A survey on cyclosporine prescribing and dispensing practices.
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Cyclosporine↗
Biomedical subjects
S Gupta
Publications and source records attributed to S Gupta.
Undifferentiated leukemia following treatment of gastric cancer with 5 fluorouracil, doxorubicin, mitomycin C chemotherapy.
Secondary leukemias are an increasingly well recognized complication of cancer chemotherapy. We report on the development of undifferentiated leukemia in a forty one year lady, eighteen months after treatment of gastric cancer with 5-fluorouracil (5 FU), doxorubicin and mitomycin C. She developed progressive weakness and pancytopenia over a period of few months. Leukemic blasts which were undifferentiated by immunophenotyping were seen in her peripheral blood. She died of intracranial haemorrhage during induction chemotherapy for the leukemia. Undifferentiated leukemia is a rare complication of FAM chemotherapy for gastric cancer.
Adenocarcinoma↗
Impact of hepatitis C virus infection on renal transplant outcome in India--a single centre study.
BACKGROUND: Hepatitis C virus (HCV) infection is currently the main cause of hepatotropic viral infection in renal transplant (RT) recipient throughout the world. Contrary reports are available as regard graft and patient survival and liver disease outcome in these patients. From India, outcome of HCV positive patients following RT has not been documented. Herewith, we present results of RT in HCV positive patients at our centre. METHODS: Study design was prospective case control with primary end point being graft and patient survival and the exposure being HCV infection. Between June 1995 till February 1998, 128 patients had RT at our hospital, of which, 37 (28.9%) were anti-HCV positive at the time of RT. All the patients were on triple immunosuppressive therapy. As a policy of unit, none of the donor had HBV and/or HCV infection. Anti-HCV positive patients formed the subjects (Gr. I), while anti-HCV negative patients severed as control (Gr. II). Anti HCV was done using 3rd generation ELISA tests kit. HCV-RNA could not be done due to non-availability. None of the positive patient was treated with anti-viral therapy. Acute rejection, serious infections, patient and graft survival and outcome of liver disease was compared in these patients. RESULTS: Mean age of the patients, number of males, number of pre-RT haemodialysis and blood transfusion, donor age and HLA-mismatch were comparable in both the groups. Mean follow-up in Gr. I was 28 +/- 9.4 months and in Gr. II 31.4 +/- 7.6 months. At the end of this follow-up, acute rejection was seen in 43% and 33.3% patient in Gr. I and II respectively. In Gr. I, serious infections were seen in 30% while the same in Gr. II was 11.8% (p < 0.01). There was no difference in graft survival in Gr. I and II (72% and 66%) and the patient survival were also similar (72% and 66%). Of the deaths in Gr. I, 80% died of sepsis and 20% died of liver cell failure related to one each of hepatitis B and hepatitis E. Of the deaths in Gr. II, 65% died of sepsis and 17% died of hepatic cell failure. But, there was no difference in causes of deaths in these two groups. In both the groups, none of liver related death was due to isolated HCV infection. There was no effect of donor age, HLA mismatch, number of haemodialysis and pre-RT blood transfusion on the survival of graft as well as patient. CONCLUSION: In conclusion, HCV infection is major problem in RT with us. In a short follow-up of nearly 30 months, graft and patient survival is same in HCV positive and negative patients. However, serious infections are significantly more common in HCV positive patients.
Adult↗
Hypoglycemic effect of aqueous extract of Enicostemma littorale Blume (chhota chirayata) on alloxan induced diabetes mellitus in rats.
The whole plant aqueous extract of E. littorale was tested for its hypoglycemic activity on normoglycemic, hyperglycemic and alloxan induced diabetic rats. Blood sugar lowering activity was not observed in normoglycemic and glucose loaded hyperglycemic rats in the short time experiment. But in case of diabetic rats, the fall of blood sugar after 30 days treatment with the aqueous extract was found to be significant (P < 0.001). The decrease in the plasma glucose level was accompanied with decrease in the level of glycosylated haemoglobin and glucose-6-phosphatase activity in liver. The potent anti-diabetic properties of E. littorale has been reported for the first time.
