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R Prasad

Publications and source records attributed to R Prasad.

At least 127 records · Page 7Linked to original sources
PubMed1997

Structure-activity studies for a novel series of N-(arylethyl)-N-(1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-N-methylamine s possessing dual 5-HT uptake inhibiting and alpha2-antagonistic activities.

In search of an alpha2-antagonist/5-HT uptake inhibitor as a potential new class of antidepressant with a more rapid onset of action, compound 3 was prepared and observed to possess high affinity for the alpha2-receptor (K(i) = 6.71 nM) and the 5-HT uptake site (20.6 nM). A series of tertiary amine analogs of 3 were synthesized and assayed for their affinity at both the alpha2-receptor and the 5-HT uptake site. The structure-activity relationship reveals that a variety of structural modifications to the arylethyl fragment are possible with retention of this dual activity. On the tetralin portion, 5-OMe substitution and the (R) stereochemistry at C-1 are optimal with alternate substitutions producing compounds retaining high affinity for the alpha2-receptor but lacking affinity for the 5-HT uptake site. Data for several rigidified 5-O-alkyl analogs suggests that the favored orientation of the oxygen lone pairs may be away from the 6-position of the tetralin.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed1997

Probing structure/function relationships of HIV-1 reverse transcriptase with styrene oxide N2-guanine adducts.

Details of the interactions between the human immunodeficiency virus (HIV-1) reverse transcriptase and substrate DNA were probed both by introducing site-specific and stereospecific modifications into DNA and by altering the structure of potential critical residues in the polymerase. Unadducted 11-mer DNAs and 11-mer DNAs containing R and S enantiomers of styrene oxide at N2-guanine were ligated with two additional oligonucleotides to create 63-mers that served as templates for HIV-1 reverse transcriptase replication. Oligonucleotides that primed synthesis 5 bases 3' to the adducts could be extended up to 1 base 3' and opposite the lesion. However, when the positions of the 3'-OH of the priming oligonucleotides were placed 1, 2, 3, 4, 5, and 6 bases downstream of the styrene oxide guanine adducts, replication was initiated, only to be blocked after incorporating 4, 5, 6, and 7 bases beyond the lesion. The sites of this adduct-induced termination corresponded to the position of the DNA where alpha-helix H makes contact with the DNA minor groove, 3-5 bases upstream of the growing 3' end. In addition, mutants of the polymerase in alpha-helix H (W266A and G262A) alter the termination probabilities caused by these DNA adducts, suggesting that alpha-helix H is a sensitive monitor of modifications in the minor groove of newly synthesized template-primer DNA several bases distal to the 3'-OH.

Base Sequence↗
PubMed1997

Prediction of the femoral neck-shaft angle from the length of the femoral neck.

A total of 171 adult South Indian femora, devoid of gross pathology, are used to measure the neck-shaft angle, length of the neck, intertrochanteric apical axis length, maximum vertical diameter of the head, kinematic radius, and maximum femoral length. The neck-shaft angle ranges from 120 degrees to 136 degrees with a mean of 126.7 degrees and no significant side difference. The angle significantly and positively correlates with neck length, intertrochanteric apical axis length, kinematic radius, and minimum femoral length (P < 0.001) but not with the vertical diameter of the head. Regression equations for the neck-shaft angle against the correlated parameters are derived but only that against the length of the neck is strongly significant. From those correlations, 1) the neck-shaft angle can be estimated from a proximal femoral fragment, and 2) the required size of the length of the neck can be determined to design prostheses for the restoration of normal neck-shaft angle. Further, any estimated defective angle can be of help for forensic identification of an individual with pathological changes leading to an abnormal gait.

Adult↗
PubMed1997

Analysis of carbohydrate deficient transferrin by capillary zone electrophoresis.

We report a capillary zone electrophoresis method to separate the various sialylated isoforms of transferrin. The separation is carried out under nondenaturing conditions and at basic pH. Under these conditions, transferrin exhibits two major and three minor peaks. Plasma samples from a population consuming varying amounts of alcohol at different intervals were studied. A cut-off value of 3% carbohydrate deficient transferrin (CDT: disialo, monosialo, and asialo transferrin), results in a clinical sensitivity of 88% in a population consuming at least 70 g/day alcohol for a minimum of two weeks. The sensitivity dropped significantly in a population consuming less than 70 g/day. This confirms previous reports of CDT as a specific marker for significant and chronic use of alcohol. Capillary electrophoresis offers an alternative method with respect to analysis time and throughput in the clinical laboratory.

