Search PubMed⌕ Search

Biomedical subjects

G Das

Publications and source records attributed to G Das.

At least 19 recordsLinked to original sources
PubMed1995

Basal promoter elements as a selective determinant of transcriptional activator function.

In eukaryotes, activation of transcription involves an interplay between activators bound to cis-regulatory elements and factors bound to basal elements near the start site of transcription. The basal elements, for example the TATA box or proximal sequence element (PSE) of small nuclear RNA (snRNA) promoters, nucleate the assembly of basal transcription complexes, components of which interact with activators. Although one basal transcription complex can interact with many activators, it is unclear whether different basal transcription complexes can direct different responses to particular activators. We show here that changing the arrangement of basal elements can alter the response to transcriptional activation domains. Indeed, in the human U6 snRNA promoter, point mutation of either a TATA box or PSE results in diametrically opposed responses to VP16- and Sp1-derived activation domains. These basal elements can even discriminate small changes in an activation domain. Thus the arrangement of basal promoter elements provides a mechanism for differential regulation of transcription.

Amino Acid Sequence↗
PubMed1995

Macrophage-T cell interaction in experimental visceral leishmaniasis: failure to express costimulatory molecules on Leishmania-infected macrophages and its implication in the suppression of cell-mediated immunity.

The most important immunopathological consequence of infection with Leishmania seen in murine and human hosts is the suppression of T cell-mediated immune responses to both mitogens and leishmanial antigens. It has been suggested that this suppression is mediated by macrophages, either by defective antigen processing and presentation or by the elaboration of suppressive mediators like prostaglandins. Optimum activation of T helper cells requires not only T cell receptor occupancy by the antigen-Ia complex, but also costimulatory signals provided by the antigen-presenting cells. We investigated the status of several costimulatory molecules on infected macrophages from both genetically susceptible BALB/c and resistant C57BL/6 mice. Our results demonstrate that upon parasitization, the macrophages become unable to deliver costimulatory signals to T helper cells, and that this effects is mediated by prostaglandins, as the inhibition of its synthesis by indomethacin recovered the defect. Upon infection with L. donovani, B7-1 expression was decreased, while ICAM-1 was marginally increased in BALB/c macrophages and there was no significant change in the expression of B7-1 and ICAM-1 in Leishmania-infected C57BL/6 macrophages. Expression of VCAM-1 did not change during infection. This selective alteration in the expression of costimulatory molecules on L. donovani-infected BALB/c macrophages was caused by the living parasite, as shown by the fact that killing of the parasites by stibogluconate led to no alteration in the levels of costimulatory molecules. We found that the change in B7-1 expression on the surface of infected macrophages resulted in the inhibition of delayed-type hypersensitivity-mediating functions of T helper cells from BALB/c mice. The results described in this study not only throw light on the possible mechanism of leishmanial pathogenesis, but also open up the possibility of immunotherapy of leishmaniasis by selective manipulation of costimulatory molecules.

Animals↗
PubMed1994

Macrophage-T cell interaction in experimental mycobacterial infection. Selective regulation of co-stimulatory molecules on Mycobacterium-infected macrophages and its implication in the suppression of cell-mediated immune response.

The most important immunopathological consequence of experimental mycobacterial infection is the suppression of T cell-mediated immune response to both mitogens and mycobacterial antigens. We registered that there was decreased concanavalin A-induced spleen cell proliferation in infected susceptible BALB/c mice as compared to normal mice. In resistant (C3H/HeJ) mice, infection with the bacteria did not induce any suppression in the mitogen-induced lymphoproliferation. Likewise, delayed-type hypersensitivity (DTH) responses, to keyhole limpet hemocyanin and mycobacterial crude soluble antigen were suppressed in infected BALB/c mice but not in C3H/HeJ mice. This depressed T helper cell function may either be due to defective T cell-receptor occupancy by antigen-Ia complex or altered co-stimulatory signals provided by antigen-presenting cells. In the present study, we have investigated the status of certain co-stimulatory molecules on the infected macrophages from both susceptible and resistant mice. Our results demonstrate that upon mycobacterial infection, the macrophages are rendered incapable of delivering the co-stimulatory signals to T helper cells, possibly due to the involvement of prostaglandin, as inhibition of its biosynthesis by indomethacin reversed the defect. Furthermore, the selective regulation was bacteria-induced as killing of the bacteria by rifampicin abrogated the derangements in the expression of co-stimulatory molecules on the Mycobacterium-infected macrophages. Our observations revealed that upon infection with Mycobacterium tuberculosis, B7 was down-regulated while ICAM-1 was increased only in BALB/c but not in C3H/HeJ mice. Expression of VCAM-1 did not change during the infection in either strain of mice. We found that these changes in ICAM-1 and B7 expression on the surface of infected macrophages resulted in inhibition of DTH-mediating functions of T helper cells from BALB/c mice. The results obtained in this study describe not only a novel immune evasion strategy adopted by Mycobacterium, but also open up the possibility of immunotherapy of mycobacterial infection by selective manipulation of co-stimulatory molecules.

