary to effect peripheral nerve degeneration. Axon and myelin damage was prominent with both agents. The relationship between these effects and those produced by certain other organophosphates such as dyflos (diisopropyl fluorophosphonate) is discussed.
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PMID:Neurotoxic syndrome produced in chickens by a cyclic phosphate metabolite of tri-o-cresyl phosphate--a clinical and pathological study. 1386 63

A histological and enzymatic examination was made of the neurological disruption produced in hens by two organophosphate esters. Intraperitoneal administration of DEF (tributyl phosphorotrithiolate) and Merphos (tributyl phosphorotrithioite) produced central and perpheral nervous system lesions accompanied by clinical signs of ataxia similar to those seen following administration of tri-o-cresyl phosphate. Histological examination (utilizing the Marchi stain) showed the occurence of spinal cord disruption before the onset of clinical ataxia. Oral administration of DEF and Merphos did not induce signs of peripheral weakness. However, severe lesions in the spinal cord and sciatic nerve were prominent. A discussion of the occurrence of central and peripheral nerve disruption either in the presence or absence of clinical ataxia is presented. Enzymatic examination of the effect of DEF on spinal cord and brain esterases at various intervals following administration showed a pattern of esterase inhibition similar to that found after tri-o-cresyl phosphate, dyflos and other organophosphates. Some prolonged inhibition is believed due to the extent of initial involvement rather than to selective prolonged inhibition.
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PMID:NEUROLOGICAL DISRUPTION PRODUCED IN HENS BY TWO ORGANOPHOSPHATE ESTERS. 1422 31

The cerebellar calcification (CC) rat is a new neurodegenerative mutant with severe Purkinje cell loss and symmetrical calcifications in the cerebellar cortex manifesting ataxia: lack of coordination in body movements. In the present study, histopathological features were examined in the Purkinje cell degeneration in postnatal homozygous suckling rats without clinical signs, which were genotyped by microsatellite markers. In addition, the calcified Purkinje cells were investigated ultrastructurally and elemental analysis was performed on the deposits. Body weight of the homozygous (cc/cc) rats was already slightly lower compared with the heterozygotes (cc/+) in the neonatal stage. The degeneration of the Purkinje cells in the cc/cc rats was recognized obviously in lobules VI, VII, VIII and IX from 14 days after birth, a few days before the appearance of the ataxic behavior. The Purkinje cells in the region along the fissure between the VIII and IX lobule areas were intensely positive for periodic acid-Schiff reaction specific to glycoconjugates, and in this region, calcium depositions were weakly positive for von Kossa's stain. Electron microscopy also revealed that the calcified Purkinje cells possessed numerous electron-dense bodies containing inclusions with cystic structures such as vesicles, mitochondria and lysosomes, and these bodies were mainly composed of calcium and phosphorous. These findings suggest abnormal storage of glycoconjugates might be a trigger of Purkinje cell degeneration and serves as a matrix for accumulation of calcium phosphate in the cerebellum of CC rats.
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PMID:Histological and ultrastructural features in the early stage of Purkinje cell degeneration in the cerebellar calcification (CC) rat. 1515 69

A three-month-old female Siberian tiger cub with hindlimb ataxia was referred to the veterinary teaching hospital of Konkuk University. The patient was fed only beef without supplementation of calcium and vitamins after weaning. The tiger was presented with ataxia and back pain on digital palpation. In addition, abnormal gait, reluctance to move, and depressed withdrawal reflex were noted at the neurological examination. The overall osteodystrophic change of the lumbosacral vertebrae was observed on the lateral and ventrodorsal view of radiographic examination. And also PTH level was increased in hormonal assay when compared to that of cat reference range. Based on the results of examinations, nutritional secondary hyperparathyroidism was diagnosed. Clinical signs of this patient were improved after administration of vitamin D and calcium. This case demonstrates that nutritional hyperparathyroidism could be occurred in wild animals raised on a meat diet containing imbalanced calcium and phosphate.
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PMID:A case of nutritional secondary hyperparathyroidism in a Siberian tiger cub. 1518 68

