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Biomedical subjects

A Prabhu

Publications and source records attributed to A Prabhu.

At least 19 recordsLinked to original sources
PubMed2006

Sequential, cycling maintenance therapy for post transplant multiple myeloma.

High-dose chemotherapy with autologous stem cell transplantation in patients with newly diagnosed multiple myeloma can prolong survival but is not curative. Maintenance therapy post transplant may prolong the disease-free interval and impact overall survival. We have conducted a phase II pilot study of 28 post transplant myeloma patients treated with a sequential, cycling maintenance regimen. The regimen was designed to include a variety of active myeloma agents chosen for ease of administration to enhance patient compliance and scheduled sequentially to minimize toxicity. The 12-month cycling schedule included dexamethasone (months 1-3); melphalan and prednisone (months 4, 5); cyclophosphamide and prednisone (months 6, 7); alpha-interferon (months 8-10); followed by a drug holiday (months 11, 12). The regimen was generally well tolerated with five patients developing reversible grade III-IV toxicity (diabetes-induced hyperglycemia in four, neutropenia in one). There was one toxic death on study due to non-neutropenic pneumonia and sepsis. Median event-free survival from transplant was 36.9 months (95% CI 23.6 - upper limit not yet reached) with median overall survival not yet reached at a median follow-up of 44 months. This concept of cycling, sequential maintenance with various agents, perhaps including newer biological, targeted agents, warrants further investigation in multiple myeloma.

Anti-Inflammatory Agents↗
PubMed2003

Isocapnic hyperpnoea accelerates recovery from isoflurane anaesthesia.

BACKGROUND: Hyperventilation should speed up elimination of volatile anaesthetic agents from the body, but hyperventilation usually results in hypocapnia. We compared recovery from isoflurane anaesthesia in patients allowed to recover with assisted spontaneous ventilation (control) and those treated with isocapnic hyperpnoea. METHODS: Fourteen patients were studied after approximately 1 h of anaesthesia with isoflurane. Control patients were allowed to recover in the routine way. Isocapnic hyperpnoea patients received 2-3 times their intraoperative ventilation using a system to maintain end tidal PCO(2) at 45-50 mm Hg. We measured time to removal of the airway and rate of change of bispectral index (BIS) during recovery. RESULTS: With isocapnic hyperpnoea, the time to removal of the airway was markedly less (median and interquartile range values of 3.6 (2.7-3.7) vs 12.1 (6.8-17.2) min, P<0.001); mean (SD) BIS slopes during recovery were 11.8 (4.4) vs 4.3 (2.7) min(-1) (P<0.01) for isocapnic hyperpnoea and control groups, respectively. Isocapnic hyperpnoea was easily applied in the operating room. CONCLUSIONS: Isocapnic hyperpnoea at the end of surgery results in shorter and less variable time to removal of the airway after anaesthesia with isoflurane and nitrous oxide.

Adult↗
PubMed2001

Anaesthetic strategies towards developments in day care surgery.

Ambulatory surgery is growing worldwide. The challenge of providing anaesthesia for longer and more complex surgery in sicker and elderly patients is a reality. To maintain the safety and good outcomes of ambulatory anaesthesia, high-risk patients will need to be evaluated carefully. Anaesthetic techniques that use short-acting drugs and minimize postoperative morbidity and mortality should become the focus. Policies on management of postoperative pain, nausea, vomiting, voiding and discharge from hospital will maintain good outcome measures.

Ambulatory Surgical Procedures↗
PubMed2000

Quantitation of Bacteroides forsythus in subgingival plaque comparison of immunoassay and quantitative polymerase chain reaction.

Our objective was to compare three methods (enzyme-linked immunosorbent assay [ELISA], endpoint and quantitative polymerase chain reaction [E-PCR and Q-PCR]) for detection and quantitation of Bacteroides forsythus in 56 plaque samples from seven subjects with progressive periodontal disease. Samples collected in buffer were pelleted and resuspended in 500 microl of water. Fifty microl aliquots were removed for an ELISA performed on bacteria or plaque immobilized on 96-well plates and probed with B. forsythus specific antibody. An occurrence of 3.7+/-0.6 x 10(4) or more bacteria were detected by ELISA in pure culture; 26 of 54 plaque samples were positive, two samples could not be analyzed. Samples for PCR were autoclaved for 10 min prior to use. The detection level of E-PCR using primers specific for B. forsythus 16S rRNA was 200 cells and 42 out of 56 samples were positive based on ethidium bromide stained agarose gels. Q-PCR using the same primers combined with a nested fluorescent oligonucleotide probe detected 10+/-0.32 bacteria in pure culture; 43 of 56 plaque samples were positive. The ELISA and Q-PCR obtained identical results with 36 of the 54 samples assayed; there were one false positive and 17 false negative ELISA results using Q-PCR as standard. The positive proportions of plaque samples were almost the same for E-PCR and Q-PCR. We conclude that the PCR methods are more appropriate for a multicenter study because of greater sensitivity and convenience of sample transportation from clinics to a central laboratory.

