Biomedical subjects

M Suresh

Publications and source records attributed to M Suresh.

At least 19 recordsLinked to original sources

PubMed2026

Factors influencing the enhancement of the new iron triangle in healthcare organisations.

PURPOSE: A new paradigm, "healthcare's new iron triangle," has been developed to emphasise the technological perspective of healthcare delivery, focusing on automation, value and empathy. The study aims to build a conceptual model and to identify factors for the enhancement of the new iron triangle in healthcare organisations. DESIGN/METHODOLOGY/APPROACH: The healthcare organisation is the primary focus point of the current study. To determine the factors, a survey of the literature and healthcare experts' opinions was conducted. The healthcare professionals validated the identified factors. Data for this study were gathered using a closed-ended questionnaire and scheduled interviews. The study employed "Total Interpretive Structural Modeling methodology and Matriced' Impacts Croise´s Multiplication Appliqué´ a UN Classement/Cross-Impact Matrix Multiplication Applied to a Classification (MICMAC) analysis" to address the "why" and "how" the factors interact and prioritise the identified factors. FINDINGS: The study found that organisational structure (F8), artificial intelligence (F1), innovation (F2) and human resources (F5) are the driving or key factors of the study. RESEARCH LIMITATIONS/IMPLICATIONS: The study primarily focused on identifying factors for the enhancement of a new iron triangle in healthcare organisations. The scope could eventually be expanded to explore more areas. PRACTICAL IMPLICATIONS: Academics and other stakeholders will have a better understanding of the key drivers for the enhancement of the new iron triangle in healthcare organisations. ORIGINALITY/VALUE: In this study, total interpretive structural modeling and cross-impact MICMAC analysis are proposed as an innovative approach to address the new iron triangle in healthcare organisations.

Humans↗

PubMed2006

Virally activated CD8 T cells home to Mycobacterium bovis BCG-induced granulomas but enhance antimycobacterial protection only in immunodeficient mice.

The effect of secondary infections on CD4 T-cell-regulated chronic granulomatous inflammation is not well understood. Here, we have investigated the effect of an acute viral infection on the cellular composition and bacterial protection in Mycobacterium bovis strain bacille Calmette-Guérin (BCG)-induced granulomas using an immunocompetent and a partially immunodeficient murine model. Acute lymphocytic choriomeningitis virus (LCMV) coinfection of C57BL/6 mice led to substantial accumulation of gamma interferon (IFN-gamma)-producing LCMV-specific T cells in liver granulomas and increased local IFN-gamma. Despite traffic of activated T cells that resulted in a CD8 T-cell-dominated granuloma, the BCG liver organ load was unaltered from control levels. In OT-1 T-cell-receptor (TCR) transgenic mice, ovalbumin (OVA) immunization or LCMV coinfection of BCG-infected mice induced CD8 T-cell-dominated granulomas containing large numbers of non-BCG-specific activated T cells. The higher baseline BCG organ load in this CD8 TCR transgenic animal allowed us to demonstrate that OVA immunization and LCMV coinfection increased anti-BCG protection. The bacterial load remained substantially higher than in mice with a more complete TCR repertoire. Overall, the present study suggests that peripherally activated CD8 T cells can be recruited to chronic inflammatory sites, but their contribution to protective immunity is limited to conditions of underlying immunodeficiency.

Animals↗

PubMed2006

Differential requirement for Lck during primary and memory CD8+ T cell responses.

