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Biomedical subjects

R Govindarajan

Publications and source records attributed to R Govindarajan.

31 records · Page 2Linked to original sources
PubMed1997

Metabolism and activities of 3'-azido-2',3'-dideoxythymidine and 2',3'-didehydro-2',3'-dideoxythymidine in herpesvirus thymidine kinase transduced T-lymphocytes.

T-lymphocytes transduced with the conditionally toxic herpesvirus thymidine kinase gene (HSV-1 TK) are increasingly becoming important tools in genetic therapy approaches for treating viral infections and cancers. Therefore, the effects of different antiviral nucleoside drugs on the growth inhibition of parental and HSV-1 TK-transduced human T-lymphocyte cell lines (H9 and CEM TK-) were examined. As expected, both transduced cell lines were most sensitive to growth inhibition by ganciclovir (GCV). While the presence of HSV-1 TK did not potentiate 3'-azido-2',3'-dideoxythymidine (AZT) growth inhibition of H9 cells containing cellular TK; transduction of HSV-1 TK into the cellular TK-deficient CEM cells (CEM TK-) restored sensitivity to AZT. In both transduced cell lines, an HSV-1 TK-dependent growth inhibition with 2',3'-didehydro-2',3'-dideoxythymidine (d4T) was observed and a Km of 143 microM for d4T and HSV-1 TK was determined. Metabolic labeling analysis showed that drug metabolism correlated with the observed effects on cell growth. The effects of HIV-1 replication in the CEM TK- cell lines in the presence of AZT or d4T was evaluated. CEM TK- cells are largely resistant to AZT or d4T inhibition of HIV-1 replication, however, transduction of HSV-1 TK into the CEM TK- cells completely restored AZT and d4T inhibition of HIV-1 replication. These studies confirm the requirement for a thymidine kinase activity for the anti-HIV activities of d4T and suggest that AZT, but not d4T, could be potentially administered to patients receiving HSV-1 TK-transduced lymphocytes.

Acyclovir↗
PubMed1996

Preceding standard therapy is the likely cause of MDS after autotransplants for multiple myeloma.

Myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) have been reported after autologous transplantation (AT) for lymphoma. It is not clear whether myeloablative therapy used in conjunction with autologous transplantation contributes to the development of MDS/AML or whether the conventional chemotherapy preceding the transplant, and administered over a prolonged period, causes these secondary malignancies. To address this issue, we examined 188 patients with multiple myeloma (MM) who had received AT. 71 patients with no more than one cycle of standard chemotherapy were enrolled in our Total Therapy program, designed to avoid exposure to alkylating agents prior to peripheral blood stem cell mobilization (group 1). The median duration of pretransplant therapy in group 1 was 7.6 months and significantly shorter than the 24 months of 117 patients (group 2) with more prolonged conventional therapy (P = 0.0001). All seven patients developing MDS post-transplantation belonged to group 2 (P = 0.02); the median durations from initial therapy and first transplant were 66 months (range 38-86) and 24 months (range 9-39), respectively. Our findings provide evidence that prolonged standard-dose alkylating agent therapy prior to transplantation, rather than autotransplant-supported myeloablative treatment, is associated with development of MDS/AML. Stem cell damaging alkylator treatment should be avoided, not to compromise PBSC collection, but also to reduce the risk of treatment-related MDS/AML.

Aged↗
PubMed1995

Precipitation reactions with Newcastle disease virus.

Acid precipitated and detergent treated Newcastle disease virus (NDV) antigen was prepared and characterised using the agar gel precipitation (AGP) test. The detergent treated NDV antigen was used to screen antibodies to NDV and the results compared with the conventional haemagglutination inhibition (HI) test titres. AGP test could detect NDV antibodies in serum samples when the corresponding HI titres were 1:8 and above. Detergent treatment of Newcastle disease virus greatly reduced its haemagglutinating ability. Simultaneous detection of antibodies to NDV and infectious bursal disease virus in AGP test was attempted and found successful.

Animals↗
PubMed1994

Delayed ultrastructural lung maturation in the fetal and newborn hypothyroid (Hyt/Hyt) mouse.

