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Biomedical subjects

D Bouchier-Hayes

Publications and source records attributed to D Bouchier-Hayes.

At least 19 recordsLinked to original sources
PubMed2006

Myocardial protection using an omega-3 fatty acid infusion: quantification and mechanism of action.

OBJECTIVES: Omega-3 fatty acids exhibit anti-inflammatory, antithrombotic, and antiarrhythmic properties. We investigated the extent and underlying mechanism of protection conferred by a pre-emptive omega-3 infusion in a model of regional cardiac ischemia-reperfusion injury. METHODS: New-Zealand White rabbits received either the omega-3 infusion or a control infusion of 0.9% saline (n = 14 in each group). The large marginal branch of the left coronary artery was occluded for 30 minutes, cardiac function was assessed during 3 hours of reperfusion, and infarct size was measured. Pretreatment-induced alterations in myocardial membrane fatty acid composition and intramyocardial heat shock protein 72 were additionally assessed (n = 5 in each group). Serum markers of myocardial membrane oxidative stress, malonaldehyde and 8-isoprostane, were also determined. Results are expressed as means +/- standard error of the mean and significance was tested with analysis of variance. RESULTS: Pretreatment increased myocardial membrane omega-3 fatty acid content 5-fold, from 0.94% +/- 0.07% in controls to 5.38% +/- 0.44% in the omega-3 group (P < .01), and it produced a 225% elevation of levels of heat shock protein 72 (P = .019) before ischemia-reperfusion. This was associated with a 40% reduction in infarct size (P < .01). Whereas the reperfusion-induced rise in malonaldehyde levels was higher with omega-3 pretreatment, 10.2 +/-1.5 micromol/L versus 6.1 +/- 0.7 micromol/L in controls (P = .04), 8-isoprostanes showed a 9-fold reduction, 679 +/- 190 pg/mL in controls vs 74 +/- 45 pg/mL in the omega-3 group (P = .0077). CONCLUSIONS: A pre-emptive omega-3 infusion significantly reduces infarct size through the dual mechanisms of upregulation of heat shock protein 72, a key preconditioning protein, and a dramatic increase in the omega-3 content of myocardial membranes, which appears to facilitate a shift in oxidant ischemia-reperfusion injury. Further study to optimally shorten the pretreatment regimen for this potentially acceptable infusion will now be pursued.

Animals↗
PubMed2006

Cancer surgery: risks and opportunities.

In the recent past, several papers have pointed to the possibility that tumour removal generates a permissive environment in which tumour growth is potentiated. This phenomenon has been coined "perioperative tumour growth" and whilst it represents a departure in terms of our attitude to the surgical process, this concept was first hinted at by Paget(1) himself. Despite this, the time interval immediately before and after cancer surgery (i.e. the perioperative period) remains an underutilised interval during which chemotherapeutic regimens are rarely implemented. Herein, we present a summarised review of the literature that supports the concept that tumour removal may potentiate the growth of residual neoplastic disease. We also outline current knowledge regarding underlying mechanisms and in this manner highlight potential therapeutic entry points. Finally, we emphasise the urgent need for trials of agents that could protect patients against the harmful host-tumour interactions that may occur during the perioperative period.

Humans↗
PubMed2006

Matrix metalloproteinases 2 and 9 in human atherosclerotic and non-atherosclerotic cerebral aneurysms.

Matrix metalloproteinases 2 and 9 (MMP 2 and -9) have been implicated in the pathogenesis of atherosclerosis and aneurysm formation. The goal of the study was to establish the role of these metalloproteinases in both human atherosclerotic and non-atherosclerotic cerebral aneurysms. Eleven cerebral aneurysms (four atherosclerotic, seven non-atherosclerotic) were immunohistochemically stained for MMP 2 and -9. As controls, atherosclerotic and normal Circle of Willis arteries were similarly immunostained. All specimens were retrieved at autopsy and were paraffin-embedded. In order to evaluate the real MMP 2 and -9 activities, gelatin zymography was also performed in only two available specimens of non-atherosclerotic intracranial aneurysms, because of the relative unavailability of fresh intracranial aneurysm tissue (i.e. reluctance to excise the aneurysm fundus at surgery). Our data establish that MMP 2 and -9 were expressed minimally or not at all in normal Circle of Willis arteries but were strongly expressed in medial smooth muscle cells of atherosclerotic Circle of Willis arteries. In the aneurysm group, both MMP 2 and -9 were strongly expressed in the atherosclerotic aneurysms, but MMP 2 alone was detected in the non-atherosclerotic aneurysms. Zymography revealed a weak enzyme activity correlating to MMP 9 standard recombinant protein. MMP 2 activity was not demonstrated in either specimen. This study shows that the expression of MMP 2 and -9 is associated with atherosclerosis, be it in aneurysmal or non-aneurysmal cerebral vessels but MMP 2 appears to be specifically expressed in aneurysms devoid of atherosclerosis perhaps suggesting a pathogenic role for MMP 2 in the alteration of the extracellular matrix of cerebral arteries during aneurysm formation.