T cell receptor (TCR) signaling mediates cell fate decisions throughout the life of a T cell. The earliest biochemical events during antigen-stimulated TCR signaling include activation of the Src-family protein tyrosine kinase, p56(Lck) (Lck), which is an integral component of the TCR signaling complex by its association with the cytoplasmic tails of CD8 or CD4. CD8 and Lck are obligatory during thymic selection of CD8+ T cells. What remain unknown are when and with what stringency Lck is required for effective TCR-mediated activation and function throughout the life of a mature CD8+ T cell. Using mice that express an inducible Lck transgene in T cells, we have investigated the temporal importance of Lck-mediated TCR signaling in antigen-specific CD8+ T cell responses during acute viral infections. We show that Lck deficiency induced in naive mice abrogated the antigen-specific activation and clonal expansion of CD8+ T cells during a primary response to acute viral infections. Moreover, the magnitude of primary CD8 T cell expansion depended on the duration of Lck-dependent TCR signaling. Quite unexpectedly, however, Lck was dispensable for enhanced functional avidity, maintenance, and reactivation of memory CD8+ T cells in vitro and in vivo. These observations suggest that the TCR signaling apparatus is rewired from an Lck-dependent state in naive CD8+ T cells to an Lck-independent state in memory CD8+ T cells. Less stringent requirements for antigen-specific TCR signaling to activate memory CD8+ T cells could, in part, account for their unique hyperreactivity to antigen, which contributes to accelerated immune control during secondary infections.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Expression and purification of two anti-CD19 single chain Fv fragments for targeting of liposomes to CD19-expressing cells.

Antibody-targeted liposomal anticancer drugs combine the specificity of antibodies with large payloads of entrapped drugs. We previously showed that liposomal doxorubicin (DXR) targeted via anti-CD19 monoclonal antibodies (mAb) or their Fab' fragments against the B-cell antigen CD19 led to improved therapeutic effects in murine B-cell lymphoma models relative to non-targeted liposomal DXR. We now are examining the use of anti-CD19 single chain fragments of the antibody variable region (scFv) as a targeting moiety, to test the hypothesis that scFv have advantages over full-sized mAb or Fab' fragments. We expressed two different anti-CD19 scFv constructs, HD37-C and HD37-CCH in E. coli, and purified the scFvs using two different methods. The HD37-CCH construct was selected for coupling studies due to its relative stability and activity in comparison to HD37-C. When coupled to liposomes, the HD37-CCH scFv showed increased binding in vitro to CD19-positive Raji cells, compared to non-targeted liposomes. Cytotoxicity data showed that HD37-CCH scFv-targeted liposomes loaded with DXR were more cytotoxic than non-targeted liposomal DXR. Our results suggest that anti-CD19 scFv constructs should be explored further for their potential in treating B-lymphoid leukemias and lymphomas.

Antibiotics, Antineoplastic↗

PubMed2006

Traumatic injury and the presence of antigen differentially contribute to T-cell recruitment in the CNS.

T-cell recruitment into the brain is critical in inflammatory and autoimmune diseases of the CNS. We use intracerebral antigen microinjection and tetramer technology to track antigen-specific CD8+ T-cells in the CNS and to clarify the contribution of antigen deposition or traumatic injury to the accumulation of T-cells in the brain. We demonstrate that, after intracerebral microinjection of ovalbumin, ovalbumin-specific CD8+ T-cells expand systemically and then migrate into the brain where they complete additional proliferation cycles. T-cells in the brain are activated and respond to in vitro secondary antigen challenge. CD8+ T-cells accumulate and persist in sites of antigen in the brain without replenishment from the periphery. Persistent survival of CD8+ T-cells at sites of cognate antigen is significantly reduced by blocking CD154 molecules. A small traumatic injury itself does not lead to recruitment of CD8+ T-cells into the brain but attracts activated antigen-specific CD8+ T-cells from cognate antigen injection sites. This process is presumably antigen independent and cannot be inhibited by blocking CD154 molecules. These data show that activated antigen-specific CD8+ T-cells accumulate in the CNS at both cognate antigen-containing and traumatic injury sites after intracerebral antigen delivery. The accumulation of activated antigen-specific T-cells at traumatic injury sites, in addition to antigen-containing areas, could amplify local inflammatory processes in the CNS. Combination therapies in neuroinflammatory diseases to block both of these processes should be considered.

Animals↗

PubMed2006

Human protein reference database--2006 update.

Human Protein Reference Database (HPRD) (http://www.hprd.org) was developed to serve as a comprehensive collection of protein features, post-translational modifications (PTMs) and protein-protein interactions. Since the original report, this database has increased to >20 000 proteins entries and has become the largest database for literature-derived protein-protein interactions (>30 000) and PTMs (>8000) for human proteins. We have also introduced several new features in HPRD including: (i) protein isoforms, (ii) enhanced search options, (iii) linking of pathway annotations and (iv) integration of a novel browser, GenProt Viewer (http://www.genprot.org), developed by us that allows integration of genomic and proteomic information. With the continued support and active participation by the biomedical community, we expect HPRD to become a unique source of curated information for the human proteome and spur biomedical discoveries based on integration of genomic, transcriptomic and proteomic data.

