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Duncan J Stewart

Publications and source records attributed to Duncan J Stewart.

At least 37 records · Page 2Linked to original sources
PubMed2005

Extra-pleural pneumonectomy for malignant pleural mesothelioma: the risks of induction chemotherapy, right-sided procedures and prolonged operations.

OBJECTIVE: With the increasing incidence of malignant pleural mesothelioma and renewed interest in radical surgery as a therapeutic option, we have examined our experience of extra-pleural pneumonectomy, to document the incidence and management of its peri-operative complications. METHODS: This analysis was conducted using prospectively entered data contained within the departmental database, with additional information from retrospective case note review. Details of patient selection criteria and operative modifications are included. RESULTS: Over a 59-month period, extra-pleural pneumonectomy was carried out on 74 patients (66 men; 8 women; median age 57 years). Fifteen patients (20%) received cisplatin-doublet induction chemotherapy. The majority (80%) of patients had epithelial tumours and 85% of patients had disease in International Mesothelioma Interest Group stages III and IV. The 30-day post-operative mortality was 6.75% (five patients) and significant morbidity was recorded in 47 patients (63%). Major complications included those of technical origin (diaphragmatic patch dehiscence 8.1%; chylothorax 6.7%; intra-thoracic haemorrhage 6.7%; bronchopleural fistula 6.7%), cardiovascular morbidity (atrial fibrillation 17.5%; mediastinal shift with subacute tamponade 10.8%; right ventricular failure 4%; pulmonary embolus 2.7%) and respiratory morbidity (pneumonia 10.8%; acute lung injury 8.1%). Admission to intensive care was required in 19 patients (26%). Univariate analysis identified the incidence of acute lung injury and mediastinal shift to be significantly associated with induction chemotherapy (P=0.005 and 0.014, respectively). In addition to this, laterality of operation influenced respiratory morbidity (P=0.018) and admission to intensive care (P=0.025). Finally, prolonged operations (greater than the median) were associated with an increased risk of technical (P=0.018) and gastro-intestinal (P=0.023) complications. CONCLUSIONS: Extra-pleural pneumonectomy is associated with a high rate of morbidity, but an acceptable mortality rate can be achieved with increasing peri-operative experience. Surgery following induction chemotherapy requires extra vigilance for the development of post-operative respiratory complications.

Adult↗
PubMed2005

Increased angiopoietin2 expression is associated with endothelial apoptosis and blood-brain barrier breakdown.

Normal intracerebral and pial vessels show constitutive expression of angiopoietin (Ang) 1 in endothelium while weak Ang2 immunoreactivity is present in occasional vessels. In the early phase postinjury, blood-brain barrier (BBB) breakdown at the lesion site is associated with decreased endothelial Ang1 and increased Ang2 expression, raising the possibility that Ang2 may have a role in early BBB breakdown. In order to determine whether Ang2 can cause BBB breakdown, the effect of recombinant Ang2 on cerebrovascular permeability to horseradish peroxidase (HRP) was studied in normal rat cortex. As hypothesized, Ang2 produced significant BBB breakdown to HRP as compared with vehicle-injected control rats. Since Ang2 is reported to have proapoptotic activity, the possibility that Ang2 may be associated with endothelial apoptosis was investigated in the rat cortical cold injury model over a period of 6 h to 6 days postinjury. Perilesion and pial vessels showed evidence of endothelial apoptosis as demonstrated by active Caspase-3 localization and TUNEL staining. Dual labeling for Ang proteins and active Caspase-3 demonstrated endothelial colocalization of Ang2 with active caspase-3. These data suggest that following injury, Ang2 may play a role in BBB breakdown of perilesional vessels, and it may also be a factor in endothelial cell apoptosis that occurs at days 1 and 2 following the injury.

Angiopoietin-1↗
PubMed2005

A novel model for post-transplant obliterative airway disease reveals angiogenesis from the pulmonary circulation.

We present a novel animal model for post-transplant obliterative airway disease in which the donor trachea is implanted into the recipient's lung parenchyma. Although this procedure is technically more challenging than the heterotopic model of implantation into a subcutaneous pouch, it has several important advantages some of which are the appropriate local environment and the possibility of local immunosuppressive therapy after transtracheal gene, cell or drug delivery. This model has revealed new insights into angiogenic potential of the pulmonary circulation.

Animals↗
PubMed2005

The role of endothelin-1 in myocarditis and inflammatory cardiomyopathy: old lessons and new insights.

Endothelin-1 has emerged as an important participant in the pathophysiology of a variety of cardiovascular diseases, where it may act on endocrine, paracrine and autocrine bases. Here we review its regulated biosynthesis, receptor-mediated signaling, and functional consequences in the heart, with particular emphasis on cardiac development and disease. Exploring published data employing molecular genetic mouse models of endothelin dysregulation, we highlight its heretofore underappreciated role as a pro-inflammatory cytokine. We also present novel micro-array data from one such mouse model, which implicate the specific downstream pathways that may mediate endothelin-1's effects.