Adolescent↗
PubMed2005

The role of hereditary hemochromatosis in aseptic loosening following primary total hip arthroplasty.

Hereditary hemochromatosis (HH) results in increased iron absorption and subsequent deposition in tissue. This condition occurs predominantly in individuals of Northern European and Celtic origin with Ireland having one of the highest allele frequencies in the world. This study examines the hypothesis that homozygosity for either the C282Y or H63D mutations in the HFE gene may be associated with aseptic loosening following total hip arthroplasty (THA). Two groups of individuals were screened for the C282Y and H63D mutations associated with HH. Group 1 were individuals who had undergone primary hip arthroplasty and group 2 were individuals who had undergone revision hip arthroplasty for aseptic loosening. Exclusion criteria included rheumatoid or other inflammatory arthropathies and revision due to causes other than aseptic loosening. Significantly more patients in the revision THA group were homozygous for the C282Y genotype (P = 0.014). Aseptic loosening occurred earlier in these patients (P = 0.009), in particular in the patients who had clinical signs of hemochromatosis. No association was seen with the H63D mutation and revision THA. The incidence of HH in the group of primary THA patients was no higher than the background incidence. Patients who require primary THA and who are homozygous for the C282Y mutation have an increased risk of developing aseptic loosening, leading to revision THA. Moreover C282Y homozygosity appears to be associated with earlier aseptic loosening than in individuals without the C282Y mutation.

Adult↗
PubMed2005

Pravastatin modulates early diabetic nephropathy in an experimental model of diabetic renal disease.

BACKGROUND: Development of diabetes causes early functional (endothelial dysfunction) and morphological abnormalities in the kidney. If left untreated, these will ultimately progress to renal failure. Apart from strategies aimed at maintaining very tight glycemic control, attention has turned to the development of adjuvant therapy to maintain endothelial function in these patients. The agents receiving the most critical appraisal due to their endothelial protective effects are the 3-hydrox 3-methylglutaryl (HMG)-Co-enzyme A (CoA) reductase inhibitors. The aim of the study was to investigate: (1) the early alterations in the renal diabetic injury; and (2) to examine the protective role of Pravastatin in this end-organ diabetic model. MATERIALS AND METHODS: Sprague Dawley rats (n = 21) were randomized into three groups: (1) control; (2) diabetic; and (3) diabetic treated with Pravastatin. Diabetic nephropathy was investigated with serum biochemical parameters (urea, creatinine), functional parameters (total urinary protein loss, glomerular filtration rate, renal cortical blood flow), and structural assessment (hemotoxylin and eosin staining). RESULTS: We demonstrated impairment in functional, biochemical, and structural parameters in the diabetic nephropathy group, which was diminished by treatment with Pravastatin. This was attributed to an up-regulation in endothelial constitutive nitric oxide synthase (ecNOS) expression in the treated diabetic group. CONCLUSIONS: We have shown that Pravastatin, in an experimental model of early diabetes nephropathy preserves microvascular endothelial function in the presence of hyperglycemia, thus inhibiting the early stage of diabetic microangiopathy.

Animals↗
PubMed2005

Anaplastic (undifferentiated) thyroid cancer: improved insight and therapeutic strategy into a highly aggressive disease.

BACKGROUND: This review article discusses the clinical and diagnostic implications of anaplastic thyroid cancer, recognizing the aggressive nature of the disease and extensive disease progression upon diagnosis. Standard treatment strategies (surgical, chemotherapy, radiation) are discussed, comparing adjuvant and neo-adjuvant regimens and the emergence of tumour resistance with expression of multidrug resistance pumps. We question the pathological evolution of anaplasia as a 'de novo' disease or a post malignant transformation or dedifferentiation and the therapeutic implications of p53 mutation. Future treatment options are reviewed with an emphasis on specific molecular targets responsible for the neoplastic phenotype. METHOD: An electronic search on Medline and Pubmed was performed under 'anaplastic thyroid carcinoma', 'anaplastic thyroid carcinogenesis', 'anaplastic thyroid carcinoma treatment reviews'. Relevant papers were systematically reviewed from 1965 to present.

Aged↗
PubMed2004

Oral vitamin C reduces the injury to skeletal muscle caused by compartment syndrome.

