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Biomedical subjects

S Vaidya

Publications and source records attributed to S Vaidya.

At least 19 recordsLinked to original sources
PubMed2001

Improved flow cytometric detection of HLA alloantibodies using pronase: potential implications in renal transplantation.

BACKGROUND: Flow cytomeric crossmatch (FCXM) has grown in popularity and has become the "standard of practice" in many programs. Although FCXM is the most sensitive method for detecting alloantibody, the B cell FCXM has been problematic. Difficulties with the B cell FCXMs have been centered around high nonspecific fluorescence background owing to Fc-receptors present on the B cells and autoantibodies. To improve the specificity and sensitivity of the B cell FCXM, we utilized the proteolytic enzyme pronase to remove Fc receptors from lymphocytes before their use in FCXM. METHODS: Lymphocytes isolated from peripheral blood, spleen, or lymph nodes were treated with pronase and then used in a three-color FCXM. A total of 167 T- and B cell FCXMs using pronase-treated and untreated cells were performed. Testing used serial dilutions of HLA allosera (22 class I and 6 class II), with the titer of each antibody at one dilution past the titer at which the complement-mediated cytotoxicity anti-human globulin crossmatch became negative. RESULTS: After pronase treatment, the actual channel values of the negative control in both T cell and B cell FCXMs declined from 78+/-10 to 57+/-4 (P<0.05) and 107+/-11 to 49+/-3 (P<0.00001), respectively. Pronase treatment resulted in improved sensitivity of the T and B cell FCXM in detecting class I antibody by 20% and 80%, respectively. In no instance was a false-positive reaction observed. In this study, pronase treatment improved the specificity of B cell FCXM for detecting class II antibodies from 75% to 100% (P=0.03). In no instance was a false-negative reaction recorded. Lastly, on the basis of these observations we re-evaluated three primary transplant recipients who lost their allografts because of accelerated rejection. One of the patients was transplanted across negative T and B cell FCXM, whereas the other two patients were transplanted across a positive T cell, but negative B cell, FCXM. After pronase treatment, T and B cell FCXMs of each patient became strongly positive, and donor-specific anti-HLA class I antibody was identi. fied in each case. CONCLUSION: Utilization of pronase-treated lymphocytes improves both the sensitivity and specificity of the FCXM.

False Negative Reactions↗
PubMed2000

Frequency, potential risk and therapeutic intervention in end-stage renal disease patients with antiphospholipid antibody syndrome: a multicenter study.

BACKGROUND: Antiphospholipid antibody syndrome (APAS) is characterized by the presence of anticardiolipin antibodies (ACA) in association with thrombotic disorders of arterial and/or venus systems, spontaneous abortion(s) or thrombocytopenia. METHODS: In this multicenter study, 502 end-stage renal disease (ESRD) patients awaiting renal transplants were screened to determine the frequency of APAS, the potential risk associated with APAS, and strategies for therapeutic intervention. Ninety-three patients (19%) had high titers of ACA. Twenty-three patients had documented evidence of one or more of the thrombotic disorders such as lupus, frequent abortions, frequent thrombosis of arteriovenous shunts, biopsy-proven microrenal angiopathy, or thrombocytopenia and thus were diagnosed with APAS. Of these 23 patients, 11 received kidney transplants either with (4 patients) or without (7 patients), concomitant anticoagulation therapy. RESULTS: All seven of the patients with APAS not treated with anticoagulation therapy lost their allografts within 1 week as a result of renal thrombosis. In contrast, three out of four transplant patients with APAS treated with anticoagulation therapy maintained their allografts for over 2 years. The fourth patient lost his graft within a week because of thrombosis. Of the remaining 70 patients with high titers of ACA but no evidence of thrombotic disorders, 37 received kidney transplants. None lost their allografts as a result of thrombosis. Our data suggest that, although 19% of our ESRD patients exhibit high titer of ACA, only 5% of the patients have APAS. CONCLUSION: In conclusion, our data suggest that the patients with APAS are at high risk of posttransplant renal thrombosis. Anticoagulation therapy could prevent patients from posttransplant thrombosis in patients with APAS.