Animals↗
PubMed2005

Canadian Cardiovascular Society and Canadian Thoracic Society position statement on pulmonary arterial hypertension.

The Canadian Cardiovascular Society and the Canadian Thoracic Society requested a position statement on pulmonary arterial hypertension from leading Canadian experts. The present document is intended to act as an update for the clinician, to provide a template for the initial evaluation of patients, to enable the understanding of current therapeutic paradigms based on approved indications for Canada, to highlight new therapies on the horizon, and to state the positions of the Canadian Cardiovascular Society and the Canadian Thoracic Society on resource management for pulmonary arterial hypertension in Canada.

Humans↗
PubMed2005

Role of angiopoietin-1 in experimental and human pulmonary arterial hypertension.

INTRODUCTION: The pulmonary microvasculature, consisting mainly of an endothelial cell (EC) monolayer and scant matrix support, is incompletely muscularized. Thus, the distal pulmonary arterioles may be predisposed to regression on exposure to environmental stresses (ie, hypoxia) and may be dependent on EC survival factors, like angiopoietin (Ang) 1, to attenuate the development of pulmonary arterial hypertension (PAH). In order to clarify the link between Ang1 expression and the development of PAH in patients, we also studied messenger RNA and protein expression in lung samples from healthy control subjects and patients with idiopathic PAH (IPAH) or PAH associated with other diseases (APAH). METHODS: Ang/Tie2 gene expression was assessed in rats that had been exposed to hypoxia (ie, 10% O2) for 1, 3, or 7 days. In a separate experiment, the cell-based gene transfer of Ang1/Ang2 was performed, and the effects were evaluated in rats with hypoxia-induced PAH. RESULTS: Hypoxia induced significant early increases in right ventricular systolic pressure (RVSP) and right ventricle/left ventricle-plus-septum mass ratio (RV/[LV + S]), with a significant decrease in Tie2 expression. Hypoxic rats receiving Ang1 demonstrated significant improvements in RVSP and RV/(LV + S), with a partial normalization in Tie2 protein levels. Robust Ang1 expression was observed in healthy human lungs. Furthermore, there were no significant changes in the levels of Ang1 or Ang2 in IPAH or APAH samples vs those in control subjects. CONCLUSIONS: Decreased activity of the Tie2 pathway with hypoxia may contribute to PAH, possibly by loss of EC survival signaling, which can be overcome by Ang1 gene transfer.

Angiopoietin-1↗
PubMed2005

Angiopoietins are expressed in the normal rat pituitary gland.

Interaction of vascular endothelial growth factor (VEGF) with the angiopoietins (Ang) is an essential component of angiogenesis. Localization of VEGF in the anterior pituitary raises the possibility that Ang must be present in the pituitary gland as well. In this study Ang expression was detected in the normal rat pituitary gland at the gene level by reverse-transcriptase polymerase chain reaction and at the protein level by immunohistochemistry. The latter was analyzed by both light and confocal microscopy. Constitutive expression of Ang1, Ang2, and their receptor Tie2 was detected at both the mRNA and protein level in all the pituitary glands studied. Of interest was the localization of both Ang1 and Ang2 in scattered PAS positive adenohypophysial cells rather than in endothelial cells. Confocal microscopy showed colocalization of both Ang1 and Ang2 proteins within the same adenohypophysial cells. Dual immunostaining for Ang1 and the anterior pituitary hormones that show PAS positivity demonstrated colocalization of Ang1 with follicle stimulating hormone and luteinizing hormone. In the posterior pituitary, strong Ang1 signal observed in vascular endothelial cells masked the weak Ang2 signal, a pattern that is similar to that reported in brain endothelial cells. The presence of both angiopoietins and VEGF in the pituitary gland suggest that these ligands interact during angiogenesis as they are known to do in other systems to maintain the rich vascular network of the gland. This first report of angiopoietin localization in the rat pituitary gland opens a new line of investigation on angiogenesis in pituitary glands that will impact human endocrinology in the future.

Angiopoietin-1↗
PubMed2005

Canadian Cardiovascular Society and Canadian Thoracic Society position statement on pulmonary arterial hypertension.

The Canadian Cardiovascular Society and the Canadian Thoracic Society requested a position statement on pulmonary arterial hypertension from leading Canadian experts. The present document is intended to act as an update for the clinician, to provide a template for the initial evaluation of patients, to enable understanding of current therapeutic paradigms based on approved indications for Canada, to highlight new therapies on the horizon, and to state the positions of the Canadian Cardiovascular Society and the Canadian Thoracic Society on resource management for pulmonary arterial hypertension in Canada.