Databases, Protein↗

PubMed2006

Influence of years since menopause on bone mineral metabolism in South Indian women.

BACKGROUND: Although an increase of bone turnover has been documented at the time of menopause, the subsequent abnormalities of bone resorption and formation in the elder women have not been investigated. AIM: To assess bone turnover among different YSM (years since menopause) groups of postmenopausal women. SETTINGS AND DESIGN: A case control study in a tertiary care hospital. MATERIALS AND METHODS: Forty-seven premenopausal (control) women and 257 postmenopausal women were included in this study. Based on YSM, the postmenopausal women were divided into four groups namely, 1-5 YSM (n = 82), 6-10 YSM (n = 77), 11-15 YSM (n = 58) and > 15 YSM (n = 40). The levels of calcium, phosphorus, total alkaline phosphatase, FSH, LH, estradiol, intact-paratharmone and 25-hydroxy vitamin D in serum and urine levels of calcium, phosphorus and bone resorption marker calcium/creatinine(Ca/Cre) ratios were analyzed in all subjects. STATISTICAL ANALYSIS USED: One way ANOVA followed by Duncan's multiple range test. RESULTS: Significantly increased levels of FSH (P < 0.001) and declined levels of urine calcium (P = 0.015) and Ca/Cre ratios (P = 0.006) were observed in > 15 YSM group over 1-5 and 6-10 YSM groups. An inverse correlation was observed between serum FSH levels and urine Ca/Cre ratios (r = -0.655, P < 0.001) in > 15 YSM group. Comparable deficient estradiol levels were observed in all YSM groups. CONCLUSIONS: The risk of bone resorption is greater in early years than late years of menopause. The decreased bone resorption risk in late postmenopausal women might be due to increased FSH levels. However, further studies are required to explore this finding.

Adult↗

PubMed2005

Proteomic resources: integrating biomedical information in humans.

Recent improvements in high-throughput proteomic technologies have unleashed the potential for generating vast amounts of data. Managing and sharing proteomic data is not an easy task. In this article, we will discuss some of the high-throughput proteomic techniques that are commonly used today. We will also review the major issues in sharing and dissemination of proteomic data and the recent community initiatives to standardize data formats and ontologies. An overview of the web-based resources and databases for analysis of proteomic data is also provided. Integration of disparate proteomic data sources with genomic and transcriptomic data should make systems biology type of approaches feasible in the near future.

Amino Acid Sequence↗

PubMed2005

TAGmapper: a web-based tool for mapping SAGE tags.

Serial Analysis of Gene Expression (SAGE) is an important means of obtaining quantitative information about expression of genes in different samples. Short SAGE tags are 10 nucleotides long and often contain enough information to uniquely identify the gene(s) corresponding to the tag. We have observed, however, that the currently available resources are not adequate for accurate mapping of all SAGE tags to genes. Here, we describe development of a web-based tool called TAGmapper (http://tagmapper.ibioinformatics.org), which provides a comprehensive and accurate mapping of SAGE tags to genes. We were able to map SAGE tags accurately in several instances where two other popular resources, SAGEmap (http://www.ncbi.nlm.nih.gov/projects/SAGE/) and SAGE Genie (http://cgap.nci.nih.gov/SAGE), provided incorrect or no assignment of tags to genes. Finally, we experimentally determined the expression of a subset of genes assigned by TAGmapper using DNA microarrays and/or quantitative PCR to confirm the reliability of the gene mappings. We anticipate that TAGmapper will be a useful tool in functional genomic approaches by providing accurate identification of genes in SAGE experiments.

Base Sequence↗

PubMed2005

Equine herpesvirus-1 infection induces IFN-gamma production by equine T lymphocyte subsets.