Antibodies, Anticardiolipin↗
PubMed1999

15-Deoxy-Delta12,1412,14-prostaglandin J2 inhibits the beta2 integrin-dependent oxidative burst: involvement of a mechanism distinct from peroxisome proliferator-activated receptor gamma ligation.

15-Deoxy-Delta12,14-PGJ2 (dPGJ2) is a bioactive metabolite of the J2 series that has been identified as a ligand for peroxisome proliferator-activated receptor gamma (PPARgamma) and has received attention for its potential antiinflammatory effects. Because neutrophils express cell-surface receptors for PGs, the effect of dPGJ2 was tested on an inflammatory response that should not require PPARgamma, the oxidative burst made by adherent human neutrophils. dPGJ2 inhibited adhesion-dependent H2O2 production with an IC50 of 1. 5 microM when neutrophils were stimulated with TNF, N-formylnorleucylleucylphenylalanine, or LPS. Inhibition by dPGJ2 occurred during the lag phase, before generation of peroxide, suggesting blockade of an early signaling step. Indeed, dPGJ2 blocked adhesion of neutrophils to fibrinogen in response to TNF or LPS with an IC50 of 3-5 micro+dPGJ2 was more potent at inhibiting the adhesion-dependent oxidative burst than several other PGs tested. Further, dPGJ2 did not appear to act through either the DP receptor or receptors for PGE2. PG receptors modulate cAMP levels, and the inhibition of adhesion and oxidative burst by dPGJ2 was enhanced in the presence of 3-isobutyl-1-methylxanthine, a cAMP phosphodiesterase inhibitor. A potent PPARgamma agonist (AD-5075) did not inhibit peroxide production or adhesion, nor did it change the IC50 for dPGJ2 inhibition. These studies suggest that dPGJ2 may interact with an unknown receptor on neutrophils, distinct from PPARgamma, to modulate the production of reactive oxygen intermediates.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1999

Position-specific gene expression in the liver lobule is directed by the microenvironment and not by the previous cell differentiation state.

Mechanisms directing position-specific liver gene regulation are incompletely understood. To establish whether this aspect of hepatic gene expression is an inveterate phenomenon, we used transplanted hepatocytes as reporters in dipeptidyl peptidase IV-deficient F344 rats. After integration in liver parenchyma, the position of transplanted cells was shifted from periportal to perivenous areas by targeted hepatic ablations with carbon tetrachloride. In controls, transplanted cells showed greater glucose-6-phosphatase and lesser glycogen content in periportal areas. This pattern was reversed when transplanted cells shifted from periportal to perivenous areas. Transplanted hepatocytes in perivenous areas exhibited inducible cytochrome P450 activity, which was deficient in periportal hepatocytes. Moreover, cytochrome P450 activity was rapidly extinguished in activated hepatocytes when these cells were transplanted into the nonpermissive liver of suckling rat pups. In cells isolated from the normal F344 rat liver, cytochrome P450 inducibility was originally greater in perivenous hepatocytes; however, periportal cells rapidly acquired this facility in culture conditions. These findings indicate that the liver microenvironment exerts supremacy over prior differentiation state of cells in directing position-specific gene expression. Therefore, persistence of specialized hepatocellular function will require interactions with regulatory signals and substrate availability, which bears upon further analysis of liver gene regulation, including in progenitor and/or stem cells.

Animals↗
PubMed1999

Transient poration and cell surface receptor removal from human lymphocytes in vitro by 1 MHz ultrasound.

The study objective was to gain insight into ultrasound-induced, sub-lytic cell surface modifications. Two primary hypotheses were tested by flow cytometric methods; viz., sonication will: 1. remove all or part of a specific cell surface marker in lymphocytes surviving insonation, and 2. induce transient pores in the cell membranes of some surviving cells. RPMI 1788 human lymphocytes were exposed in vitro to 1-MHz, continuous-wave ultrasound (approximately 8 W/cm2 ISP) for 30 s, which lysed approximately 50% of the cells. Insonation: 1. altered cell morphology, increasing the population of cells of reduced size but high structure (designated as population R2), many of which were nonviable, and diminishing the population of cells of large size and high structure (designated as population R1), most of which were viable, 2. diminished the fluorescence signal from the pan B lymphocyte marker CD19 in populations R1 and R2 to equivalent extents, and 3. increased by approximately 7-fold the number of transiently permeabilized cells in R1, as evidenced by simultaneous uptake of propidium iodide and fluorescein diacetate. The results indicate that ultrasound-induced CD19 removal from R1 cells can occur without accompanying gross membrane loss. The cell morphology/mortality shifts indicate that the ultrasound-induced morphological change is associated with lethal membrane poration, suggesting that the diminished CD19 fluorescence signal from insonated R2 cells arises partly by simultaneous loss of membrane fragments, CD19 and cytoplasm.

