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Biomedical subjects

A Madan

Publications and source records attributed to A Madan.

At least 73 records · Page 4Linked to original sources
PubMed1994

Sonographically guided needle biopsy in peripheral thoracic masses: results in 50 patients.

50 patients with thoracic lesions were selected for percutaneous biopsy guided by real-time sonography. The indications were pulmonary, pleural and mediastinal lesions which made contact with the chest wall and sonographically accessible. Included were lesions near vital structures in the mediastinum (n = 3), in the apex of the lung (n = 8), small pulmonary nodules in contact with the chest wall (n = 24), lesions with intervening pleural fluid (n = 2), pleural nodules (n = 9) and masses arising from the chest wall itself (n = 4). A definitive diagnosis was established in 38 of the 45 (84.4%) malignant lesions and in 4 of the 5 (80%) benign lesions. Complications were restricted to one pneumothorax. Sonographically guided biopsy can be carried out as a bedside procedure. Real-time monitoring compensates for respiratory movements. Its role is curbed by intervening air such as in aerated lung, pneumothorax or primarily cavitatory lesions.

Biopsy, Needle↗
PubMed1994

Diethyldithiocarbamate methyl ester sulfoxide, an inhibitor of rat liver mitochondrial low Km aldehyde dehydrogenase and putative metabolite of disulfiram.

S-methyl N,N-diethylthiolcarbamate sulfoxide (DETC-MeSO) is a potent inhibitor of rat liver mitochondrial low Km aldehyde dehydrogenase (ALDH2) both in vivo and in vitro, and has been proposed to be the metabolite responsible for ALDH2 inhibition by disulfiram. Diethyldithiocarbamate methyl ester (DDTC-Me), a key intermediate in the metabolism of disulfiram, has been shown to be bioactivated by microsomal monooxygenases to diethyldithiocarbamate methyl ester sulfoxide (DDTC-Me sulfoxide). Studies were conducted to determine if DDTC-Me sulfoxide was also an active metabolite of disulfiram and inhibitor of ALDH2. DDTC-Me sulfoxide inhibited ALDH2 in vitro with an IC50 of 10 microM, and in vivo with an ID50 of 31 mg/kg (170 mumol/kg). Maximal ALDH2 inhibition in vivo was observed 8 hr after the administration of 45.2 mg/kg DDTC-Me sulfoxide, with ALDH2 activity returning to control levels after 48 hr. Although DDTC-Me sulfoxide inhibited ALDH2 in vivo, DDTC-Me sulfoxide was not detected in plasma from rats treated with either disulfiram (75 mg/kg), DDTC-Me (122.25 mg/kg), or DDTC-Me sulfoxide (45.2 mg/kg). However, DDTC-Me and S-methyl N,N-diethylthiolcarbamate (DETC-Me) were detected in plasma from rats treated with DDTC-Me sulfoxide. In rats treated with DDTC-Me sulfoxide and challenged with ethanol, a small increase of approximately microM in blood acetaldhyde and an inconsistent drop in blood pressure was observed. In conclusion, DDTC-Me sulfoxide inhibited ALDH2 in vitro and in vivo, was less potent than DETC- MeSO, and was not detected after disulfiram administration.

Acetaldehyde↗
PubMed1994

Glutathione- and glutathione-S-transferase-dependent oxidative desulfuration of the thione xenobiotic diethyldithiocarbamate methyl ester.

Oxidative desulfuration of diethyldithiocarbamate methyl ester (DDTC-Me), a thione xenobiotic and a metabolite of disulfiram, was studied. Using a rat liver microsomal incubation system, DDTC-Me was oxidized at the thionosulfur group, forming DDTC-Me sulfine. Only minimal desulfuration of DDTC-Me to S-methyl-N,N-diethylthiolcarbamate (DETC-Me) occurred. Desulfuration of DDTC-Me increased 4-fold when the microsomal incubation was supplemented with reduced glutathione (GSH) and increased 8-fold when both GSH and glutathione-S-transferase (EC 2.5.1.18) were added. Similar results were obtained using a simplified system containing DDTC-Me sulfine, GSH, and glutathione-S-transferase. This suggested that DDTC-Me sulfine is a stable intermediate formed before DDTC-Me is desulfurated to DETC-Me. This unprecedented desulfuration process can be explained as follows. GSH attacks the oxithiirane isomer of DDTC-Me sulfine, resulting in ring opening followed by loss of glutathione hydrodisulfide, which is reduced by GSH to oxidized glutathione and H2S. GSH can also reduce DDTC-Me sulfine to DDTC-Me. This mechanism is supported by in vitro studies. An approximately 1:1 stoichiometry was observed for the formation of H2S and DETC-Me. A 1:1 stoichiometry was also observed for the consumption of DDTC-Me sulfine, formation of DETC-Me plus DDTC-Me, and formation of oxidized glutathione. Glutathione hydrodisulfide was trapped by derivatization in situ using 4-vinylpyridine. Oxidative desulfuration of a series of dithiocarbamate esters also followed a similar mechanism.

