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Biomedical subjects

D Bouchier-Hayes

Publications and source records attributed to D Bouchier-Hayes.

At least 73 records · Page 4Linked to original sources
PubMed1997

The cholesteryl ester transfer protein (CETP) locus as a candidate gene in abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is a relatively common disease of the elderly presenting as progressive dilatation of the abdominal aorta. The condition shows a pronounced tendency to cluster in families, indicating a genetic component in the disease aetiology. We have screened the cholesteryl ester transfer protein (CETP) gene, which has been proposed as a candidate gene in AAA, by means of SSCP, DNA sequencing and restriction analysis in a cohort of patients with AAA and a matching control group drawn from the Irish population. The analysis has demonstrated sequence variation at four sites in the CETP gene: an A-T transversion in exon 9 (producing a Lys309-Stop codon substitution), a G-A transition in exon 14 (producing a conservative Val421-Ile substitution), a C-T transition in intron 12 and a G-A transition in intron 15. None of the last three sites corresponded with sites of functional significance in the protein, suggesting that this reflects neutral polymorphism at the CETP locus. Furthermore, the frequencies of these four polymorphisms in the AAA patient and control groups were not significantly different. These data therefore suggest that CETP may be excluded as a candidate gene in abdominal aortic aneurysm.

Aortic Aneurysm, Abdominal↗
PubMed1997

Induction of human endothelial cell apoptosis requires both heat shock and oxidative stress responses.

Endothelial cell (EC) death may play an important role in the development of increased vascular permeability and capillary leak syndrome during systemic inflammatory response syndrome. However, the mode of EC death and the mechanisms involved remain unclear. In this study we employed the proinflammatory mediators lipopolysaccharide (LPS) and tumor necrosis factor-alpha (TNF-alpha), the chemical reagent sodium arsenite, and heat shock to trigger the stress gene responses. Human ECs were used as surrogates of the microvasculature to test the hypothesis that the induction of the heat shock response and the oxidative stress response might combine to induce apoptosis rather than necrosis in human ECs. Sodium arsenite at 80-320 microM, which induced heat shock protein 72 (HSP72) expression and reactive oxygen intermediate (ROI) generation in ECs, resulted in EC apoptosis. TNF-alpha alone (5-75 ng/ml) increased EC ROI generation but did not induce EC apoptosis. Heat shock alone (42 degrees C, 45 min) or sodium arsenite (40 microM) alone, each of which induced HSP72 expression, did not result in EC apoptosis. However, the combination of TNF-alpha with heat shock or 40 microM sodium arsenite led to EC apoptosis as HSP72 expression and ROI were induced. Furthermore, sodium arsenite (80 microM) in the presence of antioxidants failed to induce EC apoptosis. Apoptotic ECs also exhibited functional disturbances as represented by the depression of intercellular adhesion molecule-1 expression as well as the disruption of EC monolayer integrity. These results indicate that the simultaneous induction of a heat shock response and an oxidative stress response is responsible for human EC apoptosis.

Apoptosis↗
PubMed1997

Immunological and physiological responses to aortic surgery: effect of reperfusion on neutrophil and monocyte activation and pulmonary function.

BACKGROUND: The aims of this study were to evaluate the effects of aortic clamping and unclamping on neutrophil and monocyte activation and release of plasma mediators in 20 patients undergoing elective aortic aneurysm surgery, and to correlate these findings with pulmonary haemodynamics and gas exchange. METHODS: Simultaneous arterial and mixed venous samples were obtained during and after aortic clamping and unclamping. RESULTS: Neutrophil respiratory burst activity in mixed venous samples increased significantly during the period of aortic clamping. An initial increase in neutrophil CD11b expression in venous blood 5 min after clamp removal was followed by a significant decrease in level of expression. Plasma tumour necrosis factor levels increased at the end of the cross-clamp period and reached a maximum 60 min following reperfusion. There was a significant and sustained rise in plasma thromboxane B2 levels following clamp removal. This increase correlated with the development of increased pulmonary vascular resistance. CONCLUSION: This study confirms the central role played by activated neutrophils in the early stages of reperfusion injury and also suggests a role for plasma mediators in mediating cardiopulmonary dysfunction during major vascular surgery.

Aged↗
PubMed1997

Nitric oxide attenuates interleukin 2-induced lung injury.

