Biomedical subjects

John F Martin

Publications and source records attributed to John F Martin.

16 recordsLinked to original sources

PubMed2006

The effects of chronic tea intake on platelet activation and inflammation: a double-blind placebo controlled trial.

BACKGROUND: Tea drinking appears to protect against the development of coronary heart disease (CHD), but the mediating pathways are uncertain. We studied the effects of 6 weeks of black tea or placebo on platelet activation, C-reactive protein (CRP), total antioxidant status, and soluble (s) P-Selectin in a randomized double-blind trial. METHODS: Healthy non-smoking men aged 18-55 years were randomized to black tea (N=37) or placebo (N=38) following a 4-week washout period during which they drank no tea, coffee or caffeinated beverages, but consumed caffeinated placebo tea. Bloods were drawn after 6 weeks of treatment. Platelet activation was assessed by measuring leukocyte-platelet aggregates using whole blood flow cytometry. RESULTS: Following treatment, the tea group had fewer monocyte-platelet aggregates (means 5.84 versus 6.60%, P=0.027), neutrophil-platelet aggregates (P=0.017), total leukocyte-platelet aggregates (P=0.027), and lower plasma C-reactive protein (means 0.76 versus 0.97 mg/L, P=0.05) than the placebo group. There were no differences in total antioxidant status or soluble P-Selectin. CONCLUSIONS: Chronic tea consumption reduces platelet activation and plasma C-reactive protein in healthy men. Effects cannot be attributed to observer bias or lifestyle confounders. These effects of tea may contribute to sustained cardiovascular health.

Adolescent↗

PubMed2006

Stem cells and the heart: ethics, organization and funding.

The application of stem cell biology to repair of the heart offers therapeutic potential. However, randomized, double-blind, controlled trials are required to clarify under what conditions it may be effective. The unprecedented nature of the discovery of a therapeutic role for autologous stem cells brings with it unprecedented challenges in clinical application of basic biology, ethics, funding and organization. It is suggested that the academic community should show leadership.

Clinical Trials as Topic↗

PubMed2005

Role of angiogenesis in cardiovascular disease: a critical appraisal.

The role of angiogenesis in atherosclerosis and other cardiovascular diseases has emerged as a major unresolved issue. Angiogenesis has attracted interest from opposite perspectives. Angiogenic cytokine therapy has been widely regarded as an attractive approach both for treating ischemic heart disease and for enhancing arterioprotective functions of the endothelium; conversely, a variety of studies suggest that neovascularization contributes to the growth of atherosclerotic lesions and is a key factor in plaque destabilization leading to rupture. Here, we critically review the evidence supporting a role for angiogenesis and angiogenic factors in atherosclerosis and neointima formation, emphasizing the problems raised by some of the landmark studies and the suitability of animal models of atherosclerosis and neointimal thickening for investigating the role of angiogenesis. Because many of the relevant studies have focused on the role of vascular endothelial growth factor (VEGF), we consider this work in the wider context of VEGF biology and in light of recent experience from clinical trials of VEGF and other angiogenic cytokines for ischemic heart disease. Also discussed are recent findings suggesting that, although angiogenesis may contribute to neointimal growth, it is not required for the initiation of intimal thickening. Our assessment of the evidence leads us to conclude that, although microvessels are a feature of advanced human atherosclerotic plaques, it remains unclear whether angiogenesis either plays a central role in the development of atherosclerosis or is responsible for plaque instability. Furthermore, current evidence from clinical trials of both proangiogenic and antiangiogenic therapies does not suggest that inhibition of angiogenesis is likely to be a viable therapeutic strategy for cardiovascular disease.

Animals↗

PubMed2005

Placental growth factor promotes atherosclerotic intimal thickening and macrophage accumulation.

