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Biomedical subjects

R P Sharma

Publications and source records attributed to R P Sharma.

At least 109 records · Page 6Linked to original sources
PubMed1992

Effects of benzo[a]pyrene on steady-state levels of biogenic amines and metabolizing enzymes in mouse brain regions.

Benzo[a]pyrene (BaP) is a product of incomplete fossil fuel combustion, a well-known pollutant, and a carcinogenic agent. In the present study male CD-1 mice received ip injections of 0, 5, 25, and 100 mg/kg body weight BaP twice a week for 3 weeks. Endogenous levels of brain biogenic amines and their selected metabolites, norepinephrine (NE), dopamine (DA), 5-hydroxytryptamine (5-HT), vanillylmandelic acid, dihydroxyphenylacetic acid (DOPAC), homovanillic acid, and 5-hydroxyindoleacetic acid (5-HIAA) were measured using high performance liquid chromatography and electrochemical detection. The brain regions studied were cortex, striatum, hypothalamus, midbrain, medulla oblongata, and cerebellum. BaP treatment increased the steady-state levels of NE, DA, and 5-HT in the hypothalamus and striatum. Increased levels of DA and 5-HT and their major metabolites DOPAC and 5-HIAA were noticed in the same region, an indication of increased metabolism of these amines. The increase in the 5-HT level in the cortex was not dose-related. Levels of NE and DA were significantly higher in the medulla oblongata. There was a concurrent increase in activities of tyrosine hydroxylase and tryptophan hydroxylase in several brain regions. The effect of BaP on Dopa-decarboxylase was not consistent. Monoamine oxidase was occasionally inhibited. Results indicate that exposure to BaP altered the steady-state levels of biogenic amines in various brain regions and these changes were consistent with the activities of metabolizing enzymes.

Animals↗
PubMed1992

Monoamine oxidase and cortisol response in depression and schizophrenia.

The relationship between hypothalamic-pituitary-adrenal (HPA) axis function and platelet monoamine oxidase (MAO) activity was examined in drug-free depressed (n = 32) and schizophrenic (n = 36) inpatients. HPA function was measured by determining plasma cortisol levels at 8:30 a.m. and 11 p.m. before, and 8:30 a.m., 4 p.m., and 11 p.m. after administration of 1 mg of dexamethasone (DEX). There was a significant correlation between platelet MAO activity and all post-DEX cortisol levels (8:30 a.m., 4 a.m., and 11 p.m.) in depressed patients, and MAO activity and pre-DEX cortisol levels (11 p.m.) in schizophrenic patients. MAO activity was significantly higher in depressed DST nonsuppressors than in suppressors, and there were more DST nonsuppressors in high-MAO groups as compared with low-MAO groups. Our results thus suggest a strong relationship between platelet MAO activity and HPA function in depressed patients. These biochemical markers are potentially useful in the identification of biochemically and clinically homogeneous subgroups of depressed patients.

Adult↗
PubMed1992

Adjuvant activity of all-trans-retinoic acid in C57Bl/6 mice.

The effects of all-trans-retinoic acid were investigated on the immune responses in C57Bl/6 mice after daily oral administration for one week. In selected experiments the immunosuppressive chemicals, cyclophosphamide and cyclosporin A were used in conjunction with retinoic acid. Retinoic acid stimulated the production of antibodies against sheep red blood cells and DNP-Ficoll; however, retinoic acid did not reverse the depression caused by immunosuppressive chemicals. In non-immunized animals retinoic acid stimulated the production of IL-1 but not of IL-2. The mitogenic responses of splenocytes against concanavalin A, phytohemagglutinin and pokeweed mitogen were depressed after the retinoic acid treatment; those against lipopolysaccharide were not influenced. Treatment with retinoic acid did not alter the mixed leukocyte responses but increased the activity of NK cells. Results indicate that retinoic acid may act as an adjuvant via activating macrophages, however, retinoic acid cannot reverse the immunosuppression induced by potent chemicals.

Adjuvants, Immunologic↗
PubMed1992

Acute lower gastrointestinal hemorrhage: treatment by superselective embolization with polyvinyl alcohol particles.

