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Biomedical subjects

S Kumar

Publications and source records attributed to S Kumar.

At least 847 records · Page 47Linked to original sources
PubMed1999

Interaction of diclofenac and quinidine in monkeys: stimulation of diclofenac metabolism.

The cytochrome P-450 (CYP)3A4-mediated metabolism of diclofenac is stimulated in vitro by quinidine. A similar effect is observed in incubations with monkey liver microsomes. We describe an in vivo interaction of diclofenac and quinidine that leads to enhanced clearance of diclofenac in monkeys. After a dose of diclofenac via portal vein infusion at 0.055 mg/kg/h, steady-state systemic plasma drug concentrations in three male rhesus monkeys were 87, 104, and 32 ng/ml, respectively (control). When diclofenac was coadministered with quinidine (0.25 mg/kg/h) via the same route, the corresponding plasma diclofenac concentrations were 50, 59, and 18 ng/ml, representing 57, 56, and 56% of control values, respectively. In contrast, steady-state systemic diclofenac concentrations in the same three monkeys were elevated 1.4 to 2.5 times when the monkeys were pretreated with L-754,394 (10 mg/kg i.v.), an inhibitor of CYP3A. Further investigation indicated that the plasma protein binding (>99%) and blood/plasma ratio (0.7) of diclofenac remained unchanged in the presence of quinidine. Therefore, the decreases in plasma concentrations of diclofenac after a combined dose of diclofenac and quinidine are taken to reflect increased hepatic clearance of the drug, presumably resulting from the stimulation of CYP3A-catalyzed oxidative metabolism. Consistent with this proposed mechanism, a 2-fold increase in the formation of 5-hydroxydiclofenac derivatives was observed in monkey hepatocyte suspensions containing diclofenac and quinidine. Stimulation of diclofenac metabolism by quinidine was diminished when monkey liver microsomes were pretreated with antibodies against CYP3A. Subsequent kinetic studies indicated that the K(m) value for the CYP-mediated conversion of diclofenac to its 5-hydroxy derivatives was little changed (75 versus 59 microM), whereas V(max) increased 2.5-fold in the presence of quinidine. These data suggest that the catalytic capacity of monkey hepatic CYP3A toward diclofenac metabolism is enhanced by quinidine.

Animals↗
PubMed1999

Effect of physician-specific mailouts aimed at increasing influenza immunization rates.

With the Year 2000 goal being 60%, influenza immunization rates for the Medicare elderly in Louisiana remain far below the expected target rate. It is well recognized that physicians are an important group of health care providers who can contribute towards increasing influenza immunization rates for community dwelling elders. As a health care quality improvement effort, in order to increase the 1997 influenza immunization rates for Louisiana, we implemented a physician specific mailout intervention. Medicare Part B claims and influenza immunization datasets were used to compute missed opportunity rates and immunization rates. Compared to rates in 1996, the influenza immunization rate in both groups significantly increased irrespective of the intervention. However, the increase in the intervention group was more than that in the control group, indicating that mailout of indicator rate data to physicians impacts upon practice patterns.

Aged↗
PubMed1999

Adjuvant therapy in invasive thymoma: an audit of cases treated over an 8 year period.

Invasive thymomas comprise 0.1%-0.2% of all malignancies in India. This report is an audit of 11 cases (10 males and 1 female) at a mean age of 36.6 years (range 25-52 years) of invasive thymoma accrued over an eight year period treated by combined modality treatment. Nine of these presented with myaesthenia gravis. All patients underwent initial surgery (3 partial and 8 total resections) and postoperative radiotherapy. Two of the three partially resected patients received one course of chemotherapy prior to radiotherapy consisting of cyclophosphamide, vincristine, procarbazine and prednisolone. At a median follow up of 28 months (range 2-87) there have been no local relapses, one distant metastasis and one death due to uncontrolled myaesthenia. The treatment strategies with invasive thymomas would depend upon the extent of resection. Postoperative radiotherapy appears to be indicated in all cases, however the role of chemotherapy may be limited to those with partial resection.

Adult↗
PubMed1999

Frequency of HgbA1c testing as a measure of diabetes care in Louisiana.