Animals↗
PubMed1997

Capillary electrophoresis-based separation of transferrin sialoforms in patients with carbohydrate-deficient glycoprotein syndrome.

The heterogeneity associated with protein glycoforms has been a challenge to analytical chemists and the subject of structure-function studies for biochemists since their presence in biological systems had been confirmed some three decades ago. Initial investigations led to discoveries of synthetic and degradative pathways, and brief forays into functional determination of the "glyco" portion on the protein activity in glycoproteins. Only recently has it come to our understanding that variations from the "normal" glycosylation patterns might be indicative of pathological states. The presence of certain transferrin (Tf) glycoforms in human serum has been shown to correlate with certain clinical syndromes. Hence, the ability to separate and quantitatively measure the various forms of human Tf has become increasingly important. It this study, we demonstrate that a simple method utilizing a DB-17-coated capillary to slow endoosmotic flow and a sieving buffer containing hydroxyethyl cellulose allows for the resolution of sialoforms of transferrin. An analysis time of less than eight minutes allows for baseline resolution of the lower sialoforms of Tf, presenting a simple, rapid test for carbohydrate-deficient transferrin (CDT). We demonstrate the utility of this methodology for the facile diagnosis of carbohydrate-deficient glycoprotein syndrome, and postulate that it may allow for the detection of other carbohydrate-deficient protein-related disease states.

Animals↗
PubMed1997

Pepsinogen polymorphism in the Indian population and its association with duodenal ulcer.

To date, there have been few studies on pepsinogen polymorphism. The present study examines the polymorphism of pepsinogen by PAGE in 155 duodenal ulcer cases and 92 control subjects. The Indian population presents a higher frequency of the B phenotype (associated with absence of the pg 5 fraction) and the C haplotype compared to other populations. Heterozygotes, in particular AC phenotypic individuals, are found to be associated significantly with the disease compared to control subjects. All the genes of the multigene complex controlling pepsinogen polymorphism seem to be interacting, thereby leading to such an association. Thus, studies at the gene level may be helpful in explaining the genetic etiology and heterogeneity of duodenal ulcer disease.

Adult↗
PubMed1997

Alterations in isoforms of glutathione S-transferase in liver and kidney of cadmium exposed rhesus monkeys: purification and kinetic characterization.

Exposure of animals to cadmium (Cd) (25 mg kg(-1) body wt day(-1)) for 10 weeks resulted in preferential accumulation of the metal in liver and kidney. Cd accumulation concomitantly increased zinc (Zn) concentration in both the organs. However, significant decrease in copper level was observed in liver, whereas kidney showed increase in copper (Cu) level. Cd exposure resulted in decreased total GST activity in liver (63%) and kidney (41%) as compared to control group monkeys on normal diet (group I). On isoelectric focusing (IEF) control liver GST segregated into thirteen isoenzymes, while in Cd-treated experimental animals (group II) liver GST resolved into nine isoenzymes. Similarly kidney GST from control animals separated into seven isoenzymes as compared to four isoenzymes from Cd-treated animals. Kinetic analysis showed that Cd exposure did not alter the affinity constant (Km) of GST for GSH and CDNB whereas maximal velocity (Vmax) for these substrates decreased as compared to controls in both the organs, indicating inhibition in GST synthesis by Cd. Cd resulted in a noncompetitive type of inhibition with respect to GSH in vitro. On isoelectric focussing GST of liver and kidney in group II resolved into nine and four isoenzymes as compared to thirteen and seven in group I, showing loss of four basic isoenzymes in case of liver and three isoenzymes in case of kidney. Monkey liver and kidney expressed all the three classes of GST isoenzymes i.e. alpha, mu and pi, which were serologically identical to human alpha, mu and pi GSTs.

Animals↗
PubMed1997

Pituitary, gonadal and adrenal hormones after prolonged residence at extreme altitude in man.

