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Biomedical subjects

J A Thomas

Publications and source records attributed to J A Thomas.

At least 55 records · Page 3Linked to original sources
PubMed2000

IL-1 receptor-associated kinase modulates host responsiveness to endotoxin.

Endotoxin triggers many of the inflammatory, hemodynamic, and hematological derangements of Gram-negative septic shock. Recent genetic studies in mice have identified the Toll-like receptor 4 as the transmembrane endotoxin signal transducer. The IL-1 intracellular signaling pathway has been implicated in Toll-like receptor signal transduction. LPS-induced activation of the IL-1 receptor-associated kinase (IRAK), and the influence of IRAK on intracellular signaling and cellular responses to endotoxin has not been explored in relevant innate immune cells. We demonstrate that LPS activates IRAK in murine macrophages. IRAK-deficient macrophages, in contrast, are resistant to LPS. Deletion of IRAK disrupts several endotoxin-triggered signaling cascades. Furthermore, macrophages lacking IRAK exhibit impaired LPS-stimulated TNF-alpha production, and IRAK-deficient mice withstand the lethal effects of LPS. These findings, coupled with the critical role for IRAK in IL-1 and IL-18 signal transduction, demonstrate the importance of this kinase and the IL-1/Toll signaling cassette in sensing and responding to Gram-negative infection.

Animals↗
PubMed2000

Risk of lymphoid neoplasia after cardiothoracic transplantation. a cohort study of the relation to Epstein-Barr virus.

BACKGROUND: Organ transplantation is associated with a greatly increased risk of Epstein-Barr virus (EBV)-associated lymphoproliferative disease (LPD), which is often fatal. There has been little epidemiological analysis, however, of the risk factors for LPD in transplant patients and none on whether the risks of non-EBV-associated lymphoid neoplasms are also increased. METHODS: The risk of lymphoid neoplasia was assessed in a cohort of 1563 patients who underwent cardiothoracic transplantation at Harefield Hospital, UK from 1980 to 1994 and were followed until December 1995. EBV antibody was assessed in the patients before transplantation, and lymphoid neoplasms were assessed for EBV RNA and latent EBV gene expression. RESULTS: Thirty cases of LPD occurred during follow-up. One lymphoma of unknown EBV status occurred. There were also six cases of EBV-negative non-Hodgkin's lymphoma (EBV-negative NHL), a highly significant excess over expectations from the general population rates of NHL (standardized incidence ratio 10.2 [95% confidence interval, 4.6-22.8]). The risk of LPD was significantly 10-fold raised in individuals who were EBV seronegative before transplantation; independently of this, it decreased steeply with age at transplantation and was greatest in the first year after transplantation. The risk was significantly raised in young seronegative recipients if the donor was older than the recipient. EBV-negative NHL occurred entirely in men 45 years old and older who were EBV seropositive before transplantation, and risk was not related to duration since transplantation. CONCLUSIONS: The risk factors found for LPD accord with EBV etiology and with greater hazard from primary infection than from reactivation. A second non-Hodgkin's lymphoid neoplasm, not related to EBV, seems also to be a consequence of transplantation and immunosuppression but is unlikely to be due to first infection by a ubiquitous agent. Its etiology and prevention need investigation separately from LPD.

Adolescent↗
PubMed2000

Surface expression of O-specific lipopolysaccharide in Escherichia coli requires the function of the TolA protein.

