Biomedical subjects

Sudhir Gupta

Publications and source records attributed to Sudhir Gupta.

At least 37 records · Page 2Linked to original sources

PubMed2004

Polyclonal B-cell expansion in the cerebrospinal fluid of patients with pseudotumor cerebri.

To investigate the hypothesis that pseudotumor cerebri (PTC) is associated with humoral immunity, we analyzed immunoglobulin heavy chain variable region (Ig-VH) genes of B cells in the cerebrospinal fluid (CSF) of 10 patients with PTC. Using RT-PCR and sequencing techniques, intrathecal B-cell Ig-VH genes were amplified in 6 of 10 PTC samples. Sequence analysis of complementarity-determining region 3 (CDR 3) and VH genes revealed a polyclonal intrathecal B-cell expansion in these patients. The nucleotide sequences showed that one-third of analyzed sequences had a high replacement to silent nucleotide substitution ratio, indicating an antigen-driven T-cell-dependent intrathecal B-cell proliferation. Moreover, other one-third had germline VH genes without or with a few nucleotide mutations, suggesting a T-cell-independent natural B-cell-mediated humoral immunity in the CNS of these patients. Our results suggest that both T-cell-dependent and T-cell-independent humoral immunity are present in the CSF of PTC.

Adolescent↗

PubMed2004

Characterization of naïve, memory and effector CD8+ T cells: effect of age.

Aging is associated with progressive decline in T cell functions and increased frequency of infections, autoimmune phenomenon, and cancer. Memory T cells rapidly acquire effector functions to kill infected and malignant cells and/or inhibit their replication. Recently, memory T cells have been further classified into central and effector memory T cells (and early and intermediate T cells by some investigators). In aging, memory T cells are accumulated; however, these subpopulations of memory and effector T cells have not been fully characterized and changes in central memory and effector memory T cells in aged humans have not been described. In this article, we have further defined naïve, central memory, effector memory, and effector CD8+ T cells in humans and their changes in aged humans.

Aging↗

PubMed2004

A role of inhibitor of apoptosis (IAP) proteins in increased lymphocyte apoptosis in aged humans.

Lymphocytes from aged humans show increased death-receptor-mediated apoptosis, which is associated with an increased and early activation of caspases. Inhibitor of apoptosis (IAP) proteins inhibit apoptosis by inhibiting activation and activity of caspases. Therefore, we examine the expression of two of the IAPs, the cIAP-2 and XIAP in lymphocytes from young and aged subjects by Western blotting. Lymphocytes from aged expressed significantly less cIAP2 whereas no difference was observed in XIAP expression between young and aged subjects. These data may suggest that decreased cIAP2 may play a role in increased apoptosis in aged humans. Possible mechanisms for the regulation of IAPs in aging are discussed.

Adolescent↗

PubMed2004

Cellular immunodeficiency and autoimmunity in long-term mineral oil administration.

BACKGROUND: Subcutaneous mineral oil injection is an old-fashioned practice used mostly for cosmetic purposes. Infection, ulceration, subcutaneous nodules, and autoimmune activation are among the known adverse effects. Immunodeficiency has not been previously reported in association with mineral oil injection. OBJECTIVE: To report the case of a 43-year-old woman who performed long-term self-administration of mineral oil and was found to have both cellular immunodeficiency and autoimmunity. METHODS: We performed an immunological evaluation. Throat, induced sputum, urine, and blood cultures were examined for microorganisms. Pelvic computed tomography, inguinal lymph node biopsy, bone marrow biopsy, and liver biopsy were also performed. RESULTS: Laboratory results revealed peripheral lymphopenia, very low absolute numbers of lymphocyte subpopulations, and a markedly impaired lymphocyte proliferative response to mitogens (phytohemagglutinin and concanavalin A) and recall antigens (mumps, Candida albicans, purified protein derivative, and tetanus toxoid). The cultures were negative for microorganisms. The pelvic computed tomogram demonstrated areas of diffuse oil-density signals throughout the subcutaneous tissue in the gluteal area and proximal lower extremities, as well as bilateral inguinal lymphadenopathy. A lymph node biopsy specimen showed lipid granulomas and necrotizing lymphadenitis. A bone marrow biopsy specimen demonstrated hypercellular marrow with normal trilineage hematopoesis. Increased serum transaminase levels, hypoalbuminemia, positive anti-extractable nuclear antigen and anti-Ro antibodies, and plasma cells in the liver suggested an autoimmune process. CONCLUSIONS: Mineral oil administration may be associated with both cellular immunodeficiency and autoimmunity. Patients who have received long-term administration of a foreign substance should undergo a comprehensive immunological evaluation.

