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M Barry

Publications and source records attributed to M Barry.

At least 19 recordsLinked to original sources
PubMed1996

Mechanisms involved in the induction of human endothelial cell necrosis.

The effects of the inflammatory mediators lipopolysaccharide (LPS) and tumor necrosis factor-alpha (TNF) and unstimulated and activated neutrophils (PMNs) on endothelial cell (EC) necrosis were studied using the cultured human EC line (ECV-304) and human PMNs in vitro. LPS and TNF alone or their combination failed to induce EC necrosis. Activated PMNs, as evidenced by augmentations in CD11b expression and respiratory burst, induced significant EC necrosis commencing at 12 hr of coculture, which was strongly dependent on the ratio of PMN:ECs and the duration of PMN:EC coculture. In contrast, unstimulated PMNs induced no significant increases in EC necrosis. To examine the mechanisms of activated PMN-mediated EC necrosis, the oxygen radical scavengers superoxide dismutase (SOD) and catalase, as well as the protease inhibitors phenylmethylsulfonyl fluoride (PMSF), alpha 1-antitrypsin (alpha 1-AT), soybean trypsin-chymotrypsin inhibitor (TCI), and aprotinin, were studied in coculture experiments. EC necrosis induced by activated PMNs could be markedly attenuated by SOD, PMSF, alpha 1-AT, TCI, aprotinin, or their combinations. Although aprotinin enhanced respiratory burst, this agent inhibited necrosis by downregulating PMN CD11b and PMN-EC adhesion. These results demonstrate that the inflammatory mediators LPS and TNF and quiescent PMNs fail to induce EC necrosis. However, PMNs activated by inflammatory mediators can induce EC necrosis through oxidative and nonoxidative mechanisms and this process is dependent on PMN-EC adhesion.

Adult↗
PubMed1996

Intracellular glutathione in the peripheral blood cells of HIV-infected patients: failure to show a deficiency.

OBJECTIVE: To determine whether HIV-infected patients have a deficiency of intracellular glutathione (GSH) in peripheral blood mononuclear cells (PBMC) and erythrocytes. DESIGN: Initial experiments determining the stability of intracellular GSH preceded the measurement of GSH levels in 33 HIV-positive patients and 40 control subjects within 1 h of isolation of their blood cells. In addition, the susceptibility of erythrocytes to dapsone hydroxylamine-induced methaemoglobinaemia was evaluated. METHODS: GSH levels were determined by an high-performance liquid chromatography method utilizing a fluorescent probe, monobromobimane. The bimane-GSH adduct formed in PBMC was also characterized by mass spectrometry. Methaemoglobin formation on exposure to dapsone hydroxylamine was determined spectrophotometrically. RESULTS: GSH levels remained stable for only 1 h after cell isolation, thereafter showing a decrease of 20 and 60% at 4 and 24H, respectively, There was no difference in the GSH levels in PBMC and erythrocytes of the HIV-positive patients compared with controls. The GSH levels were not related to the disease stage or to CD4+ cell counts. There was no difference in GSH levels in PBMC taken from trimethoprim-sulphamethoxazole-hypersensitive and non-hypersensitive patients. Methaemoglobinaemia on exposure of erythrocytes to dapsone hydroxylamine was concentration-dependent, but there was no significant difference between patients and controls. CONCLUSION: In contrast to previous studies, no deficiency of intracellular GSH in the PBMC and erythrocytes of HIV-infected patients was found. The discrepancy between studies may be methodological reflecting the instability of GSH, which requires prompt sample analysis.

Adult↗
PubMed1996

Disruption of M-T5, a novel myxoma virus gene member of poxvirus host range superfamily, results in dramatic attenuation of myxomatosis in infected European rabbits.

