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Biomedical subjects

J J F Belch

Publications and source records attributed to J J F Belch.

At least 19 recordsLinked to original sources
PubMed2007

Mechanisms influencing the vasoactive effects of lidocaine in human skin.

The vasodilator properties of lidocaine are believed to be due mainly to the inhibition of action potentials via sodium channel blocking in vasoconstrictor sympathetic nerves. However, mechanisms involving the vascular endothelium may also play a role, and in this study we investigated the potential influences of nitric oxide release, the cyclo-oxygenase pathway and the beta-adrenoceptors of vascular smooth muscle. Laser Doppler imaging was used to measure microvascular blood flow responses to intradermal injection of lidocaine 2%, with or without the addition of preservatives, in eight healthy, male volunteers. Co-injection of the nitric-oxide-synthase inhibitor Nomega-nitro-L-arginine methyl ester caused a 60% reduction in the response after about 20 min, and this reduction was enhanced with the lidocaine solution containing the preservatives methylhydroxybenzoate and propylhydroxybenzoate. No reduction in response was seen after blocking the cyclo-oxygenase or beta-adrenoceptor pathways. Nitric oxide release contributes to the vasoactivity of lidocaine in human skin.

Adult↗
PubMed2006

High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid.

BACKGROUND: Allopurinol has been shown to improve endothelial function in chronic heart failure. This study aimed to establish its mechanism of action and to construct a dose-response curve for the effect of allopurinol. METHODS AND RESULTS: Two randomized, placebo-controlled, double-blind, crossover studies were performed for 1 month on patients with New York Heart Association Class II-III chronic heart failure, comparing 300 mg allopurinol, 600 mg allopurinol, and placebo for the first study and 1000 mg probenecid versus placebo in the second study. Endothelial function was assessed by standard forearm venous occlusion plethysmography. Allopurinol 600 mg/d significantly increased forearm blood flow response to acetylcholine compared with both allopurinol 300 mg/d and placebo (% change in forearm blood flow [mean+/-SEM]: 240.31+/-38.19% versus 152.10+/-18.21% versus 73.96+/-10.29%, P<0.001). For similar levels of urate lowering, the uricosuric agent probenecid had no effect on endothelial function. Sodium nitroprusside response was unchanged by all treatments. Vitamin C and acetylcholine coinfusion data showed that 600 mg/d allopurinol completely abolished the oxidative stress that was sensitive to high-dose vitamin C. CONCLUSIONS: For the first time, we have shown that a steep dose-response relationship exists between allopurinol and its effect on endothelial function. We also showed that the mechanism of improvement in endothelial function with allopurinol lies in its ability to reduce vascular oxidative stress and not in urate reduction. The reduction in vascular oxidative stress was profound because high-dose allopurinol totally abolished the oxidative stress that was sensitive to the high-dose vitamin C that was used in this study.

Acetylcholine↗
PubMed2006

Effects of poor glucose handling on arterial stiffness and left ventricular mass in normal children.

AIM: Cardiovascular risk factors can be present in children and young adults. We previously found abnormal microvascular function in children who had glucose intolerance and insulin resistance. The aim of the present study was to investigate whether they also have abnormalities in left ventricular mass (LVM) and arterial stiffness. METHODS: We measured heart dimensions and LVM using echocardiography, and arterial stiffness using pulse wave analysis in 23 children with good glucose handling (postfeeding glucose: 3.9 to 5 mmol/L) and 21 with poor glucose handling (7.7 to 11.4 mmol/L). RESULTS: The time to pulse reflection was slightly shorter in the poorer glucose handlers (mean+/-SD: 143+/-10 vs 153+/-20 ms, P=0.04), suggestive of increased arterial stiffness. Also in this group, there were significant relationships between intraventricular septal thickness, blood pressure and body mass index, but not in the normal glucose handlers. CONCLUSIONS: We have found that normal children who are in the lowest quintile of glucose tolerance in comparison with their peers are exhibiting the first signs of arterial stiffening. In addition, we have seen the beginnings of a relationship between blood pressure, body mass index and left ventricular enlargement in this group. While these changes may not yet be clinically significant, their emergence might be further evidence of early predisposition to cardiovascular disease.