Adult↗

PubMed2004

A role of fas-associated death domain (FADD) in increased apoptosis in aged humans.

Fas-associated death domain (FADD) is an adapter protein that is recruited to the death-inducing signaling complex (DISC) during signaling via death receptors. FADD is a common conduit in both CD95-mediated and TNF-R-mediated apoptosis. In aging, T cells show increased susceptibility to death receptor-induced apoptosis. Therefore, in this investigation, we have examined the role of FADD in increased TNF-alpha-induced apoptosis of lymphocytes from aged humans. Our study shows that FADD expression is increased in lymphocytes from aged humans as compared to those from young subjects. Furthermore, transfection of aged lymphocytes with FADD dominant negative (FADD dn) plasmid resulted in the reduction of TNF-induced apoptosis in aged lymphocytes to a level comparable to that of young subjects. In addition, overexpression of FADD by transfection of lymphocytes from young subjects with wild-type FADD (FADD wt) resulted in increased apoptosis of young lymphocytes to a level comparable to that of young subjects. These data suggest that FADD plays an important role in increased apoptosis in aged lymphocytes signaled via TNF-R.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Chronic HIV type 1 infection down-regulates expression of DAP kinase and p19ARF-p53 checkpoint and is associated with resistance to CD95-mediated apoptosis in HUT78 T cells.

Death-associated protein kinase (DAP kinase) is a proapoptotic serine/threonine kinase that has been shown to play a role in both death-receptor signaling and mitochondrial signaling pathways of apoptosis. DAP kinase activates the p19ARF-p53 apoptotic checkpoint. In this study we report that the expression of DAP kinase, p19ARF, p53, and p21WAF1 was significantly down-regulated in the chronically HIV-1SF2-infected HUT78 T cells (HUT78/HIV-1SF2) as compared to uninfected HUT78 cells. An increased proportion of HUT78/HIV1SF2 cells was detected in S phase and a decreased proportion in G0/G1 phase indicating that more HUT78/HIV1SF2 cells progressed through the G1/S transition. Furthermore, HUT78/HIV-1SF2 cells showed increased resistance to CD95-mediated apoptosis as compared to HIV-1SF2-uninfected HUT78 cells and activation of caspase-3, -8, and -9 was significantly reduced in HUT78/HIV-1SF2 cells. These data suggest that down-regulation of DAP kinase and downstream signaling factors may be one of the mechanism that HIV-1 may employ to protect the infected host cells from cell death and to allow persistent HIV-1 replication.

Apoptosis↗

PubMed2003

The role of arginine vasopressin and its receptors in the normal and failing rat heart.

OBJECTIVE: To evaluate the role of arginine vasopressin (AVP) in the normal and post-myocardial infarction (post-MI) hearts, and to investigate whether chronic AVP receptor antagonism can attenuate post-infarct ventricular remodeling. BACKGROUND: A number of neurohormones, like norepinephrine and angiotensin II, have detrimental effects in heart failure (HF) and inhibiting them is beneficial. AVP shares some important properties with these hormones and is activated in HF. However, its role in the syndrome of HF, especially the effect of AVP inhibition, is largely undefined. METHODS AND RESULTS: Effects of AVP-V1a and AVP-V2 receptor stimulation on normal rat cardiomyocyte contractile function, intracellular calcium [Ca2+]i, inositol 3 phosphate (IP3) generation and cell survival were studied. In post-MI rats, AVP receptor function was assessed in cardiomyocytes as well as isolated working hearts. AVP receptor total number (ligand binding) and mRNA levels (RT-PCR) were measured in myocytes. Finally, the effects of chronic AVP-V1a blockade were assessed in post-MI rats using echo and morphometry to measure ventricular remodeling. Normal cardiomyocytes showed a dose-dependent increase in myocyte contractile function, [Ca2+]i, and IP3 generation in response to AVP-V1a receptor stimulation. AVP-V2 agonists had no effect. Cells from MI hearts showed reduced inotropic response to AVP-V1a stimulation. Myocyte AVP-V1a receptor number and receptor mRNA were decreased. Prolonged exposure to AVP reduced cellular viability. However, chronic AVP-V1a blockade did not attenuate structural remodeling or improve function in post-MI hearts. CONCLUSIONS: Isolated adult rat cardiomyocytes bear AVP-V1a receptors that mediate inotropic effects through the IP3 pathway. These receptors are functionally and numerically downregulated in the post-MI remodeled hearts. Despite evidence that AVP is cytotoxic to cells, chronic AVP-V1a receptor blockade does not attenuate post-MI ventricular remodeling in this model. Thus, AVP may not play a major role in the structural progression of HF.