Thyroid hormones influence fetal and neonatal lung growth and maturation. However, the effect of naturally occurring, genetically determined hypo- or hyperthyroidism on fetal or neonatal lung maturation has not been examined. In the hyt/hyt mouse, primary hypothyroidism, which is characterized by a high serum TSH concentration, is transmitted as an autosomal recessive trait. It occurs due to a mutational defect in the beta-subunit of the TSH receptor. We studied the lung ultrastructure of the fetal [18-d-gestation (term = approximately 19.5 d)] and neonatal (< 1-d-old) hyt/hyt mouse. In addition, disaturated phosphatidylcholine and total phospholipid contents of newborn hyt/hyt mouse lungs were determined. Male and female hyt/hyt mice with a high serum TSH concentration were made euthyroid by adding 3,5,3'-triiodothyronine to drinking water and then mated. Balb-c mice served as euthyroid controls. Fetal and neonatal hyt/hyt mice had a higher serum TSH concentration than the Balb-c controls. Fetal hyt/hyt mouse lungs showed a large amount of intracellular glycogen and fewer lamellar bodies in epithelial type II cells compared with Balb-c fetal mouse lungs. The neonatal hyt/hyt mouse also showed signs of lung immaturity such as persistent epithelial cell glycogen, few lamellar bodies, reduced disaturated phosphatidylcholine content, and absent tubular myelin. We conclude that fetal and neonatal lung maturation is delayed in the hyt/hyt mouse with primary hypothyroidism.

Animals↗
PubMed1993

Mutational analysis of the transforming and apoptosis suppression activities of the adenovirus E1B 175R protein.

The role of the adenovirus-2 E1B 19-kDa (175R) T antigen in E1a-cooperative transformation was determined by cotransfection of plasmids expressing E1A or E1B 175R T antigens into primary rat kidney (BRK) cells. Transformed cells were selected by virtue of their resistance to the antibiotic Geneticin (G418) conferred by neo gene co-expression from plasmids coding for 175R. 175R cooperated efficiently with genomic E1a and specifically with the 289R protein coded by the 13S mRNA in the transformation of primary BRK cells. Mutational analysis of the 175R protein revealed that the N terminus and the C-terminal 30 amino acids are not essential for E1a-cooperative transformation. Several conserved sequences located in the middle of the 175R protein are essential for transformation. The effect of various mutants to suppress apoptosis (programmed cell death) induced by an anti-cancer agent, cisplatin, was examined in cells producing the E1A and E1B 175R proteins. Apoptosis was measured by flow cytometric analysis and indicates that the 175R protein efficiently prevents cisplatin-induced apoptosis. This suggests that the 175R function involved in transformation segregates with its ability to suppress cisplatin-induced apoptosis.

Adenovirus E1A Proteins↗
PubMed1991

Heterologous basic domain substitutions in the HIV-1 Tat protein reveal an arginine-rich motif required for transactivation.

The Tat protein coded by HIV-1 is a unique eukaryotic transactivator. It activates gene expression from the viral LTR by its interaction with a nascent RNA element (TAR) located at the 5' end of all HIV-1 transcripts. Tat appears to bind to its target RNA structure in a highly sequence-specific manner. The TAR-binding activity of Tat has been localized in an Arg-rich basic domain located between residues 49 and 57 of the Tat protein. We have carried out domain substitution studies with heterologous basic domains which are also implicated in RNA binding. Here, we report that a 19 or a 12 amino acid region from the N-terminus of HTLV-I Rex can functionally substitute for the Tat basic domain. In contrast, the Arg-rich domains of the N gene products of bacteriophages lambda and 21 do not functionally substitute for the Tat basic domain. The positive and negative effects of various domain substitution mutants have facilitated identification of a consensus sequence (Arg/Lys-X-X-Arg-Arg-X-Arg-Arg) in the basic domain required for Tat activity. Conversion of the functionally inactive basic domain of the lambda N protein to the consensus motif restored the transactivation function of the Tat-N chimeric protein. Similarly, the Rex basic domain containing scrambled sequences unrelated or partially related to the consensus motif were either totally defective in transactivation or exhibited reduced activity. Our results further suggest that the activity of the core Arg motif may be enhanced by the presence of Gln or Asn within the basic domain.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1990

Ascovirus infectivity and effects of infection on the growth and development of noctuid larvae.