The Frequency of HgbA1c Testing Project is a continuous quality improvement project designed to measure and improve the frequency of HgbA1c testing among Medicare diabetic patients in Louisiana. Louisiana Medicare Part B electronic claims data from June 1995 to December 1996 were used to construct diabetes quality of care type indicators. A total of 47,270 Medicare, Part B eligible, non-HMO, diabetic patients were identified and studied. The statewide baseline results indicated that only 24% of the Medicare diabetic patients were covered by an HgbA1c test within 180 days from their last physician office visit. Twenty-one percent (21%) of practicing primary care physicians had none of their diabetic patients tested for HgbA1c within 180 days from the patient's last office visit. Overall, only 18% of all primary care physicians "seized" the opportunity to perform an HgbA1c test within this time frame. Twenty-two percent (22%) of Louisiana primary care physicians had never seized the opportunity to check for HgbA1c on eligible patients. Interventions and strategies are being implemented statewide in order to improve the low HgbA1c testing rates.

Diabetes Mellitus↗
PubMed1999

Antigenotoxic properties of Terminalia arjuna bark extracts.

Compounds possessing antimutagenic properties (polyphenols, tannins, vitamins, etc.) have been identified in fruits, vegetables, spices, and medicinal plants. Terminalia arjuna (Combretaceae), a tropical woody tree occurring throughout India and known locally as Kumbuk, is a medicinal plant rich in tannins and triterpenes that is used extensively in Ayurvedic medicine as a cardiac tonic. The aim of the present collaborative work was to test six solvent extracts from the bark of Terminalia arjuna for antigenotoxic activity using in vitro short-term tests. Terminalia arjuna extracts were obtained by sequential extraction using acetone, methanol, methanol + HCl, chloroform, ethyl acetate, and ethyl ether. The antigenotoxic properties of these extracts were investigated by assessing the inhibition of genotoxicity of the directacting mutagen 4-nitroquinoline-N-oxide (4NQO) using the "comet" assay and the micronucleus (MN) test. Human peripheral blood leukocytes were incubated with different concentrations of the six extracts (from 5 to 100 microg/ mL) and with 4NQO (1 and 2 microg/mL, for the "comet" assay and MN test, respectively). Each extract/4NQO combination was tested twice; in each experiment, positive control (4NQO alone) and negative control (1% DMSO) were set. "Comet" assay results showed that acetone and methanol extracts were highly effective in reducing the DNA damage caused by 4NQO, whereas the acidic methanol, chloroform, ethyl acetate, and ethyl ether extracts showed less marked or no antigenotoxic activity. In the MN test, a decrease in 4NQO genotoxicity was observed by testing this mutagen in the presence of acetone, methanol, chloroform, and ethyl acetate extracts, even though the extent of inhibition was not always statistically significant.

4-Nitroquinoline-1-oxide↗
PubMed1999

Extranodal peripheral T-cell and NK-cell neoplasms.

Mature or peripheral T-cell lymphomas are uncommon, accounting for only 10% to 15% of all non-Hodgkin lymphomas, and their classification has been controversial. In contrast to B-cell lymphomas, cytologic features have not been useful in defining disease entities, and cytologic grade has not been useful in predicting the clinical course. Similarly, many entities of T-cell or NK-cell derivation do not have a specific immunophenotype. Clinical features are of major importance, sometimes more important than the precise cell of orgin, in defining T-cell and NK-cell neoplasms. Most extranodal T-cell/NK-cell lymphomas have a cytotoxic phenotpye. The expression of cytotoxic molecules may predispose to apoptosis by tumor cells and normal bystander cells. Three major categories of extranodal T/NK cell tumors are nasal, intestinal, and subcutaneous panniculitis-like. Hepatosplenic gamma delta T-cell lymphoma is a more systemic disease derived from functionally immature cytotoxic cells. Many extranodal T-cell and NK-cell neoplasms are associated with Epstein-Barr virus (EBV); the association seems site dependent and shows some geographic variation. Tumors resembling any of the 3 prototypes may occur in a variety of extranodal sites. Extranodal T/NK cell lymphomas occur with increased frequency in the setting of immune suppression, especially after organ transplantation.

Humans↗
PubMed1999

Role of the liver and gut in systemic diphenhydramine clearance in adult nonpregnant sheep.