Animals↗

PubMed2003

Effect of age on molecular signaling of TNF-alpha-induced apoptosis in human lymphocytes.

Aging in humans is associated with progressing decline in T cell numbers and functions. In addition, there is an increased production of tumor necrosis factor-alpha (TNF-alpha) during human aging. TNF-alpha mediates both survival and cell death signals. TNF-alpha exerts its biological effects via TNFR-I and TNFR-II. Here we discuss signaling pathways induced by TNF-alpha and the effect of age on TNF-alpha-induced apoptosis in T cells and T cell subsets. T cells and T cell subsets from aged humans are more sensitive to TNF-alpha-induced apoptosis, which appears to be due to both an increased apoptotic signaling and decreased survival signals.

Aging↗

PubMed2003

Severe T- and B-cell immune deficiency associated with malignant thymoma.

BACKGROUND: Immunodeficiency with thymoma syndrome is a rare disorder that generally occurs after the fourth decade of life. Typically, thymic tumors are benign, and gradually developing immunodeficiency consists of hypogammaglobulinemia with low B-cell counts and an inverted CD4+/CD8+ T-cell ratio due to excessive CD8+ T cells. OBJECTIVE: To report the case of a 32-year-old, white man with an invasive malignant thymoma and profound combined T- and B-cell immunodeficiency associated with a normal CD4+/CD8+ T-cell ratio, absence of circulating B cells, and infection with an unusual organism. METHODS: The patient presented with a superior vena cava syndrome caused by a malignant thymoma. During chemotherapy and radiotherapy, he experienced recurrent episodes of pulmonary infections due to Haemophilus influenza and Serratia marcescens and persistent oral thrush. He was diagnosed as having thymoma and underwent immunological evaluation. RESULTS: Sixteen months after the diagnosis of thymoma, the immunological evaluation revealed profound lymphopenia, eosinopenia, very low counts of both CD4+ T cells and CD8+ T cells, and a normal CD4+/CD8+ ratio with negative delayed-type hypersensitivity skin test results. Hypogammaglobulinemia and absent specific antibody responses were associated with a lack of peripheral blood CD19+ B cells. Despite treatment with intravenous immunoglobulin, the patient died of respiratory insufficiency and sepsis secondary to a chronic pulmonary infection. CONCLUSIONS: Malignant thymoma may be associated with severe combined immunodeficiency. A normal CD4+/CD8+ ratio and the absence of peripheral B cells suggest a bone marrow defect that affects both T and B cells in the pathogenesis of this syndrome. Comprehensive immunological evaluation should be performed when thymoma is diagnosed to initiate an early and effective treatment to prevent life-threatening complications.

Adult↗

PubMed2003

Molecular basis of rifampicin-induced inhibition of anti-CD95-induced apoptosis of peripheral blood T lymphocytes: the role of CD95 ligand and FLIPs.

Rifampicin modulates immune response; however, mechanisms by which it exerts these effects are incompletely understood. Recently, rifampicin has been shown to bind to and activate glucocorticoid receptors. Because of the evidence for a role of glucocorticoids in lymphocyte apoptosis, we hypothesized that rifampicin may exert its influence on the immune system by regulating apoptosis. Therefore, we examined the effect of rifampicin on signaling pathway of anti-CD95-induced apoptosis in peripheral blood lymphocytes. Rifampicin, in a concentration-dependent manner, inhibited anti-CD95-induced apoptosis in both CD4+ and CD8+ T cells, which was associated with the inhibition of activation of both caspase-3 and caspase-8. In addition, rifampicin down-regulated the expression of CD95L and Bax. The inhibitory effects of rifampicin on apoptosis and caspase activation as well as its effect on the expression of CD95L and FLIPs were reversed by RU486, an antagonist of glucocorticoid receptor. These data suggest that rifampicin inhibits anti-CD95-mediated apoptosis in lymphocytes by modulating the expression of certain proteins that regulate apoptosis, at least in part, via glucocorticoid receptors.

Adult↗

PubMed2003

Molecular signaling in death receptor and mitochondrial pathways of apoptosis (Review).