Antigens, CD19↗
PubMed1998

Role of stress-activated mitogen-activated protein kinase (p38) in beta 2-integrin-dependent neutrophil adhesion and the adhesion-dependent oxidative burst.

Bacterial LPS elicits both rapid activation of the stress-activated MAP kinase p38 in polymorphonuclear leukocytes (PMN) and rapid adhesion of the PMN to ligands for the leukocyte integrin CD11b/CD18. The functional correlation between these two events was examined. The time course for tyrosine phosphorylation of p38 in PMN in response to 10 ng/ml LPS in 1% normal human serum was consistent with participation in signaling for leukocyte integrin-dependent adhesion, with transient phosphorylation peaking at 10 to 20 min. The concentration dependence of p38 phosphorylation also resembled that for PMN adhesion, with <1 ng/ml LPS eliciting a response. Phosphorylation was inhibited by mAb 60b against CD14, but not by mAb 26ic, a nonblocking anti-CD14. The function of p38 in integrin-dependent adhesion and the adhesion-dependent oxidative burst was tested using a specific inhibitor of p38, SB203580. SB203580 inhibited adhesion by diminishing the initial rate of adherence in response to both LPS and TNF, with a half-maximal concentration in the range of 0.1 to 0.6 microM. It did not, however, block adhesion in response to formyl peptide or PMA. The p38 inhibitor also blocked the adhesion-dependent oxidative burst with a half-maximal concentration similar to that for adhesion. Timed delivery of the compound during the lag phase preceding H2O2 production suggested that p38 kinase activity was required throughout the lag but not after the oxidase was assembled. These results suggest that p38 functions in PMN to signal leukocyte integrin-dependent adhesion and the subsequent massive production of reactive oxygen intermediates.

CD18 Antigens↗
PubMed1998

Massive production of farnesol-derived dicarboxylic acids in mice treated with the squalene synthase inhibitor zaragozic acid A.

The zaragozic acids are potent inhibitors of squalene synthase. In vivo studies in mice confirmed our earlier observations that inhibition of squalene synthase by zaragozic acid A was accompanied by an increase in the incorporation of label from [3H]mevalonate into farnesyl-diphosphate (FPP)-derived isoprenoic acids (J. D. Bergstrom et al., 1993, Proc. Natl. Acad. Sci. USA 90, 80-84). Farnesyl-diphosphate-derived metabolites appear transiently in the liver. We were unable to detect any farnesol formation in the zaragozic acid-treated animals which indicates that FPP is readily converted to farnesoic acid and dicarboxylic acids in the liver. These metabolites were found to be produced only in the liver and not in the kidney. trans-3,7-Dimethyl-2-octaen-1,8-dioic acid and 3, 7-dimethyloctan-1,8-dioic acid were identified as the major end products of farnesyl-diphosphate metabolism in the urine of mice treated with zaragozic acid A. Quantitative analysis of these FPP-derived dicarboxylic acids by gas-liquid chromatography revealed that approximately 11 mg of total dicarboxylic acids is excreted per day into the urine of a mouse after 3 days of treatment with zaragozic acid A.

Animals↗
PubMed1998

Avascular necrosis of bone--a complication of aggressive therapy for acute lymphoblastic leukemia.