Adolescent↗
PubMed2005

Vasoactive characteristics of bupivacaine and levobupivacaine with and without adjuvant epinephrine in peripheral human skin.

BACKGROUND: Epinephrine is added to local anaesthetic preparations to prolong their action and reduce their systemic absorption. Bupivacaine and levobupivacaine cause vasodilatation at clinical doses, but lower doses appear to cause vasoconstriction. The aim of this study was to characterize fully the vasoactive effects of these anaesthetics, using an objective measure of blood flow, and to assess the influence of adding epinephrine. METHODS: Laser Doppler imaging was used to measure the forearm skin blood flow responses to intradermal injection of eight doses of bupivacaine and levobupivacaine in 10 healthy male volunteers. The doses tested ranged from 0.008% to 0.75%, and the five highest doses were administered both with and without adjuvant epinephrine 2.5 microg ml(-1). RESULTS: The cumulative responses to the lower subclinical concentrations (0.008-0.0625%) of both anaesthetics were smaller than or similar to that produced by saline alone, indicating a net vasoconstrictive effect. Higher doses caused net vasodilatation, and the levobupivacaine responses were generally lower than the corresponding bupivacaine responses (P=0.022). Epinephrine 2.5 microg ml(-1) significantly reduced the responses to clinical doses of both drugs (P<0.001), producing net vasoconstriction. CONCLUSIONS: Bupivacaine and levobupivacaine have a biphasic vascular effect when injected intradermally, with subclinical doses causing net vasoconstriction. The addition of epinephrine 2.5 microg ml(-1) decreases these responses markedly.

Adjuvants, Anesthesia↗
PubMed2005

Endothelin-1 levels predict 3-year survival in patients who have amputation for critical leg ischaemia.

BACKGROUND: Most patients with critical leg ischaemia (CLI) have co-existing coronary heart disease, which is the main cause of their increased mortality rate. The aim of this study was to investigate whether any markers of endothelial function could predict death in these patients. METHODS: In a cohort of 39 patients with CLI who were scheduled for lower-limb amputation, blood levels of vascular endothelial growth factor, homocysteine, endothelin (ET) 1, von Willebrand factor and vascular cell adhesion molecule 1 were measured, as well as forearm vascular responses to the endothelium-dependent vasodilator acetylcholine. RESULTS: Levels of ET-1 were significantly higher in patients who subsequently died within 3 years than in those who were still alive (P = 0.002) and Cox proportional hazards regression analysis demonstrated that ET-1 was an independent predictor of all-cause mortality:hazard ratio 3.53 (95 per cent confidence interval (c.i.) 1.29 to 9.70; P = 0.007) and cardiovascular mortality:hazard ratio 4.15 (95 per cent c.i. 1.30 to 13.23); P = 0.014. CONCLUSION: ET-1 was an independent predictor of death in these patients with CLI.

Adult↗
PubMed2005

Pilot study of the effects of local pressure on microvascular function in the diabetic foot.

AIM: The aim of the study was to determine whether areas of the diabetic foot that experience high pressures during normal activity also demonstrate reductions in cutaneous microvascular flow and/or endothelial function. METHODS: Sixteen patients with diabetes mellitus and eight healthy, age-matched control subjects were recruited. Maps of dynamic pressure on the plantar aspect of both feet were recorded during a normal gait cycle, and the skin microvascular blood flow response to the endothelium-dependent vasodilator acetylcholine was assessed at the sites of highest and lowest plantar pressure over the metatarsal heads. RESULTS: Patients with diabetes had higher plantar pressures than control subjects (P = 0.002), but there were no significant differences in basal skin blood flow or acetylcholine response between the groups. In the patients, baseline flow was increased (P = 0.041) but the acetylcholine response reduced (P = 0.03) at the high-pressure compared with the low-pressure site; this was most apparent in those who were particularly at risk of ulceration due to high plantar pressures. CONCLUSIONS: Chronically raised plantar pressure in the diabetic foot is associated with increased basal skin blood flow, compared with lower pressure areas on the same foot. Further work is required to determine whether, and under what conditions, this additional hyperaemia is protective or maladaptive. In addition, high-pressure areas have a reduced responsiveness to an endothelium-dependent vasodilator, although the clinical significance of these changes is not clear.