Compartment syndrome is a unique form of ischaemia of skeletal muscle which occurs despite patency of the large vessels. Decompression allows the influx of activated leucocytes which cause further injury. Vitamin C is a powerful antioxidant which concentrates preferentially in leucocytes and attenuates reperfusion-induced muscle injury. We have evaluated the use of pretreatment with oral vitamin C in the prevention of injury caused by compartment syndrome in a rat cremasteric muscle model. Acute and delayed effects of pretreatment with vitamin C were assessed at one and 24 hours after decompression of compartment syndrome. Muscle function was assessed electrophysiologically. Vascular, cellular and tissue inflammation was assessed by staining of intercellular adhesion molecule-1 (ICAM-1) and by determination of the activity of myeloperoxidase (MPO) in neutrophils and tissue oedema. Compartment syndrome impaired skeletal muscle function and increased the expression of ICAM-1, activity of MPO and muscle weight increased significantly. Pretreatment with vitamin C preserved muscle function and reduced the expression of ICAM-1, infiltration of the neutrophils and oedema.

Administration, Oral↗
PubMed2003

Neutrophil bactericidal function is defective in patients with recurrent urinary tract infections.

Urinary tract infection (UTI), most frequently caused by Escherichia coli, is one of the most common bacterial infections in humans. It is a host inflammatory response to bacterial invasion in which large numbers of neutrophils are recruited into the bladder in response to cytokines secreted by the infected bladder epithelium. We hypothesise that an impaired host neutrophil response leads to susceptibility to recurrent UTI (rUTI). Therefore, the neutrophil inflammatory response of patients with a history of rUTI was compared to healthy controls. No difference in neutrophil adhesion receptor expression or complement receptor expression following bacterial stimulus was detected between the two groups. However, the expression of the IgG receptor CD16, bacterial phagocytosis and reactive oxygen intermediate (ROI) production were significantly reduced in UTI patient neutrophils compared to controls. Neutrophils from rUTI patients have a significantly reduced bactericidal function when compared to healthy controls, with the former showing a reduced capacity for activation. This reduced neutrophil function may result in defective bacterial clearance and lead to susceptibility to recurrent infection.

Adult↗
PubMed2003

Endotoxin/lipopolysaccharide activates NF-kappa B and enhances tumor cell adhesion and invasion through a beta 1 integrin-dependent mechanism.

Beta(1) integrins play a crucial role in supporting tumor cell attachment to and invasion into the extracellular matrix. Endotoxin/LPS introduced by surgery has been shown to enhance tumor metastasis in a murine model. Here we show the direct effect of LPS on tumor cell adhesion and invasion in extracellular matrix proteins through a beta(1) integrin-dependent pathway. The human colorectal tumor cell lines SW480 and SW620 constitutively expressed high levels of the beta(1) subunit, whereas various low levels of alpha(1), alpha(2), alpha(4), and alpha(6) expression were detected. SW480 and SW620 did not express membrane-bound CD14; however, LPS in the presence of soluble CD14 (sCD14) significantly up-regulated beta(1) integrin expression; enhanced tumor cell attachment to fibronectin, collagen I, and laminin; and strongly promoted tumor cell invasion through the Matrigel. Anti-beta(1) blocking mAbs (4B4 and 6S6) abrogated LPS- plus sCD14-induced tumor cell adhesion and invasion. Furthermore, LPS, when combined with sCD14, resulted in NF-kappaB activation in both SW480 and SW620 cells. Inhibition of the NF-kappaB pathway significantly attenuated LPS-induced up-regulation of beta(1) integrin expression and prevented tumor cell adhesion and invasion. These results provide direct evidence that although SW480 and SW620 cells do not express membrane-bound CD14, LPS in the presence of sCD14 can activate NF-kappaB, up-regulate beta(1) integrin expression, and subsequently promote tumor cell adhesion and invasion. Moreover, LPS-induced tumor cell attachment to and invasion through extracellular matrix proteins is beta(1) subunit-dependent.

Adjuvants, Immunologic↗
PubMed2003

Excisional surgery for cancer cure: therapy at a cost.

Excisional surgery is one of the primary treatment modalities for cancer. Minimal residual disease (MRD) is the occult neoplastic disease that remains in situ after curative surgery. There is increasing evidence that tumour removal alters the growth of MRD, leading to perioperative tumour growth. Because neoplasia is a systemic disease, this phenomenon may be relevant to all patients undergoing surgery for cancer. In this review we discuss the published work that addresses the effects of tumour removal on subsequent tumour growth and the mechanisms by which tumour excision may alter residual tumour growth. In addition, we describe therapeutic approaches that may protect patients against any oncologically adverse effects of tumour removal. On the basis of the evidence presented, we propose a novel therapeutic paradigm; that the postoperative period represents a window of opportunity during which the patient may be further protected against the oncological effects of tumour removal.

Chemotherapy, Adjuvant↗
PubMed2003

Peripheral and central arterial haemodynamic interactions are early abnormalities in young male cigarette smokers.