The purpose of the present paper was to report cases of avascular necrosis of bone (AVNB) arising as a complication of chemotherapy for acute lymphoblastic leukemia (ALL). X-rays and 99mtechnicium-MDP bone scans were performed on patients with symptoms of bone pain, whereby five patients out of 850 patients were detected to have avascular necrosis of the femoral head. All had received aggressive chemotherapy with steroids. Two patients were still on therapy for the primary disease. In these patients further chemotherapy was continued without steroids. The median period from diagnosis of ALL to development of AVNB was 29 months. Three patients underwent corrective surgical procedures. To conclude, the data suggest that patients receiving combination chemotherapy, especially those with high cumulative doses, run a risk of developing AVNB. Awareness of this complication is important in order to have an early diagnosis so as to limit disability.

Adolescent↗
PubMed1998

Combining aspirin with angiotensin converting enzyme inhibitors in heart failure: how safe is it?

The above discussion on the interaction of aspirin and ACE inhibitors seems to suggest that aspirin in high doses may have adverse interaction with ACE inhibitors in patients with heart failure but the data obtained is not sufficient or conclusive to recommended omission of aspirin in patients with heart failure. This raises a query in the mind of the physician whether to use a combination or not? The role of aspirin in the early period after myocardial infarction is well established so is the role of ACE inhibitors. Hence in patients with myocardial infarction and preserved left ventricular function it would not be wrong to administer combination of ACE inhibitors and aspirin. Albeit at a lower dose. In patients with large myocardial infarction or heart failure, warfarin may be an option but still needs to be documented in large trials. As suggested long term use of aspirin after infarction is still ambiguous and may be harmful in patients with heart failure with its anticedent side effects. But long term benefits of ACE inhibitors in heart failure are well documented. Hence if a choice has to be made whether to discontinue either of the two drugs it would be preferable to stop the aspirin. To answer the issue of use of aspirin in patients with heart failure it would be essential to conduct a double blind randomized trial comparing known anti-thrombotic treatment, aspirin and anti-coagulants on mortality in patients with heart failure, especially caused by coronary artery disease. Such a trial is underway at the present and till the results are available it should be left to clinical judgement of the physician whether to administer aspirin in patients with heart failure after weighing the benefits versus risk.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

Influence of Coccinia indica on certain enzymes in glycolytic and lipolytic pathway in human diabetes.

Dried extract of C Indica in doses of 500 mgm/kg body weight were administered orally to 30 diabetic patients for six weeks. Blood samples were collected 15 minutes after administration of 10 IU heparin for estimation of LPL, before and after treatment with C. Indica Non heparinised samples were utilized for estimation for G-6-p (ase), LDH and blood sugar. Severity of disease were assessed by the findings of blood sugar level. Mild diabetes had no effect on LPL, LDH and G-6-P (ase). But, reduced activity of enzyme LPL and raised level of G-6-P (ase) and LDH in plasma of severe diabetics were found to be highly significant (p < 0.001). The alteration in these parameters in untreated diabetics were restored after treatment with C. indica Hence, it can be postulated that the ingredients present in the extract of C. indica, act like insulin, correcting the elevated enzymes G-6-p (ase), LDH in glycolytic pathway and restore the LPL activity in lypolytic pathway with the control of hyperglycemia in diabetes.

Diabetes Mellitus↗
PubMed1998

Relative risk of post-transplant renal thrombosis in patients with antiphospholipid antibodies.

INTRODUCTION: Antiphospholipid antibody syndrome (APAS) is a condition associated with recurrent arterial and venous thrombosis, recurrent abortions, and thrombocytopenia either with or without lupus. In this study we have evaluated the impact of APAS on the renal transplant outcome of 174 patients. METHOD: Patients' APAS status was determined by the presence of anticardiolipin antibodies (ACA) and a history of clotting disorders. Serum samples from each patient were tested for the presence of ACA by the ELISA method. Transplant outcomes were monitored for > or = 1 yr. RESULTS: Of 174 patients, 78 received renal transplants. Six of these 78 patients had APAS as evidenced by either recurrent microrenal angiopathy (2 patients), thrombocytopenia (1 patient) or frequent A-V shunt thrombosis (3 patients) along with high titers of ACA of IgM, IgG, or both subtypes at the time of their transplants. Each of these 6 patients thrombosed their renal allografts within a week of their transplants. The other 72 transplanted patients with no APAS were all doing well 1 yr post-transplant. The association between APAS and post-transplant renal thrombosis among these patients is highly significant (p < 0.0001). In contrast, no association was discerned between post-transplant thrombosis and prior sensitization to HLA CONCLUSION: Our data demonstrates that patients with APAS are at high risk for development of post-transplant renal thrombosis.