Acetylcholine↗
PubMed2004

Acetylcholine mediated vasodilatation in the microcirculation of patients with chronic fatigue syndrome.

The aetiology of chronic fatigue syndrome (CFS) remains controversial and a number of hypotheses have been put forward to explain it. Research into the condition is hindered by the considerable heterogeneity seen across patients but several reports have highlighted disturbances to cholinergic mechanisms in terms of central nervous system activity, neuromuscular function and autoantibodies to muscarinic cholinergic receptors. This paper examines an altogether separate function for acetylcholine and that is its role as an important and generalized vasodilator. Most diseases are accompanied by a blunted response to acetylcholine but the opposite is true for CFS. Such sensitivity is normally associated with physical training so the finding in CFS is anomalous and may well be relevant to vascular symptoms that characterise many patients. There are several mechanisms that might lead to ACh endothelial sensitivity in CFS patients and various experiments have been designed to unravel the enigma. These are reported here.

Acetylcholine↗
PubMed2004

Sudden unexpected death in heart failure may be preceded by short term, intraindividual increases in inflammation and in autonomic dysfunction: a pilot study.

OBJECTIVE: To see whether sudden unexpected death in chronic heart failure is preceded by intraindividual worsening in inflammation and in ECG criteria. DESIGN AND SETTING: Prospective cohort study conducted in the community. PATIENTS: 34 patients with chronic heart failure were studied. Their mean (SD) age was 68 (8) years, 29 were men, mean (SD) left ventricular ejection fraction was 29 (9)%, and they were in New York Heart Association functional class II (n = 20), III (n = 11), and IV (n = 3). The patients were examined monthly over 24 months, with sequential measurement of C reactive protein and neutrophil counts and 24 hour ambulatory ECG monitoring measuring heart rate variability, mean heart rate, and arrhythmias. Intraindividual changes in these parameters were related to subsequent cardiac deaths. RESULTS: During follow up, nine patients died: five patients had a sudden unexpected death (SUD) and four died of progressive heart failure (PHF). There were significant intraindividual changes in neutrophil counts (p = 0.02), C reactive protein (p = 0.039), and heart rate variability (p < or = 0.018) in those who died of SUD and PHF. In contrast no significant changes were seen in ventricular extrasystoles, ventricular tachycardia episodes, brain natriuretic peptide, or aldosterone in the SUD group, but all of these parameters did increase as expected in those who died of PHF. CONCLUSIONS: This is preliminary evidence that SUD may be preceded by intraindividual increases in both inflammation and autonomic dysfunction. Both may be causal in genesis but, even if they are not, intraindividual increases in either may be convenient markers to identify patients at high risk of impending SUD. Larger studies are needed to confirm the observation from this pilot study.

Aged↗
PubMed2004

Increased neutrophil apoptosis in chronic fatigue syndrome.

BACKGROUND/AIMS: Many patients with chronic fatigue syndrome (CFS) have symptoms that are consistent with an underlying viral or toxic illness. Because increased neutrophil apoptosis occurs in patients with infection, this study examined whether this phenomenon also occurs in patients with CFS. METHODS: Apoptosis was assessed in patients with CFS in conjunction with concentrations of the anti-inflammatory cytokine, transforming growth factor beta1 (TGFbeta1). RESULTS: The 47 patients with CFS had higher numbers of apoptotic neutrophils, lower numbers of viable neutrophils, increased annexin V binding, and increased expression of the death receptor, tumour necrosis factor receptor-I, on their neutrophils than did the 34 healthy controls. Patients with CFS also had raised concentrations of active TGFbeta1 (p < 0.005). CONCLUSIONS: These findings provide new evidence that patients with CFS have an underlying detectable abnormality in their immune cells.