BACKGROUND: Placental growth factor (PlGF) has been implicated in the pathophysiological angiogenesis and monocyte recruitment that underlie chronic inflammatory disease, but its role in atherosclerosis has not been examined. We investigated the effects of exogenous PlGF, delivered by adenoviral gene transfer, on atherogenic intimal thickening and macrophage accumulation induced by collar placement around the rabbit carotid artery and examined the effects of PlGF deficiency on atherosclerosis in apolipoprotein E-deficient (apoE(-/-)) mice. METHODS AND RESULTS: Periadventitial transfer of PlGF2-encoding adenoviruses significantly increased intimal thickening, macrophage accumulation, endothelial vascular cell adhesion molecule-1 expression, and adventitial neovascularization in the collared arteries of hypercholesterolemic rabbits and increased the intima-to-media ratio in rabbits fed a normal diet. Neointimal macrophages were associated with increased expression of the PlGF receptor Flt-1. The size and macrophage content of early atherosclerotic lesions were reduced in mice deficient in both apoE and PlGF compared with apoE-deficient mice. CONCLUSIONS: Local adenoviral PlGF2 delivery promotes atherogenic neointima formation in hypercholesterolemic rabbits, and PlGF is required for macrophage infiltration in early atherosclerotic lesions in apoE(-/-) mice. These findings support a novel role for PlGF in the pathogenesis of atherosclerotic disease.

Animals↗

PubMed2005

What causes acute coronary syndromes? Applying Koch's postulates.

The term "acute coronary syndromes" (ACS) is used to describe a heterogeneous spectrum of clinical conditions. This includes myocardial infarction, non-ST-elevation myocardial infarction, and unstable angina. These conditions are linked by a similar constellation of signs and symptoms but not necessarily by a common pathophysiology. They are syndromes. Several different hypotheses exist that have attempted to explain the pathological mechanisms that are involved in these conditions, however, it is not clear whether ACS are caused by variations of a single disease process or by several disease processes. The contribution of both vessel wall- and blood-related factors in the pathogenesis of acute coronary syndromes is herein discussed with the guidance of Koch's postulates.

Acute Disease↗

PubMed2005

Psychological stress activates interleukin-1beta gene expression in human mononuclear cells.

The pathophysiological mechanisms underlying the association between psychological stress and cardiovascular disease are unclear. Interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) are inflammatory cytokines playing a pivotal role in atherosclerosis. IL-1beta activates IL-6, and both cytokines are produced by peripheral blood mononuclear cells. One mechanism through which stress could promote atherosclerosis is by regulating mononuclear cell cytokine gene expression. We studied cardiovascular and cytokine responses in 32 healthy men participating in two 5-min mental tasks and in 10 controls. Blood pressure and heart rate, assessed using a Portapres-2, increased significantly following tasks in all participants. Plasma IL-6 levels, determined by ELISA, also increased following tasks, with maximum levels detected 2h post-stress. Quantitative RT-PCR analysis showed that mononuclear cell IL-1beta gene expression rose significantly at 30 min post-stress and remained elevated at 75 and 120 min. Increases in IL-1beta gene expression correlated positively with plasma IL-6 responses, cardiovascular responses, subjective stress ratings, and anxiety symptoms. No changes were detected in controls. Stress-induced activation of mononuclear IL-1beta is a novel mechanism potentially linking stress and heart disease. This mechanism could also play a role in other inflammatory diseases exacerbated by stress.

Adult↗

PubMed2005

Platelet hyper-function in acute coronary syndromes.

Previous studies have demonstrated shortened bleeding times in patients with acute coronary syndromes, especially in myocardial infarction (MI). In this study we have investigated platelet hyper-function using the PFA-100 with collagen/adenosine diphosphate and collagen/epinephrine cartridges in 78 patients presenting with acute chest pain. Patients were classified into MI, unstable angina (UA) and non-specific chest pain. All patients received 300 mg aspirin (ASA) more than 2 h before blood samples were collected. Twenty healthy normal subjects were also tested before and 2 h after 300 mg ASA (n = 10). The collagen/adenosine diphosphate closure time was significantly shorter in MI patients (median, 71 s; P = 0.0237) but not in UA patients (median, 81 s; P > 0.05) compared with normal subjects (median, 92.5 s). The collagen/epinephrine closure times were significantly longer in UA patients (median, 233 s) than in untreated controls (median, 125 s; P < 0.0001), as expected, but there was no difference in MI patients (median, 149.24 s; P > 0.05), suggesting that the MI patients were not all responding to ASA. Analysis of a subset of the apparent ASA non-responders (n = 5) by platelet aggregation demonstrated that this was not related to failure of ASA to block cyclo-oxygenase activity. Von Willebrand factor levels were significantly elevated in both UA and MI patients compared with normal subjects (mean, 175.5 and 248.9 versus 89.1 s; P < 0.0001 and P < 0.0001, respectively) and were also significantly higher in the MI group compared with the UA group (P < 0.05). There is evidence for platelet hyper-function and elevated von Willebrand factor levels in the MI group that could explain their decreased responsiveness to ASA on the collagen/epinephrine cartridge.