OBJECTIVE: The major risk of transcatheter embolotherapy for acute hemorrhage in the lower gastrointestinal tract is irreversible intestinal ischemia. The authors studied the efficacy and safety of superselective transcatheter embolization with polyvinyl alcohol particles in arresting acute hemorrhage in the lower gastrointestinal tract. SUBJECTS AND METHODS: All patients with clinical or scintigraphic evidence of acute hemorrhage in the lower gastrointestinal tract were considered for superselective embolization. The nine patients with angiograms that showed active hemorrhage in the lower gastrointestinal tract underwent the procedure. Superselective embolization was done through a 3-French catheter and was accomplished by using 100- to 590-microns polyvinyl alcohol particles. The segments of the intestinal tracts involved in the embolizations were examined for the presence of ischemia by endoscopy (n = 7) or histologic evaluation of a surgical specimen (n = 2) 2-44 days (mean, 11 days) after embolization or by clinical evaluation (n = 1). RESULTS: The lesions treated by this method were located in the colon (n = 8) and jejunum (n = 1). Immediate hemostasis was achieved in every case. Three patients had recurrent lower gastrointestinal hemorrhage 1-24 days (mean, 9 days) after initial embolization. Two of these patients had surgery, while one had a successful second embolization. Two asymptomatic patients were found endoscopically to have small areas of ischemia involving only the mucosa. Only one patient was shown to have severe mucosal ischemia; this involved the colon in a distribution that suggested it was not caused by the embolization. CONCLUSION: Ten superselective embolization procedures that used polyvinyl alcohol particles successfully controlled hemorrhage in the lower gastrointestinal tract in nine patients. In no case was intestinal infarction induced by the procedure, and only two endoscopically proved cases of asymptomatic mucosal ischemia occurred.

Acute Disease↗
PubMed1992

The efficacy of psychotropic drugs: implications for power analysis.

The estimation of the correct sample size to successfully test a hypothesis has become critical. A common approach to this problem is for the investigating team to complete a pilot study of a few patients to establish the "active drug-placebo" difference, using this "effect size" to perform the power analysis for sample size estimation. Given the variability evident in the effect size from completed and published studies, the pilot study approach may not be entirely dependable. The authors propose a method to obtain this initial "active drug-placebo" difference, in the field of psychotropic drug research. They apply meta-analysis to statistically summarize effect sizes obtained from an exhaustive review of the literature for a specific psychotropic drug in a given clinical condition. All double-blind, random assignment studies are used to calculate the effect size; therefore, no selection bias exists. These literature-based effect sizes are then used to perform the traditional power analysis for sample size estimation. The authors propose these estimations as a convenient reference source for future clinical investigators.

Humans↗
PubMed1991

Behavioral and biochemical effects of methylphenidate in schizophrenic and nonschizophrenic patients.

The authors examined the specific behavioral and biochemical effects of intravenous methylphenidate in a sample of schizophrenic and nonschizophrenic patients. Twenty drug-free patients participated in a double-blind, placebo randomized study of methylphenidate, with multiple samples of plasma homovanillic acid (HVA) and serum growth hormone (GH) obtained during the infusion procedure. Methylphenidate caused a significant increase in positive symptoms that was relatively specific to the schizophrenic patients and was evident even in those with otherwise dormant symptomatology. When behavioral response was correlated with the biochemical responses (i.e., changes in plasma HVA and GH), there was a significant positive relationship between the increase in the BPRS-positive symptoms as well as the hostility/suspiciousness factor, and the increase in GH. These results suggest that the expression of psychotic symptoms may be associated with increased dopaminergic postsynaptic sensitivity, although the nonspecific nature of methylphenidate's actions discourages a stronger interpretation of the results.

Adult↗
PubMed1991

Dephosphorylation of autophosphorylated insulin and epidermal-growth-factor receptors by two major subtypes of protein-tyrosine-phosphatase from human placenta.