In recent years major progress has been made in understanding the molecular steps of death receptor and mitochondrial pathway of apoptosis. Mechanisms of NF-kappaB-mediated survival (anti-apoptotic) signal have been delineated. A novel anti-apoptotic mechanism of FLIP in the recruitment of RIP and TRAF-1 and TRAF-2 to activate ERK and NF-kappaB has been defined. These are some of the recent discoveries in death receptor and mitochondrial pathways of apoptosis that have been reviewed in this article.

Animals↗

PubMed2003

Blue toe syndrome: a rare complication of acute pancreatitis.

CONTEXT: Blue toe syndrome is an unusual complication of acute pancreatitis. It is characterized by tissue ischemia secondary to cholesterol crystal or atherothrombotic embolization leading to the occlusion of small vessels. Clinical presentation can range from a cyanotic toe to a diffuse multiorgan systemic disease that can mimic other systemic illnesses. CASE REPORT: Here we describe a young male who developed this complication after acute alcoholic pancreatitis.

Acute Disease↗

PubMed2003

Changes in mitochondrial membrane potential and mitochondrial mass occur independent of the activation of caspase-8 and caspase-3 during CD95-mediated apoptosis in peripheral blood T cells.

Although death receptor pathway and mitochondrial pathways of apoptosis are connected through Bid cleavage, such activation of mitochondrial pathway by death receptor signaling is observed in type II cells and not in type I cells (peripheral blood T cells). Furthermore, activation of mitochondria via Bid is associated with release of cytochrome c and caspase-9 activation. In this study we demonstrate that anti-CD95-induced apoptosis in T cells is associated with both depolarization of mitochondrial membrane potential (Delta(psi)m) and increase in mitochondrial mass and activation of caspase-8 and caspase-3 but without caspase-9 activation. Furthermore, changes in mitochondrial membrane potential and mitochondrial mass by anti-CD95 monoclonal antibodies were unaffected by inhibitors of caspase-8 and caspase-3, suggesting that anti-CD95-induced changes in Delta(psi)m and mitochondrial mass are independent of caspase-8 and caspase-3 activation.

Adult↗

PubMed2003

Arsenic trioxide induces apoptosis in peripheral blood T lymphocyte subsets by inducing oxidative stress: a role of Bcl-2.

Arsenic trioxide (As(2)O(3)) has been used successfully in the treatment of acute promyelocytic leukemia. However, effects of As(2)O(3) in normal peripheral blood T cells have not been studied in detail. The purpose of this study was to investigate whether As(2)O(3) would induce apoptosis in normal T cells and therefore may have immunosuppressive side effects. Apoptosis was measured by terminal deoxynucleotidyl transferase-mediated nick end labeling assay, caspase activation by flow cytometry and colorimetric assay, mitochondrial transmembrane potential (deltapsi(m)), intracellular reactive oxygen species (ROS), and intracellular reduced glutathione (GSH) by flow cytometry. The release of cytochrome c and apoptosis-inducing factor (AIF) from the mitochondria was measured by confocal microscopy, and the expression of molecules regulating apoptosis was measured by Western blotting. As(2)O(3), at clinically achievable therapeutic concentrations, induces apoptosis in peripheral blood T cells. As(2)O(3)-induced apoptosis was associated with reduced deltapsi(m), enhanced generation of intracellular ROS, decreased levels of intracellular GSH, release of cytochrome c and AIF from the mitochondria, activation of caspases, down-regulation of Bcl-2 and Bcl-x(L), and up-regulation of Bax expression. In addition, exogenous GSH protected lymphocytes from As(2)O(3)-induced apoptosis. Furthermore, overexpression of Bcl-2 inhibited As(2)O(3)-induced apoptosis and blocked depolarization of deltapsi(m), generation of ROS, and release of both cytochrome c and AIF. These data indicate that As(2)O(3) induces apoptosis in T cells by enhancing oxidative stress and that Bcl-2 appears to play a major role in As(2)O(3)-induced apoptosis.

Antineoplastic Agents↗

PubMed2002

T cells and aging, January 2002 update.