BACKGROUND: The pathogenesis of interleukin (IL) 2-induced vascular leak syndrome may be related to neutrophil-mediated endothelial injury. Nitric oxide inhibits neutrophil superoxide anion synthesis and adherence to endothelial cells. The role of systemic nitric oxide in preventing IL-2-induced lung injury was studied in an experimental model. METHODS: Sprague-Dawley rats (seven per group) were randomized to control, IL-2 treatment (1 x 10(6) units), and IL-2 with sodium nitroprusside 0.2 mg/kg. Lung injury was measured by estimation of extravascular lung water (wet:dry weight) and bronchoalveolar lavage (BAL) protein concentration, and by histological findings. Neutrophil infiltration was evaluated by measuring myeloperoxidase activity and BAL neutrophil concentration. RESULTS: IL-2 produced significant lung damage characterized by leucocyte sequestration (increased myeloperoxidase and BAL neutrophil concentrations), pulmonary congestion and microvascular protein leakage (increased wet:dry weight ratio and BAL protein concentration). This injury was reduced significantly by the addition of sodium nitroprusside, the nitric oxide donor. CONCLUSION: Nitric oxide reduces IL-2-induced lung injury.

Animals↗
PubMed1996

Neutrophils undergo apoptosis following ingestion of Escherichia coli.

Apoptosis is a distinct mechanism by which eukaryotic cells die. Neutrophils (PMN) play a fundamental role in the systemic inflammatory response syndrome. Clearance of PMN during resolution of the acute inflammatory process occurs by apoptosis, but factors inducing this process are unknown. The aims of this study were to determine whether PMN ingestion of Escherichia coli would result in PMN apoptosis and whether the mechanism was related to the respiratory burst. PMN from 10 healthy volunteers were cultured with different ratios of PMN:E. coli (1:0 to 1:25) for 12 h. Apoptosis was then assessed by propidium iodide DNA staining, morphology, gel electrophoresis, and Fc gamma RIII expression. There was a significant induction of PMN apoptosis on incubation with E. coli at a ratio of 1:10 and 1:25 PMN:E. coli as well as decreases in Fc gamma RIII. This correlated with increased ingestion of FITC-labeled E. coli and intracellular reactive oxygen intermediates after a 2-h coculture. To clarify the role of reactive oxygen intermediates in E. coli-induced PMN apoptosis, we assessed the effects of the antioxidants catalase, DMSO, glutathione, and N-acetylcysteine. There was a significant decrease in E. coli-induced PMN apoptosis on incubation with DMSO (1.0%), glutathione (25 mM), and N-acetylcysteine (25 mM) compared with control PMN:E. coli. This study demonstrates for the first time that E. coli induces PMN apoptosis through an oxygen-dependent mechanism. The removal of effete PMN by the process of apoptosis rather than necrosis may be teleologically beneficial during Gram-negative septicemia.

Antioxidants↗
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

Taurine attenuates nitric oxide- and reactive oxygen intermediate-dependent hepatocyte injury.

OBJECTIVE: To evaluate the potential role of the semi-amino acid taurine in the prevention of hepatocyte (HC) apoptosis and necrosis mediated by nitric oxide (NO) and reactive oxygen intermediates. DESIGN: Isolated rat HCs were cultured with lipopolysaccharide (LPS), antioxidants, taurine, and sodium nitroprusside to examine the effect of these agents on HC injury. RESULTS: Lipopolysaccharide, in the presence of antioxidants, led to HC apoptosis, while LPS alone failed to induce HC apoptosis. Taurine significantly attenuated LPS plus antioxidant-mediated HC apoptosis, and this correlated with taurine-mediated NO inhibition. Taurine also significantly reduced LPS-mediated hepatocellular enzyme release and HC necrosis, and this correlated with HC free radical and peroxynitrite inhibition. However, taurine did not prevent sodium nitroprusside-mediated HC apoptosis and necrosis. CONCLUSIONS: Taurine attenuates HC apoptosis and necrosis through inhibition of both NO and reactive oxygen intermediate. While taurine acts directly as an antioxidant, its effects on NO may occur at the messenger RNA level. Our findings indicate a potential prophylactic and therapeutic role for this amino acid during systemic inflammatory response syndrome.

Animals↗
PubMed1996

Mechanisms involved in sodium arsenite-induced apoptosis of human neutrophils.