Administration, Oral↗

PubMed2004

Angiogenesis-dependent and independent phases of intimal hyperplasia.

BACKGROUND: Neointimal vascular smooth muscle cell (VSMC) proliferation is a primary cause of occlusive vascular disease, including atherosclerosis, restenosis after percutaneous interventions, and bypass graft stenosis. Angiogenesis is implicated in the progression of early atheromatous lesions in animal models, but its role in neointimal VSMC proliferation is undefined. Because percutaneous coronary interventions result in induction of periadventitial angiogenesis, we analyzed the role of this process in neointima formation. METHODS AND RESULTS: Local injury to the arterial wall in 2 different animal models induced periadventitial angiogenesis and neointima formation. Application of angiogenesis stimulators vascular endothelial growth factor (VEGF-A165) or a proline/arginine-rich peptide (PR39) to the adventitia of the injured artery induced a marked increase in neointimal thickening beyond that seen with injury alone in both in vivo models. Inhibition of either VEGF (with soluble VEGF receptor 1 [sFlt1]) or fibroblast growth factor (FGF) (with a dominant=negative form of FGF receptor 1 [FGF-R1DN]), respectively, signaling reduced adventitial thickening induced by VEGF and PR39 to the level seen with mechanical arterial injury alone. However, neither inhibitor was effective in preventing neointimal thickening after mechanical injury when administered in the absence of angiogenic growth factor. CONCLUSIONS: Our findings indicate that adventitial angiogenesis stimulates intimal thickening but does not initiate it.

Angiogenesis Inducing Agents↗

PubMed2004

Post-natal diet determines insulin resistance in fetally malnourished, low birthweight rats (F1) but diet does not modify the insulin resistance of their offspring (F2).

We examined the effects of prenatal and postnatal nutrition on birthweight and insulin sensitivity, indicated by the glucose/insulin (G/I) ratio, in adult rats (F1 generation) and in their adult offspring (F2 generation). Rat pups (F1) whose dams consumed low-protein diets during gestation (malnourished) consumed either nutritionally adequate (control) or high-fat diets ad libitum post-weaning. The offspring of these rats (F2) were maintained on the same diets as their respective dams. Separate pups (F1) whose dams consumed high-fat diets during gestation (over-nourished) were maintained on high-fat diets post-weaning, as were their offspring (F2). Birthweights were significantly reduced in all fetally malnourished F1 animals. At approximately 70 d of age, fasting insulin sensitivity in over-nourished F1 rats was significantly reduced compared to controls regardless of whether they were malnourished or over-nourished in utero; however, fetally malnourished F1 rats consuming control diets post-natally had significantly greater fasting insulin sensitivity than control animals. At 30 and 120 min post-glucose load, insulin sensitivity was reduced 12-65% in both groups of over-nourished F1 rats as compared to the fetally malnourished F1 rats consuming the control diet. Birthweights were significantly lower in F2 animals whose dams (F1) were fetally malnourished and weaned to high fat diets. Insulin sensitivity was significantly reduced in all F2 animals versus control animals, regardless of dietary treatment. Thus, post-natal diets alter insulin sensitivity in fetally malnourished, adult rats; and maternal malnutrition during gestation results in insulin resistance in offspring, irrespective of offsprings' birthweight or diet.

Animal Nutritional Physiological Phenomena↗

PubMed2003

The 4830C>A polymorphism within intron 5 affects the pattern of alternative splicing occurring within exon 6 of the thrombopoietin gene.

OBJECTIVE: A common variant in intron 5 of the thrombopoietin (TPO) gene (4830C>A) has been associated with risk of myocardial infarction (MI). To explore the molecular mechanism of this association, the ability of the intron to act as a transcription enhancer and to influence mRNA splicing was tested. METHOD AND RESULTS: In HepG2 cells the presence of intron 5 upstream of the TPO promoter decreased promoter activity to between 60% and 30%. This effect was orientation dependent; in the reverse orientation, intron 5 caused a twofold greater decrease in promoter activity compared to the forward orientation. However, the effects were similar with either the C or the 4830A allele. An in vitro exon trapping system was used to study the effect of the polymorphism on splicing events in exon 6. The full-length (TPO-1) and three previously reported splice variants (TPO-2, TPO-3, and TPO-5) were identified. The 4830A allele resulted in a small but statistically significant increase in production of the TPO-3 splice variant relative to the full-length transcript (10.6%+/-0.6%) compared to the 4830C allele (8.3%+/-0.6%) (p=0.02). Generation of TPO-5 was also slightly increased, but this did not reach significance. CONCLUSION: The identification of a potential "silencer" sequence in intron 5 of the TPO gene demonstrates the complexity of control of expression of the gene. Although the precise role of the different splice variants is not known, the finding that the 4830C>A sequence change alters their relative amounts, suggests a possible molecular mechanism whereby TPO genotype may influence the risk of MI.