We investigated the involvement of Tol proteins in the surface expression of lipopolysaccharide (LPS). tolQ, -R, -A and -B mutants of Escherichia coli K-12, which do not form a complete LPS-containing O antigen, were transformed with the O7+ cosmid pJHCV32. The tolA and tolQ mutants showed reduced O7 LPS expression compared with the respective isogenic parent strains. No changes in O7 LPS expression were found in the other tol mutants. The O7-deficient phenotype in the tolQ and tolA mutants was complemented with a plasmid encoding the tolQRA operon, but not with a similar plasmid containing a frameshift mutation inactivating tolA. Therefore, the reduction in O7 LPS was attributed to the lack of a functional tolA gene, caused either by a direct mutation of this gene or by a polar effect on tolA gene expression exerted by the tolQ mutation. Reduced surface expression of O7 LPS was not caused by changes in lipid A-core structure or downregulation of the O7 LPS promoter. However, an abnormal accumulation of radiolabelled mannose was detected in the plasma membrane. As mannose is a sugar unique to the O7 subunit, this result suggested the presence of accumulated O7 LPS biosynthesis intermediates. Attempts to construct a tolA mutant in the E. coli O7 wild-type strain VW187 were unsuccessful, suggesting that this mutation is lethal. In contrast, a polar tolQ mutation affecting tolA expression in VW187 caused slow growth rate and serum sensitivity in addition to reduced O7 LPS production. VW187 tolQ cells showed an elongated morphology and became permeable to the membrane-impermeable dye propidium iodide. All these phenotypes were corrected upon complementation with cloned tol genes but were not restored by complementation with the tolQRA operon containing the frameshift mutation in tolA. Our results demonstrate that the TolA protein plays a critical role in the surface expression of O antigen subunits by an as yet uncharacterized involvement in the processing of O antigen.

Bacterial Proteins↗
PubMed2000

Epidermoid cysts of the testis: the case for conservative surgery.

The series comprises 6 patients (mean age, 21 years) who presented with an epidermoid cyst of the testis between 1991 and 1998. Pre-operative ultrasonography suggested the presence of a testicular cancer in 3 patients who underwent a radical orchidectomy. The ultrasound successfully predicted the true diagnosis in 3 patients who had a wedge excision of the cyst together with a cuff of normal surrounding tissue. All patients are free of disease with a mean follow-up of 3 years. With increasing awareness of the condition coupled with accurate pre-operative radiological imaging, local excision of an epidermoid cyst with preservation of the remainder of the testis is now a feasible and rational alternative to more radical surgery.

Adolescent↗
PubMed2000

Improving pharmacy supply-chain management in the operating room.

Anesthesia services can account for a significant portion of a healthcare organization's costs. Deaconess Hospital of Evansville, Indiana, used a collaborative, multidisciplinary effort to implement process improvements that yielded significant cost savings while improving patient care. Shifting responsibility for drug distribution from the operating room (OR) nurses to a pharmacist, the hospital established a satellite pharmacy service for the OR. As a result, the hospital was able to improve control of drug distribution and record-keeping, reduce turnaround time for medication preparation, lower its medication charge error rate, and increase the percentage of surgeries that start on time. The success of the OR satellite pharmacy led the hospital to expand satellite pharmacy services to labor and delivery, the cardiac cath laboratory, and the intensive care units.

Anesthetics↗
PubMed1999

Impaired cytokine signaling in mice lacking the IL-1 receptor-associated kinase.

Stimulation of the type 1 IL-1R (IL-1R1) and the IL-18R by their cognate ligands induces recruitment of the IL-1R-associated kinase (IRAK). Activation of IRAK leads in turn to nuclear translocation of NF-kappaB, which directs expression of innate and adaptive immune response genes. To study IRAK function in cytokine signaling, we generated cells and mice lacking the IRAK protein. IRAK-deficient fibroblasts show diminished activation of NF-kappaB when stimulated with IL-1. Immune effector cells without IRAK exhibit a defective IFN-gamma response to costimulation with IL-18. Furthermore, mice lacking the Irak gene demonstrate an attenuated response to injected IL-1. Deletion of Irak, however, does not affect the ability of mice to develop delayed-type hypersensitivity or clear infection with the intracellular parasite, Listeria monocytogenes. These results demonstrate that although IRAK participates in IL-1 and IL-18 signal transduction, residual cytokine responsiveness operates through an IRAK-independent pathway.

Animals↗
PubMed1999

Posttransplantation B lymphoblastic leukemia with Burkitt-like features.

BACKGROUND: Posttransplantation Epstein-Barr virus-associated lymphoproliferative disease (PTLPD) occurs as a spectrum of disease ranging from benign, polyclonal, localized lymphoid hyperplasia to malignant, monoclonal, disseminated lymphoma, sometimes involving the bone marrow. To our knowledge, PTLPD has not been previously reported to present as acute lymphoblastic leukemia. METHODS: We report the case of a boy who developed PTLPD in the form of acute lymphoblastic leukemia 6 years after cardiac transplantation. He had greater than 90% bone marrow invasion by Epstein-Barr virus-positive B lymphoblasts with Burkitt-like features and a t(8;14) translocation. RESULTS: He was successfully treated with combination chemotherapy but unfortunately died, 6 months after completing treatment, from ischemic heart disease. CONCLUSIONS: B lymphoblastic leukemia may occur as a manifestation of PTLPD and should be included in the classification of these diseases. Bone marrow examination should be an essential part of the investigation of patients suspected of having PTLPD.