Adult↗
PubMed2004

Elevated soluble cell adhesion molecules E-selectin and intercellular cell adhesion molecule-1 in type-2 diabetic patients with and without asymptomatic peripheral arterial disease.

AIM: Cell adhesion molecules may serve as markers of endothelial cell activation, and they may well have a role in the pathogenesis of atherosclerotic vascular disease in diabetes mellitus. METHODS EXPERIMENTAL DESIGN: a cross sectional, comparative study. SETTING: a teaching University Hospital. Patients and controls. A cohort of diabetic patients with absent peripheral arterial pulses but no history of cardiovascular or cerebrovascular disease i.e. asymptomatic (n=29), median age 68 (36-80) years, (range), diabetes duration 10 (1-43) years and HbA1c 7.7% (4.8-9.6). They were compared to 12 age and sex matched normal non-diabetic controls. INTERVENTION: none. MEASURES: soluble cell adhesion molecules intercellular cell adhesion molecule-1 (ICAM-1) and E-selectin levels measured by ELISA methods. RESULTS: The 29 patients with diabetes, as a whole, were found to have significantly higher median plasma sICAM-1 and sE-selectin of 283 ng/ml (154-1000) (range), and 65.8 ng/ml (20.6-145) vs 237 (147-312.4) and 37.7 (19.8-46.6) respectively, Mann Whitney U test p<0.02, and p<0.002. In the diabetic group, E-selectin correlated with ICAM-1, age and HbA1c: r=0.524 p<0.01, r=0.385 p<0.05 and r=0.393 p<0.05 respectively (Spearman correlation coefficient). CONCLUSION: These results confirm that elevated levels of adhesion molecules, E-selectin and ICAM-1 occur in Type-2 diabetes early in the course of asymptomatic peripheral arterial occlusive disease, and this is related to glycemic control. This suggests that adhesion molecules may have a role in the pathogenesis of atherosclerotic vascular disease in diabetes.

Adult↗
PubMed2004

Non spiral and spiral (helical) flow patterns in stenoses. In vitro observations using spin and gradient echo magnetic resonance imaging (MRI) and computational fluid dynamic modeling.

AIM: Physiological blood flow patterns are themselves poorly understood despite their impact on arterial disease. Stable spiral (helical) laminar flow (SLF) has been observed in normal subjects. The purpose of the present study is to develop a method of magnetic resonance (MR) flow pattern visualization and to analyze spiral and non-spiral flow patterns with and without luminal narrowing in vitro. The flow conditions were then modeled using computational fluid dynamics (Star-CD). METHODS: Laminar integrity was examined in a flow-rig using spin and gradient echo magnetic resonance imaging (MRI) in non-stenosed and stenosed conduits in the presence of non-spiral and spiral flow. RESULTS: No difference was observed in a non-stenosed conduit between non-spiral and spiral flow. In the presence of a stenosis spiral flow preserves flow velocity coherence whereas non-spiral flow increasingly lost coherence beginning proximal to the stenosis. Computational fluid dynamic modeling of the in vitro experiment showed marked differences between the 2 flow patterns. Non-spiral flow produced greater inwardly directed forces just beyond the stenosis and greater outward pressures at more distal sites. The near wall turbulent energy was up to 700% less with spiral flow over non-spiral flow beyond the stenosis. CONCLUSIONS: Spiral flow appears to offer clear flow profile stabilizing advantages over non-spiral flow, by significantly reducing the turbulence caused by a stenosis. Spiral flow also produces lower forces acting on the vessel wall.

Blood Flow Velocity↗
PubMed2003

Are national cardiac guidelines being applied by vascular surgeons?