Alloxan↗
Role of volatile oil pretreatment and skin cholesterol on permeation of ion-paired diclofenac sodium.
This study was designed to investigate the influence of volatile oil pretreated skin on in vitro permeation from films containing ionized and dodecylamine ion-paired diclofenac sodium (DS). The involvement of skin cholesterol was investigated to determine its possible role in enhancing the permeation of ion-paired DS. Cardamom oil produced the maximum (10 x) in vitro permeation enhancement for ion-paired DS. The carrageenan induced rat paw oedema reduction (up to 12 hr) by cardamom oil was comparable to that of diclofenac injection (s c). Leaching of cholesterol from excised skin in addition to increased partition coefficient following volatile oil skin pretreatment appears to be responsible for in vitro permeation enhancement of DS. Whereas, a mild barrier perturbation effect due to altered cholesterol levels following pretreatment with volatile oils appears to increase the permeation of ion-paired DS across viable skin, thereby producing significant reduction of carrageenan induced paw oedema.
Administration, Cutaneous↗
Lineage-specific modulation of interleukin 4 signaling by interferon regulatory factor 4.
Interleukin (IL)-4 is an immunoregulatory cytokine that exerts distinct biological activities on different cell types. Our studies indicate that interferon regulatory factor (IRF)-4 is both a target and a modulator of the IL-4 signaling cascade. IRF-4 expression is strongly upregulated upon costimulation of B cells with CD40 and IL-4. Furthermore, we find that IRF-4 can interact with signal transducer and activator of transcription (Stat)6 and drive the expression of IL-4-inducible genes. The transactivating ability of IRF-4 is blocked by the repressor factor BCL-6. Since expression of IRF-4 is mostly confined to lymphoid cells, these data provide a potential mechanism by which IL-4-inducible genes can be regulated in a lineage-specific manner.
B-Lymphocytes↗
Amelioration of radiation-induced liver damage in partially hepatectomized rats by hepatocyte transplantation.
Hepatic tumors often recur in the liver after surgical resection. Postoperative radiotherapy (RT) could improve survival, but curative RT may induce delayed life-threatening radiation-induced liver damage. Because RT inhibits liver regeneration, we hypothesized that unirradiated, transplanted hepatocytes would proliferate preferentially in a partially resected and irradiated liver, providing metabolic support. We subjected F344 rats to hepatic RT and partial hepatectomy with/without a single intrasplenic, syngeneic hepatocyte transplantation. Hepatocyte transplantation ameliorated radiation-induced liver damage and improved survival of rats receiving RT after partial hepatectomy. We further demonstrated that transplanted hepatocytes extensively repopulate and function in a heavily irradiated rat liver.
Animals↗
Anticlastogenic effects of centchroman and its enantiomers in Swiss albino mice. I. Acute study and their comparison with tamoxifen.
Centchroman (CC), a non steroidal oral contraceptive and a candidate drug for breast cancer, has been reported to exhibit partial to complete remission of lesions in 40.5% of breast cancer patients. Recently, we have reported the antimutagenic effects of CC in multiple mutational assays. The potent antioestrogenic activity, negligible side effects, anti-breast cancer activity and antimutagenic effects of CC prompted us to evaluate the anticlastogenic effects of CC and two of its enantiomers. i.e. D-centchroman (DC) and L-centchroman (LC) in the acute in vivo studies in female Swiss albino mice as measured by chromosome aberrations (CA) and sister chromatid exchange (SCE) assays against two known positive mutagen compounds, i.e. dimethylbenz[a]anthracene (DMBA) and cyclophosphamide (CP). The results of anti-mutagenicity assays of CC and its enantiomers have been compared to the known breast cancer drug tamoxifen (TM). CC and LC reduced both DMBA and CP induced CA when compared with the group treated with only DMBA and CP. DC did not reduce the DMBA-induced CA when compared with the DMBA-treated group alone. It reduces only the CP induced CA. TM also reduces both DMBA and CP induced CA when compared with group received only DMBA or CP. SCE were carried out only for LC. A weak but significant decrease in SCE was observed in both LC plus DMBA- and LC plus CP-treated groups when compared with respective positive controls alone. Thus the overall results indicate that both CC and LC are more effective in reducing the genotoxic effects of DMBA and CP than DC.
