Biomedical subjects
Publications and source records attributed to S George.
Brain tissues from 38 patients with a clinical suspicion of encephalitis or encephalopathy were examined by two immunoenzymatic techniques for the detection of arboviral antigen. Group B arboviral antigen was identified in 23 of these tissues. This simple method could be used for the diagnosis of the causal agent of encephalitis.
A variety of folate analogues were synthesized to explore the specificity of the folate binding site of hog liver folylpolyglutamate synthetase and the requirements for catalysis. Modifications of the internal and terminal glutamate moieties of folate cause large drops in on rates and/or affinity for the protein. The only exceptions are glutamine, homocysteate, and ornithine analogues, indicating a less stringent specificity around the delta-carbon of glutamate. It is proposed that initial folate binding to the enzyme involves low-affinity interactions at a pterin and a glutamate site and that the first glutamate bound is the internal residue adjacent to the benzoyl group. Processive movement of the polyglutamate chain through the glutamate site and a possible conformational change in the protein when the terminal residue is bound would result in tight binding and would position the gamma-carboxyl of the terminal glutamate in the correct position for catalysis. Steric limitations imposed on the internal glutamate residues that loop out and additional steric constraints imposed by binding of different pterin moieties would be expected to effect slight conformational changes in the protein and/or the terminal glutamate and would explain the decrease in on rate and catalytic rate with increased polyglutamate chain length, and the differential effect of one-carbon substitution on the catalytic rate with polyglutamate derivatives. The 4-amino substitution of folate increases the on rate for monoglutamate derivatives but severely impairs catalysis with diglutamate derivatives. Pteroylornithine derivatives are the first potent and specific inhibitors of folylpolyglutamate synthetase to be identified and may act as analogues of reaction intermediates.(ABSTRACT TRUNCATED AT 250 WORDS)
The regulation of folate and folate analogue metabolism was studied in vitro by using purified hog liver folylpolyglutamate synthetase as a model system and in vivo in cultured mammalian cells. The types of folylpolyglutamates that accumulate in vivo in hog liver, and changes in cellular folate levels and folylpolyglutamate distributions caused by physiological and nutritional factors such as changes in growth rates and methionine, folate, and vitamin B12 status, can be mimicked in vitro by using purified enzyme. Folylpolyglutamate distributions can be explained solely in terms of the substrate specificity of folylpolyglutamate synthetase and can be modeled by using kinetic parameters obtained with purified enzyme. Low levels of folylpolyglutamate synthetase activity are normally required for the cellular metabolism of folates to retainable polyglutamate forms, and consequently folate retention and concentration, while higher levels of activity are required for the synthesis of the long chain length derivatives that are found in mammalian tissues. The synthesis of very long chain derivatives, which requires tetrahydrofolate polyglutamates as substrates, is a very slow process in vivo. The slow metabolism of 5-methyltetrahydrofolate to retainable polyglutamate forms causes the decreased tissue retention of folate in B12 deficiency. Although cellular folylpolyglutamate distributions change in response to nutritional and physiological modulations, it is unlikely that these changes play a regulatory role in one-carbon metabolism as folate distributions respond only slowly. 4-Aminofolates are metabolized to retainable forms at a slow rate compared to folates. Although folate accumulation by cells is not very responsive to changes in folylpolyglutamate synthetase levels and cellular glutamate concentrations, cellular accumulation of anti-folate agents would be highly responsive to any factor that changes the expression of folylpolyglutamate synthetase activity.
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A 250 mg tablet of timegadine was given twice daily for 15 days to 13 healthy volunteers. On Day 16 a single morning dose of timegadine was supplemented by two 200 mg tablets of a proprietary brand of ibuprofen. Serum concentrations of timegadine were measured by high pressure liquid chromatography, and steady state was achieved between Days 5 and 8. Serum concentrations of two metabolites of timegadine, MI and MII were measured by thin layer chromatography by Leo Pharmaceutical Products, Denmark. Ibuprofen did not significantly affect the serum half-time of timegadine, but did reduce the maximum measured serum timegadine concentration, the area under the serum concentration versus time curve and the time to achieve maximum measured serum concentration. Serum liver enzymes remained within the normal ranges and there were no changes in hepatic microsomal enzyme activity as assessed by urinary excretion of D-glucaric acid.
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Use of the single-radial-haemolysis (SRH) technique for the diagnosis of flavivirus infections is described. A large number of paired and single convalescent serum samples collected from cases of encephalitis during two major outbreaks in Kolar district of Karnataka State in India during 1977 and 1979 were tested by this technique. The results were compared with those obtained in the haemagglutination inhibition (HI) test in all cases, and the complement fixation (CF) and neutralization tests in some cases. Japanese encephalitis virus was shown by the SRH test to be the major etiologic agent responsible for both epidemics. This was corroborated by the HI, CF and neutralization test results. The single-radial-haemolysis test was found to be simpler and more specific and sensitive than the haemagglutination inhibition test.
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A method is described for the preparation of viable hepatocytes from a marine fish, the plaice. Their ability to detoxify organic compounds was measured by the formation of glucuronic acid and sulphate conjugates with the model substrates 1-naphthol and phenolphthalein. 1-Naphthol was conjugated three- to four-fold faster than phenolphthalein and glucuronidation predominated with both substrates. Strong substrate inhibition of glucuronidation was observed with 200 microM 1-naphthol or phenolphthalein. No measurable sulphate conjugation was detected with phenolphthalein. Treatment of fish with 3-methylcholanthrene induced formation of both glucuronide and sulphate conjugates by two- to three-fold. Compared with rat hepatocytes, the extent of sulphation was 100-fold lower in plaice hepatocytes whereas glucuronide formation was only 10-fold lower. The observations indicate that isolated plaice hepatocytes provide a suitable system for studies of the detoxication of xenobiotic pollutants in fish liver.
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Fifty one patients with suspected pulmonary embolus were studied by radionuclide ventilation-perfusion scanning and intravenous digital subtraction pulmonary angiography. In 31 patients the results of both investigations were reported as negative and in a further 11 both results were reported as positive, giving a concordance rate of 82.3%. In nine patients there was disagreement between the two investigations and an attempt to resolve this difference on the basis of clinical data was made. On this basis digital subtraction angiography would have falsely classified three patients as not having an embolus who were correctly identified by radioisotope scanning. Angiography would, however, have correctly classified four patients misclassified by ventilation-perfusion scanning. The relative merits of digital subtraction angiography and radionuclide lung scanning are discussed.
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