Animals↗
PubMed1991

Enhanced thermodynamic stabilities of yeast iso-1-cytochromes c with amino acid replacements at positions 52 and 102.

We have determined the structures and thermodynamic stabilities of the wild type Asn-52 and unusually thermostable mutant Ile-52 yeast iso-1-cytochromes c (Das, G., Hickey, D. R. McLendon, D., McLendon, G., and Sherman, F. (1989) Proc. Natl. Acad. Sci. U.S.A. 86, 496-499). Although both structures were similar, Water-166, buried within the wild type protein, is excluded from the Ile-52 mutant, which substantially reorganizes the local hydrogen bonding. Wild type Cys-102 was replaced with alanine or serine to eliminate dimerization in vitro. The Cys-102 (wild type), Ala-102, and Ser-102 proteins were equally stable, whereas the chemically modified Cys-102-SCH3 was less stable. The order of stability observed with replacements at positions 52 and 102 was as follows: Ile-52 Ala-102 greater than Ala-52 Ala-102 greater than Asn-52 Ala-102 ("normal") greater than Gly-52 Ala-102. No significant stabilization was attributed to potential energy interactions expressed as helix-forming propensities of replacements at position 52. A high correlation between differences in free energy changes and transfer free energies suggests hydrophobic interactions are the main factor for enhancing stability in the Ile-52 mutant. Additional possible contributions to the thermostability of the Ile-52 variant are energetic effects due to packing and hydrogen bonding changes surrounding position 52.

Amino Acids↗
PubMed1991

Percutaneous balloon mitral valvuloplasty in rheumatic mitral stenosis: an experience of 50 patients in India.

We attempted percutaneous balloon mitral valvuloplasty in 50 patients (27 female and 23 male, age 10-38 years) with rheumatic mitral stenosis. The procedure could be completed in 40 patients. The failures were caused by problems related to transseptal puncture in eight cases and inability to cross the mitral valve in two cases. Immediately after valvuloplasty there was a remarkable reduction in the mean pulmonary artery pressure, left atrial mean pressure, mean diastolic gradient across the mitral valve, and the calculated pulmonary vascular resistance. The calculated mitral valve area increased and the cardiac index increased marginally. Inadequate results with a post valvuloplasty mitral valve area of 0.9 cm2 were seen in only one patient. Repeat hemodynamic evaluation in 25 patients within two weeks of valvuloplasty showed persistent benefit in all except one patient, who showed partial restenosis. Follow-up cardiac catheterization at 3-6 months in 13 patients showed evidence of restenosis (mitral valve area less than 1.0 cm2 and mean diastolic gradient of greater than 10 mmHg) in one patient, while all others maintained hemodynamic benefit. Repeat hemodynamic evaluation at 9-18 months after valvuloplasty in eight patients showed evidence of restenosis in an additional two cases. The patients in our series are young (28 patients less than 20 years), small body surface area (1.35-0.2 m2), and have high left atrial and pulmonary arterial pressures.

Adolescent↗
PubMed1990

QT interval and repolarization time in patients with intraventricular conduction delay.