We investigated the contribution of the liver and gut to systemic diphenhydramine (DPHM) clearance in adult nonpregnant sheep in two separate studies. In the first study, a simultaneous 50-mg bolus each of DPHM and its deuterium-labeled analog ([2H10]DPHM) was administered to five sheep via the femoral (i.v.) and the portal venous (p.v.) routes in a randomized manner. Arterial plasma concentrations of DPHM, [2H10]DPHM, and their deaminated metabolites, DPMA (diphenylmethoxyacetic acid) and [2H10]DPMA, were measured using gas chromatography-mass spectrometry. The hepatic first-pass extraction of DPHM after p.v. administration was 94.2 +/- 3.7%. However, the area under the plasma concentration versus time profile of the metabolite after i.v. dosing was only 32.5 +/- 14.0% relative to that after p.v. administration. Thus, only approximately 32.5% of the i.v. dose is metabolized in the liver and a significant extrahepatic systemic clearance component is evident. Using the calculated total hepatic blood flow values, it was found that 98.6 +/- 9.2% of the i.v. dose eventually was delivered to the "hepatoportal" system. Because the drug delivered to the hepatoportal system is almost completely eliminated in a single pass (hepatic extraction approximately 94%), this indicates a lack of any significant pulmonary drug uptake. Also, because only approximately 32.5% of the i.v. dose is metabolized in liver, the gut is most likely responsible for the clearance of the remainder. This gut contribution to systemic DPHM clearance was confirmed in a separate direct study in four sheep where the steady-state DPHM gut extraction ratio was 49.0 +/- 3.0%. Thus, gut accounts for a significant proportion (>/=50%) of DPHM systemic clearance in sheep in spite of a very high hepatic drug extraction efficiency.

Animals↗
PubMed1998

NT-3-mediated TrkC receptor activation promotes proliferation and cell survival of rodent progenitor oligodendrocyte cells in vitro and in vivo.

We have previously described the expression of a functional full-length trkC transcript for neurotrophin-3 (NT-3) receptor in oligodendroglia (OL) cells (Kumar and de Vellis, 1996). To date, the role of NT-3 and its signal transduction cascade in OL remains poorly defined. We report that the NT-3 responsive population of cells in the OL lineage are the progenitor cells and that the addition of NT-3 results in the autophosphorylation of p145TrkC. Furthermore, NT-3-mediated activation of p21ras and mitogen-activated protein kinase (MAPK), extracellular signal-regulated protein kinase2 (ERK2), were also observed in the progenitor OL cells. These protein tyrosine kinase (PTK)-induced responses were sensitive to the presence of K252a, an inhibitor for tyrosine kinase. We have determined that NT-3 promotes progenitor OL cell commitment to enter into S-phase of cell cycle to initiate DNA synthesis, in a manner similar to platelet-derived growth factor-AA (PDGF-AA). NT-3 thus plays a role in cell proliferation when present alone, while augmenting the proliferation capacity of PDGF-AA as indicated by the nuclear binding activity of the transcription factor, E2F-1. Both the initiation and progression of mitotic events were confirmed by the expression of c-myc and cdc2 in the presence of NT-3, PDGF-AA or NT-3 plus PDGF-AA. A cell survival assay examining interleukin 1-beta-converting enzyme (ICE)-like protease-mediated cleavage of poly (ADP-ribose) polymerase (PARP) revealed an increase in OL progenitor cell death in the absence of NT-3 or PDGF-AA. In corroboration with our in vitro studies, in vivo results show an increased expression of the progenitor OL cell marker, glycerol phosphate dehydrogenase (GPDH) within 48 hr following an intracranial injection of NT-3, PDGF-AA, or NT-3 plus PDGF-AA in PN4-5 rats. These novel findings suggest that PDGF-AA potentiates the OL progenitor cell's ability to enter into the S-phase of the cell cycle and that NT-3 can augment this activity. Furthermore, PDGF-AA and NT-3 can block ICE-like protease-mediated PARP fragmentation in progenitor OL cells. These results provide important information which further delineates the signal transduction cascades and the role of NT-3 and PDGF-AA on OL progenitor cells.

Animals↗
PubMed1998

Role of transforming growth factor beta3 in lymphatic metastasis in breast cancer.