Administration, Oral↗
PubMed1999

S-nitrosylation and S-glutathiolation of protein sulfhydryls by S-nitroso glutathione.

The modification of reactive protein sulfhydryls by S-nitrosoglutathione and other NO donors has been studied by gel isoelectric focusing. S-nitrosylated, unmodified, and S-glutathiolated protein forms are differentiated by this method. With specific antibodies for the protein of interest, both S-nitrosylation and S-glutathiolation of the protein were analyzed in mixtures obtained as soluble tissue or cell extracts. The effect of S-nitrosoglutathione (GSNO) on purified phosphorylase b, on carbonic anhydrase III in an extract from rat liver, and on H-ras expressed in Escherichia coli was examined. When fresh GSNO reacted with pure phosphorylase b, only S-nitrosylated forms of the protein were observed. Likewise the NO donors, amyl nitrite, spermine NONOate, and diethylamine NONOate, all generated S-nitrosylated phosphorylase b. When crude mixtures of proteins from rat liver (containing carbonic anhydrase III) or from E. coli (containing an overexpressed form of H-ras) were exposed to fresh GSNO, both the S-nitrosylated and the S-glutathiolated forms of the proteins were observed. It is suggested that reactive intermediates from the breakdown of GSNO are responsible for the observed S-glutathiolation. These experiments show that both S-nitrosylated and S-glutathiolated forms of proteins may be generated by the addition of GSNO to mixtures containing proteins with reactive sulfhydryls. These protein modifications may exhibit metabolic consequences independent of the release of nitric oxide.

Animals↗
PubMed1999

The philosophy of benchmark testing a standards-based picture archiving and communications system.

The Department of Defense issued its requirements for a Digital Imaging Network-Picture Archiving and Communications System (DIN-PACS) in a Request for Proposals (RFP) to industry in January 1997, with subsequent contracts being awarded in November 1997 to the Agfa Division of Bayer and IBM Global Government Industry. The Government's technical evaluation process consisted of evaluating a written technical proposal as well as conducting a benchmark test of each proposed system at the vendor's test facility. The purpose of benchmark testing was to evaluate the performance of the fully integrated system in a simulated operational environment. The benchmark test procedures and test equipment were developed through a joint effort between the Government, academic institutions, and private consultants. Herein the authors discuss the resources required and the methods used to benchmark test a standards-based PACS.

Benchmarking↗
PubMed1999

Benchmark testing the Digital Imaging Network-Picture Archiving and Communications System proposal of the Department of Defense.

The Department of Defense issued a Request for Proposal (RFP) for its next generation Picture Archiving and Communications System in January of 1997. The RFP was titled Digital Imaging Network-Picture Archiving and Communications System (DIN-PACS). Benchmark testing of the proposed vendors' systems occurred during the summer of 1997. This article highlights the methods for test material and test system organization, the major areas tested, and conduct of actual testing. Department of Defense and contract personnel wrote test procedures for benchmark testing based on the important features of the DIN-PACS Request for Proposal. Identical testing was performed with each vendor's system. The Digital Imaging and Communications in Medicine (DICOM) standard images used for the Benchmark Testing included all modalities. The images were verified as being DICOM standard compliant by the Mallinckrodt Institute of Radiology, Electronic Radiology Laboratory. The Johns Hopkins University Applied Physics Laboratory prepared the Unix-based server for the DICOM images and operated it during testing. The server was loaded with the images and shipped to each vendor's facility for on-site testing. The Defense Supply Center, Philadelphia (DSCP), the Department of Defense agency managing the DIN-PACS contract, provided representatives at each vendor site to ensure all tests were performed equitably and without bias. Each vendor's system was evaluated in the following nine major areas: DICOM Compliance; System Storage and Archive of Images; Network Performance; Workstation Performance; Radiology Information System Performance; Composite Health Care System/Health Level 7 communications standard Interface Performance; Teleradiology Performance; Quality Control; and Failover Functionality. These major sections were subdivided into workable test procedures and were then scored. A combined score for each section was compiled from this data. The names of the involved vendors and the scoring for each is contract sensitive and therefore can not be discussed. All of the vendors that underwent the benchmark testing did well. There was no one vendor that was markedly superior or inferior. There was a typical bell shaped curve of abilities. Each vendor had their own strong points and weaknesses. A standardized benchmark protocol and testing system for PACS architectures would be of great value to all agencies planning to purchase a PACS. This added information would assure the purchased system meets the needed functional requirements as outlined by the purchasers PACS Request for Proposal.