High altitude-induced alterations in pituitary, gonadal and adrenal hormones were studied in (i) eugonadal men from the armed forces who were resident at sea level (SL), (ii) SL residents staying at an altitude of 3542 m for periods ranging from 3 to 12 months (acclimatized lowlanders, ALL), (iii) ALL who stayed at 6300 m for 6 months, (iv) ALL who trekked from 3542 to 5080 m and stayed at an altitude of more than 6300 m in the glacier region for 6 months, and (v) high-altitude natives (HAN) resident at an altitude of 3300-3700 m. Circulating levels of LH, FSH, prolactin, cortisol, testosterone, dihydrotestosterone (DHT) and progesterone in ALL at 3542 m and in HAN were not significantly different (p > 0.05) from the SL control values. When the ALL living at 3542 m trekked to an extreme altitude of 5080 m, their testosterone levels showed a significant decrease (p < 0.01) compared to the preceding altitude values but had returned to SL values when measured after 6 months' continuous stay at 6300 m. As with testosterone, the levels of DHT and oestradiol-17 beta (E2) after prolonged stay at extreme altitude were also not significantly different (p > 0.05) from the SL values. The LH levels after trekking to 5080 m were significantly higher (p < 0.01) than at an altitude of 3542 m, but decreased to levels found at 3542 m or SL after prolonged residence at extreme altitude. Plasma levels of ACTH, prolactin, FSH and cortisol on arrival at 5080 m, and after a 6-month stay at extreme altitude, were not significantly different (p > 0.05) from the SL values. Plasma progesterone levels tended to increase on arrival at 5080 m but a significant increase (p < 0.001) was evident only after a 6-month stay at extreme altitude. These observations suggest that prolonged residence at lower as well as at extreme altitude does not appreciably alter blood levels of pituitary, gonadal or adrenal hormones except for plasma levels of progesterone. The exact mechanism and significance of this increase remains unknown, but may be important in increasing the sensitivity of the hypoxic ventilatory response and activation of haemoglobin synthesis.

Acclimatization↗
PubMed1997

Changing the transport of a cell.

The review deals with some of the transport functions of different systems that have been implicated with several pathological disorders. Membrane transport role in parasitic diseases and metal resistance is discussed as a few selected examples. Among various limitations that are encountered in recombinant technology and in heterologous expression of proteins, transport functions of the host organisms cannot be ignored. Recently, membrane transport has acquired a new emerging role in multidrug resistance. Several membrane transporters, particularly ATP binding cassette (ABC) proteins that are involved in drug resistance, have been identified throughout the evolutionary scale. The review briefly emphasizes that membranes are not only important as structural elements but are also adopted to perform diverse functions.

ATP-Binding Cassette Transporters↗
PubMed1997

Electrolyte disturbances due to ouabain sensitive sodium potassium pump in erythrocytes of children with sepsis.

The possible mechanism of hyponatraemia in septicaemic children was studied by measuring the intracellular red cell sodium in relation to ouabain sensitive Na(+)-K(+) pump by flame photometry. Hyponatraemia and hyperkalaemia were observed in most of the patients. There was a marked elevation in serum sodium levels and a significant reduction in serum potassium levels on recovery following therapy. The alteration in the distribution of electrolytes between plasma and erythrocytes resulted in significantly high levels of sodium and low levels of potassium within the erythrocytes of septicaemic patients which normalized on recovery. The ouabain sensitive sodium efflux rate and ouabain sensitive efflux rate constant were significantly decreased in the membranes of erythrocytes of septicaemic patients which also normalized on recovery. Our findings suggest that it is the intrinsic alterations in the transport capacity of Na(+)-K+ pump which could account for the rise in intracellular erythrocyte sodium and fall in intracellular potassium contents in septicaemic children.

Child↗
PubMed1997

Intravenous magnesium sulfate in acute severe asthma not responding to conventional therapy.

OBJECTIVE: To evaluate the effectiveness of early administration of intravenous Magnesium sulfate (i.v. MgSO4) in children with acute severe asthma not responding to conventional therapy. DESIGN: Randomized double-blind, placebo-controlled trial. SETTING: Pediatric emergency service of a large teaching hospital. SUBJECTS: 47 children aged between 1-12 years with acute severe asthma showing inadequate or poor response to 3 doses of nebulized salbutamol given at an interval of 20 min each. INTERVENTION: The MgSO4 group received 0.2 ml/kg of 50% MgSO4 as intravenous (i.v.) infusion over 35 minutes and the placebo group received normal saline infusion in the same dose and at the same rate. MgSO4 solution and normal saline were coded and dispensed in identical containers. Decoding was done at the completion of the study. All the patients received oxygen, nebulized salbutamol, i.v. aminophylline and corticosteroids. RESULTS: MgSO4 group showed early and significant improvement as compared to placebo group in PEFR and SaO2 at 30 min and 1, 2, 3 and 7 hours after stopping the infusion (p ranging from < 0.05 to < 0.01). The clinical asthma score also showed significant improvement in the MgSO4 group 1, 2, 3 and 11 hours after stopping the infusion (p < 0.01). CONCLUSION: Addition of MgSO4 to conventional therapy helps in achieving earlier improvement in clinical signs and symptoms of asthma and PEFR in patients not responding to conventional therapy alone.