Apoptosis is a distinct mechanism by which eukaryotic cells die. Factors governing the induction of polymorphonuclear leukocyte (PMN) apoptosis should be important in understanding resolution of acute inflammation. The mechanisms for induction of PMN apoptosis remain uncertain; however, oxidative stress has been suggested. The aims of this study were to determine whether reactive oxygen intermediates play a role in PMN apoptosis and to investigate inhibition of this process by selective use of antioxidants. PMN were isolated from 10 healthy volunteers. PMN (1 x 10(6) PMN/mL) were cultured in 40, 80, and 160 microM of arsenite for 2, 6, 12, 18, and 24 h. Apoptosis was assessed qualitatively by morphology and gel electrophoresis and quantitatively by CD16 receptor expression and propidium iodide DNA staining. There was a significant (P < 0.05) increase in the rate of apoptosis on incubation with arsenite (80 and 160 microM). To investigate the mechanism of this process, intracellular respiratory burst activity was measured following arsenite culture. We found that arsenite-induced PMN apoptosis correlated with an increase in intracellular respiratory burst. To further investigate the role of oxidative injury in inducing apoptosis, the antioxidants catalase, dimethyl sulfoxide (DMSO), glutathione (GSH), N-acetylcysteine (NAC), and taurine were investigated and we demonstrated that GSH, NAC, and taurine were significantly protective against arsenite-induced apoptosis. However, catalase and DMSO failed to induce protection. This study demonstrates that arsenite induces PMN apoptosis through an oxygen-dependent mechanism that can be prevented through selective antioxidants.

Acetylcysteine↗
PubMed1996

Granulocyte-macrophage colony-stimulating factor inhibits tumor growth during the postoperative period.

BACKGROUND: Granulocyte-macrophage colony-stimulating factor (GM-CSF) may have important antineoplastic properties because it induces macrophage tumoricidal activity in vitro. We examined the inhibitory effect of GM-CSF on tumor growth in a murine carcinoma model and whether this inhibitory effect would persist during the postoperative period. Potential macrophage-mediated mechanisms were studied. METHODS: The effect of GM-CSF on macrophage function in vitro was assessed by measuring superoxide anion and interleukin-6 production, percentage phagocytosis of Candida albicans, and percentage Ia expression. GM-CSF's effect on tumor volume was assessed first in a murine tumor model and second to examine whether these effects also occurred during the postoperative period in the same model after laparotomy. Macrophage function in the latter study was assessed by measuring superoxide anion, cytotoxicity, and tumor necrosis factor production. RESULTS: GM-CSF treatment was associated with a decrease in tumor volume on day 4 after the initiation of GM-CSF treatment (0.93 +/- 0.08 cm3 for control versus 0.34 +/- 0.08 cm3 for GM-CSF; p < 0.05). This effect was also seen after laparotomy (1.07 +/- 0.2 cm3 for laparotomy+saline versus 0.16 +/- 0.04 cm3 for laparotomy+GM-CSF, p < 0.05). In vivo macrophage function showed increased superoxide anion, cytotoxicity, and tumor necrosis factor-alpha production from macrophages obtained from GM-CSF treated animals compared with saline treated controls. CONCLUSIONS: Tumor growth is inhibited by GM-CSF treatment, and this effect also occurs after laparotomy. Thus, GM-CSF may have a therapeutic role in the treatment of the tumor bearing host after operation.

Analysis of Variance↗
PubMed1996

Bacterial ingestion, tumor necrosis factor-alpha, and heat induce programmed cell death in activated neutrophils.

Resolution of acute inflammation requires the removal of sequestered neutrophils (PMN) from the inflammatory site by apoptosis and ingestion by tissue macrophages; however, sequestered PMN are prevented from undergoing programmed cell death by some of the mediators of the acute inflammatory process, including lipopolysaccharide (LPS), granulocyte-macrophage colony-stimulating factor, and interleukin 2. This delay in apoptosis could lead to necrosis resulting in tissue damage. Tumor necrosis factor-alpha (TNF-alpha), Escherichia coli ingestion resulting in a respiratory burst, and heat have been shown to induce PMN apoptosis. The effects of TNF-alpha, E. coli ingestion, and heat shock on the one hand and LPS on the other, on PMN apoptosis are unknown. The aim of this study was to determine if TNF-alpha, E. coli ingestion, and heat shock, which have been shown to induce PMN apoptosis, could override the delay in apoptosis associated with LPS. PMN (10(6)) isolated from 10 healthy volunteers were cultured in either medium alone or PMN cultured with LPS (10 ng/mL/1 h). PMN activation was assessed subsequently by phagocytosis of E. coli and CD11b expression. PMN were then further studied under four culture conditions: medium alone, TNF-alpha (100 U/mL), E. coli (1:25, PMN:E. coli), and heat shock (42 degrees C for 45 min). Apoptosis was assessed over time by propidium iodide staining of DNA and Fc gamma RIII receptor expression. The results demonstrate, for the first time, that the mechanisms by which LPS delays PMN apoptosis are overridden by the mechanisms by which TNF-alpha, E. coli ingestion, and heat shock induce programmed cell death. Factors regulating PMN apoptosis have an important role to play in the resolution of acute inflammation. Identification of these factors and their interaction have important implications for the development of therapeutic strategies aimed at modulating the acute inflammatory response.