A commercial bovine IFN-gamma-specific monoclonal antibody was used to measure antigen-specific IFN-gamma production by equine lymphocytes. Paired PBMC samples were collected from six ponies prior to and 10 days after challenge infection with equine herpesvirus-1 (EHV-1). Each sample was stimulated in vitro with EHV-1, virus-free medium, or PMA and ionomycin, and labelled with monoclonal antibodies specific for various equine lymphocyte subset markers. Following fixation, intracellular IFN-gamma was detected using a FITC-conjugated bovine IFN-gamma-specific monoclonal antibody. In vitro restimulation of PBMC with EHV-1 induced IFN-gamma production by a significantly higher percentage of total (CD5(+)) T lymphocytes, and CD4(+) and CD8(+) T lymphocyte subsets among post-EHV-1 infection PBMC samples compared to pre-infection samples. This response was associated with an increase in virus-specific CTL activity, a critical immune effector for the control of EHV-1 infection and disease. No significant increase in IFN-gamma production by B lymphocytes was observed. These data demonstrate that EHV-1 challenge infection of ponies results in increased production of IFN-gamma by virus-specific T lymphocytes, and that this response can be quantitated using flow cytometry.

Animals↗

PubMed2005

Plasma Proteome Database as a resource for proteomics research.

Plasma is one of the best studied compartments in the human body and serves as an ideal body fluid for the diagnosis of diseases. This report provides a detailed functional annotation of all the plasma proteins identified to date. In all, gene products encoded by 3778 distinct genes were annotated based on proteins previously published in the literature as plasma proteins and the identification of multiple peptides from proteins under HUPO's Plasma Proteome Project. Our analysis revealed that 51% of these genes encoded more than one protein isoform. All single nucleotide polymorphisms involving protein-coding regions were mapped onto the protein sequences. We found a number of examples of isoform-specific subcellular localization as well as tissue expression. This database is an attempt at comprehensive annotation of a complex subproteome and is available on the web at http://www.plasmaproteomedatabase.org.

Amino Acid Motifs↗

PubMed2005

Role of tumor necrosis factor receptors in regulating CD8 T-cell responses during acute lymphocytic choriomeningitis virus infection.

The role of tumor necrosis factor (TNF) in regulating various phases of the antiviral T-cell response is incompletely understood. Additionally, despite strong evidence ascribing a role for TNF in protecting against T-cell-dependent autoimmunity, the underlying mechanisms are still obscure. To address these issues, we have investigated the role of tumor necrosis factor receptors (TNFRs) I (p55R) and II (p75R) in regulating CD8 T-cell responses to lymphocytic choriomeningitis virus (LCMV) with wild-type, p55R-deficient (p55(-/-)), p75R-deficient (p75(-/-)), and p55R- and p75R-deficient (DKO) mice. Loss of p55R increased the number of memory CD8 T cells to only one of the two immunodominant epitopes, and p75R deficiency had a minimal impact on the T-cell response to LCMV. Strikingly, deficiency of both p55R and p75R had a more dramatic effect on the LCMV-specific CD8 T-cell response; in the DKO mice, as a sequel to enhanced expansion and a reduction in contraction of CD8 T cells, there was a substantial increase in the number of memory CD8 T cells (specific to the two immunodominant epitopes). While the majority of LCMV-specific memory CD8 T cells in wild-type mice were CD62Lhi CCR7hi (central memory), a major proportion of memory CD8 T cells in DKO mice were CD62Llo CCR7hi. TNFR deficiency did not affect the proliferative renewal of memory CD8 T cells. Taken together, these data suggested that TNFRs p55R and p75R have overlapping roles in downregulating CD8 T-cell responses and establishment of immune homeostasis during an acute viral infection.

Acute Disease↗

PubMed2005

Role of thymic output in regulating CD8 T-cell homeostasis during acute and chronic viral infection.

