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Biomedical subjects

M G Walker

Publications and source records attributed to M G Walker.

At least 19 recordsLinked to original sources
PubMed2006

Intimal neovascularisation is a prominent feature of atherosclerotic plaques in diabetic patients with critical limb ischaemia.

INTRODUCTION: Neovascularisation of atherosclerotic plaques correlates with increased plaque instability and subsequent risk of vascular complications. Diabetics have widespread atherosclerotic involvement of the arterial tree and a more aggressive form of the disease culminating in increased plaque instability. This results in a greater incidence of ischaemic sequelae than in non-diabetics. Previous studies have examined neovascularisation as a marker of plaque instability in both the carotid and coronary territories and revealed a greater degree in both symptomatic and diabetic patients. This is the first study to examine intimal neovascularisation in lower limb peripheral arterial disease. METHODS: Arterial specimens were taken from 20 patients, ten of whom were type 2 diabetics, undergoing major lower limb amputation for unreconstructable critical ischaemia. Sections were stained with H&E for morphological assessment and inflammatory cell characterisation. Additional sections underwent immunohistochemical staining for CD31 and von-Willebrand Factor (vWF) and the number of intimal vessels per four 40x magnification fields assessed. RESULTS: There was a more prominent inflammatory infiltrate in diabetic subjects compared to non-diabetic controls. Diabetic patients had a greater degree of intimal neovascularisation compared to controls with a median of 11.5 and 2.0 vessels per field respectively (P<0.05). Sub-group analysis revealed that diabetic patients medicating with HMG-CoA Reductase inhibitors (Statins) had a greater degree of neovascularisation compared to those not taking this class of medication. CONCLUSION: Diabetic patients with critical limb ischaemia requiring amputation demonstrate a greater degree of plaque intimal neovascularisation and inflammatory infiltrate compared to their non-diabetic counterparts. This may explain the greater plaque instability and subsequent cardiovascular complications seen in these patients.

Aged↗
PubMed2006

Expression of growth factors and growth factor receptor in non-healing and healing ischaemic ulceration.

OBJECTIVES: To characterise the histological and cytokinetic characteristics of purely ischaemic ulcers and the processes that underpin healing following successful revascularisation. DESIGN: Prospective observational study. MATERIALS AND METHODS: Biopsies were taken immediately pre- and 6 weeks following successful revascularisation of solely ischaemic ulceration. They were evaluated for morphological differences using H&E staining for the platelet derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR), TGFbeta receptorIII (TGFbetaRIII), transforming growth factor beta 1 and 3 (TGFbeta1 and TGFbeta3) and von Willebrand factor (vWF) expression using immunohistochemistry. Localisation and quantification of these growth factors and receptors was assessed systematically by three independent investigators who were blinded to the timing of biopsy. RESULTS: Pre-operatively, small vessel vasculitis, necrosis and infection with a profuse neutrophil and macrophage infiltrate was observed in all samples. Post-operative biopsies revealed a proliferation of new capillaries in and around the ulcer edge and base. vWF staining confirmed an endothelial layer within these new vessels. Following successful revascularisation there was less infection and inflammation with minimal vasculitis. These newly formed capillaries had increased staining for TGFbeta3, PDGFR and TGFbetaRIII with staining for PDGFR also localised to dermal fibroblasts which were larger and more numerous. Accelerated epithelial cell proliferation was observed with detachment from the underlying dermis. CONCLUSIONS: Healing of purely ischaemic ulcers is characterised by vasculogenesis associated with increased presence of the proangiogenic cytokines PDGF and TGFbeta3. These findings show promise for the use of growth factor manipulation to aid healing in ischaemic ulcers.

Adult↗
PubMed2006

Tissue engineering of blood vessels.