A prolonged QT interval is an important prognostic indicator for cardiac arrhythmias and sudden death. The conventional QT interval measurement, however, includes in its measure the cardiac depolarization (QRS) as well as the cardiac repolarization (JT) intervals. To evaluate the relative contribution of the depolarization and the repolarization time prolongation to the prolonged QT interval in patients with intraventricular conduction delay (IVCD), the QRS, QT, and JT intervals were measured in 72 subjects with various types of IVCD. The observed intervals in IVCD subjects were compared to similar intervals in 33 healthy individuals in whom there was no evidence for intraventricular conduction abnormalities. The QTc (QT interval corrected for heart rate) in subjects with IVCD were 445 +/- 6.8 msec (mean +/- SEM) in those with LAD, 470 +/- 9.1 msec with RBBB, and 489 +/- 6.9 msec with LBBB. All of these intervals were significantly prolonged compared to 430 +/- 4.3 msec in the control group. The prolongation of QTc interval in each category of IVCD subjects was entirely secondary to a prolonged depolarization time, as the repolarization intervals were not significantly different from those observed in the control group (F = 0.5, p = NS). These observations may provide an explanation for the differential prognosis for subjects with prolonged QT interval with prolonged repolarization time as compared to those with prolonged QT interval with prolonged depolarization time.

Adult↗
PubMed1990

Multicentre controlled trial of indoramin in the symptomatic relief of benign prostatic hypertrophy.

A group of 139 patients with symptoms of bladder outflow obstruction due to benign prostatic hypertrophy were entered into a double-blind, parallel group, multicentre study of 2 doses of indoramin versus placebo. There were 18 withdrawals or exclusions, leaving 121 patients for analysis. After 8 weeks, mean peak flow rates increased more in patients treated with indoramin 20 mg bd than in those with placebo. The difference between indoramin 20 mg nocte and placebo was not significant. The change in mean peak flow rate for the higher dose of indoramin represented an increase of 50%. Both patients and investigators reported that the patients' symptoms had improved significantly on both indoramin 20 mg bd and 20 mg nocte; 9 patients were withdrawn because of adverse events, 5 taking placebo and 2 in each of the treatment groups. It was concluded that indoramin 20 mg bd was both effective and well tolerated in the management of symptomatic benign prostatic hypertrophy.

Aged↗
PubMed1990

Artificial cardiac pacemakers.

Artificial pacemakers are electronic devices used primarily to control cardiac rate in patients in whom the intrinsic heart rate is inadequate for a normal life style. These devices automatically and rhythmically provide electrical impulses to stimulate the heart. Electrical stimulation of various organs of the human body was already in practice more than two centuries ago. These applications, however, were in experimental stages until recently when electrical stimulation of the heart has emerged as a new therapy. In view of the astonishing progress made in the field of pacemaker technology and the current indications for the specific types of pacing systems, it behooves physicians caring for patients with heart disease to become familiar with the use of cardiac pacemakers and the not infrequent problems associated with their use. The primary purpose of this review is to present fundamental knowledge in the electrical stimulation of the heart and the various pacing systems available.

Cardiac Output↗
PubMed1990

Cocaine and the cardiovascular system.

Cocaine abuse is widespread and increasing in North America. One in every four Americans has used cocaine for its euphorogenic properties. The cardiovascular actions of cocaine are similar to those observed following intense sympathetic stimulation. Cocaine increases heart rate, blood pressure and myocardial oxygen demand. Yet, paradoxically it decreases oxygen supply by inducing coronary vasoconstriction, leading to myocardial ischemia. This myocardial ischemia undoubtedly forms the substrate for most of the cardiovascular complications observed with cocaine use. In this article, the history, clinical pharmacology and complications of cocaine abuse are reviewed.

Cardiovascular System↗
PubMed1989

Esmolol versus verapamil in the acute treatment of atrial fibrillation or atrial flutter.

