Biomedical subjects
R C Sharma
Publications and source records attributed to R C Sharma.
Exfoliative dermatitis and malignant melanoma: coincidence or association.
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Preparation of electrocompetent E. coli using salt-free growth medium.
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Need-based planning versus individual ambition.
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Distribution of uranium in human organs of an urban Indian population and its relationship with clearance half-lives.
This organ burdens of uranium were estimated for an urban Indian (Bombay) population living in a normal background environment, using the technique of neutron activation analysis, in combination with post-irradiation chemical separation. The total organ burdens were: skeleton > muscle > soft tissue > lungs > kidney > liver > heart. A comparison was made between the observed organ burdens of uranium for skeleton, kidney, and muscle with those obtained by applying the metabolic model of uranium as recommended by International Commission on Radiological Protection (ICRP) to its daily intake by urban population. The observed organ burdens for kidney and muscle were found to be 4 and 70 times higher than the derived burden values; however, the two estimates were similar in the case of skeleton. This observation indicated that the clearance half-lives for uranium present in kidney and muscle tissue are likely to be longer than those reported by ICRP. For skeleton, however, the clearance half-life reported by the ICRP appeared to be reasonable.
Studies on the biological half-lives of three important radionuclides released in nuclear power reactor operations.
The four important parameters involved in the calculation of internal radiation dose to the human body, per unit intake of a radionuclide are 1) weight and size of the body organs; 2) the biological (retention) half-life of the radionuclide; 3) radiation weighting factors for the type of radiations emanating from the radionuclide; and 4) the organ weighting factors for the organs being irradiated (target organs). Whereas, for a particular radionuclide, the radiation weighting factor and the organ weighting factors may remain constant for all humans, the other two parameters, namely, the organ weights and biological half-life, are population specific and may differ from one population group to another. For a realistic dose estimation, the population specific data on organ weights and biological half-lives for various radionuclides therefore, are needed.
Tuberous sclerosis: unusual associations.
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Inhibitors of blood platelet cAMP phosphodiesterase: a QSAR analysis.
A quantitative structure-activity relationship (QSAR) analysis of two related series of the derivatives of 7-substituted imidazo [4,5-b]-quinolin-2-one active as inhibitors of human blood platelet cAMP phosphodiesterase (PDE) is presented with a view to reflecting upon the parametric requirements of the side chain as well as of the N-1 and N-3 substitutions on the heterocycle. For the first series (Figure 1) consisting of 114 congeners and having a more flexible functionalized side chain at the 7-position and only binary variations (Me or H) at N-1 and N-3, it has been shown that bulk (Vw), of the functionalized side chain tends to potentiate the inhibitory activity of a derivative while positions N-1 and N-3 should better remain unsubstituted, as reflected through the dummy variables. A similar analysis of the compounds of the second series (Figure 2), where a less flexible side chain is linked through a basic nitrogen, has provided a parabolic dependence of inhibition activity on Vw. From this relationship, a limiting size of the side chain, seems to be necessary for triggering a minimal response.
A theoretical structure-activity relationship study of 2-alkoxy-adenosines: selective agonists at the coronary artery A2-adenosine receptor.
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Limits of lipid-lowering therapy: the benefits of amlodipine as an anti-atherosclerotic agent.
Treatment of atherosclerosis has mainly focused on decreasing low-density lipoprotein cholesterol (LDL-C). However, recent coronary angiographic trials revealed that aggressive lowering of LDL-C below 100 mg/dl arrests atherosclerosis progression in only 50-60% of patients. Furthermore, quantitative coronary angiography in these trials showed significant regression only in advanced fibrous-fatty plaques (> or = 50% stenosis) and not in the younger, more cell-proliferative lesions (< 50% stenosis). It is clear that lipid-lowering therapy has limited efficacy and there is therefore a need for other drugs, especially anti-proliferative agents, for secondary and primary prevention. To test this hypothesis, a new calcium antagonist, amlodipine, was studied for its anti-atherogenicity in non-human primates because of its known in vitro anti-cell proliferant, cell membrane stabilising and anti-oxidant properties. Amlodipine was found to normalise elevated plasma levels of oxidised LDL without reducing elevated total LDL-C levels in monkeys fed an atherogenic diet which, however, significantly suppressed atherosclerosis progression. These data suggest that amlodipine may be an excellent candidate, in combination with lipid-lowering drugs, for dual therapy of atherosclerotic vascular disease and may also be effective as monotherapy even when LDL-C is not lowered satisfactorily.