Bacteroides↗
PubMed2000

Murine monoclonal antibodies biologically active against the amino region of HIV-1 gp120: isolation and characterization.

The human immunodeficiency virus (HIV)-1 envelope glycoprotein is synthesized as a precursor (gp160) and subsequently cleaved to generate the external gp120 and transmembrane gp41 glycoproteins. Both gp120 and gp41 have been demonstrated to mediate critical functions of HIV, including viral attachment and fusion with the cell membrane. The antigenic variability of the HIV-1 envelope glycoprotein has presented a significant problem in the design of appropriate and successful vaccines and offers one explanation for the ability of HIV to evade immune surveillance. Therefore, the development and characterization of functional antibodies against conserved regions of the envelope glycoprotein is needed. Because of this need, we generated a panel of murine monoclonal antibodies (MuMabs) against the HIV-1 envelope glycoprotein. To accomplish this, we immunized Balb/C mice with a recombinant glycoprotein 160 (gp160) that was synthesized in a baculovirus expression system. From the growth-positive hybridomas, three MuMabs were generated that demonstrated significant reactivity with recombinant gp120 but failed to show reactivity against HIV-1 gp41, as determined by enzyme-linked immunosorbent assay (ELISA). Using vaccinia constructs that synthesize variant truncated subunits of gp160, we were able to map reactivity of all three of the Mabs (ID6, AC4, and AD3) to the first 204 residues of gp120 (i.e., the N terminus of gp120) via Western blot analysis. Elucidation of the epitopes for these Mabs may have important implications for inhibition of infection by HIV-1. Our initial attempts to map these Mabs with linear epitopes have not elucidated a specific antigenic determinant; however, several physical characteristics have been determined that suggest a continuous surface epitope. Although these antibodies failed to neutralize cell-free or cell-associated infection by HIV-1, they did mediate significant antibody-dependent cellular cytotoxicity (ADCC) activity, indicating potential therapeutic utility. In summary, these data suggest the identification of a potentially novel site in the first 200 aa of gp120 that mediates ADCC.

Amino Acid Sequence↗
PubMed1999

Developmental regulation of the kappa locus involves both positive and negative sequence elements in the 3' enhancer that affect synergy with the intron enhancer.

Expression of the mouse immunoglobulin kappa locus is regulated by the intron and 3' enhancers. Previously, we have reported that these enhancers can synergize at mature B cell stages. Here we present our recent studies on the identification and characterization of the 3' enhancer sequences that play important roles in this synergy. By performing mutational analyses with novel reporter constructs, we find that the 5' region of the cAMP response element (CRE), the PU. 1/PIP, and the E2A motifs of the 3' enhancer are critical for the synergy. These motifs are known to contribute to the enhancer activity. However, we also show that mutating other functionally important sequences has no significant effect on the synergy. Those sequences include the 3' region of the CRE motif, the BSAP motif, and the region 3' of the E2A motif. We have further demonstrated that either the 5'-CRE, the PU.1/PIP, or the E2A motif alone is sufficient to synergize with the intron enhancer. Moreover, the PU.1 motif appears to act as a negative element at pre-B cell stages but as a positive element at mature B cell stages. We have also identified a novel negative regulatory sequence within the 3' enhancer that contributes to the regulation of synergy, as well as developmental stage and tissue specificity of expression. While the levels of many of the 3' enhancer binding factors change very little in cell lines representing different B cell stages, the intron enhancer binding factors significantly increase at more mature B cell stages.

Animals↗
PubMed1998

Cellular proliferation and cytokine responses of murine macrophage cell line J774A.1 to polymethylmethacrylate and cobalt-chrome alloy particles.