The identity of protein-tyrosine-phosphatases (PTPases) active against autophosphorylated insulin receptor was probed by using an insulin-receptor-related peptide phosphorylated on tyrosine (peptide 1142-1153). Two major peaks of PTPase activity were resolved from the particulate (Triton X-100-soluble) fraction of human placenta by chromatography on DEAE-cellulose. The two peaks were purified 1300-2300-fold; other peaks of PTPase activity (greater than 15%) were not detected. Properties of the PTPases indicated that they corresponded to subtypes 1A and 1B. Both subtypes appeared capable of catalysing dephosphorylation of all autophosphorylation sites in three domains of the insulin receptor, with no appreciable difference in the pattern of dephosphorylation detected by two-dimensional tryptic-peptide mapping. The tyrosine-1150 domain of the insulin receptor in triply phosphorylated form was found to be highly sensitive to the action of both PTPases, and was dephosphorylated at least 4 times faster than the doubly and singly phosphorylated forms of the tyrosine-1150 domain or phosphorylation sites in other domains by either PTPase. This is significant, as the level of the triphosphotyrosine-1150 species has been shown to correlate well with the capacity of the insulin-receptor tyrosine kinase to phosphorylate other proteins. Both subtypes also dephosphorylated autophosphorylated epidermal-growth-factor (EGF) receptor by greater than 95%. Placental particulate (and cytosolic) PTPase activity against either receptor distributed approximately 2:1 between subtypes 1A and 1B as assayed in the presence of EDTA. In summary, PTPases within two major subtypes have been identified as phosphotyrosyl-insulin and -EGF-receptor phosphatases in vitro. The PTPases identified exhibit high affinities for substrates and high activities in cells, which is commensurate with the PTPases being important in vivo in controlling or reversing autophosphorylation-induced regulatory or signalling events.

Chromatography, DEAE-Cellulose↗
PubMed1991

Pharmacokinetics of intratracheally administered aflatoxin B1.

High concentrations of the carcinogen aflatoxin B1 (AFB1) are commonly found in respirable, airborne grain dusts, and inhaled AFB1 has been shown to be a risk factor for occupational pulmonary carcinogenesis. The fate of AFB1 exposure via the respiratory tract is therefore of interest in an evaluation of potential occupational risk. The pharmacokinetic disposition of intratracheally administered AFB1 was studied in male Sprague-Dawley rats. Blood and tissues were sampled at selected intervals for 3 weeks following administration of a single dose of grain dust-adsorbed or microcrystalline [3H]AFB1 (6 micro-Ci: microgramsg/kg). The blood concentration-time profiles from both groups best approximated a two-compartment open model with first-order absorption. The first-order absorption rate constant was significantly less in the animals given dust-adsorbed AFB1 than in those receiving microcrystalline AFB1 (0.083 vs -0.1060 min -1, respectively), although the first-order elimination rate constants for both groups were nearly identical (0.00928 and 0.00921 hr-1, respectively). Blood concentrations of the AFB1 metabolites AFM1, AFQ1, AFL, and AFP1 showed little differences among the two groups. The tissue concentrations of aflatoxins for the microcrystalline group were significantly greater at 3 hr in all tissues examined except for the trachea and lung in which those for the dust-adsorbed group were greater. At 3 days and 3 weeks, no significant differences between exposure groups were seen in any tissue except fat, where the amount of aflatoxins was greater for the dust-adsorbed group. AFB1 binding to DNA was significantly greater in the trachea and lung of the dust-adsorbed group compared to that in the microcrystalline group at 3 hr, whereas in the liver the AFB1-DNA binding in the microcrystalline group was significantly greater during this time. Thus, particle association of AFB1 increased the respiratory tract retention of this compound at early time intervals, which might be a factor in the reputed carcinogenic action of this compound in the respiratory tract. These findings may be useful as part of a comprehensive study to evaluate the disposition of AFB1 in individuals exposed to grain dusts laden with this carcinogen.

Absorption↗
PubMed1991

Site-specific dephosphorylation and deactivation of the human insulin receptor tyrosine kinase by particulate and soluble phosphotyrosyl protein phosphatases.

Insulin receptor tyrosine kinase activation, induced by insulin-stimulated autophosphorylation, was measured using a synthetic peptide containing residues 1142-1153 of the insulin receptor and shown to be reversed by both particulate and soluble phosphotyrosyl protein phosphatases from rat liver. Deactivation of the tyrosine kinase was highly sensitive to phosphatase action and was correlated best with disappearance of insulin receptors triphosphorylated in the tyrosine-1150 domain. Dephosphorylation of the di- and mono-phosphorylated forms of the tyrosine-1150 domain generated during dephosphorylation or of phosphorylation sites in the C-terminal or putative juxta-membrane domains occurred 3- greater than 10-fold more slowly than deactivation of the tyrosine kinase, and these phosphorylated species did not appear to appreciably (less than 20%) contribute to tyrosine kinase activation. These results indicate that the transition from the triply to the doubly phosphorylated form of the tyrosine-1150 domain acts as an important switch for deactivation of the insulin receptor tyrosine kinase during dephosphorylation. The exquisite sensitivity of this dephosphorylation/deactivation event to phosphotyrosyl protein phosphatase action, combined with the high affinities of this phosphatases for substrates and the high activities of the phosphatases in cells, suggests that the tyrosine kinase activity expressed by insulin-stimulated insulin receptors is likely to be stringently regulated.