9,10-Dimethyl-1,2-benzanthracene↗
IFN-alpha activates Stat6 and leads to the formation of Stat2:Stat6 complexes in B cells.
IFN-alpha consists of a family of highly homologous proteins, which exert pleiotropic effects on a wide variety of cell types. The biologic activities of IFN-alpha are mediated by its binding to a multicomponent receptor complex resulting in the activation of the Janus kinase-STAT signaling pathway. In most cell types, activation of Stat1 and Stat2 by IFN-alpha leads to the formation of either STAT homo-/heterodimers or of the IFN-stimulated gene factor 3 complex composed of Stat1, Stat2, and p48, a non-STAT protein. These distinct transcriptional complexes then target two different sets of cis-elements, gamma-activated sites and IFN-stimulated response elements. Here, we report that IFN-alpha can activate complexes containing Stat6, which, until now, has been primarily associated with signaling by two cytokines with biologic overlap, IL-4 and IL-13. Induction of Stat6 complexes by IFN-alpha appears to be cell type specific, given that tyrosine phosphorylation of Stat6 in response to IFN-alpha is predominantly detected in B cells. Activation of Stat6 by IFN-alpha in B cells is accompanied by the formation of novel Stat2:Stat6 complexes, including an IFN-stimulated gene factor 3-like complex containing Stat2, Stat6, and p48. B cell lines resistant to the antiproliferative effects of IFN-alpha display a decrease in the IFN-alpha-mediated activation of Stat6. Activation of Stat6 as well as of Stat2:Stat6 complexes by IFN-alpha in B cells may allow modulation of target genes in a cell type-specific manner.
B-Lymphocytes↗
Comparative antimutagenic effects of D- and L-centchroman and their comparison with tamoxifen in Salmonella assay.
Centchroman (CC)--a contraceptive and a candidate drug for breast cancer has been developed by the Central Drug Research Institute. It has been successfully marketed as a contraceptive for last several years. CC has also been reported to exhibit partial to complete remission of lesions in 40.5% breast cancer patients. Recently, we have reported the antimutagenic effects of CC in Ames Salmonella assay and in vivo and in vitro mammalian cells in multiple mutational assay. The potent antimutagenic activity of CC and its anti-breast cancer activity prompted us to evaluate the antimutagenic effects of its enantiomers, i.e., D-centchroman (DC) and L-centchroman (LC) in the Ames Salmonella strains TA97a, TA98, TA100 and TA102 against known bacterial mutagens. Attempts have also been made to compare the results of antimutagenicity assays of CC and its enantiomers with the known breast cancer drug tamoxifen (TM). The main objective was to identify the best suitable form of CC having antimutagenic effects with anticancer profile similar to TM, would replace the latter for toxicity reasons. When mutagenicity assays were carried out with these compounds as expected like CC, none of these enantiomers or TM showed any mutagenic effects in these Salmonella strains. In the antimutagenicity assay a significantly reduced number of bacterial histidine revertant colonies were observed when positive compounds were co-incubated with certain concentrations of LC compared with bacterial plates treated with respective positive compound. This was observed in some concentrations in all the four strains in both plate incorporation and preincubation tests. The protective effects of LC in preincubation tests were slightly more than in plate incorporation tests. Both the DC and TM showed protective effects only in certain concentrations in some strains in either plate or preincubation tests. Thus the above results indicate that LC showed more protective effects in Salmonella strains TA97a, TA98, TA100 and TA102 than either DC or TM.
Animals↗
Audit of implantable cardioverter-defibrillators in a single UK centre.