BACKGROUND: Tissue engineering techniques have been employed successfully in the management of wounds, burns and cartilage repair. Current prosthetic alternatives to autologous vascular bypass grafts remain poor in terms of patency and infection risk. Growing biological blood vessels has been proposed as an alternative. METHODS: This review is based on a literature search using Medline, PubMed, ISIS and CAS of original articles and reviews, and unpublished material and abstracts. RESULTS AND CONCLUSIONS: Complete incorporation into host tissues and the maintenance of a viable and self-renewing endothelial layer are the fundamental goals to be achieved when developing a tissue-engineered blood vessel. Sourcing of cells and modulating their interaction with extracellular matrix and supporting scaffold have been the focus of intense research. Although the use of tissue-engineered blood vessels in humans is so far limited, advances in our knowledge of stem cell precursors and the development of new biomaterials should enable this technology to reach routine clinical practice within a decade.

Biotechnology↗
PubMed2005

Colonic epithelial apoptosis during conventional and endoluminal aortic surgery.

BACKGROUND: This study characterized the initial modes of colonic mucosal injury during aneurysm surgery and correlated these with proinflammatory cytokine release into the colonic and systemic circulations. METHODS: Twenty-four patients undergoing conventional open aortic aneurysm repair and ten who had endovascular aneurysm repair (EVAR) were recruited. Mucosal biopsies were taken from the sigmoid colon immediately before and after surgery, for histological examination. Inferior mesenteric vein (IMV) and peripheral blood from patients who had conventional surgery was assayed for interleukin (IL) 1 beta, IL-6 and tumour necrosis factor (TNF) alpha. Only peripheral blood from patients who had EVAR was assayed. RESULTS: Conventional aneurysm repair resulted in a threefold increase in columnar epithelial apoptosis. There was a 26-fold increase in IL-6 in IMV blood within 5 min of reperfusion, with an equivalent rise in peripheral blood after 30 min. A 20-fold rise in peripheral blood TNF-alpha was observed after surgery. Splanchnic IL-6 correlated positively with cross-clamp time and increased apoptosis. No histological changes were seen after EVAR. There were no intraoperative cytokine changes during EVAR, although a postoperative increase in IL-6 and TNF-alpha was observed. CONCLUSION: The lack of columnar epithelial apoptosis following EVAR reflects the relatively minor ischaemic injury incurred during this procedure.

Aged↗
PubMed2005

The influence of asymptomatic significant carotid disease on mortality and morbidity in patients undergoing coronary artery bypass surgery.

OBJECTIVES: Controversy exists regarding the optimal management of patients with coexisting coronary and extracranial carotid artery disease. This study investigates the incidence of death, cerebrovascular events and myocardial infarction (MI) in patients with asymptomatic significant carotid artery disease undergoing coronary artery bypass graft (CABG) surgery. DESIGN: Prospective cohort. METHODS: Fifty patients with asymptomatic carotid stenoses > or =70% associated with cervical bruits undergoing CABG without prophylactic carotid endarterectomy (CEA) were followed up over a median period of 68 months following surgery cerebrovascular events, MI and mortality were recorded. All patients received optimal secondary prevention for cardiovascular disease unless contraindicated. RESULTS: No cerebrovascular events occurred within 30 days of surgery. One patient suffered an ipsilateral transient ischaemic attack (TIA) 14 months after CABG. Two patients died within 30 days; one from an MI, the other from pancreatitis. Three deaths occurred after 30 days; one from MI, one from primary lung cancer and one following rupture of an abdominal aortic aneurysm. No non-fatal MIs occurred. CONCLUSIONS: In this patient group the overall risk of death, cerebrovascular events and MI was 4% during the first 30 days postoperatively and 8% thereafter. This compares favourably with published series for staged or combined CEA-CABG procedures. For asymptomatic significant carotid disease, prophylactic CEA prior to CABG does not appear to confer any advantage over CABG alone.

Aged↗
PubMed2001

Outcome of transaxillary rib resection for thoracic outlet syndrome--a 10 year experience.