Myxoma virus is a pathogenic poxvirus that induces a lethal myxomatosis disease profile in European rabbits, which is characterized by fulminating lesions at the primary site of inoculation, rapid dissemination to secondary internal organs and peripheral external sites, and supervening gram-negative bacterial infection. Here we describe the role of a novel myxoma virus protein encoded by the M-T5 open reading frame during pathogenesis. The myxoma virus M-T5 protein possesses no significant sequence homology to nonviral proteins but is a member of a larger poxviral superfamily designated host range proteins. An M-T5- mutant virus was constructed by disruption of both copies of the M-T5 gene followed by insertion of the selectable marker p7.5Ecogpt. Although the M-T5- deletion mutant replicated with wild-type kinetics in rabbit fibroblasts, infection of a rabbit CD4+ T-cell line (RL5) with the myxoma virus M-T5- mutant virus resulted in the rapid and complete cessation of both host and viral protein synthesis, accompanied by the manifestation of all the classical features of programmed cell death. Infection of primary rabbit peripheral mononuclear cells with the myxoma virus M-T5-mutant virus resulted in the apoptotic death of nonadherent lymphocytes but not adherent monocytes. Within the European rabbit, disruption of the M-T5 open reading frame caused a dramatic attenuation of the rapidly lethal myxomatosis infection, and none of the infected rabbits displayed any of the characteristic features of myxomatosis. The two most significant histological observations in rabbits infected with the M-T5-mutant virus were (i) the lack of progression of the infection past the primary site of inoculation, coupled with the establishment of a rapid and effective inflammatory reaction, and (ii) the inability of the virus to initiate a cellular reaction within secondary immune organs. We conclude that M-T5 functions as a critical virulence factor by allowing productive infection of immune cells such as peripheral lymphocytes, thus facilitating virus dissemination to secondary tissue sites via the lymphatic channels.

Animals↗
PubMed1995

Interruption of cytokine networks by poxviruses: lessons from myxoma virus.

Myxoma virus is an infectious poxvirus pathogen that induces a virulent systemic disease called myxomatosis in European rabbits. The disease is rapidly and uniformly fatal to susceptible rabbits and is characterized by generalized dysfunction of cellular immunity and multiple interruptions of the host cytokine network. A number of virus genes are classified as virulence factors because virus constructs bearing targeted gene disruptions induce attenuated disease symptoms. Many of these genes encode proteins that interact directly with effector elements of the host immune system. Included among these immunosubversive viral proteins are secreted mimics of host ligands or regulators (virokines) and homologues of cellular cytokine receptors (viroceptors). Five examples of these immune modulator proteins encoded by myxoma virus are reviewed: (1) myxoma growth factor, a member of the epidermal growth factor ligand superfamily; (2) SERP-1, a secreted serine proteinase inhibitor; (3) M11L, a receptor-like surface protein; (4) T2, a tumor necrosis factor receptor homologue; and (5) T7, an interferon-gamma receptor homologue. The origin of viral strategies designed to subvert immune regulation by host cytokines is considered in the context of the biology of myxoma virus within immunocompetent hosts.

Animals↗
PubMed1995

Pharmacokinetics of zidovudine and dideoxyinosine alone and in combination in children with HIV infection.

The pharmacokinetics of zidovudine (ZDV) and dideoxyinosine (ddI) were investigated following administration alone and in combination to children with symptomatic HIV disease. The children were studied on three separate occasions and received ZDV 200 mg m-2, ddI 100 mg m2 or a combination of ZDV 200 mg m-2 plus ddI 100 mg m-2. The administration of ddI did not significantly alter ZDV pharmacokinetics. The area under the curve (AUC) was 14.2 +/- 4.9 and 15.8 +/- 7.2 mumol l-1 h and elimination half-life (t1/2, z) was 1.4 +/- 0.4 and 1.2 +/- 0.2 h in the absence and presence of ddI respectively. The peak concentration (Cmax), time to peak (tmax) and apparent oral clearance (CL/F) were also unchanged. The administration of ZDV had no significant effect on ddI Cmax, tmax, t1/2,z, or CL/F, however the AUC was reduced by 19% (5.9 +/- 2.9 to 4.8 +/- 2.7 mumol l-1 h; P < 0.05). This study suggests that ZDV and ddI may be co-administered to children with symptomatic HIV disease without concern of a clinically relevant pharmacokinetic drug interaction.

Administration, Oral↗
PubMed1995

Myxoma virus induces extensive CD4 downregulation and dissociation of p56lck in infected rabbit CD4+ T lymphocytes.

Myxoma virus is a pathogenic poxvirus that induces extensive dysregulation of cellular immunity in infected European rabbits. Infection of a rabbit CD4+ T-cell line (RL-5) with myxoma virus results in dramatic reductions of cell surface levels of CD4 as monitored by flow cytometry. The virus-induced downregulation of CD4 requires early but not late viral gene expression and could not be inhibited by staurosporine, an inhibitor of protein kinase C, which effectively blocks phorbol 12-myristate-13-acetate-induced downregulation of CD4. The decrease in total cellular levels of CD4 during myxoma virus infection could be inhibited by the lysosomotrophic agent NH4Cl, suggesting a lysosomal fate for CD4 during myxoma virus infection. Steady-state levels of the CD4-associated protein tyrosine kinase p56lck remained unchanged during myxoma virus infection, suggesting that p56lck dissociates from CD4 prior to CD4 degradation in virus infected cells. Total p56lck kinase activity was unaffected during myxoma virus infection, although the amount of p56lck physically associated with CD4 declined in parallel with the loss of CD4. Thus, myxoma virus infection of CD4+ T lymphocytes triggers CD4 downregulation via a protein kinase C-independent pathway, causing the dissociation of p56lck and the degradation of CD4 in lysosomal vesicles.