The effects of esmolol, an ultrashort-acting beta blocker, and verapamil were compared in controlling ventricular response in 45 patients with atrial fibrillation or atrial flutter, in a randomized, parallel, open-label study. Patients with either new onset (less than 48 hours, n = 31) or old onset (greater than 48 hours, n = 14) of atrial fibrillation or flutter with rapid ventricular rate were stratified to receive esmolol (n = 21) or verapamil (n = 24). Drug efficacy was measured by ventricular rate reduction and conversion to sinus rhythm. The heart rate declined with esmolol from 139 to 100 beats/min (p less than 0.001) and with verapamil from 142 to 97 beats/min (p less than 0.001). Fifty percent of esmolol-treated patients with new onset of arrhythmias converted to sinus rhythm, whereas only 12% of those who received verapamil converted (p less than 0.03). Mild hypotension was observed in both treatment groups. Esmolol compares favorably with verapamil with respect to both efficacy and safety in acutely decreasing ventricular response during atrial fibrillation or flutter. Moreover, conversion to sinus rhythm is significantly more likely with esmolol.

Adrenergic beta-Antagonists↗
PubMed1989

Dramatic thermostabilization of yeast iso-1-cytochrome c by an asparagine----isoleucine replacement at position 57.

Two Saccharomyces cerevisiae yeast mutants, cyc1-73 and cyc1-190, contain nonfunctional and presumably unstable forms of iso-1-cytochrome c due to Gly-34----Ser and His-38----Pro replacements, respectively. Second-site reversions that produced Asn-57----Ile replacements at least partially restored function, presumably by alleviating the instability of these two altered iso-1-cytochromes c. Introduction of the Ile-57 replacement by site-directed mutagenesis in an otherwise normal protein resulted in a 17 degrees C increase in the transition temperature (Tm), corresponding to over a 2-fold increase in the free energy change (delta G degrees) for thermal unfolding.

Amino Acid Sequence↗
PubMed1989

Therapeutic review. Cardiac effects of atropine in man: an update.

The use of atropine in cardiovascular disorders is mainly in the management of patients with bradycardia. Atropine increases the heart rate and improves the atrioventricular conduction by blocking the parasympathetic influences on the heart. Recent observations that atropine in low doses results in paradoxical effects at the sinoatrial node (vagotonic) and the atrioventricular node (vagolytic) have lead to a concern for its safety in patients with acute myocardial infarction and bradycardia. This review discusses the basic cardiovascular pharmacology of the atropine, explores the mechanisms responsible for its paradoxical effects and discusses the clinical implications of these observations.

Atropine↗
PubMed1989

Beta-methyl digoxin: a better absorbable digoxin.

Since Megges and Repke [1961] showed that acetylation of the hydroxyl groups in the aglycone or the sugar side chain of the digitalis molecule results in a derivative with enhanced and more complete absorption from the gastrointestinal tract, several new compounds resulting from acetylation or methylation of digoxin molecule have been developed. Beta-methyl digoxin (beta-methyl digoxin) is a methyl derivative (methyl group in position 4 of the digitoxose residue) of digoxin. Enhanced and more complete gastrointestinal absorption of tritium labeled beta-methyl digoxin [Rennekamp et al. 1972] has been confirmed. Weiss et al. [1975], based on the serum levels following oral administration, calculated that to achieve comparable levels, digoxin dose would have to be increased by 1.55 times compared to that of beta-methyl digoxin. These and other studies supported an earlier notion that beta-methyl digoxin was a better and desirable cardiotropic agent than the digoxin. Comparison of cardiac effects using equivalent doses of the two compounds however, showed no difference [Das et al. 1977]. Following oral administration, the serum glycoside levels to beta-methyl digoxin indeed were significantly greater than those with digoxin. However, these differences in serum levels were not of sufficient magnitude to influence detectable cardiac inotropic effects, hence, the search for a better digoxin should continue.

Digoxin↗
PubMed1989

Fish oil in heart disease.

Observations of significantly lower total cholesterol, low density lipoprotein (LDL) cholesterol and higher levels of high density lipoprotein (HDL) cholesterol among Eskimos as compared to Danes in all age groups and both genders, and the current emphasis on the role of cholesterol in atherosclerosis have stimulated several studies that have examined the effects of dietary fish or fish oil supplements on plasma lipids. Conclusions from these studies suggest a favorable change in the plasma lipids in subjects with higher intake of dietary fish or those receiving fish oil supplements towards a decreased incidence of atherosclerosis and hence the coronary artery disease. This article is an attempt to review the current understanding of the effects of fish oil on blood lipids and its role in the heart disease.

Animals↗