Tri-ortho-cresyl phosphate (TOCP) is an organophosphorus ester. It is capable of producing organophosphorus ester induced delayed neurotoxicity (OPIDN) in human being and sensitive animals, which is characterized by ataxia that progresses to paralysis after 1-3 weeks following exposure to some organophosphorus ester. In present study, 18 adult hens were divided randomly into three groups, i.e. two experimental groups and control group (n = 6 each group). All hens were 10 months old and weighted 1.5-2.0 kg. The hens in two experimental groups were treated with TOCP by gavage at single dosages of 375 and 750 mg/kg respectively. TOCP was dissolved in corn oil and administered at 0.65 ml/kg. Six control hens received an equivalent volume of corn oil by gavage. All hens were sacrificed after 21 days of treatment and the sciatic nerves were dissected, homogenized and used for the determination of cytoskeletal proteins by western blotting. The levels of neurofilament (NF) subunits were decreased both in supernatant and pellet of sciatic nerves, and the most noticeable decrease in levels of NF subunits protein was observed in neurofilament medium (NF-M). Compared to the control hens, neurofilament heavy (NF-H) level decreased by 36 and 38% (P < 0.01) in the pellet and by 27 and 26% (P < 0.05) in the supernatant of sciatic nerves of hens treated with 375 and 750 mg/kg TOCP respectively. The reduction of NF-M were 36 and 68% (P < 0.01) in pellet, 50 and 67% (P < 0.01) in supernatant at 375 and 750 mg/kg dosage respectively. The neurofilament light (NF-L) lessened slightly, but the relative percentage of integrated optical density (IOD) was no significant alteration when compared to the control hens. There were significant decreases in levels of alpha-tubulin, beta-tubulin in pellet and alpha-tubulin, beta-tubulin, beta-actin in supernatant of sciatic nerves in TOCP-treated hens. Thus, the decreases of cytoskeletal proteins suggested the possible involvement of them in delayed neurotoxicity.
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PMID:Tri-ortho-cresyl phosphate (TOCP) decreases the levels of cytoskeletal proteins in hen sciatic nerve. 1530 95

Combretastatin A4 phosphate (CA4P) represents the lead compound in a group of novel tubulin depolymerising agents being developed as vascular targeting agents (VTAs). VTAs are drugs that induce rapid and selective vascular dysfunction in tumours. CA4P is a water-soluble prodrug of the cis-stilbene CA4 originally isolated from the tree Combretum caffrum. Preclinical studies have shown that CA4P induces blood flow reductions and subsequent tumour cell death in a variety of preclinical models. Moreover, this activity has been linked to its ability to rapidly alter the morphology of immature endothelial cells by disrupting their tubulin cytoskeleton. Phase I clinical trials have established a maximum tolerated dose in the range 60-68 mg/m2 and in addition have established that significant changes to tumour perfusion can be achieved across a wide range of doses. The dose-limiting toxicities include tumour pain, ataxia and cardiovascular changes. The maximum tolerated dose was independent of schedule, indicating the absence of cumulative toxicity. Although unexpected from preclinical studies, some evidence of clinical response was seen using CA4P as a single modality. Based on the Phase I data, combination studies of CA4P with established therapies are in progress and should determine whether the exciting preclinical data obtained when VTAs are used in combination with cytotoxic chemotherapy, radiation, radioimmunotherapy and even antiangiogenic agents, can be translated into man.
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PMID:Combretastatin A4 phosphate: background and current clinical status. 1533 Jul 48

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a DNA repair enzyme that acts upon protein-DNA covalent complexes. Tdp1 hydrolyzes 3'-phosphotyrosyl bonds to generate 3'-phosphate DNA and free tyrosine in vitro. Mutations in Tdp1 have been linked to patients with spinocerebellar ataxia, and over-expression of Tdp1 results in resistance to known anti-cancer compounds. Tdp1 has been shown to be involved in double-strand break repair in yeast, and Tdp1 has also been implicated in single-strand break repair in mammalian cells. Despite the biological importance of this enzyme and the possibility that Tdp1 may be a molecular target for new anti-cancer drugs, there are very few assays available for screening inhibitor libraries or for characterizing Tdp1 function, especially under pre-steady-state conditions. Here, we report the design and synthesis of a fluorescence-based assay using oligonucleotide and nucleotide substrates containing 3'-(4-methylumbelliferone)-phosphate. These substrates are efficiently cleaved by Tdp1, generating the fluorescent 4-methylumbelliferone reporter molecule. The kinetic characteristics determined for Tdp1 using this assay are in agreement with the previously published values, and this fluorescence-based assay is validated using the standard gel-based methods. This sensitive assay is ideal for kinetic analysis of Tdp1 function and for high-throughput screening of Tdp1 inhibitory molecules.
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PMID:Design and synthesis of fluorescent substrates for human tyrosyl-DNA phosphodiesterase I. 1533 97


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