Alternative Splicing↗

PubMed2003

Rise of circulating thrombopoietin following cardiothoracic surgery is potentiated in patients with coronary atherosclerosis: correlation with a preceding increase in levels of interleukin-6.

Thrombopoietin (TPO) is the major regulator of platelet production. Plasma levels of TPO are thought to be regulated by its binding to platelets and megakaryocytes. Here we have used a model of cardiac surgery with cardiopulmonary bypass (CBP) to test the possibility that changes in TPO levels are influenced by the presence of coronary artery disease (CAD) and by changes in interleukin-6 (IL-6). After surgery patients with CAD (n = 22) or with normal coronary arteries (n = 11) showed a significant thrombocytopaenia followed by a reactive thrombocytosis. The platelet recovery was preceded by a significant rise in TPO (from 62.6 +/- 9.4 pg/ml at baseline to 129.2 +/- 19 pg/ml at 60 h, P <0.001), which in turn was preceded by, and was positively correlated with, a marked increase in circulating IL-6 (from 1.5 +/- 0.3 pg/ml at baseline to 269.3 +/- 30.6 pg/ml at 3-12 h, P <0.001). The rise of both IL-6 and TPO was significantly larger in patients with CAD. No correlation was found between the post-operative drop in platelet mass and changes in either the TPO or IL-6 levels. These findings suggest that in man circulating TPO levels, besides being controlled by changes in platelet mass, are influenced by inflammatory processes, including the presence of coronary atherosclerosis.

Adult↗

PubMed2002

S-nitrosoglutathione reduces asymptomatic embolization after carotid angioplasty.

BACKGROUND: The major complication of carotid angioplasty is embolic stroke, which may occur after balloon inflation and deflation or in the early postintervention period. Platelet adhesion and aggregation to the angioplasty site with subsequent embolization seems to plays a major role in early postangioplasty embolization and stroke. During this period, asymptomatic embolic signals can be detected in patients by transcranial Doppler ultrasound despite aspirin and heparin treatment. S-nitrosoglutathione (GSNO) is a nitric oxide donor that appears to have relative platelet specificity. We evaluated its effectiveness in reducing embolization after carotid angioplasty. METHODS AND RESULTS: Sixteen patients undergoing carotid angioplasty and stenting for symptomatic > or =70% internal carotid artery stenosis were randomized in a double-blind manner to GSNO or placebo given after surgery for 90 minutes. All patients were pretreated with aspirin and given heparin for 24 hours after the procedure. Transcranial Doppler recordings were made from the ipsilateral middle cerebral artery for 1 hour before treatment and at 0 to 3, 6, and 24 hours after treatment. GSNO resulted in a rapid reduction in the frequency of embolic signals of 95% at 0 to 3 hours and 100% at 6 hours (P=0.007 and P=0.01 versus placebo, respectively). In the placebo group, 2 patients experienced ipsilateral stroke after the angioplasty. No cerebrovascular events occurred in the GSNO group. CONCLUSIONS: S-nitrosoglutathione was highly effective in rapidly reducing the frequency of embolic signals after endovascular treatment for symptomatic high-grade carotid stenosis.

Angioplasty↗

PubMed2002

Switching off embolization from symptomatic carotid plaque using S-nitrosoglutathione.