Canada↗
PubMed2004

Reciprocal regulation of angiopoietin-1 and angiopoietin-2 following myocardial infarction in the rat.

OBJECTIVE: This study sought to characterize changes in the angiopoietin system in a rat model of myocardial infarction (MI). BACKGROUND: Angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) bind to the endothelial-specific receptor tyrosine kinase, TIE-2. Ang-2 has been suggested to be an antagonist of TIE-2, possibly acting to release endothelial cells from the tonic stabilizing influence of Ang-1. However, on prolonged exposure, Ang-2 has been shown to acquire agonistic activity at TIE-2, raising the possibility that this isoform may play a direct role in neovascularization. METHODS: Sprague-Dawley rats were subjected to left coronary ligation and myocardial tissues were harvested from the infarct and peri-infarct regions, or from non-infarcted myocardium. Changes in gene expression were determined by RT-PCR and confirmed by Northern analysis. Changes in protein expression were confirmed by Western analysis and immunocytochemistry, and TIE-2 activity was determined by immunoprecipitation with anti-TIE-2 and antiphosphotyrosine immunoblotting. RESULTS: At 24 h, Ang-1 mRNA and protein expression within the infarct and peri-infarct regions were decreased compared to non-infarcted myocardium, whereas Ang-2 mRNA levels were markedly increased and TIE-2 expression was unchanged. Immunohistochemical staining revealed Ang-1 and TIE-2 immunoreactivity localized to vascular endothelium. In the infarct territory, Ang-2 immunostaining was localized primarily to invading leukocytes at 24 h. At 1 week, Ang-1 expression was partially restored, whereas Ang-2 expression remained elevated. At the time of peak elevation in Ang-2, Tie2 phosphorylation was found to be markedly increased, consistent with receptor activation. CONCLUSIONS: Thus, myocardial ischemia induced by left coronary artery ligation resulted in a sustained increase in Ang-2 expression and a reciprocal decrease in Ang-1, consistent with a predominant role for Ang-2 in the angiogenic response to MI.

Angiopoietin-1↗
PubMed2004

C-reactive protein attenuates endothelial progenitor cell survival, differentiation, and function: further evidence of a mechanistic link between C-reactive protein and cardiovascular disease.

BACKGROUND: Myocardial ischemia provides a potent stimulus to angiogenesis, and the mobilization and differentiation of endothelial progenitor cells (EPCs) has been shown to be important in this process. An elevated level of C-reactive protein (CRP) has emerged as one of the most powerful predictors of cardiovascular disease. However, the impact of CRP on EPC biology is unknown. METHODS AND RESULTS: EPCs were isolated from the peripheral venous blood of healthy male volunteers. Cells were cultured in endothelial cell basal medium-2 in the absence and presence of CRP (5 to 20 microg/mL), rosiglitazone (1 micromol/L), and/or vascular endothelial growth factor. EPC differentiation, survival, and function were assayed. CRP at concentrations > or =15 microg/mL significantly reduced EPC cell number, inhibited the expression of the endothelial cell-specific markers Tie-2, EC-lectin, and VE-cadherin, significantly increased EPC apoptosis, and impaired EPC-induced angiogenesis. EPC-induced angiogenesis was dependent on the presence of nitric oxide, and CRP treatment caused a decrease in endothelial nitric oxide synthase mRNA expression by EPCs. However, all of these detrimental CRP-mediated effects on EPCs were attenuated by pretreatment with rosiglitazone, a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist. CONCLUSIONS: Human recombinant CRP, at concentrations known to predict adverse vascular outcomes, directly inhibits EPC differentiation, survival, and function, key components of angiogenesis and the response to chronic ischemia. This occurs in part via an effect of CRP to reduce EPC eNOS expression. The PPARgamma agonist rosiglitazone inhibits the negative effects of CRP on EPC biology. The ability of CRP to inhibit EPC differentiation and survival may represent an important mechanism that further links inflammation to cardiovascular disease.

Apoptosis↗
PubMed2004

Defective lung vascular development and fatal respiratory distress in endothelial NO synthase-deficient mice: a model of alveolar capillary dysplasia?

Endothelium-derived NO plays a critical role in the regulation of cardiovascular function and structure, as well as acting as a downstream mediator of the angiogenic response to numerous vascular growth factors. Although endothelial NO synthase (eNOS)-deficient mice are viable, minor congenital cardiac abnormalities have been reported and homozygous offspring exhibit high neonatal mortality out of proportion to the severity of these defects. The aim of the present report was to determine whether abnormalities of the pulmonary vascular development could contribute to high neonatal loss in eNOS-deficient animals. We now report that eNOS-deficient mice display major defects in lung morphogenesis, resulting in respiratory distress and death within the first hours of life in the majority of animals. Histological and molecular examination of preterm and newborn mutant lungs demonstrated marked thickening of saccular septae, with evidence of reduced surfactant material. Lungs of eNOS-deficient mice also exhibited a striking paucity of distal arteriolar branches and extensive regions of capillary hypoperfusion, together with misalignment of pulmonary veins, which represent the characteristic features of alveolar capillary dysplasia. We conclude that eNOS plays a previously unrecognized role in lung development, which may have relevance for clinical syndromes of neonatal respiratory distress.