INTRODUCTION: National cardiac guidelines recommend that patients with intermittent claudication should be managed in the same way as those with established coronary heart disease. This survey aimed to determine the attitudes of vascular consultants to risk factor management in new patients attending their out-patient clinic. METHODS: An anonymous postal questionnaire was sent to all 394 members of the Vascular Surgical Society in June 2002. Questions were asked about the following measures: serum cholesterol levels, the presence of diabetes, antiplatelet therapy, exercise regimens, blood pressure, thrombophilia, smoking and the availability of local guidelines and expertise. RESULTS: A response rate of 65% was obtained. Most (85%) consultants would measure a random cholesterol, but 34% would only treat claudicants if the cholesterol was greater than 5.5 mmol/l. Furthermore, 23% would inappropriately use diet alone as initial cholesterol lowering therapy. Over a quarter of consultants would not screen for diabetes or measure blood pressure. Nearly all (99%) would recommend aspirin and 66% would recommend nicotine replacement therapy. Only 55% had access to a smoking cessation clinic, and 34% to a formal exercise program. The majority (56%) did not have local risk factor management guidelines, only 16% had access to a vascular physician, and 65% would prefer to have this expertise available for difficult cases. DISCUSSION: Management of major risk factors was found to be sub-optimal. Thus guidelines for the prevention of coronary disease in clinical practice are not being applied to claudicants.

Adult↗
PubMed2003

Mechanisms contributing to the vaso-active effects of prilocaine in human skin.

We investigated the roles of the endothelial nitric oxide and cyclo-oxygenase pathways in mediating the vasoactivity of prilocaine in the skin. We injected prilocaine 1% intradermally into forearm skin of 10 healthy, male subjects. Nitric oxide synthesis was inhibited at a second site by co-injecting prilocaine with l-NAME 1%. We then repeated the injections while blocking the cyclo-oxygenase pathway with aspirin (4 x 600 mg). We measured blood flow responses to the injections using laser Doppler imaging. We found that, after the traumatic effects of injection had subsided, l-NAME reduced the vascular response to prilocaine by a third (p = 0.012), indicating an influence specifically on the drug response. Aspirin had no effect on the response (p = 0.588). We conclude that the vasoactive effects of prilocaine in human skin are mediated partly through the release of endothelial nitric oxide and, although other mechanisms might also be involved, the cyclo-oxygenase pathway does not appear to play a role.

Adolescent↗
PubMed2003

A study of whole blood platelet and white cell aggregation using a laser flow aggregometer.

Both platelet aggregation and white blood cell aggregation are involved in pathological processes such as thrombosis, atherosclerosis and chronic inflammation. People in older age groups are likely to suffer from cardiovascular diseases and may have increased white cell and platelet aggregation which could contribute to this increased risk. This study aimed to compare white cell and platelet aggregation between different age and gender groups. Whole blood white cell aggregation and platelet aggregation were carried out on healthy volunteers using cytometric techniques. It was found that both white cell and platelet aggregation in the elderly group (white cell aggregation median value, 0.08; range, 0.02-0.14; platelet aggregation median value, 0.32; range, 0.1-0.39) were significantly higher (P = 0.017 for white cell aggregation, P = 0.007 for platelet aggregation) than in the younger group (white cell aggregation median value, 0.05; range, 0.01-0.14; platelet aggregation median value, 0.18; range, 0.07-0.36). No significant differences were found between the gender groups.

Adult↗
PubMed2003

Rheumatoid arthritis and macrovascular disease.