BACKGROUND: smoking, result in endothelial dysfunction and this affects systemic and local haemodynamics. The aim was to assess interactions of the left ventricle and arterial system of smokers at baseline and after a physiological stimulus--the cold pressor test (CPT) which causes a sympathetically driven vasoconstriction that counteracts the normal endothelial dependent vasodilatation. MATERIALS AND METHODS: male smokers and controls were compared using applanation tonometry. Parameters included systolic and diastolic blood pressure, ejection duration, heart rate, aortic augmentation index (AAI), and sub-endocardial viability ratio (SEVR). The CPT was performed at 1 and 3 min following immersion of the hand in ice. RESULTS: smokers have abnormal baseline cardiac timing (heart rate and ejection duration), systolic and diastolic blood pressures which are due to increased peripheral wave reflection (AAI) and thus affect the SEVR. Following CPT, the pressure wave differential, dP/dt, was significantly increased in smokers compared to non-smokers who had a decrease at 1 min in ice. Mean systolic and diastolic pressure was significantly increased in both groups at 1 and 3 min as was end systolic pressure in non-smokers. CONCLUSIONS: baseline ventriculo-vascular dynamics, are abnormal as was the evoked response to CPT. The blunted blood pressure increase of smokers compared to controls following CPT, may represent altered nitric oxide production in the macro and microcirculation through differential upregulation of endothelial nitric oxide synthase (eNOS) and inducible NOS respectively. The potential for therapeutic intervention and prevention of ongoing endothelial injury, requires further investigation.

Adult↗
PubMed2002

Homocysteine and occlusive arterial disease.

BACKGROUND: An increased plasma level of homocysteine has been proposed as an independent risk factor for atherosclerosis; this review examines the evidence. METHODS: A Medline search was undertaken for English language articles on homocysteine and vascular disease. Further papers were identified by cross-referencing from the reference lists of relevant major articles. RESULTS: Although much interest has been generated about homocysteine and atherosclerotic disease, contradictory data exist regarding its role in disease progression. There is insufficient current evidence to regard increased homocysteine level as a causative factor in atherosclerotic disease. CONCLUSION: It is not known whether lowering plasma homocysteine concentration will reduce cardiovascular risk in the long term. Until such data become available, there is no evidence for the widespread use of folic acid therapy to reduce cardiovascular disease risk.

Arteriosclerosis↗
PubMed2002

A reduction in serum cytokine levels parallels healing of venous ulcers in patients undergoing compression therapy.

INTRODUCTION: vascular endothelial growth factor (VEGF) and tumour necrosis factor alpha (TNF(alpha)) have been specifically implicated in the tissue damage associated with chronic venous disease (CVD). Furthermore, production of both factors is known to be upregulated in vessel wall cells subject to hypertension. The aim of this study was to determine the local venous levels of VEGF and TNF(alpha) in limbs with venous ulcers before and after treatment with graduated compression. PATIENTS AND METHODS: eight patients with venous ulcers and 8 patients with varicose veins only were included in the study. For ulcer patients, serum samples were taken from the superficial veins in lower limbs and repeated after 4 weeks of treatment with 4-layered graduated compression. Serum from the arms of the same patients served as controls. Determination of the concentrations of VEGF and TNF(alpha) proteins were performed with sandwich enzyme-linked immunosorbent assays. RESULTS: both groups of patients had elevated levels of VEGF and TNF(alpha). In patients with venous ulcers there was a reduction in the levels of both cytokines to below control values with treatment. These changes correlated with healing of the ulcers as determined by reduction in ulcer size. CONCLUSION: these data, for the first time, suggest a central role for both TNF(alpha) and VEGF in the pathogenesis of venous ulceration which may constitute a causative link between venous hypertension and tissue pathology.

Aged↗
PubMed2002

Development of resistant strains of Staphylococcus epidermidis on gentamicin-loaded bone cement in vivo.

We have compared the rates of infection and resistance in an animal model of an orthopaedic procedure which was contaminated with a low-dose inoculum of Staphylococcus epidermidis. We randomised 44 Sprague-Dawley rats to have bone cement implanted subcutaneously containing either gentamicin or saline (control). The wound was inoculated with a dilute solution of gentamicin-sensitive Staphylococcus epidermidis. At two weeks the cement was retrieved and microbiologically tested. A lower overall rate of infection was seen in the gentamicin-loaded cement group, but there was a significantly higher rate of gentamicin-resistant infection in this group (Fisher's exact test, p < 0.01). Antibiotic-impregnated cement has an optimum surface for colonisation and prolonged exposure to antibiotic allows mutational resistance to occur. Gentamicin-loaded cement may not be appropriate for revision surgery if it has been used already in previous surgery.

Animals↗