Transforming growth factor-betas (TGFbetas) play a prominent role in tumour growth and metastasis by enhancing angiogenesis and suppressing immune surveillance. Despite the increased interest in the effect of TGFbetas on tumour progression, little is known about the importance of TGFbeta3 and its receptor CD105 in breast cancer. In the present study, we measured the plasma levels of TGFbeta3, CD105-TGFbeta3 complexes and TGFbeta1 in 80 patients with untreated early-stage breast cancer using an enhanced chemiluminescence ELISA method. Of the 80 patients, 14 were histologically confirmed as having axillary lymph node metastases, while the remainder had no evidence of lymph node involvement. The results showed that levels of both TGFbeta3 and CD105-TGFbeta3 complex were significantly elevated in patients with positive lymph nodes compared to those without node metastasis. Furthermore, the levels of both TGFbeta3 and CD105-TGFbeta3 complex correlated with lymph node status. The only patient who died of the disease had very high plasma levels of TGFbeta3 and CD105-TGFbeta3 complex and positive lymph nodes; this patient developed lung metastases within 2 years of diagnosis. No significant correlation was seen between either TGFbeta3 or CD105-TGFbeta3 complex levels and tumour stage, size or histological grade. Plasma TGFbeta1 levels were not correlated with node metastasis, tumour stage, grade or size. Our data suggest that plasma levels of TGFbeta3 and CD105-TGFbeta3 complex may be of prognostic value in the early detection of metastasis of breast cancer.

Adult↗
PubMed1998

Regulation of Bcr-Abl-induced SAP kinase activity and transformation by the SHPTP1 protein tyrosine phosphatase.

The oncogenic Bcr-Abl variant of the c-Abl tyrosine kinase transforms cells by a mechanism dependent on activation of the stress-activated protein kinase (SAPK). Other work has shown that c-Abl interacts with the SHPTP1 protein tyrosine phosphatase in induction of SAPK activity by genotoxic stress. The present studies demonstrate that Bcr-Abl binds constitutively to SHPTP1. We show that Bcr-Abl phosphorylates SHPTP1 on C-terminal Y536 and Y564 sites. The functional significance of the Bcr-Abl/SHPTP1 interaction is supported by the finding that SHPTP1 regulates Bcr-Abl-induced SAPK activity. Importantly, SHPTP1 also decreases Bcr-Abl-dependent transformation of fibroblasts. These findings indicate that SHPTP1 functions as a tumor suppressor in cells transformed by Bcr-Abl.

3T3 Cells↗
PubMed1998

The optimization principle in phylogenetic analysis tends to give incorrect topologies when the number of nucleotides or amino acids used is small.

In the maximum parsimony (MP) and minimum evolution (ME) methods of phylogenetic inference, evolutionary trees are constructed by searching for the topology that shows the minimum number of mutational changes required (M) and the smallest sum of branch lengths (S), respectively, whereas in the maximum likelihood (ML) method the topology showing the highest maximum likelihood (A) of observing a given data set is chosen. However, the theoretical basis of the optimization principle remains unclear. We therefore examined the relationships of M, S, and A for the MP, ME, and ML trees with those for the true tree by using computer simulation. The results show that M and S are generally greater for the true tree than for the MP and ME trees when the number of nucleotides examined (n) is relatively small, whereas A is generally lower for the true tree than for the ML tree. This finding indicates that the optimization principle tends to give incorrect topologies when n is small. To deal with this disturbing property of the optimization principle, we suggest that more attention should be given to testing the statistical reliability of an estimated tree rather than to finding the optimal tree with excessive efforts. When a reliability test is conducted, simplified MP, ME, and ML algorithms such as the neighbor-joining method generally give conclusions about phylogenetic inference very similar to those obtained by the more extensive tree search algorithms.

Amino Acids↗
PubMed1998

Conversion of procaspase-3 to an autoactivating caspase by fusion to the caspase-2 prodomain.

Caspases are cysteine proteases that play an essential role in apoptosis. Initial activation of caspases defines the key step in apoptotic execution. Based on primary structure, caspases can be divided into two groups, those with long amino-terminal prodomains (class I), and those with relatively short prodomains (class II). On overexpression in mammalian cells, class I caspases can induce cell death that is dependent on their autocatalytic activity. Recent studies suggest that the long prodomains in some class I caspases are able to mediate dimerization of procaspase molecules, thereby promoting autoprocessing. In this communication, we demonstrate that fusion of the prodomain of a class I caspase (Nedd2/caspase-2) with procaspase-3 greatly augments autocatalysis and apoptosis induction by the chimeric caspase-3 molecule. The chimeric caspase-3 molecules were able to form homodimers in Saccharomyces cerevisiae and were efficiently processed in transfected mammalian cells. These results provide direct evidence for a role of a class I caspase prodomain in caspase autoactivation and processing and establish a basis for functional hierarchy among the two classes of caspases.

3T3 Cells↗