Apoptosis↗
PubMed1996

The beneficial effect of taurine on the prevention of human endothelial cell death.

This study was designed to test the hypothesis that the antioxidant taurine may modulate human endothelial cell (EC) death (apoptosis versus necrosis). Sodium arsenite (80 microM) alone and in combination with tumor necrosis factor-alpha (25 ng/mL) caused EC apoptosis after 24 h of treatment. Taurine (.5 mg/mL) added at 0 and 6 h could significantly attenuate EC apoptosis, and oxidative state in response to lipopolysaccharide and tumor necrosis factor-alpha stimulation. EC necrosis was induced by activated neutrophils (PMNs). Taurine reduced PMN-mediated EC necrosis in a dose-dependent manner. Moreover, treatment of ECs with a calcium ionophore, A23187 (1.0-4.0 microM), resulted in both EC apoptosis and necrosis. Taurine significantly abrogated A23187-mediated intracellular calcium elevation and EC death. These data indicate that taurine, possibly through its antioxidant activity and regulation of intracellular calcium flux, can prevent EC dysfunction and cell death, which may have implications for the application of this amino acid in the amelioration of acute lung injury during systemic inflammatory response syndrome.

Apoptosis↗
PubMed1995

Mechanisms mediating cancer cachexia.

BACKGROUND: Cancer cachexia encompasses a wide range of metabolic, hormonal, and cytokine-related abnormalities that result in a wasting syndrome possibly accounting for up to 30% of cancer-related deaths. METHODS: A literature search was performed to review those pathways of metabolic interference involved in cancer cachexia. RESULTS: An elevated basal metabolic rate and increased energy expenditure combined with systemic catabolism of muscle and adipose tissue are the predominant manifestations of the metabolic and physiologic perturbations noted in this pathologic state. CONCLUSIONS: To date, although some of the cachexia-related metabolic abnormalities have been elucidated, there has been little success in relation to therapeutic manipulation of these pathways. This review evaluates current knowledge relating to cancer cachexia and cautions against generalizations concerning treatment regimens.

Animals↗
PubMed1995

The role of tumor rejection antigens in host antitumor defense mechanisms.

BACKGROUND: Normal cells undergo contact inhibition of growth when their surface molecules interact. Tumor cells, however, have undergone a mutation that prevents this arrest of growth upon contact inhibition and allows constant growth. Thus, growth inhibition fails to occur despite the interaction of surface molecules. In recent years a subgroup of these surface molecules has been of interest to cancer investigators. This subgroup has been termed the tumor rejection antigens (TRAs). As the name implies, these are specific to the tumor of origin and may direct the immune system of the host to target the tumor cells and kill them. METHODS: A literature search was carried out on TRAs to ascertain the current thinking on the subject. RESULTS: Initial studies of TRAs have revealed that some of them may be heat shock proteins (HSPs). In particular, grp96, a number of the HSP90 family, has been implicated. More recent studies, however, have shown that HSPs alone may not be immunogenic but may act as carrier proteins for tumor specific peptides. CONCLUSION: Such findings have led to speculation that HSPs or their associated peptides may have a role in the diagnosis and/or treatment of specific cancers. Immunotherapy and bispecific antibodies in particular are areas in which HSPs may prove to be useful.

Antigens, Neoplasm↗
PubMed1995

Induction of heat shock protein 72 prevents neutrophil-mediated human endothelial cell necrosis.