Wear debris from orthopedic joint implants have been postulated to initiate a cascade of complex cellular events that results in aseptic loosening of the prosthesis and eventually in loss of function of the device. The impact of biomaterials used in these devices on host inflammatory response has not been examined extensively. Polymethylmethacrylate (PMMA) and cobalt-chrome alloy (CoCr) are biomaterials widely used in orthopedic implant devices. Macrophages are an important component of the host inflammatory response, and we have examined the effect of PMMA and CoCr particles on the murine macrophage cell line J774A.1. Our objective was to obtain a comprehensive analysis of the particle-macrophage interaction, and we examined a number of basic biological responses of the J774A.1 cell line, including cell proliferation, apoptosis, cytokines secreted into the culture supernatant (TNFalpha, IL-1alpha, IL-6, and IL-12) and mRNA expression of the cytokines (TNFalpha, IL-1alpha, IL-6, IFN-alpha, M-CSF, and TGF-beta) in response to PMMA and CoCr particles. Our results indicate that the relative contribution of PMMA and CoCr particles in J774A.1 activation is negligible, and we observed a change in metabolic activity of J774A.1 cells only at higher concentrations of CoCr particles.

Animals↗
PubMed1997

Plasma IgE levels, activation marker expression, and cytokine production in non-atopic individuals.

BACKGROUND: Since human IgE serum levels are very low compared with the other immunoglobulin isotypes, most studies have examined the regulation of IgE production in severely atopic individuals where serum IgE levels are increased. Since atopy is a pathologic consequence of increased IgE production, this disease state could have other influences that result in abnormal expression of these parameters and may not reflect normal IgE regulatory mechanisms. OBJECTIVE: To study nonatopic individuals to examine the expression of IgE regulatory cytokines as well as additional cell surface activation markers in relation to serum IgE levels. METHOD: We selected ten individuals at both the lower and higher end of a spectrum of plasma IgE concentrations from 29 nonatopic individuals and compared the differences in cytokine and activation marker expression in relation to IgE production. RESULTS: We found that even upon extensive examination of activation markers on T, B, and NK cell subsets, there are no significant differences in the cell populations or surface marker expression between the high IgE and low IgE groups. Messenger RNA expression in peripheral blood mononuclear cells (PBMCs) of the cytokines IL-4 and IL-6 was significantly higher, whereas IL-10 was lower in the high IgE group. In addition upon in vitro polyclonal stimulation of peripheral blood mononuclear cells, individuals of the high IgE group produced lower levels of IL-2, IFN gamma and IL-10 compared to the low IgE donors. CONCLUSION: Since our results differ from studies using atopic individuals, this study demonstrates the importance of using nonatopic individuals for examining associations between various immune parameters and IgE.

Antigens, CD↗
PubMed1996

Octamer independent activation of transcription from the kappa immunoglobulin germline promoter.

Previous analyses of immunoglobulin V region promoters has led to the discovery of a common octamer motif which is functionally important in the tissue-specific and developmentally regulated transcriptional activation of immunoglobulin genes. The germline promoters (Ko) located upstream of the J region gene segments of the kappa locus also contain an octamer motif (containing a single base pair mutation and referred to as the variant octamer) which has been shown previously to bind Oct-1 and Oct-2 transcription factors in vitro. To further elucidate the role of this variant octamer motif in the regulation of germline transcription from the unrearranged kappa locus, we have quantitated the relative binding affinity of Oct-1 and Oct-2 for the variant octamer motif and determined the functional role of this octamer motif in transcriptional activation. We find that, although the variant octamer motif binds Oct-1 and Oct-2 in vitro with 5-fold lower affinity than the consensus octamer motif, mutation of the variant octamer motif to either a consensus octamer or non-octamer motif has no effect on transcriptional activation from the germline promoter. We also find significant differences in activation of germline and V region promoters by kappa enhancers. Our results suggest that the germline promoters and V region promoters differ in their dependence on octamer for activation and respond differently to enhancer activation. These findings have important implications in regulation of germline transcription as well as concomitant activation of the V-J recombination of the kappa light chain locus.

Animals↗
PubMed1996

Maximal voluntary contraction as a functional indicator of adult chronic undernutrition.