BACKGROUND: This study assessed the outcome of transaxillary first and/or cervical rib resection in a unit, which has a policy of combined assessment by a neurologist and vascular surgeon. METHODS: 61 patients underwent 83 transaxillary rib resections for thoracic outlet syndrome. A retrospective case note review of these patients was undertaken. All patients completed a telephone questionnaire regarding long-term outcome. RESULTS: Post-operative outpatient assessment at a median of 6 months recorded 91.5% improved, of whom 61.5% were symptom-free. 61% were available for the telephone questionnaire at a median follow-up of 4 yr. 74% reported an improvement, with complete resolution in 58%. Six described temporary improvement following surgery. CONCLUSION: Transaxillary rib resection is a safe and effective procedure, allowing almost two thirds of patients a return to normal activity. Combined assessment by vascular and neurological teams may help in patient selection for surgery, as well as the accurate long-term assessment of outcome.

Adolescent↗
PubMed2001

A comparison of para-anastomotic compliance profiles after vascular anastomosis: nonpenetrating clips versus standard sutures.

PURPOSE: Anastomotic compliance is an important predictive factor for long-term patency of small diameter vascular reconstruction. In this experimental study we compare the compliance of continuous and interrupted sutured vascular anastomoses with those using nonpenetrating clips. METHODS: Both common carotid arteries in nine goats (average weight, 57 +/- 5.7 kg) were transected, and end-to-end anastomoses were constructed with nonpenetrating clips or polypropylene sutures. The latter were applied with both interrupted and continuous techniques. Intraluminal pressure was measured with a Millar Mikro-tip transducer, and vessel wall motion was determined with duplex ultrasound equipped with an echo-locked wall-tracking system. Diametrical compliance was determined. Environmental scanning electron microscopy was performed on explanted anastomoses. RESULTS: There was a reduction in anastomotic compliance and associated proximal and distal para-anastomotic hypercompliant zones with the use of all techniques. However, compliance loss was significantly less in those anastomoses with clips and interrupted sutures when compared with continuous suture (P <.001). Furthermore, the total compliance mismatch across anastomoses with continuous sutures was significantly greater than those with clips or interrupted sutures (P <.05). The mean time for constructing clipped anastomoses was 5.7 +/- 1.4 minutes, which was significantly less than either continuous (P <.0001) or interrupted sutures (P <.0001). Furthermore, environmental scanning electron microscopy demonstrated minimal intimal damage with good intimal apposition in the clip group. CONCLUSION: Anastomoses performed with nonpenetrating clips resulted in improved para-anastomotic compliance profiles and reduced intimal damage when compared with those with polypropylene sutures. These benefits may enhance long-term graft patency by reducing the risk of anastomotic intimal hyperplasia.

Anastomosis, Surgical↗
PubMed2001

A randomized study to evaluate the effect of a perioperative infusion of dopexamine on colonic mucosal ischemia after aortic surgery.

PURPOSE: Colonic ischemia after aortic surgery is associated with increased mortality and morbidity rates. This study was conducted as a single-center side arm to a multicenter, randomized, placebo-controlled study to evaluate the effect of dopexamine hydrochloride on its incidence. METHODS: Thirty patients, mean age 65.1 years (range, 46-84), undergoing elective infrarenal aortic surgery were entered. Preoperative hemodynamic and respiratory parameters were optimized. Patients were then randomly assigned to receive a perioperative infusion of dopexamine at 2 microg/kg per minute (n = 12) or 0.9% saline placebo (n = 18). All patients underwent colonoscopy and biopsy preoperatively and 1 week postoperatively. Specimens were assessed for evidence of mucosal ischemia, presence of mast cell tryptase, myeloperoxidase activity, and both the inducible and endothelial isoforms of nitric oxide synthase. RESULTS: There was no significant difference in perioperative fluid and blood requirements or hemodynamic and respiratory parameters between the two groups. However, there was significantly less evidence of mucosal ischemic changes in dopexamine-treated patients (n = 1) compared with placebo (n = 8) (P =.049). Furthermore, when preoperative biopsies were compared with those performed 1 week postoperatively, nine (50%) patients in the placebo group and two (16.7%) in the dopexamine group scored worse. Although there was no significant difference in inflammatory markers between the two groups, both mast cell tryptase and myeloperoxidase expression were increased in patients with histologic evidence of ischemia (P <.05). Furthermore, inducible nitric oxide synthase staining within the vascular (P =.001) and lamina propria (P <.05) components of the mucosa was also significantly greater. CONCLUSION: A perioperative dopexamine infusion affords significant histologic protection to colonic mucosa after aortic surgery.