Amino Acid Sequence↗
PubMed1991

Temporal distribution of retinoic acid and cellular retinoic acid-binding protein (CRABP) in the fetal hamster.

The temporal relationship between the distribution of retinoic acid, a known human and rodent teratogen, and that of cellular retinoic acid-binding protein (CRABP) was investigated from Day 11 to Day 14 of hamster prenatal development. The 11,12-(3)H2 and 15(-14C) forms of all-trans-retinoic acid were used for quantitative distribution studies and autoradiography, respectively, and were evaluated 15 min after a single intravenous injection. Radioactivity was detected in all fetal tissues examined (brain, liver, heart, spinal cord, limb, and skin), and at Day 14, approximately 66% of the total radioactivity was present as parent all-trans-retinoic acid. High concentrations of total radioactivity were observed by autoradiography in the midbrain and hindbrain (mesencephalon, metencephalon, and myelencephalon) and spinal cord, but not in the forebrain. At the earliest time studied, limb buds showed relatively high concentrations of radioactivity. Levels of radioactivity were also high in portions of the developing face, nose, and tongue. Immunohistochemical analyses indicated that the amount of CRABP in Day 14 tissues was the highest in spinal cord followed by limb and skin; heart and liver contained only relatively small amounts of this protein. From Day 11 to Day 14, the amount of CRABP, as measured by high-performance size-exclusion liquid chromatography, in the whole body decreased as gestation progressed. Microscopic immunohistochemical localization of CRABP found the highest concentration in the ventral midbrain and in the ventral and lateral sides of the hindbrain and spinal cord; CRABP was also abundant in tongue, limb, and skin. The distribution of CRABP-positive cells in the central nervous system was similar to the distribution of retinoic acid. The data presented here indicate that fetal CRABP appears to play a role in differential accumulation of retinoic acid in certain structures of the developing hamster. The patterns of tissue retinoid and CRABP distribution observed here are consistent with the patterns of congenital malformations induced by prenatal retinoid exposure.

Animals↗
PubMed1991

Agrobacterium mediated genetic transformation of chickpea, Cicer arietinum L.

In leaf and stem explants of chickpea, wild type strains of Agrobacteria were able to induce tumors. These tumors were capable of phytohormone independent growth. A supervirulent strain A281 was found to be most effective. Thus, using an agrobacterium R1601, which carries genes conferring supervirulent phenotype along with a plant selectable marker gene (npt II), transformed calli of chickpea were selected in the presence of 100 micrograms/ml level of kanamycin. Molecular analyses of genomic DNA from transformed calli confirmed the integration of the marker gene into chickpea genome.

Fabaceae↗
PubMed1991

Effects of unilateral-nondominant vs. bilateral ECT on memory and depression: a preliminary report.

Reported are preliminary results from a randomized, double-blind study comparing the differential effects of unilateral-nondominant (UND) and bilateral (BL) electroconvulsive therapy (ECT) on memory function and clinical efficacy. The study included the serial administration (before, shortly after, and 6 months following a course of ECT) of behavioral ratings and memory tests for dominant and nondominant, anterograde and retrograde memory functions. Thus far, clinical improvement shortly after a course of ECT and 6 months later was significant for the entire sample and did not differ between the UND and BL groups. Most memory ratings worsened significantly after ECT, but returned to baseline levels 6 months later. Surprisingly, the scores generally did not differ between the UND and BL groups at any time point. Clinical implications for choice of administration are discussed.

Aged↗
PubMed1991

Steady-state plasma level prediction for haloperidol from a single test dose.

Due to large interindividual variabilities in kinetics of haloperidol (HPDL), empirically adjusting the dose to achieve steady-state plasma levels (Css) is a time consuming process. We report a method to individualize doses to achieve the desired Css from the observed plasma level 24 hours after a single test dose. Twenty-eight acutely psychotic patients, after up to 2 weeks of inhospital drug washout, received a 15-mg oral "test" dose of HPDL and 24- and 48-hour plasma levels were measured. They were then randomly assigned to empirically determined doses of HPDL (2, 4, or 10 mg b.i.d.) to achieve a low, medium, or high Css. The 24-hour plasma level after the test dose, the final Css, and the dose required to achieve that Css were analyzed by a linear regression model. The log Css in terms of the log dose revealed a strong linear relationship (R2 = .78, n = 28), which was further improved by the addition of the 24-hour log plasma level (R2 = .87).