Maximal voluntary contraction (MVC) using a handgrip dynamometer was assessed in seventy-two young adult males. The subjects were divided into two groups on the basis of a BMI of 18.5 kg/m2. The subjects with a BMI < 18.5 kg/m2 (n 38) were further divided into an underweight (UW; n 20) group and a chronically energy-deficient (CED; n 18) group. The CED subjects had significantly lower MVC (30.1, SD 5.9 kg) than either the well-nourished controls (BMI > 18.5 kg/m2: 39.8, SD 5.8 kg) or the underweight group (37.6, SD 4.9 kg). The differences between the CED and UW groups persisted even after the MVC were corrected for forearm muscle area and stature. The results suggest that MVC may be a useful functional indicator of nutritional status particularly in differentiating subjects with chronic undernutrition from individuals who are underweight and not undernourished but have similar BMI.

Adolescent↗
PubMed1996

Decreased levels of circulating IFN-alpha and increased sCD23 in patients with acute infectious mononucleosis.

Epstein-Barr virus (EBV) is the etiological agent for acute infectious mononucleosis (AIM). It is also associated with certain malignant disorders in individuals with immunodeficiencies such as B cell lymphoproliferative disorder (BLPD). Our previous study with BLPD patients had demonstrated significantly higher serum IL-4 and IgE levels and significantly decreased IFN-alpha levels. These observations were consistent with the model of regulation of B cell growth by T cell-derived cytokines, in which IL-4 promotes B cell growth and switch to IgE synthesis whereas IFN-alpha and IFN-gamma inhibit these IL-4 mediated effects. Since AIM is also EBV associated, this study was designed to examine IL-4, IFN-alpha, IFN-gamma, IgE, and soluble CD23 (sCD23) serum levels in AIM patients. In this study we report for the first time that in contrast to BLPD patients, AIM patients did not exhibit increased levels of IL-4 and IgE; however AIM patients to exhibit decreased IFN-alpha levels and, additionally, also exhibit significantly higher sCD23 levels. This could result in B cell activation and have implications for the survival of the virus in B cells.

Acute Disease↗
PubMed1996

Detection of local and systemic cytokines in adult periodontitis.

Periodontitis is a chronic inflammatory disease of the soft and hard supporting tissues of the teeth and is a major cause of tooth loss in adults. The local host response to periodontopathic bacteria results in the release of inflammatory mediators and cytokines. Since cytokines are indicative of effector functions, we compared the pattern of cytokine production in periodontal patients and healthy controls. Specifically, we investigated the simultaneous presence of cytokines produced by T helper (Th)1, Th 2, and inflammatory cells which could be involved in periodontitis. We also compared the expression of these cytokine mRNAs in healthy and diseased tissues. No significant differences were detected at the protein or mRNA levels of the cytokines in the systemic circulation of patients and controls. The surface markers CD16 and CD56 were expressed on significantly fewer peripheral mononuclear cells of patients when compared to controls. gamma delta + T cells were found in half of the diseased tissues, but in none of the healthy tissues of either patients or controls. Finally, significant differences were observed between healthy and inflamed gingival tissues in the cytokine mRNA profile. Expression of IL-6 and IFN-alpha mRNA was significantly higher in diseased tissues compared to healthy tissues in patients.

Adult↗
PubMed1995

Effect of IL-7 or IL-4 on reconstitution of donor lymphoid cells in congenic murine bone marrow transplantation.

IL-7 and IL-4 are known to influence the growth of cells of the lymphoid lineage. In this study, we investigated the effects of in vivo administration of IL-7 or IL-4 in mice subjected to congenic BM transplant. C57BL/6 Ly5.1+ mice were subjected to TBI, followed by transfer of B and T cell-depleted BM from C57BL/6 Ly5.2+ donor mice. Recipient mice were implanted with 14-day miniosmotic pumps that delivered IL-7, IL-4 or PBS and were examined for reconstitution of lymphoid cells using flow cytometry on different days. We observed no significant difference in the number of splenocytes, thymocytes and PBLs between recipient mice administered with cytokines or normal control mice. However, we observed that IL-4 infusion resulted in appearance of increased numbers of donor CD23+B220+ cells and also donor cells expressing Fc receptors for IgM (Fc micro R) and B220. Since CD23 is present only on mature B cells, our data demonstrate that following BMT, IL-4 treatment results in the development of more mature B cells compared to control mice. Additionally, we observed that IL-7 infusion resulted in significantly decreased expression of donor sIgM+B220+ cells. However, the effects of IL-7 or IL-4 were observed when the cytokines were actively administered and rapidly abated upon cessation of cytokine therapy.

Animals↗