Alkaloids↗
PubMed1995

Histological changes associated with an artificial anterior cruciate ligament.

AIMS: To investigate the histopathological features of the synovial lining of the knee following implantation of an artificial cruciate ligament. METHODS: Eighty two patients underwent anterior cruciate ligament reconstruction for chronic, symptomatic instability of the knee. The cruciate ligament was reconstructed with a scaffold type prosthetic ligament. All patients underwent arthroscopy at the time of cruciate reconstruction and also as a "second look" procedure at a mean 26.5 months later, at which time synovial biopsy specimens were obtained in all cases. RESULTS: The most frequent histological finding was granulomatous synovitis in 48% (39/82) of patients. Particulate polyester debris produced a greater response than carbon fibres. In 24% (20/82), nonspecific inflammation was present and in 28% (23/82) the synovium was considered normal. When the prosthetic ligament was fully covered by soft tissue in-growth, a granulomatous reaction was present in 42% (24/57), irrespective of whether the ligament was partially or totally uncovered. Stabilisation of the joint did not prevent subsequent deterioration in the articular cartilage; other factors such as increasing patient age, interval between injury and reconstruction and altered knee kinematics after reconstruction are probably important. Granulomatous synovitis was not associated with progressive chondral changes. CONCLUSIONS: Although present in 48% of cases, granulomatous synovitis was not shown to have adverse effects on either chondral surface or the prosthetic material of the ligament. Rupture of the implant is caused by mechanical factors and granulomatous synovitis is not responsible for implant failure.

Adolescent↗
PubMed1995

Autonomic measures associated with chemotherapy-related nausea: techniques and issues.

Advances in antiemetic therapy for cancer patients have been hindered by a lack of understanding of the physiological mechanisms associated with nausea and their corresponding measurement techniques. Here we review conceptual and methodological issues involved in developing an autonomic frame of reference for nausea and outline two strategies for assessing autonomic function. A primarily research-oriented strategy uses heart rate, blood volume pulse, pallor, and skin temperature to assess autonomic activity and reactivity over 24 hr. Peak values of these measures relative to time of emesis, heart rate spectral analyses of autonomic activity, and analyses of the standard deviation of successive differences of beat-to-beat intervals were all associated with subsequent nausea. A primarily clinically oriented strategy assesses normal and abnormal results on eight common bedside clinical tests of autonomic function. The total number of abnormal tests was associated with subsequent nausea. A better understanding of chemotherapy side effect mechanisms is likely to result in less polypharmacy and more effective individualized treatment for cancer patients.

Arrhythmia, Sinus↗
PubMed1994

Role of the mevalonate pathway of isoprenoid synthesis in IL-8 generation by activated monocytic cells.

The highly regulated enzyme HMG-CoA reductase generates mevalonate, the precursor of a complex series of isoprenoids that posttranslationally modify (isoprenylate) certain proteins (e.g., the low-molecular-weight GTP-binding proteins) or that are incorporated into cholesterol and other end products. We recently reported that isoprenoids are required for NADPH oxidase activity in granulocytes via LMW GTP-binding protein isoprenylation. In this study, we evaluated the effects of isoprenoid depletion on the expression of proinflammatory genes in human monocytic THP-1 cells. We selected conditions under which pretreatment for 24 h with isoprenoid synthesis inhibitors (HMG-CoA reductase inhibitor lovastatin or compactin at 10 microM) did not compromise cell viability but markedly suppressed H2O2 generation. Under these conditions interleukin-8 (IL-8) production was attenuated (by 50-90%) in response to lipopolysaccharide, granulocyte-macrophage colony-stimulating factor, and phorbol myristate acetate. Coincubation of reductase inhibitor-treated cells with mevalonate prevented the attenuation of IL-8 production by reductase inhibitors. The effects of isoprenoid depletion on cytokine production were selective: IL-1 beta generation was not inhibited but the production of IL-6 and IL-8 was concomitantly suppressed. IL-8 induction was suppressed at least in part through attenuation of the increase in mRNA in stimulated cells. We conclude that isoprenoid generation through the mevalonate pathway is a requirement for IL-8 induction by activated monocytic cells in vitro. Isoprenylation inhibitors have the potential to alter monocyte proinflammatory function.

Cell Division↗