Adult↗
PubMed2001

Pharmaceutical target identification by gene expression analysis.

The majority of newly-identified genes in the human genome show no significant sequence similarity to genes whose function is known, so they are not easily recognized as potential drug targets. Expression analysis is an alternative method to suggest possible functions of genes. We review statistical methods for gene expression analysis to identify potential pharmaceutical targets. Specifically, we illustrate the analysis of differential gene expression (using discriminant analysis, t-tests, and analysis of variance) and co-expression (using correlation, clustering, and chi-square). We present an example of the use of expression analysis to identify co-expressed cardiomyopathy-associated genes.

Analysis of Variance↗
PubMed2001

Drug target discovery by gene expression analysis: cell cycle genes.

Gene expression microarrays and gene expression databases provide new opportunities for the discovery of drug targets and for determination of a drug's mode of action. We review gene expression analysis methods and describe studies that have identified cell cycle genes using differential expression analysis and co-expression analysis. We present an example of the identification of previously-unrecognized human cell cycle genes, CDCA1 through CDCA8, that are co-expressed with known cell cycle genes including CDC2, CDC7, CDC23, cyclin, MCAK, mki67a, topoisomerase II, and others.

Animals↗
PubMed2000

The significance of CD105, TGFbeta and CD105/TGFbeta complexes in coronary artery disease.

We have quantified levels of CD105, its ligand TGFbeta and receptor-ligand complexes in sera from healthy individuals (n=31), patients with triple vessel disease documented by coronary angiography (TVD; n=36) and patients with chest pain and a positive exercise electrocardiogram but with normal coronary angiogram (NCA; n=30). Both active TGFbeta1 and active plus acid-activatable TGFbeta1 [(a+l)TGFbeta1] were significantly depressed in patients with TVD compared with the other two groups (P</=0.04). CD105 levels in TVD patients were also diminished but elevated in NCA patients. In contrast, patients with TVD had more CD105/TGFbeta1 complex in their sera than the other two groups, suggesting that this may be the reason why TVD patients had low levels of receptor and ligand. TGFbeta3 levels were similar in the three groups, but elevated CD105/TGFbeta3 levels were noted in patients with NCA compared with those with TVD and healthy individuals (P< or =0.02). CD105 was correlated with both active TGFbeta1 and (a+l)TGFbeta1 (P=0.02). CD105 also strongly correlated with TGFbeta3 and CD105/TGFbeta3 complexes (P=0.001 in both cases). The changes in levels of CD105, TGFbeta1 and the receptor-ligand complexes in sera of patients with atherosclerosis suggest that these molecules may be important in the pathobiology of the atherosclerotic disease. Further studies on sequential samples from a larger cohort of patients are needed to define a causal relationship between these molecules and the disease progression.

Aged↗
PubMed1999

Prediction of gene function by genome-scale expression analysis: prostate cancer-associated genes.

We wish to identify genes associated with disease. To do so, we look for novel genes whose expression patterns mimic those of known disease-associated genes, using a method we call Guilt-by-Association (GBA), on the basis of a combinatoric measure of association. Using GBA, we have examined the expression of 40,000 human genes in 522 cDNA libraries, and have discovered several hundred previously unidentified genes associated with cancer, inflammation, steroid-synthesis, insulin-synthesis, neurotransmitter processing, matrix remodeling, and other disease processes. The majority of the genes thus discovered show no sequence similarity to known genes, and thus could not have been identified by homology searches. We present here an example of the discovery of eight genes associated with prostate cancer. Of the 40,000 most-abundant human genes, these 8 are the most closely linked to the known diagnostic genes, and thus are prime targets for pharmaceutical research.