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Adult↗
Prostate cancer chemoprevention by green tea: in vitro and in vivo inhibition of testosterone-mediated induction of ornithine decarboxylase.
Recently, we have shown that ornithine decarboxylase (ODC), a rate-controlling enzyme in the polyamine biosynthetic pathway, is overexpressed in prostate cancer (PCA) and prostatic fluid in humans (R. R. Mohan et al., Clin. Cancer Res., 5: 143-147, 1999). ODC is also characterized as an androgen-responsive gene, and the androgenic stimulation regulates the development and growth of both normal and tumorigenic prostate cells. Thus, chemopreventive approaches aimed toward the modulation of ODC could be effective against PCA. Green tea polyphenols (GTPs) possess strong chemopreventive properties against a variety of animal tumor models and in some human epidemiological studies. At least two epidemiological studies have suggested that people who consume tea regularly may have a decreased risk of PCA. In this study, we investigated the effect of GTPs against testosterone-mediated induction of ODC in human prostate carcinoma cells, LNCaP as an in vitro model, and in Cpb:WU rats and C57BL/6 mice as in vivo models. Treatment of LNCaP cells with testosterone resulted in induction of ODC activity in a dose-dependent manner. Pretreatment of the cells with GTPs resulted in a significant inhibition of testosterone-caused induction of ODC activity in a dose-dependent manner. Similar effects of GTPs were observed in anchorage-independent growth assay of LNCaP cells where pretreatment of the cells with GTP was found to result in dose-dependent inhibition of colony formation. Testosterone treatment of the cells resulted in a significant increase in the level of ODC mRNA, and this increase was almost completely abolished by prior treatment of the cells with GTPs. The administration of testosterone (10 mg/kg body weight, i.p.) to sham-operated and castrated Cpb:WU rats resulted in 2- and 38-fold increases in ODC activity, respectively, in the ventral prostate. Oral feeding of 0.2% GTPs in drinking water for 7 days before testosterone administration resulted in 20 and 54% decreases in testosterone-caused induction of ODC activity in sham-operated and castrated rats, respectively. Similar results were obtained with C57BL/6 mice, where testosterone treatment at similar dosage resulted in a 2-fold increase in ODC activity in the ventral prostate and prior oral feeding with 0.2% GTPs resulted in 40% inhibition in this induction.
Adenocarcinoma↗
The effects of host heterogeneity on pathogen population structure.
We have shown that among pathogens, populations may self-organize into strains with non-overlapping repertoires of antigenic variants as a consequence of strong immune selection operating on polymorphic antigens. Recently, we have also demonstrated that over a wide range of intermediate levels of immune selection, pathogens may still be structured into discrete strains, but different sets of non-overlapping pathogen types will replace each other in a cyclical or chaotic manner. These models assume that the ranking of antigens in terms of the strength of the induced immune response is the same for every host. However, host immune responses may be restricted by the genotype of the individual. To explore this issue, a mathematical model was constructed under the assumption that a proportion of the host population responds principally to a variable antigen while the remainder of the population responds principally to a conserved antigen. The results of this analysis indicate that discrete strain structure (DSS) will be maintained even with a high frequency of hosts that do not respond in a variant-specific manner. Furthermore, the range of the immune selection pressure over which DSS prevails is increased (and the region of cyclical or chaotic behaviour reduced) by the inclusion of hosts that respond in a cross-reactive rather than a variant-specific manner.
Animals↗
Prevention of collagen-induced arthritis in mice by a polyphenolic fraction from green tea.