Adult↗
PubMed1997

Farnesol-derived dicarboxylic acids in the urine of animals treated with zaragozic acid A or with farnesol.

Farnesyl diphosphate, the substrate for squalene synthase, accumulates in the presence of zaragozic acid A, a squalene synthase inhibitor. A possible metabolic fate for farnesyl diphosphate is its conversion to farnesol, then to farnesoic acid, and finally to farnesol-derived dicarboxylic acids (FDDCAs) which would then be excreted in the urine. Seven dicarboxylic acids were isolated by high performance liquid chromatography (HPLC) from urine of either rats or dogs treated with zaragozic acid A or rats fed farnesol. Their structures were determined by nuclear magnetic resonance analysis. Two 12-carbon, four 10-carbon, and one 7-carbon FDDCA were identified. The profile of urinary dicarboxylic acids from rats fed farnesol was virtually identical to that produced by treating with zaragozic acid A, establishing that these dicarboxylic acids are farnesol-derived. By feeding [1-14C]farnesol and comparing the mass of the dicarboxylic acids produced with the ultraviolet absorption of the HPLC peaks, a method to quantitate the ultraviolet-absorbing FDDCAs was devised. When rats were treated with zaragozic acid A, large amounts of FDDCAs were excreted in the urine. The high level of FDDCAs that were found suggests that their synthesis is the major metabolic fate for carbon diverted from cholesterol synthesis by a squalene synthase inhibitor. A metabolic pathway is proposed to explain the production of each of these FDDCAs.

Animals↗
PubMed1997

Preliminary report of an intensified, short duration chemotherapy protocol for the treatment of pediatric non-Hodgkin's lymphoma in India.

BACKGROUND: In the past, the results of the treatment of non-Hodgkin's lymphomas (NHL) in Indian children have been poor, due to inadequate chemotherapy and poor supportive care. In an attempt to overcome these problems, we conducted a clinical trial in Bombay with a new protocol, MCP842. PATIENTS AND METHODS: Seventy-four previously untreated patients < 25 years were entered on study at the Tata Memorial Hospital, Bombay. Patients with lymphoblastic lymphoma (LL) (38) without bone marrow involvement and all patients with small noncleaved cell lymphoma (SNCL) (18) and large cell lymphoma (LCL) (18) were eligible. Treatment consisted of alternating cycles of two regimens, A and B. Patients with St. Jude stages I and II received six cycles, and those with stages III or IV received eight cycles. A cycles included cyclophosphamide, adriamycin, vincristine and ara-C, and B cycles, etoposide, vincristine, methotrexate, ifosfamide and mesna. RESULTS: Complete response was achieved in 67 (91%) of patients. Event free survival (EFS) for all patients was 58%; 68% for patients with SNCL and LCL combined, and 48% for patients with LL. There was no significant difference in EFS by histology (LL versus non-LL), or stage. There were nine (12%) toxic deaths, two during induction and seven in patients in remission; six occurred in patients with LL. CONCLUSIONS: These results are better than past results in Bombay. Unlike earlier CCG protocols, in which the outcome between patients with LL and non-LL differed, this was not so in MCP842. Even patients with extensive LL without bone marrow disease received only eight cycles of therapy, suggesting that short duration therapy is curative in as many as half of such patients--an important observation in a country with limited resources.

Adolescent↗
PubMed1997

Gamma radiation induced leukemia in ICRC strain of mice: a murine model closely simulating human disease for experimental chemotherapy.

We report here a murine model of transplantable lymphoblastic leukemia closely simulating human disease in albino mice of ICRC strain. Both male and female mice of this strain developed leukemia with high incidence (approximately 70%) following whole body exposure to 60Co Gamma Rays (Dose: 1.5 Gray/Week x4). The latent period for development of leukemia was six months. In the leukemic mice there is marked leucocytosis with presence of lymphoblasts in peripheral blood. These blasts infiltrate various organs like liver, spleen, kidney, lymph nodes, testes and brain, Neoplastic cells are T lymphoblasts expressing weak Thy 1.2 membrane antigen and found sensitive to anticancer drugs. Salient features of the murine model are described.