Gene Expression Profiling↗
PubMed1999

Cardiovascular surgery in the elderly.

Throughout the developed world, the population is aging at an alarming rate. This has become an issue of great concern. The growing number of elderly people within the community has several health and economic implications. The prevalence of atherosclerosis increases with age and directly impacts on the workload of both cardiac and vascular surgeons. The decision to operate should not be based on age alone but reflect an assessment of the risk benefit ratio of individual cases. Increased life expectancy, safer anaesthesia and less invasive surgical techniques have led to more patients being considered for surgical intervention. However, this will inevitably result in an overwhelming burden on national health resources, a factor that may force some practitioners to deny treatment on the grounds of chronological and not biological age.

Age Factors↗
PubMed1999

Pharmaceutical target discovery using Guilt-by-Association: schizophrenia and Parkinson's disease genes.

We wish to identify genes associated with disease. To do so, we look for novel genes whose expression patterns mimic those of known disease-associated genes, a method we call Guilt-by-Association (GBA). GBA uses a combinatoric measure of association that provides superior results to those from correlation measures used in previous expression analyses. Using GBA, we have examined the expression of 40,000 human genes in 522 cDNA libraries, and have identified several hundred genes associated with known cancer, inflammation, steroid-synthesis, insulin-synthesis, neurotransmitter processing, matrix remodeling and other disease genes. The majority of the genes thus discovered show no significant sequence similarity to known genes, and thus could not have been identified by homology searches. We present here an example of the discovery of five genes associated with schizophrenia and Parkinson's disease. Of the 40,000 most-abundant human genes, these five genes are the most closely linked to the known disease genes, and thus are prime targets for pharmaceutical intervention.

Algorithms↗
PubMed1998

Histological study of colonic ischaemia after aortic surgery.

BACKGROUND: Colonic ischaemia is a well documented complication of abdominal aortic reconstruction. In this prospective study patients had routine preoperative and postoperative colonoscopy and biopsy, in order to determine the true incidence and implications. METHODS: Fifty-six patients undergoing elective infrarenal aortic surgery, 28 for aneurysm and 28 for occlusive disease, had colonoscopy and biopsy before and 1 week after operation. RESULTS: Colonic ischaemia was identified histologically in biopsies from 16 (30 per cent) of 53 patients. Almost half the patients had normal macroscopic appearances. Two factors exhibited a statistically significant association with the development of ischaemia: prolonged cross-clamp time (P < 0.05) and postoperative diarrhoea (P< 0.001). Co-morbidity was much higher in patients with colonic ischaemia (P< 0.005). Overall morbidity was significantly greater in the aneurysm group (P < 0.05). CONCLUSION: Colonic ischaemia is common after aortic reconstruction. When suspected, colonoscopy with biopsy is diagnostic.

Aged↗
PubMed1997

Production of plasminogen activator inhibitor-1 by human saphenous vein endothelial cells seeded onto endarterectomy surfaces in vitro.

PURPOSE: Endothelial cells produce many biologically important factors that may be used as functional markers, including plasminogen activators and their inhibitors (PAI). PAI-1 is a common peptide with a central role in the balance of thrombosis and fibrinolysis in vivo, and its production by vascular endothelial cells has been demonstrated for many in vitro cell lines. METHODS: The basal rate of PAI-1 release from cultured human adult endothelial cells was studied in both a well-plate-seeding model and after seeding onto human endarterectomy specimens. The effect of nonspecific stimulation with thrombin on PAI-1 release was examined in well-plate cultures. PAI-1 was measured by enzyme-linked immunosorbent assay. RESULTS: Cultured human saphenous endothelial cells release PAI-1 constitutively at a steady rate, which can be increased in the short term by the addition of thrombin. CONCLUSION: After seeding onto endarterectomy specimens, seeded endothelial cells release significant amounts of PAI-1, which suggests that they retain functional integrity and may potentially influence thrombosis in vivo after seeding.

Adult↗