The infectivity per os and by inoculation of ascoviruses isolated from Heliothis zea, Spodoptera frugiperda, and Trichopulsia ni and the effects of infection by these viruses on host growth and development were studied in the species from which these viruses were originally isolated, or in the case of the H. zea isolate, in H. virescens. Mortality caused by all three viral isolates averaged less than 15% in third instars fed doses of 10 to 10(5) viral vesicles per larva incorporated into diet, whereas inoculation with as few as 10 viral vesicles consistently yielded mortality rates greater than 90%. In tests where groups of 10 larvae were inoculated sequentially with a minuten pin that had been inserted into the hemocoel of an infected larva and then dried for up to 24 hr, mortality rates were consistently greater than 90%. The latter results suggest that ascoviruses in the field may be vectored by insect parasites. The studies of the effects of infection on larval growth and development demonstrated a marked loss of appetite and a decrease in weight gain within 24-48 hr of infection in all three isolates. Third instars inoculated at a weight of ca. 15 mg gained little weight after infection and had difficulty molting, but survived in an arrested state of development for 2-5 weeks. Controls pupated within 5-7 days after attaining weights, depending on the host species, in the range of 300-500 mg. Arrested development and lack of weight gain appear to be due to decreased feeding, whereas the long survival of infected larvae is likely due to the limited destruction of host tissues.

Animals↗
PubMed1990

Comparative histopathology of three ascovirus isolates in larval noctuids.

The histopathology caused by three ascoviruses isolated respectively from Heliothis zea, Spodoptera frugiperda, and Trichoplusia ni was studied in the host species from which the viruses were isolated originally, or in the case of the H. zea isolate, in H. virescens. In all three isolates, infected cells and virion-containing vesicles in the hemolymph were observed by 3 days postinoculation. The isolates from H. zea and T. ni exhibited relatively broad tissue tropisms infecting the tracheal matrix, epidermis, and connective tissue, and in the latter isolate, the fat body. Although considered variants of the same virus, these isolates varied slightly in their tissue tropism in that the isolate from H. zea replicated more extensively in the epidermis. The isolate from T. ni replicated in the fat body during early stages of disease, but not in advanced stages, and was not as common in the epidermis as the isolate from H. zea. The isolate from S. frugiperda replicated only in the fat body and completely destroyed this tissue by 12 days postinoculation. The progression of disease within the tissues was correlated with a rise in the concentration of virion-containing vesicles in the hemolymph of all three isolates. Vesicle concentrations rose from 10(7) on day 2 to 10(8)/ml of hemolymph on day 9, plateaued for 5-7 days, and then declined gradually through day 20. These results indicate that the chronic nature of the diseases caused by ascoviruses is due to the limited degree to which they infect major tissues (isolates from T. ni and H. zea) or the infection of tissues less essential to the maintenance of larval life (isolate from S. frugiperda).

Animals↗
PubMed1977

Left ventricular wall resection for aneurysm and akinesia due to coronary artery disease: fifty consecutive patients.

Left ventricular wall resection with or without vein bypass grafting was performed in 50 consecutive patients with aneurysm or an akinetic segment with poor left ventricular hemodynamics. Ejection fraction averaged 29% and left ventricular end-diastolic pressure averaged 20 mm Hg. Associated valve disease was present in 14 patients (28%). Hospital mortality was 22% (11 patients) and late mortality was 20% (10 patients). The lowest mortality (3%, 1 death) was found in patients who had anterior apical resection with associated vein bypass, in whom prophylactic balloon pumping was used when needed for ejection fractions of less than 30%. A high mortality occurred with associated valve replacement (6 deaths, 86%) and posterior aneurysm. Among 39 patients followed for an average of twenty-four months, 34 (87%) improved one class and 18 (46%) improved two classes of the New York Heart Association Functional Classification.

Adult↗