BACKGROUND: Current antiplatelet regimens fail to prevent the majority of recurrent strokes. Asymptomatic circulating emboli can be detected by transcranial Doppler ultrasound, are frequent in patients with symptomatic carotid stenosis, and predict recurrent stroke risk. S-nitrosoglutathione (GSNO) is a nitric oxide donor that appears to have relative platelet specificity. We evaluated its effectiveness in reducing embolization in patients with symptomatic carotid stenosis who already were taking aspirin. METHODS AND RESULTS: Twenty patients with > or =50% internal carotid artery stenosis and with > or =3 embolic signals detected during a half-hour screening recording were recruited. All had taken aspirin for at least 7 days. They were randomly assigned in a double-blind fashion to either GSNO (4.4 mmol/kg per minute) or saline placebo for 90 minutes. Transcranial Doppler recordings were made from the ipsilateral middle cerebral artery for 1 hour before treatment and at 0 to 3, 6, and 24 hours after treatment. Before treatment, the mean (range) of embolic signals per hour was 6.9 (3 to 13) in the GSNO group and 7.3 (4 to 12) in the placebo group (P=0.68). GSNO resulted in a rapid reduction in the frequency of embolic signals of 84% at 0 to 3 hours, 95% at 6 hours, and 100% at 24 hours (P<0.0001, P=0.003, and P<0.0001 versus placebo, respectively). CONCLUSIONS: Continued embolization is common in patients with carotid stenosis despite aspirin therapy. GSNO was highly effective in rapidly reducing the frequency of embolic signals in this patient group. Despite its short administration time and its short half-life, it resulted in therapeutic effects lasting 24 hours.

Aged↗

PubMed2002

Correlation of increased vascular endothelial growth factor with neovascularization and permeability in ischemic central vein occlusion.

OBJECTIVE: To establish a role for vascular endothelial growth factor (VEGF) during the onset and clinical course of neovascularization of the iris (NVI) in ischemic central retinal vein occlusion. METHODS: Sixteen patients with ischemic central retinal vein occlusion were followed up for 12 months by clinical examination, retinal and iris angiography, and serial anterior chamber sampling of aqueous humor. Aqueous VEGF level was determined by enzyme-linked immunoassay, and permeability changes were estimated by capillary zone electrophoretic assessment of aqueous albumin. RESULTS: A correlation was found between aqueous VEGF concentrations and the onset, persistence, and regression of NVI; extent of retinal capillary nonperfusion; and vascular permeability. The NVI occurred when aqueous VEGF concentrations were 849 to 1569 pg/mL and regressed fully when they fell below 550 pg/mL. Aqueous concentrations of serum albumin, a marker of increased permeability, correlated with increased VEGF. Placental growth factor was found at low levels only when VEGF levels exceeded 330 pg/mL. The NVI remained VEGF-dependent during the course of the disease, regressing only if VEGF concentrations were reduced after laser ablation of hypoxic retina. CONCLUSIONS: The close temporal correlation between aqueous VEGF levels and the course of neovascularization and permeability in human ischemic central retinal vein occlusion indicates that increased aqueous VEGF level may predict the need for treatment, and that anti-VEGF therapy at an early stage of ischemic central retinal vein occlusion may be therapeutically beneficial.

Adult↗

PubMed2001

Cloning and characterization of Scavidin, a fusion protein for the targeted delivery of biotinylated molecules.

We have constructed a novel fusion protein "Scavidin" consisting of the macrophage scavenger receptor class A and avidin. The Scavidin fusion protein is transported to plasma membranes where the avidin portion of the fusion protein binds biotin with high affinity and forms the basis for the targeted delivery of biotinylated molecules. Subcellular fractionation analysis, immunostaining, and electron microscopy demonstrated endosomal localization of the fusion protein. According to pulse-labeling and cross-linking studies Scavidin is found as monomers (55 kDa), dimers, and multimers, of which the 220-kDa form was the most abundant. The biotin binding capacity and active endocytosis of the biotinylated ligands were demonstrated in rat malignant glioma. Local Scavidin gene transfer to target tissues could have general utility as a universal tool to deliver biotinylated molecules at systemic low concentrations for therapeutic and imaging purposes, whereby high local concentration is achieved.

Animals↗

PubMedDate not supplied

A stable bis-allyloxycarbonyl biotin aldehyde derivative for biotinylation via reductive alkylation: application to the synthesis of a biotinylated doxorubicin derivative.

A novel, stable, biotin aldehyde derivative is reported in which the biotin moiety is N1,N3-protected by the allyloxycarbonyl group. The derivative is stable to sodium cyanoborohydride mediated reductive alkylation and is cleaved under mild Pd [0] catalysis. This novel biotin aldehyde should have wide application in avidin- and streptavidin-based detection systems and bioassays. The derivative is utilized in the synthesis of a biotinylated doxorubicin analogue that retains topoisomerase activity.

Affinity Labels↗