Age-related changes in the immune system may contribute to morbidity and mortality due to decreased resistance to infection and, possibly, certain cancers in the aged. Many studies mostly performed in mice, rats and man but also including monkeys and dogs have established that age-associated immune decline is characterized by decreases in both humoral and cellular responses. The former may be largely a result of the latter, because observed changes both in the B cell germline-encoded repertoire and the age-associated decrease in somatic hypermutation of the B cell antigen receptors are now known to be critically affected by helper T cell aging. As antigen presenting cell (APC) function appears to be well-maintained in the elderly, this review will focus on the T cell. Factors contributing to T cell immunosenescence may include a) altered production of T cell progenitors (stem cell defects, stromal cell defects), b) decreased levels of newly-generated mature T cells (thymic involution), c) aging of resting immune cells, d) disrupted activation pathways in immune cells (stimulation via the T cell receptor for antigen, costimulation, apoptosis control), e) replicative senescence of clonally expanding cells. This review aims to consider the current state of knowledge on the scientific basis for and potential clinical relevance of those factors in immunosenescence in humans. Experiments in other species will be touched upon with the proviso that there are clearly differences between them, especially between humans and rodents, but exactly what those differences are is not completely clear. Given its potential importance and the increasing proportion of elderly people the world over, coupled with the realisation that whereas mortality is decreasing, morbidity may not be decreasing in parallel (1), a better understanding of the causes and impact of immunosenescence may offer the possibility of identifying where prevention or delay of onset, as well as therapeutic intervention, might be beneficial. Amelioration of the effects of dysregulated immune responses in the elderly by replacement therapy, supplementation therapy or other approaches may result in an enhancement of their quality of life, and significant reductions in the cost of medical care in old age.

Aging↗

PubMed2002

The case definition of chronic fatigue syndrome.

The 1994 case definition of chronic fatigue syndrome is widely used not only for diagnosis but also for clinical and laboratory-based observations of this clinical entity. The criteria for the 1994 case definition are based primarily on symptoms and not on physical signs or chemical or immunological tests. This situation has resulted in conflicting clinical and laboratory observations that in all likelihood is due to different populations of patients being studied in different centers. Based on some of the recent publications, there appears to be an emerging picture of this disease entity that we propose could be used to subgroup chronic fatigue syndrome into four different subclasses. These subclasses would consist of chronic fatigue with primarily nervous system disorders such as impaired memory or concentration and headache, chronic fatigue with primarily endocrine system disorders such as unrefreshing sleep and postexertional malaise, chronic fatigue with musculoskeletal system disorders such as muscle pain and joint pain, and chronic fatigue with immune system/infectious disorders such as sore throat and tender lymph nodes. It is suggested that if clinical and laboratory-based studies on chronic fatigue syndrome were conducted on more homogeneous subgroups of patients, the data from one center to the other might not be as conflicting and more insights can be shed on the nature of this clinical condition.

Endocrine Glands↗

PubMed2002

Rifampicin inhibits CD95-mediated apoptosis of Jurkat T cells via glucocorticoid receptors by modifying the expression of molecules regulating apoptosis.

Rifampicin and its analogues are increasingly used in the treatment and prophylaxis of mycobacterial infections. Recently, it has been demonstrated that rifampicin binds to and activates glucocorticoid receptors (GR). Glucocorticoids may inhibit or promote apoptosis in various cell types. Therefore, we investigated the effect of rifampicin on anti-CD95-induced apoptosis in Jurkat T cells. Rifampicin, in a concentration-dependent manner, inhibited anti-CD95-induced apoptosis. Furthermore, rifampicin down-regulated the expression of Bax and CD95L and up-regulated the expression of Bcl-2, Bcl-xL, and Flice-inhibitory protein-L (FLIPL); however, rifampicin had no effect on CD95 or XIAP expression. Rifampicin did not inhibit the binding of anti-CD95 monoclonal antibody to CD95 receptor. A GR-specific antagonist RU480 reversed the inhibition of apoptosis by rifampicin. Furthermore, rifampicin failed to inhibit anti-CD95-induced apoptosis in a dominant negative IKBalpha (IKBaM) Jurkat T cells. Taken together, these findings suggest that rifampicin inhibits anti-CD95-induced apoptosis in Jurkat T cells by modulating the expression of various molecules regulating apoptosis and its effect appears to be mediated via GR and at least in part through NF-kappaB signaling pathway.

Antibiotics, Antitubercular↗

PubMed2002

A decision between life and death during TNF-alpha-induced signaling.

Tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine, exerts its biological activity by signaling via its two receptors, TNF-RI and TNF-RII, and by activating NF-kappaB. NF-kappaB is essential for survival of many cell types; however, TNF-alpha also induces cell death. In this article, both the survival and cell death signaling by TNF-alpha and the role of caspases in turning off NF-kappaB survival signal are reviewed. Furthermore, a role of DAP kinase in TNF-induced apoptosis is discussed. Finally, the molecular basis of the effect of age on TNF-alpha-induced apoptosis in human T cells is reviewed.

Aging↗