Identification of common dietary substances capable of affording protection or modulating the onset and severity of arthritis may have important human health implications. An antioxidant-rich polyphenolic fraction isolated from green tea (green tea polyphenols, GTPs) has been shown to possess anti-inflammatory and anticarcinogenic properties in experimental animals. In this study we determined the effect of oral consumption of GTP on collagen-induced arthritis in mice. In three independent experiments mice given GTP in water exhibited significantly reduced incidence of arthritis (33% to 50%) as compared with mice not given GTP in water (84% to 100%). The arthritis index also was significantly lower in GTP-fed animals. Western blot analysis showed a marked reduction in the expression of inflammatory mediators such as cyclooxygenase 2, IFN-gamma, and tumor necrosis factor alpha in arthritic joints of GTP-fed mice. Histologic and immunohistochemical analysis of the arthritic joints in GTP-fed mice demonstrated only marginal joint infiltration by IFN-gamma and tumor necrosis factor alpha-producing cells as opposed to massive cellular infiltration and fully developed pannus in arthritic joints of non-GTP-fed mice. The neutral endopeptidase activity was approximately 7-fold higher in arthritic joints of non-GTP-fed mice in comparison to nonarthritic joints of unimmunized mice whereas it was only 2-fold higher in the arthritic joints of GTP-fed mice. Additionally, total IgG and type II collagen-specific IgG levels were lower in serum and arthritic joints of GTP-fed mice. Taken together our studies suggest that a polyphenolic fraction from green tea that is rich in antioxidants may be useful in the prevention of onset and severity of arthritis.
Animals↗
Analysis, expression and prevalence of the Mycobacterium tuberculosis homolog of bacterial virulence regulating proteins.
We have previously reported the identification of a gene from Mycobacterium tuberculosis, H37Rv, which on the basis of its nucleotide sequence encoded a protein product of 38 kDa. This 38-Kda mycobacterial protein designated as VirS exhibits homology with the VirF protein of Shigella, the VirFy protein of Yersinia and the Cfad, Rns and FapR proteins from various enterotoxigenic Escherichia coli strains. In this communication, we show the close sequence and structural similarities of the VirS protein with VirF, VirFy, Cfad, Rns and FapR and describe the results of our studies on the characterization of the virS gene promoter and its expression in E. coli and mycobacteria. virS was present exclusively in the species belonging to the M. tuberculosis complex as revealed by Southern blot and PCR analysis. Our findings suggest the involvement of virS in the regulation of pathogenesis of M. tuberculosis.
Amino Acid Sequence↗
Differential contribution of the ERK and JNK mitogen-activated protein kinase cascades to Ras transformation of HT1080 fibrosarcoma and DLD-1 colon carcinoma cells.
Although an important contribution of ERK and JNK mitogen-activated protein kinase (MAPK) activation in Ras transformation of rodent fibroblasts has been determined, their role in mediating oncogenic Ras transformation of human tumor cells remains to be established. We have utilized the human HT1080 fibrosarcoma and DLD-1 colon carcinoma cell lines, which contain endogenous mutated and oncogenic N- and K-ras alleles, respectively, to address this role. Study of these cells is advantageous over Ras-transformed rodent model cell systems for two key reasons. First, the ras mutations occurred naturally in the progression of the tumors from which the cell lines were derived, rather than due to overexpression of an exogenously introduced gene. Second, although these tumor cells possess defects in multiple genetic loci, it has been established that mutated Ras contributes significantly to the transformed phenotype of these cells. Clonal variant lines of HT1080 and DLD-1 have been isolated which have lost the oncogenic ras allele and exhibit a corresponding impairment in growth transformation in vitro and in vivo. We found that upregulation of Raf/MEK/ERK and JNK correlated with expression of oncogenic Ras in HT1080, but not DLD-1 cells. Furthermore, inhibition of ERK activation in parental HT1080 cells caused the same changes in cell morphology and actin stress fiber organization seen with loss of expression of activated N-Ras(61K). Thus, we suggest that constitutive activation of the Raf/MEK/ERK and JNK pathways is necessary for Ras-induced transformation of HT1080 but not DLD-1 cells. These results emphasize that cell type differences exist in the signaling pathways by which oncogenic Ras causes transformation.
3T3 Cells↗
Involvement of retinoblastoma (Rb) and E2F transcription factors during photodynamic therapy of human epidermoid carcinoma cells A431.