Aldehyde Dehydrogenase↗
PubMed1993

Role of flavin-dependent monooxygenases and cytochrome P450 enzymes in the sulfoxidation of S-methyl N,N-diethylthiolcarbamate.

Disulfiram is bioactivated to S-methyl N,N-diethylthiolcarbamate sulfoxide (DETC-MeSO), the metabolite proposed to be responsible for the action of disulfiram as an aldehyde dehydrogenase inhibitor. This bioactivation process includes a reduction, an S-methylation, and two successive oxidations. Sulfur-containing functional groups are substrates for cytochrome P450 enzymes or flavin-containing monooxygenases (FMO). In the present study, we investigated the contribution of these monooxygenases to the formation of DETC-MeSO from its immediate precursor S-methyl N,N-diethylthiolcarbamate (DETC-Me). Liver microsomes obtained from mature male rats were incubated with DETC-Me. The formation of DETC-MeSO was blocked completely by solubilization of the microsomes with the detergent Emulgen 911, or by the presence of the cytochrome P450 inhibitor 1-benzylimidazole. However, thermal-inactivation of FMO resulted in only a partial loss in DETC-MeSO formation. Liver microsomes from phenobarbital-treated rats showed a 4- to 5-fold increase in the rate of formation of DETC-MeSO, compared with controls. Liver microsomes from pyrazole-treated rats showed a 50% decrease in the sulfoxidation of DETC-Me compared with controls. In a purified reconstituted system, cytochrome P450 2B1 (CYP2B1) catalyzed the formation of DETC-MeSO at a rate of 51 nmol DETC-MeSO formed/min/nmol cytochrome P450. Antibodies to CYP2B1 caused a 60% inhibition of DETC-MeSO formation by liver microsomes from phenobarbital-treated rats. These results suggest that in male rat liver microsomes, cytochrome P450 plays a major role in catalyzing the sulfoxidation of DETC-Me, whereas FMO plays a minor role (< 10%). Also, in liver microsomes from phenobarbital-treated rats, CYP2B1 is the major catalyst for the sulfoxidation of DETC-Me.

Animals↗
PubMed1993

A 24-base-pair sequence 3' to the human erythropoietin gene contains a hypoxia-responsive transcriptional enhancer.

Erythropoietin (Epo) synthesis increases in response to hypoxia. The hepatoma cell line Hep 3B produces low basal levels of Epo mRNA which increase markedly with hypoxia. To define the sequences necessary for this response, we linked fragments of the human Epo gene to a luciferase vector, introduced these plasmids into Hep 3B cells and assayed for luciferase activity after growth in 1% or 21% oxygen. A 621-bp Epo promoter fragment resulted in a 2.4-fold increase in luciferase activity with hypoxia. We tested several Epo gene fragments upstream of this Epo promoter fragment and found that a 613-bp Bgl II-Pvu II 3' fragment had a 10-fold increase in activity with hypoxia regardless of orientation. This fragment had a similar level of activity when linked to a simian virus 40 promoter. Portions of this fragment retained activity, including a 38-bp Apa I-Taq I fragment that had a 17-fold increase in activity with hypoxia. Deletion of nt 4-13 or 19-28 from this 38-bp fragment resulted in a loss of activity. The 24-bp upstream portion of the 38-bp fragment showed an 8-fold increase in activity with hypoxia. However, deletion of nt 19-24 or mutagenesis of nt 21 or 22 in this 24-bp fragment resulted in loss of activity. Our studies indicate that the transcriptional response of the human Epo gene to hypoxia is mediated in part by promoter sequences and to a greater degree by an enhancer element located in a 24-bp portion of the 3' flanking sequence of the gene.

Base Sequence↗
PubMed1992

Acute hemorrhagic gastritis in the newborn infant.

We report three cases of hemorrhagic gastritis in term infants that led to massive bleeding of life--threatening proportions in the first 24 hours of life. In all three cases, bleeding was controlled by conservative therapeutic management. Management of this unusual entity in the newborn infant is discussed.

Acute Disease↗
PubMed1991

Preliminary observation on drug resistant cases of typhoid fever.