Although it is well documented that CD8 T cells play a critical role in controlling chronic viral infections, the mechanisms underlying the regulation of CD8 T-cell responses are not well understood. Using the mouse model of an acute and chronic lymphocytic choriomeningitis virus (LCMV) infection, we have examined the relative importance of peripheral T cells and thymic emigrants in the elicitation and maintenance of CD8 T-cell responses. Virus-specific CD8 T-cell responses were compared between mice that were either sham thymectomized or thymectomized (Thx) at approximately 6 weeks of age. In an acute LCMV infection, thymic deficiency did not affect either the primary expansion of CD8 T cells or the proliferative renewal and maintenance of virus-specific lymphoid and nonlymphoid memory CD8 T cells. Following a chronic LCMV infection, in Thx mice, although the initial expansion of CD8 T cells was normal, the contraction phase of the CD8 T-cell response was exaggerated, which led to a transient but striking CD8 T-cell deficit on day 30 postinfection. However, the virus-specific CD8 T-cell response in Thx mice rebounded quickly and was maintained at normal levels thereafter, which indicated that the peripheral T-cell repertoire is quite robust and capable of sustaining an effective CD8 T-cell response in the absence of thymic output during a chronic LCMV infection. Taken together, these findings should further our understanding of the regulation of CD8 T-cell homeostasis in acute and chronic viral infections and might have implications in the development of immunotherapy.

Acute Disease↗

PubMed2004

Enhanced virulence of influenza A viruses with the haemagglutinin of the 1918 pandemic virus.

The 'Spanish' influenza pandemic of 1918-19 was the most devastating outbreak of infectious disease in recorded history. At least 20 million people died from their illness, which was characterized by an unusually severe and rapid clinical course. The complete sequencing of several genes of the 1918 influenza virus has made it possible to study the functions of the proteins encoded by these genes in viruses generated by reverse genetics, a technique that permits the generation of infectious viruses entirely from cloned complementary DNA. Thus, to identify properties of the 1918 pandemic influenza A strain that might be related to its extraordinary virulence, viruses were produced containing the viral haemagglutinin (HA) and neuraminidase (NA) genes of the 1918 strain. The HA of this strain supports the pathogenicity of a mouse-adapted virus in this animal. Here we demonstrate that the HA of the 1918 virus confers enhanced pathogenicity in mice to recent human viruses that are otherwise non-pathogenic in this host. Moreover, these highly virulent recombinant viruses expressing the 1918 viral HA could infect the entire lung and induce high levels of macrophage-derived chemokines and cytokines, which resulted in infiltration of inflammatory cells and severe haemorrhage, hallmarks of the illness produced during the original pandemic.

Adolescent↗

PubMed2004

CD8 T cell responses to lymphocytic choriomeningitis virus in early growth response gene 1-deficient mice.

Previous in vitro work has implicated a role for transcriptional factor early growth response gene 1 (EGR1) in regulating immune responses. However, the in vivo role of EGR1 in orchestrating T cell responses has not been studied. To investigate the importance of EGR1 in T cell immunity, we compared Ag-specific CD8 T cell responses between wild type (+/+) and EGR1-deficient (EGR1-/-) mice following an acute infection with lymphocytic choriomeningitis virus (LCMV). These studies revealed that the expansion of LCMV-specific CD8 T cells was substantially reduced in EGR1-/- mice, as compared with +/+ mice. The reduced numbers of LCMV-specific CD8 T cells in EGR1-/- mice were not due to an intrinsic T cell defect per se because purified EGR1-deficient T cells exhibited normal proliferative response to anti-CD3 stimulation in vitro, and underwent normal activation and expansion in response to LCMV upon adoptive transfer into T cell-deficient mice. Furthermore, adoptive transfer of CD8 T cells bearing a transgenic TCR into EGR1-/- mice showed that EGR1 deficiency in non-CD8 T cells impaired CD8 T cell expansion in vivo following an LCMV infection. Further investigations on accessory cells showed that bone marrow-derived dendritic cells from EGR1-/- mice did not exhibit detectable impairment to prime Ag-specific CD8 T cell responses in vivo. However, in LCMV-infected mice, EGR1 deficiency selectively impaired the maturation of CD8alpha(+ve) plasmacytoid dendritic cells. Taken together, our findings suggest that EGR1 might promote expansion of CD8 T cells during an acute viral infection by modulating the cues in the lymphoid microenvironment.

Acute Disease↗

PubMed2004

7-12 Dimethylbenz[a]anthracene-induced bone marrow hypocellularity is dependent on signaling through both the TNFR and PKR.