Female↗
PubMed1990

Transmembranous organization of (Ca2(+)-Mg2+)-ATPase from sarcoplasmic reticulum. Evidence for lumenal location of residues 877-888.

An antipeptide antibody was produced against a peptide corresponding to residues 877-888 of fast twitch rabbit sarcoplasmic reticulum ATPase. This antipeptide antibody bound strongly to the ATPase in sarcoplasmic reticulum vesicles only after the vesicles had been solubilized with the detergent C12E8 indicating that its epitope was located in the lumen of the sarcoplasmic reticulum. Digestion of sarcoplasmic reticulum or purified (Ca2(+)-MG2+)-ATPase by proteinase K for up to 1 h resulted in a stable ATPase fragment of 30 kDa containing the epitope for the above antibody and the epitope for an antibody directed against the C terminus. Further proteolysis revealed smaller fragments (Mr 19,000 and 13,000) containing both epitopes. By contrast, small fragments of the ATPase (less than 29 kDa) containing the N-terminal epitope were not observed even after short exposures to proteinase K. These data support the view that the (Ca2(+)-MG2+)-ATPase has 10 transmembranous helices.

Amino Acid Sequence↗
PubMed1990

Dithiocarbamates and prevention of cadmium teratogenesis in the hamster.

Certain dithiocarbamates (DTC) have been reported to protect against cadmium (Cd)-induced lethality and to decrease Cd body burden. The present study evaluated the influence of sodium N-benzyl-D-glucamine dithiocarbamate, sodium N-di(hydroxyethyl)amine dithiocarbamate, sodium 4-carboxyamidopiperidine-N-dithiocarbamate, and sodium N-methyl-D-glucamine dithiocarbamate on Cd-induced teratogenesis in the hamster. When given as a single ip injection at 2.2 mmol/kg 15 min prior to iv CdCl2 (2 mg/kg), all of the DTC afforded significant protection against Cd-induced developmental toxicity and reduced kidney [Cd] in the dam. Maternal liver [Cd] was reduced with the glucamine and dihydroxyethyl amine analogs, but treatment with the piperidine failed to influence hepatic [Cd]. Pretreatment of the dams with DTC 24 hr prior to Cd challenge failed to protect against Cd-induced embryotoxicity, and provided minimal, if any, reduction in renal or hepatic [Cd]. Pretreatment with the N-methyl-D-glucamine congener 24 hr prior to Cd exposure increased embryolethality. The dose-time relationships found here suggest that pharmacologically effective levels of these DTC decline within 24 hr of treatment and that induction of metallothionein does not play a major role in DTC antagonism of Cd poisoning.

Animals↗
PubMed1990

Subclinical effects of groundwater contaminants. III. Effects of repeated oral exposure to combinations of benzene and toluene on immunologic responses in mice.

Toxicity of environmental pollutants may be expressed as combined effects of a chemicals. Benzene, a proven hematotoxic agent, frequently occurs with toluene in cocontaminated groundwater. Groups of CD-1 male mice were exposed continuously for 4 weeks to benzene (166 mg/l), toluene (80 and 325 mg/l), and combinations of benzene (166 mg/l) + toluene (80 mg/l or 325 mg/l) in drinking water. Benzene-induced anemia was alleviated by simultaneous toluene treatment. Leukopenia and lymphopenia were observed in the case of benzene only and benzene + toluene (80 mg/l)-treated mice. The cytopenia, however, was less severe in the benzene + toluene (325 mg/l)-treated group. Immunotoxicity induced by benzene treatment alone was characterized by involution of thymic mass and suppressions of both B- and T-cell mitogeneses, mixed lymphocyte culture response to alloantigens, the tumor lytic ability of cytotoxic T-lymphocytes as determined by 51Cr-release assay, and antibody production response to T-dependent antigen (sheep red blood cells). IL-2 secretion by Con A-stimulated mouse T-cells was decreased in the benzene-treated group. Toluene (325 mg/l) completely inhibited these adverse effects when it was coadministered with benzene, while the low dose of toluene (80 mg/l) did not protect against benzene-induced depressions of immune functions. Toluene administered alone at levels up to 325 mg/l showed no obvious immunotoxic effects. Results of this study demonstrated that toluene, in sufficient amounts, has an antagonistic effect on benzene immunotoxicity.

Administration, Oral↗