Benchmarking↗
PubMed1999

Diet, micronutrients, and the prostate gland.

Diseases of the prostate gland, particularly adenocarcinoma and benign prostatic hyperplasia (BPH), are age-related. Prostate cancer is the most commonly occurring tumor in U.S. men. Differences in the incidence of this disease among ethnic populations are not due solely to genetic differences. Many efforts have been devoted to studying associations between nutrition and prostate cancer. The strongest association appears to be related to total fat intake and increased risk of this malignancy. Evidence also exists to suggest a role for certain micronutrients, such as zinc, selenium, vitamin E, lycopene, phytoestrogens, and phytosterols, although the role of nutrition and micronutrients in protection against prostate cancer is less convincing. Further research is necessary.

Adenocarcinoma↗
PubMed1999

Heat shock does not attenuate low-frequency fatigue.

Whole-body hyperthermia or heat shock confers protection to myocardial contractility against reperfusion-induced injury. The purpose of this study was to determine whether heat shock could provide similar protection to skeletal muscle contractility against low-frequency fatigue. Male Sprague-Dawley rats (6 rats/group) were heat shocked at 41.5 degrees C for 15 min either 24 h or 4 days prior to fatiguing stimulation to compare the contractile responses of the plantaris muscle with those of a nonheated group. Both 24 h and 4 days after heat shock, the 72-kDa heat shock protein (HSP72) was elevated above control levels. There were no differences between the heat-shocked and non-heat-shocked animals in measures of contractility prior to fatiguing contractions or in resistance to fatigue. Heat-shock preconditioning did not lead to improved postfatigue force recovery above control responses and, in fact, delayed the recovery of force. This study does not support the use of heat-shock therapy to improve skeletal muscle contractile performance under fatiguing conditions.

Animals↗
PubMed1998

Resting respiratory tract dendritic cells preferentially stimulate T helper cell type 2 (Th2) responses and require obligatory cytokine signals for induction of Th1 immunity.

Consistent with their role in host defense, mature dendritic cells (DCs) from central lymphoid organs preferentially prime for T helper cell type 1 (Th1)-polarized immunity. However, the "default" T helper response at mucosal surfaces demonstrates Th2 polarity, which is reflected in the cytokine profiles of activated T cells from mucosal lymph nodes. This study on rat respiratory tract DCs (RTDCs) provides an explanation for this paradox. We demonstrate that freshly isolated RTDCs are functionally immature as defined in vitro, being surface major histocompatibility complex (MHC) II lo, endocytosishi, and mixed lymphocyte reactionlo, and these cells produce mRNA encoding interleukin (IL)-10. After ovalbumin (OVA)-pulsing and adoptive transfer, freshly isolated RTDCs preferentially stimulated Th2-dependent OVA-specific immunoglobulin (Ig)G1 responses, and antigen-stimulated splenocytes from recipient animals produced IL-4 in vitro. However, preculture with granulocyte/macrophage colony stimulating factor increased their in vivo IgG priming capacity by 2-3 logs, inducing production of both Th1- and Th2-dependent IgG subclasses and high levels of IFN-gamma by antigen-stimulated splenocytes. Associated phenotypic changes included upregulation of surface MHC II and B7 expression and IL-12 p35 mRNA, and downregulation of endocytosis, MHC II processing- associated genes, and IL-10 mRNA expression. Full expression of IL-12 p40 required additional signals, such as tumor necrosis factor alpha or CD40 ligand. These results suggest that the observed Th2 polarity of the resting mucosal immune system may be an inherent property of the resident DC population, and furthermore that mobilization of Th1 immunity relies absolutely on the provision of appropriate microenvironmental costimuli.

Animals↗