We report here a sudden and marked increase in the occurrence, in a captive population, of typhoid fever cases showing multiple drug resistance. Fifty one cases of typhoid fever were seen from January '90 to June '90 of which 49% showed multiple drug resistance. Comparative figures for resistance in the previous three years were 0% (1987), 5% (1988), 14% (1989). Shared resistance to chloramphenicol, ampicillin, amoxycillin and sensitivity to gentamicin, kanamycin, sisomycin, cephazolin, norfloxacin and ciprofloxacin in most of our cases suggest infection by a common strain with R-factor, mediated resistance. The illness was prolonged and associated with serious complications. Therapy with combination of quinolone derivatives and aminoglycoside antibiotics seemed justified on the basis of the in-vitro tests and clinical response. Efforts to identify the strain and stern public health measures to prevent further development of drug resistant S typhi are urgently indicated.

Chloramphenicol Resistance↗
PubMed1990

Hepatopulmonary amoebiasis. Efficacy of various treatment regimens containing dehydroemetine and/or metronidazole.

Thirty three patients with hepatopulmonary amoebiasis were studied. Pulmonary involvement was observed in 55%, pleuro-pulmonary lesions in 30%. Typical chocolate coloured sputum was obtained in 24% and pleural fluid in 21% of patients. Entamoeba histolytica were demonstrable in the sputum in only 6% and in the pleural fluid in 15%. The best therapeutic results were obtained with a combination of dehydroemetine and metronidazole. However, metronidazole was found to be nearly as effective as dehydroemetine, and metronidazole 400 mg and 800 mg were equally effective.

Adolescent↗
PubMed1989

Bronchogenic carcinoma. A study of 109 cases.

The clinical profile of 109 cases of bronchogenic carcinoma has been studied. Definite histopathological typing of malignancy was possible in 61 patients, squamous cell carcinoma being the commonest tumour in 27 followed by small cell carcinoma in 16, adenocarcinoma in 11 and large cell carcinoma in 7. Another 23 patients showed changes suggestive of malignancy on histological/cytological examination. Definitive diagnosis was obtained in half of the patients by bronchial biopsy, in 16% by bronchial aspiration fluid cytology, in 13% by pleural biopsy, in 11% by lymph node biopsy and in others by pleural fluid cytology, lung biopsy and skin biopsy. Commonest radiological involvement among different cell types was hilar involvement in small cell carcinoma in 62%, evidence of bronchial obstruction (collapse/consolidation) in squamous cell carcinoma in 56%, peripheral mass in adenocarcinoma in 54% and cavitation in a mass in squamous cell carcinoma in 15% cases.

Adenocarcinoma↗
PubMed1987

Unique immunological behaviour of CD8+ (suppressor T cell) leukaemia cells.

A patient with chronic lymphocytic leukaemia and elevated serum IgM antibody is described. A multiparameter surface marker analysis of his peripheral blood lymphocytes demonstrated a unique phenotype of OKT3-, OKT11+, E-rosetting+, OKT4-, OKT8+, OKIa1+, OKCLL+, OKDR+, Tac+, characterizing the disease as suppressor (CD8+) T cell chronic lymphocytic leukaemia. Because of the uncommon phenotype and the abnormal serum immunoglobulin pattern, in vitro functional assays were performed that showed decreased mitogenic response to the phytohaemagglutinin, but increased response to concanavalin A. However, these leukaemic T cells demonstrated phytohaemagglutinin-specific suppressor cell activity on normal blood lymphocytes. In vitro functional studies indicated that a defect in the patient's T cells may cause IgM hypergammaglobulinaemia. The regulatory function of the patient's T cells on immunoglobulin synthesis by normal B cells was found to be mediated by a soluble factor secreted from neoplastic T cells.

Antigens, Surface↗
PubMedDate not supplied

Autocrine stimulation by erythropoietin in transgenic mice results in erythroid proliferation without neoplastic transformation.

Erythropoietin (Epo) autocrine stimulation has been implicated in erythroleukemia. To develop a model of Epo autocrine stimulation, we made transgenic mice using a construct that linked the human Epo gene to an erythroid-specific regulatory element, designated 5'HS-2, from the human beta-globin locus control region. We hypothesized that Epo gene expression would be targeted to erythroid cells in these mice, resulting in autocrine stimulation of erythroid progenitor cell growth in culture, and that chronic autocrine Epo stimulation would result in erythroleukemia. Transgenic mice containing intact copies of the 5'HS-2Epo construction had elevated hematocrits, reticulocyte counts and serum Epo levels and marked splenic enlargement. Analysis of RNA isolated from organs of transgenic mice revealed constitutive Epo mRNA expression primarily in spleen, blood and bone marrow. RNA samples from anemic transgenic mice revealed Epo gene induction only in the liver. Marrow derived from 5'HS-2Epo mice grew BFU-E in the absence of exogenous Epo. Despite observation of up to 2 years, no mouse developed erythroleukemia, demonstrating that Epo autocrine stimulation alone is insufficient for progression to malignancy. These studies show that 5'HS-2 can be used to target Epo gene expression to erythroid tissue. These mice could provide a model system for studying autocrine growth regulation.

Animals↗