Animals↗
PubMed1996

Prevention of graft-versus-host disease by intrathymic injection of recipient-type splenocytes into donor.

We have prevented graft-versus-host disease (GVHD) by tolerizing graft donors to host antigens by intrathymic injection of recipient-type splenocytes into donors. A unidirectional GVHD model was used in which intravenous injection of 3-4 x 10(8) Lewis rat (donor) lymphocytes into (Lewis x Brown Norway)F1 rats (recipients) causes lethal GVHD. The donor animals were divided into five treatment groups. The group 1 donor animals received no treatment. The group 2 donors received a single intraperitoneal injection of 1 ml of antilymphocyte antiserum (ALS). The group 3 donors received an intrathymic injection of 50x10(6) host splenocytes. The group 4 donors received both ALS (intraperitoneally) and intrathymic allograft. The group 5 donors received both ALS (intraperitoneally) and intravenous allograft. Two weeks after these treatments, 3-4x10(8) lymphocytes from each of these donors were injected (intravenously) into the recipients. The clinical signs of GVHD, as measured by profound weight loss, hair loss, inflammation of foot pads and ears, and profound splenomegaly, were evident in recipients of groups 1, 2, and 3 between days 9 and 10 and in the recipients (two of four) of group 5 on day 17. No GVHD was observed by histopathology in all 14 hosts that received lymphocyte injection from the group 4 donor animals (up to 300 days). These results demonstrate that GVHD can be eliminated by tolerizing donors toward host by intrathymic injection of the recipient-type lymphocytes into the donor. A single injection of ALS is necessary to possibly eliminate antihost response from the donor for the tolerance induction. The thymic route appears to be superior to the intravenous route for tolerance induction.

Adoptive Transfer↗
PubMed1995

Human T-cell recognition of Listeria monocytogenes: recognition of listeriolysin O by TcR alpha beta + and TcR gamma delta + T cells.

The cell-mediated immune response to Listeria monocytogenes has been well characterized in the mouse. Listeriolysin O (LLO) is a major antigen in murine T-cell recognition of L. monocytogenes. In this study, we show that LLO is also recognized by human TcR alpha beta T cells and TcR gamma delta T cells. Human peripheral blood mononuclear cells (PBMC) cultured in vitro with live listeriae and then expanded with interleukin 2 were shown to respond to purified LLO. The generation of LLO-responsive T cells was dependent on the use of live bacteria during the initial in vitro challenge. LLO-induced proliferation of T cells expanded by exposure of PBMC to live listeriae was major histocompatibility complex restricted. PBMC cultured with formalin-fixed listeriae and subsequently expanded by interleukin 2 gave high proliferative responses to fixed bacteria but failed to respond to LLO. PBMC stimulated in vitro with fixed listeriae contained predominantly TcR alpha beta + T cells. In contrast, PBMC obtained from 85% of the donors studied generated high numbers of TcR gamma delta + T cells following in vitro culture with live listeriae. Using a panel of synthetic amphipathic LLO peptides, we found that LLO-specific T cells from different individuals recognized both common and unique peptides. LLO 470-508 was recognized by three of five individuals, while LLO 203-226 and LLO 107-126 were recognized by two of six individuals. A TcR gamma delta + T-cell line was established from PBMC stimulated with live listeriae and was shown to recognize LLO 470-508. Proliferative responses could be induced in this cell line by peptide-pulsed autologous PBMC but not by peptide-pulsed allogeneic PBMC. Our results establish the importance of LLO in human T-cell recognition of listeriae and show that both TcR alpha beta + T cells and TcR gamma delta + T cells recognize this antigen. Finally, since LLO 470-508 has a high degree of homology with other gram-positive bacterial toxins, the recognition of this peptide by TcR gamma delta + T cells suggests that an important role of these T cells in host defense is the recognition of bacterium-derived toxins.

Amino Acid Sequence↗