Heterogeneity in the mitotic checkpoint control of BALB/3T3 cells and a correlation with gene amplification propensity.
Chinese hamster ovary (and many rodent cell lines) transiently delay mitosis and progress into a second cell cycle without undergoing cytokinesis when treated with Colcemid, whereas HeLaS3 (and most human cell lines) arrest permanently in mitosis. We have discussed these differences and their consequences for cell survival under cell cycle-perturbing conditions within the context of mitotic checkpoint control (Schimke et al., Cold Spring Harbor Symp. Quant. Biol., 56: 417-425, 1991). Here, we report studies with mouse BALB/3T3 cell populations which, by the criterion of response to Colcemid, constitute a heterogeneous population with respect to mitotic checkpoint control. Clonal and subclonal populations retain population heterogeneity but with a bias for enrichment of cell populations that respond as do HeLaS3 cells. We have analyzed clones for their propensity for gene amplification as assessed by a stepwise increment selection protocol in methotrexate and report that there are significant differences in amplification propensities that correlate with differences in mitotic checkpoint control properties.
The propensity for gene amplification: a comparison of protocols, cell lines, and selection agents.
We have studied cell lines of rodent and human origin for their propensity to become resistant to antifolates (methotrexate, trimetrexate), phosphonacetyl-L-aspartate (PALA), and colcemid, resistances associated with amplification of the DHFR, CAD, and MDR1 genes, respectively. We have employed two different methods: (1) a shallow step-wise selection protocol, where time to attain specified resistance is the quantitative measure, (2) the frequency of resistant colonies at specified drug concentrations. Although there are advantages and disadvantages to both methods, the two methods gave the same relative ranking of cell lines. Striking differences in the propensity for gene amplification (resistance) were found: human cell lines were less prone to amplify genes than Chinese hamster ovary (CHO) cells. This ranking was similar with all of the agents employed. Additionally, we observed that whereas PALA resistance in CHO cells is associated with amplification of the CAD gene, PALA resistance in the two human cell lines studied (HeLaS3 and VA13) was not associated with amplification and/or overexpression of the CAD gene, and thus this resistance to PALA occurs by an unknown mechanism.
Accuracy of self reporting malaria in Orissa--a case study.
For rapid assessment of malaria in difficult forested areas in Orissa a study on the accuracy of self-reporting of malaria showed 72 per cent accuracy along with the sensitivity and specificity values of 46 per cent and 76 per cent respectively. The study clearly indicates its utility in the ongoing national malaria eradication programme and can be effectively used for rapid assessment of the disease prevalence. The information so gathered can be used for rapid assessment by the planners and programme managers in devising the strategies for the containment of malaria in the forested areas of Orissa.
A quantitative structure-activity relationship study of ligands exhibiting agonist and antagonist actions with cholecystokinin-receptors.
Observed biological activities of substituted phenyl urea/thiourea tetrapeptides as agonists with the cholecystokinin-alimentary canal (CCK-A) receptor, and (R)-4-benzamido-5-oxopentanoic acid derivatives with both peripheral (CCK-A) and the central (CCK-B) (brain) receptors have been shown to be correlated with various physicochemical, e.g. pi, sigma, and structural, e.g. Vw and dummy, I, parameters. These results were, then interpreted to predict promising criteria for having ligands with better affinity with the CCK receptors.
A quantitative analysis of binding affinities of ligands active at adenosine receptors.