OBJECTIVE: To measure the extent of subclinical atherosclerosis in patients with rheumatoid arthritis (RA) compared with controls, and to evaluate any potential vascular risk factors. METHODS: Forty RA patients were compared with an age- and sex-matched control group. Non-invasive vascular tests, i.e. carotid duplex scanning [measuring common carotid artery intima-media thickness (IMT)], ankle-brachial blood pressure index (ABPI) and QT dispersion on ECG (QTD), were performed. Traditional risk factors such as high blood pressure, blood sugar, lipids and steroid usage were assessed. RESULTS: The average IMT (S.E.) in RA patients was 0.73 (0.03) mm, compared with 0.62 (0.03) mm in the control group (P=0.01, Mann-Whitney). Ten out of 40 RA patients (25%) had an ABPI < 1.0 compared with 1/40 (2.5%) in the control group (P=0.007, Fisher's). QTD was higher in RA patients; mean (S.E.) 55 (2.70) ms compared with 40 (2.50) ms in the control group (P < 0.001, t-test). There were no significant differences in the prevalence of high blood pressure, diabetes or lipid profiles. However, patients on steroids had a higher mean QTD (S.E.): 63.5 (4) compared with 48 (2.7) ms in those patients who had not received long-term steroids (P=0.003, t-test). CONCLUSION: RA patients have an increased risk of subclinical vascular disease as was shown by a higher prevalence of carotid disease, peripheral arterial disease and increased QTD. Among traditional risk factors we found a history of steroid usage to be one of the potential risk factors.

Adult↗
PubMed2003

Influence of the hormonal changes during the normal menstrual cycle in healthy young women on soluble adhesion molecules, plasma homocysteine, free radical markers and lipoprotein fractions.

AIM: Female sex hormones are known to exert a protective role on the vascular endothelial function, but the exact mechanisms of such protection is not known. We aimed to study the possible regulatory role of the female sex hormones changes during the normal menstrual cycle on soluble adhesion molecules E-selectin and ICAM-1, plasma homocyteine, free radical markers and lipoproteins in healthy young women. METHODS EXPERIMENTAL DESIGN: a cross sectional study of healthy female volunteers studied during a single normal menstrual cycle at 3 specific time points. SETTING: North Staffordshire Hospitals NHS Trust. SUBJECTS: 20 healthy young menstruating women, aged (mean +/- SEM) 34 +/- 1 years, with normal menstruation, defined as a menstrual cycle of 21-35 days were studied at 3 time points of the same menstrual cycle. First in the early follicular phase (M-phase), at mid-follicular phase (F-phase), and during the luteal phase (L-phase). INTERVENTION: none. MEASUREMENT: serum levels of soluble E-selectin, ICAM-1, plasma homocysteine, vitamin E and malondialdehyde (MDA), as well as lipoprotein fractions were measured at each time points. RESULTS: The mean percentage change for E-selectin between the M-phase and L-phase, F-phase and L-phase were 6% and 4%, respectively, p<0.005, p<0.066. Levels of ICAM-1, vitamin E and malondialdehyde did not vary through the cycle. Homocysteine was not different between M-phase and F-phase (10.39 +/- 0.68 micromol/l vs 10.33 +/- 0.65), nor between M-phase and L-phase (10.39+/-0.68 vs 9.77 +/- 0.75 micromol/l). Although the mean percentage decrease in homocysteine between F- and L-phases was significant (5.36 +/- 0.53%, p=0.029), the absolute decrease in concentrations was not (p=0.07). There were no cyclical changes in total, LDL, HDL cholesterol, triglycerides, apo A-I, apo B or Lp(a). Using a linear regression model, after correction for age, smoking, body mass index (BMI) and waist/hip ratio (WHR), oestrogen levels were the only predictor of E-selectin during the L-phase p<0.005. There were no significant correlations between oestrogen with lipids, apolipoproteins or homocysteine. There was an interesting significant univariate correlation between homocysteine with low-density-lipoprotein (LDL) cholesterol and apo B throughout all phases of the cycle, which persisted after correction for the effects of age, BMI, WHR and smoking history. Multiple regression analysis with all these factors showed homocysteine to be a significant predictor of apo B concentration during M (p=0.030) and L-phases (p=0.023) of the cycle and of LDL cholesterol in the M-phase (p=0.033). CONCLUSION: Female sex hormones may have small, though significant modulating role on E-selectin and homocysteine metabolism in healthy premenopausal women. Furthermore, the correlation between homocysteine, LDL and apo B levels suggests that induction of cholesterol synthesis by homocysteine, shown previously in vitro, may be of relevance in vivo.

Adult↗