Acute Disease↗
PubMed1997

Quo vadis, IMA.

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Developing Countries↗
PubMed1996

Kinetic characterization of zinc binding to brush border membranes from rat kidney cortex: interaction with cadmium.

Extravesicular and intravesicular zinc bindings were evaluated in brush border membrane vesicles isolated from rat kidney cortex. The process was found to be time-, temperature- and substrate concentration-dependent and displayed saturability. Zn2+ influx measurements revealed a progressive uptake and massive accumulation at equilibrium which was 50 times higher than the amount that could have been accommodated by the intravesicular space calculated from the equilibrium uptake of D-glucose. Initial (5 s) and equilibrium uptakes (2 h) were found not to be osmotically sensitive as modified by adding mannitol to the medium. It was concluded from these results that the uptake involved massive binding of the Zn2+ to the brush border membranes components. The ionophore A23187 enhanced the rates of uptake and efflux of Zn2+ without affecting equilibrium values, suggesting binding of Zn2+ to interior sites of the membranes. Zn2+ flux measurements led to the conclusion that two vesicular pools of Zn2+ bindings existed: a small external pool, accessible to cation chelator (EGTA) or competitive cation cadmium and large intravesicular pool. Accumulated 65Zn was quickly removed from its internal sites only after the membrane had been permeabilized by the cation ionophore A23187 in association with exchangeable ions like zinc and cadmium. Scatchard plot analysis revealed two distinct types of extravesicular binding sites. High affinity extravesicular zinc binding sites reached saturation at 1.6 mM zinc, had a Kd of 137 microM and the number of binding sites were 12 nmol/mg protein. Low affinity extravesicular zinc binding sites could not be saturated under experimental conditions up to 3.2 mM zinc. It had a Kd of 526 microM and the number of binding sites 28 nmol/mg protein. Interestingly intravesicular binding of zinc revealed only one type of high affinity binding sites (Kd of 104 microM and number of maximal binding sites 400 nmol/mg protein). Furthermore, kinetic analysis of inhibitory effect of Cd2+ on extravesicular zinc bindings showed an increase in Kd of both types of binding sites but there was no significant change in number of maximal binding sites. Extravesicular zinc binding was temperature-sensitive. Arrhenius plot showed the break point at 30 degrees C. The apparent energies of activation were 13.36 Kcal/mol and 3.1 Kcal/mol below and above the break points respectively. The inhibitory effect of sulfhydryl blocking agents on extravesicular zinc binding suggest the involvement of -SH groups in zinc translocation. An increase in initial zinc uptake was observed in the presence of outwardly directed proton gradient. Intravesicular pool of 65Zn was displaced by unlabelled 2 mM Zn2+ or 2 mM Cd2+ but not by calcium present in the bathing medium. It is inferred that intravesicular binding sites have a high affinity and are specific for zinc. It is concluded from the present study that in the first instance the binding of zinc to the exofacial zinc binding component and concomitantly its translocation across the membrane, and subsequently massive binding of zinc to interior sites of brush border membranes occurs.

Animals↗
PubMed1996

dNTP binding to HIV-1 reverse transcriptase and mammalian DNA polymerase beta as revealed by affinity labeling with a photoreactive dNTP analog.

The dNTP binding pocket of human immunodeficiency virus type 1 reverse transcriptase (RT) and DNA polymerase beta (beta-pol) were labeled using a photoreactive analog of dCTP, exo-N-[beta-(p-azidotetrafluorobenzamido)-ethyl]-deoxycytidine-5'- triphosphate (FABdCTP). Two approaches of photolabeling were utilized. In one approach, photoreactive FABdCTP and radiolabeled primer-template were UV-irradiated in the presence of each enzyme and resulted in polymerase radiolabeling. In an alternate approach, FABdCTP was first UV-cross-linked to enzyme; subsequently, radiolabeled primer-template was added, and the enzyme-linked dCTP analog was incorporated onto the 3'-end of the radiolabeled primer. The results showed strong labeling of the p66 subunit of RT, with only minor labeling of p51. No difference in the intensity of cross-linking was observed with either approach. FABdCTP cross-linking was increased in the presence of a dideoxyterminated primer-template with RT, but not with beta-pol, suggesting a significant influence of prior primer-template binding on dNTP binding for RT. Mutagenesis of beta-pol residues observed to interact with the incoming dNTP in the crystal structure of the ternary complex resulted in labeling consistent with kinetic characterization of these mutants and indicated specific labeling of the dNTP binding pocket.

Affinity Labels↗