Binding affinities, pKi's, of 1,3-dipropyl-8-phenylxanthines and 8-substituted xanthines as selective antagonists at A(1)- and A(2)- adenosine receptors, were quantitatively analysed in terms of hydrophobic parameter, pi, and van der Waals volume, Vw. For ligands of the first series, the hydrophobicity of para-substituents and the bulk of meta-substituents are shown to be the deciding factors. Similarly, for the other series, the binary substitutions at X-, Y- and R-positions, highlighted by respective dummy variables, and the bulk rendered by groups at R(1)-position, are found to be significantly correlated with A(1)- and A(2)-receptor affinities. Additionally, the Free-Wilson study of this series resulting into individual substituent contribution, provides similar inferences to these, but in a more exact manner. This study also hints at the possibility of a different accommodation site at the receptor for the R(1)-substituents of the congeners on account of conformational dissimilarity of A(1)- and A(2)-receptors.
Cellular detoxification of tripeptidyl aldehydes by an aldo-keto reductase.
Calpain inhibitor I, N-acetyl-leucyl-leucyl-norleucinal (ALLN), a cell-permeable synthetic tripeptide with an aldehyde at its C terminus specifically inhibits the activity of cysteine proteases. Since the regulated degradation of 3-hydroxy-3-methylglutaryl-CoA reductase in Chinese hamster ovary (CHO) cells is blocked by ALLN and ALLN has a cytotoxic effect on cells, we attempted to isolate ALLN-resistant cells that overproduce an ALLN-sensitive protease(s). However, we obtained an ALLN-resistant cell line that overproduced P-glycoprotein (Sharma, R. C., Inoue, S., Roitelman, J., Schimke, R. T., and Simoni, R. D. (1992) J. Biol. Chem. 267, 5731-5734). To circumvent the multidrug resistance (MDR) phenotype during selection, we have stepwise selected an ALLN-resistant cell line of CHO cells in the presence of verapamil, a competitive inhibitor of P-glycoprotein. These non-MDR ALLN-resistant cells overexpress a 35-kDa protein and have increased aldo-keto reductase activity. Partial amino acid sequences of the 35-kDa protein are highly homologous to members of the aldo-keto reductase superfamily. The aldo-keto reductases are NADPH-dependent oxidoreductases and catalyze reduction of a wide range of carbonyl compounds such as aldehydes, sugars, and ketones. Our findings support the concept that a physiological function for aldo-keto reductases may be detoxification.
Body fat and fat distribution by anthropometry and the response to high-fat cholesterol-containing diet in monkeys.
Considerable variability exists among individuals in the response of plasma cholesterol to changes in dietary fat and cholesterol, and obesity is one variable reported to affect this response. This study was performed to determine the relationship between body fat and changes in plasma cholesterol in cynomolgus monkeys fed a high-fat cholesterol-containing diet for 12 months. The animals gained significant body weight (body mass index increased from 30.5 +/- 0.5 to 35.7 +/- 2.8 kg/m2) and skinfold parameters of body fat increased as well. Total cholesterol increased from 109 +/- 4 to 390 +/- 25 mg/dl (P < 0.001), and there were also significant increases in LDL- and HDL-cholesterol and triglyceride. While there was very little relationship between body fat and plasma lipids before the diet, after 12 months, there were significant negative correlations between total and LDL-cholesterol and anthropometric measures of body fat (r ranged from -0.37 to -0.55, P < 0.01). The correlations were not affected when the effects of baseline body mass index and serum cholesterol and total food intake were controlled by partial correlation analysis. In this sample of animals, the acquisition of greater body fat appeared to protect against rises in cholesterol in response to consumption of a high-fat cholesterol-containing diet.
Dyskeratosis congenita: a case report.
Dyskeratosis congenita, an uncommon situation in females, is described in a 30-year-old woman. The expression of the disease was partial and was characterized by mottled pigmentation, nail dystrophy, palmoplantar keratoderma, and hyperhidrosis.