Animals↗
PubMed2004

Conditional cardiac overexpression of endothelin-1 induces inflammation and dilated cardiomyopathy in mice.

BACKGROUND: Myocardial expression of endothelin-1 (ET-1) and its receptors ET(A) and ET(B) is increased in heart failure. However, the role of ET-1 and its signaling pathways in the pathogenesis of myocardial diseases is unclear. METHODS AND RESULTS: Human ET-1 cDNA was placed downstream of a promoter responsive to a doxycycline (DOX)-regulated transcriptional activator (tTA). This line (ET+) was bred with one harboring cardiac myocyte-restricted expression of tTA (alphaMHC-tTA). Myocardial ET-1 peptide levels were significantly increased in binary transgenic (BT, ET+/tTA+) compared with nonbinary transgenic (NBT, ET+/tTA-; ET-/tTA+; ET-/tTA-) or DOX-treated BT littermates (40.1+/-4.7 versus 2.6+/-1.2 fmol/mL, P<0.003). BT mice demonstrated progressive mortality between 5 and 11 weeks after DOX withdrawal, associated with left ventricular dilatation and contractile dysfunction (peak +dP/dT, 4673+/-468 versus 5585+/-658 mm Hg/s, P<0.05). An interstitial inflammatory infiltrate, including macrophages and T lymphocytes, was evident in the myocardium of BT mice, associated with sequential increases in nuclear factor-kappaB translocation and expression of tumor necrosis factor-alpha, interferon-gamma, interleukin-1 and interleukin-6. Significant prolongation of survival was observed with the combined ET(A)/ET(B) antagonist LU420627 (n=8, P<0.05) in BT mice but not the ET(A)-selective antagonist LU135252 (n=5, P=0.9), consistent with an important role for ET(B) in this model. CONCLUSIONS: These are the first data to demonstrate that cardiac overexpression of ET-1 is sufficient to cause increased expression of inflammatory cytokines and an inflammatory cardiomyopathy leading to heart failure and death.

Animals↗
PubMed2004

The effect of extent of local resection on patterns of disease progression in malignant pleural mesothelioma.

BACKGROUND: We sought to determine whether or not there are differences in disease progression after radical or nonradical (debulking) surgical procedures for malignant pleural mesothelioma. METHODS: Over a 49-month period, 132 patients with malignant pleural mesothelioma underwent surgery. Fifty-three underwent extrapleural pneumonectomy and 79 underwent nonradical procedures. Time to evidence of clinical disease progression was recorded, as was the site(s) of that disease. RESULTS: One-hundred nineteen patients were evaluable, of which 59% (22 radical; 48 nonradical) had disease progression. Overall 30-day mortality was 8.5% (7.5% radical; 9% nonradical). The median time to overall disease progression was considerably longer after extrapleural pneumonectomy than debulking surgery (319 days vs 197 days, p = 0.019), as was the time to local disease progression (631 days vs 218 days, p = 0.0018). There was no preponderance of earlier stage disease in the radical surgery group. There was a trend toward prolonged survival in those undergoing radical surgery, but no significant difference between the groups (497 days vs 324 days, p = 0.079). In those who had extrapleural pneumonectomy, time-to-disease progression significantly decreased with N2 disease compared with N0/1 involvement (197 days vs 358 days, p = 0.02). CONCLUSIONS: Extrapleural pneumonectomy may be preferable to debulking surgery in malignant pleural mesothelioma to delay disease progression and give greater control of local disease. Involvement of N2 nodes is associated with accelerated disease progression and is therefore a contraindication to extrapleural pneumonectomy.

Abdominal Neoplasms↗
PubMed2004

Therapeutic neovascularization for ischemic heart disease.

The demonstration that angiogenic growth factors stimulate new blood vessel growth and restore perfusion in animal models of myocardial and peripheral vascular ischemia has prompted the translation of therapeutic angiogenesis from bench to bedside. The enthusiasm generated from early, open-label, safety trials using primarily vascular endothelial growth factors or fibroblast growth factor protein or gene therapy has been tempered by double-blind randomized placebo controlled studies that have yielded variable though potentially promising results. This article reviews the basis of angiogenic therapy, lessons learned from the latest major trials and potential refinements for future therapy.

Clinical Trials, Phase II as Topic↗