In addition to being carcinogenic, polycyclic aromatic hydrocarbons (PAHs) are known to cause deleterious effects on the immune system, including a marked reduction in bone marrow granulocytes and B lymphocytes. The molecular mechanisms underlying bone marrow hypocellularity are incompletely understood. Hematopoiesis is governed by the production of cytokines and the resultant signaling pathways that they initiate. Our hypothesis was that PAHs may disrupt cytokine production in the bone marrow resulting in the perturbation in bone marrow cellularity observed after PAH administration. TNF-alpha and IFN-gamma are two cytokines that are involved in the regulation of hematopoiesis. Based on observations made in previous research, we sought to determine if the effects of 7-12 dimethylbenz[a]anthracene (DMBA) on the murine bone marrow were mediated through the actions of these molecules. Transgenic mice that were null for either IFN-gamma or TNF-alpha receptors were injected with DMBA and the resulting bone marrow cellularity compared with wild-type mice. We observed that tumor necrosis factor alpha receptor (TNFR) null mice were protected against DMBA-induced bone marrow hypocellularity, while IFN-gamma null mice were not. In addition, we found that dsRNA-dependent protein kinase (PKR) null mice were also protected from DMBA-induced hypocellularity. PKR is an intracellular signaling molecule that has been demonstrated to be activated by TNFR-mediated signaling. Furthermore, we observed upregulation of PKR in the bone marrow after DMBA administration that was dependent on signaling through TNFR. These results point to a role for TNFR-dependent signaling, operating at least in part via PKR activation, as a mechanism for DMBA-induced bone marrow toxicity.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2004

Role of cell cycle regulator E2F1 in regulating CD8 T cell responses during acute and chronic viral infection.

To determine the role of cell cycle regulatory protein E2F1 in T cell immunity, we compared antigen-specific CD8 T cell responses between wild type (+/+) and E2F1-deficient (E2F1-/-) mice following an acute and chronic infection with lymphocytic choriomeningitis virus (LCMV). During an acute LCMV infection, although LCMV-specific effector CD8 T cells from E2F1-/- mice were less susceptible to activation-induced cell death (AICD) in vitro, E2F1 deficiency had no significant effect on the: (1) expansion or contraction of virus-specific CD8 T cell responses; (2) proliferative renewal of memory CD8 T cells in both lymphoid and non-lymphoid organs. Importantly, under conditions of repeated antigenic stimulation in the setting of a chronic LCMV infection, E2F1 deficiency did not preclude the exhaustion of CD8 T cells specific to the immunodominant epitope nucleoprotein 396-404 (NP396-404). Taken together, our studies show that E2F1, an important tumor suppressor and cell cycle regulator, may not have a non-redundant role in regulating CD8 T cell responses in acute and chronic LCMV infections.

Animals↗

PubMed2004

Effect of chronic viral infection on epitope selection, cytokine production, and surface phenotype of CD8 T cells and the role of IFN-gamma receptor in immune regulation.

Regulation of CD8 T cell responses in chronic viral infections is not well understood. In this study, we have compared the CD8 T cell responses to immunodominant and subdominant epitopes during an acute and a chronic lymphocytic choriomeningitis virus (LCMV) infection in mice. The epitope hierarchy of the primary CD8 T cell response was similar in acute and chronic LCMV infections. However, strikingly, the epitope hierarchy of the primary CD8 T cell response was conserved in the T cell memory only in an acute but not in a chronic LCMV infection. Interestingly, in an acute infection, increasing the viral dose caused significant changes in the epitope hierarchy of the LCMV-specific memory CD8 T cell pool, with no effect on the primary CD8 T cell response. Functional and phenotypic analyses revealed that exposure of CD8 T cells to extended periods of antigenic stimulation could lead to long-term defects in cytokine production and alteration in expression of cell surface L-selectin (CD62L). Whereas expression of CD44 was minimally altered, a greater proportion of LCMV-specific memory CD8 T cells were CD62L(low) in mice that have recovered from a chronic LCMV infection, compared with acutely infected mice. Mechanistic studies showed that IFN-gammaR deficiency altered the epitope hierarchy of the pool of LCMV-specific memory CD8 T cells without significantly affecting the immunodominance of the primary CD8 T cell response in an acute infection. Taken together, these findings should further our understanding about the regulation of T cell responses in human chronic viral infections.

Acute Disease↗