Photodynamic therapy (PDT), a promising new therapeutic modality for the management of a variety of solid malignancies and many non-malignant diseases, is a bimodal therapy using a porphyrin based photosensitizing chemical and visible light. The proper understanding of the mechanism of PDT-mediated cancer cell-kill may result in improving the efficacy of this treatment modality. Earlier we have shown (Proc. Natl. Acad. Sci. USA; 95: 6977-6982, 1998) that silicon phthalocyanine (Pc4)-PDT results in an induction of the cyclin kinase inhibitor WAF1/CIP1/p21 which, by inhibiting cyclins (E and D1) and cyclin dependent kinases (cdk2 and cdk6), results in a G0/G1-phase arrest followed by apoptosis in human epidermoid carcinoma cells A431. We have also demonstrated the generation of nitric oxide during PDT-mediated apoptosis (Cancer Res.; 58: 1785-1788, 1998). Retinoblastoma (pRb) and E2F family transcription factors are important proteins, which regulate the G1-->S transition in the cell cycle. Here, we provide evidence for the involvement of pRb-E2F/DP machinery as an important contributor of PDT-mediated cell cycle arrest and apoptosis. Western blot analysis demonstrated a decrease in the hyper-phosphorylated form of pRb at 3, 6 and 12 h post-PDT with a relative increase in hypo-phosphorylated pRb. Western blot analysis also revealed that PDT-caused decrease in phosphorylation of pRb occurs at serine-780. The ELISA data demonstrated a time dependent accumulation of hypo-phosphorylated pRb by PDT. This response was accompanied with down-regulation in the protein expression of all five E2F (1-5) family transcription factors, and their heterodimeric partners DP1 and DP2. These results suggest that Pc4-PDT of A431 cells results in a down regulation of hyper-phosphorylated pRb protein with a relative increase in hypo-phosphorylated pRb that, in turn, compromises with the availability of free E2F. We suggest that these events result in a stoppage of the cell cycle progression at G1-->S transition thereby leading to a G0/G1 phase arrest and a subsequent apoptotic cell death. These data provide an evidence for the involvement of pRb-E2F/DP machinery in PDT-mediated cell cycle arrest leading to apoptosis.
Animals↗
Increased TNF-alpha-induced apoptosis in lymphocytes from aged humans: changes in TNF-alpha receptor expression and activation of caspases.
Aging is characterized by increased T cell lymphopenia, T cell dysfunction, and increased serum TNF levels. In this study, we have examined the role of TNF-induced apoptosis in T cell deficiency in lymphocytes from aged humans. The constitutive expression of TNF receptors (TNFRI and TNFRII) and the adapter molecules, including TNFR-associated death domain protein (TRADD), TNFR-associated factor 2 (TRAF-2), and receptor interacting protein (RIP), were analyzed both at the protein level by flow cytometry or Western blotting, and at the mRNA level using quantitative PCR or Northern blotting in lymphocytes from aged and young subjects. The susceptibility of T cells to undergo TNF-induced apoptosis was analyzed using terminal deoxynucleotidyltransferase-mediated UTP-end-labeling (TUNEL) and DNA ladder assays. Caspase (caspase-8 and caspase-3) activation was compared between aged and young subjects using Western blotting and colorimetric assays. In lymphocytes from aged humans, there was an increased susceptibility of CD4+ and CD8+ T cells to undergo TNF-alpha-induced apoptosis, as observed by TUNEL assay and DNA fragmentation ladder assay. Increased TNF-alpha-induced apoptosis was also observed in both CD45RA+ and CD45RO+ T cells from aging subjects. An increased constitutive expression of TNFRI and TRADD and decreased expression of TNFRII and TRAF-2 were observed in lymphocytes from aged as compared with young controls. In addition, there was an early and increased activation of caspases (caspase-8 and caspase-3) involved in TNFR/TNF signaling pathway, as evident by early cleavage of caspase-8, poly(ADP-ribose) polymerase (PARP), and caspase-3 substrate DEVD-p-nitroamilide NA. These data suggest that an increased TNF-alpha-induced apoptosis may play a role in T cell deficiency associated with human aging.
Adult↗