OBJECTIVE: To examine the hypothesis that induction of heat shock proteins in human endothelial cells (ECs) by either heat shock or sodium arsenite could prevent subsequent EC necrosis induced by activated human polymorphonuclear neutrophil leukocytes (PMNs). DESIGN: Cultures of ECs were exposed to heat shock (42 degrees C, 30 to 60 minutes) or sodium arsenite (40 to 320 mumol/L) for 6 hours to induce the expression of a heat shock protein of 72-kd molecular weight (HSP-72). Activated PMNs were subsequently added to these ECs for 24 hours to evaluate the ability of HSP-72 to prevent activated PMN-mediated EC necrosis. RESULTS: Neither EC necrosis nor apoptosis was induced by heat shock. Sodium arsenite (40 to 80 mumol/L) did not induce EC necrosis, although 320-mumol/L sodium arsenite caused a significant increase in EC necrosis. Sodium arsenite (80 to 320 mumol/L) also induced dose-dependent EC apoptosis. Endothelial cells exposed to heat shock and sodium arsenite (40 and 80 mumol/L) significantly attenuated subsequent EC necrosis induced by activated PMNs. However, sodium arsenite at 320 mumol/L aggravated activated PMN-mediated EC necrosis. Expression of HSP-72 was detected after ECs were treated both with heat shock and sodium arsenite (40 to 320 mumol/L) for 6 hours. CONCLUSION: Induction of HSP-72 in ECs by a thermal or nonthermal mechanism could prevent activated PMN-mediated EC necrosis, which may favor increased vascular permeability during systemic inflammatory response syndrome.

Apoptosis↗
PubMed1995

Abdominal aortic aneurysm in the Irish population: a familial screening study.

A pilot screening programme was undertaken in Ireland to determine the incidence of abdominal aortic aneurysm (AAA) (diameter 3 cm or greater) in the siblings of 120 patients known to have AAA. There were 621 siblings; 270 of them were dead, 32 were over 80 years old and 85 lived outside Ireland, leaving 234 under 80 years of age still living in Ireland who were invited to attend for ultrasonographic screening. Of the 270 siblings who had died, 102 were women and 168 men; eight men (4.8 per cent) had died from ruptured AAA. Only 125 (53.4 percent) of the 234 siblings agreed to participate in the screening programme, 60 brothers from 31 families and 65 sisters from 35 families. Fifteen (12.0 per cent) of the 125 siblings had an AAA (median size 4.2 (range 3.1-6.8) cm), 13 (22 per cent) of the 60 male siblings and two (3 per cent) of the 65 female siblings. The prevalence of AAA among siblings was not affected by the age or sex of the patient with aneurysm. Seven of the 14 male siblings with hypertension had an AAA, compared with only six of the 46 who were normotensive (P = 0.01). The high incidence of AAA in brothers of affected patients highlights the need to counsel this group on their risk of aneurysm. The relatively low participation rate by siblings in this screening programme indicates that a hospital-based unit is unlikely to be effective in recruiting all patient siblings at risk from an AAA.

Adult↗
PubMed1995

Endoscopically guided surface repair of inguinal hernia.

A novel tension-free prosthetic mesh repair for an inguinal hernia is described. This is performed through a 2-cm groin incision and the inguinal canal is traversed with the aid of a 5-mm videoendoscope. Spermatic cord mobilization, identification and excision of the indirect sac, and posterior wall repair are carried out under endoscopic guidance. Between October 1993 and January 1994, 22 primary unilateral hernia, and two bilateral repairs were undertaken. The mean (range) age was 47 (35-64) years in 23 men and one woman. The mean (range) operative time was 42 (35-58) min. All patients left hospital on the day after surgery. One patient developed a scrotal swelling that required a scrotal support.

Adult↗
PubMed1995

Exposure of the peritoneal cavity to air regulates early inflammatory responses to surgery in a murine model.

Factors in circulating air may play a role in immune responses after surgery through induction of gut-derived lipopolysaccharide (LPS) translocation across the gut. CD-1 mice were randomized to one of four treatment groups: controls, laparoscopy with carbon dioxide inflation, laparoscopy with air inflation and laparotomy. The peritoneal and systemic immune response was assessed by evaluating peritoneal macrophage, blood monocyte and neutrophil activity. In a second study, the effect of each of the treatments on fluorescein isothiocyanate (FITC)-LPS translocation across the gut was assessed. There were significant (P < 0.05) increases in peritoneal tissue macrophage release of superoxide and tumour necrosis factor after laparoscopy with air and laparotomy compared with control procedures and carbon dioxide laparoscopy. However, peritoneal macrophage FITC-Candida albicans ingestion was significantly decreased after air laparoscopy and laparotomy compared with controls and carbon dioxide laparoscopy (P < 0.05). These findings correlated with a significant (P < 0.05) decrease in CD11b expression. Significant translocation into the peritoneal cavity and systemic circulation occurred after air laparoscopy and laparotomy only. Factors in circulating air can induce LPS translocation and subsequent stimulation of postoperative immune responses. The beneficial effects of laparoscopic surgery may be explained by the minimal air contamination of the peritoneal cavity.

Abdomen↗