Biomedical subjects

Vidya Mohamed-Ali

Publications and source records attributed to Vidya Mohamed-Ali.

11 recordsLinked to original sources

PubMed2005

Adipokine dysregulation in turner syndrome: comparison of circulating interleukin-6 and leptin concentrations with measures of adiposity and C-reactive protein.

Women with Turner syndrome (TS) have increased risks of atherosclerosis, diabetes mellitus, and obesity. We hypothesized that women with TS have adverse metabolic or inflammatory markers for cardiovascular disease compared with normal women and estrogen-deficient controls. This was a cross-sectional study conducted at University College London Hospitals, UK. One hundred seventeen estrogen-treated women with TS and normal fasting blood glucose were compared with 30 age-matched normal controls and 31 estrogen-treated women with 46,XX premature ovarian failure (POF). The main outcome measures were markers of the metabolic syndrome, including the adipokines IL-6 and leptin, and C-reactive protein (CRP). TS women were more obese than controls (waist circumference, 79.9 +/- 12.4, 73.5 +/- 6.9, and 74.7 +/- 8.6 cm in TS, normal subjects, and POF controls, respectively; P = 0.005; body mass index, 26.8 +/- 5.8, 23.7 +/- 3.2, and 22.9 +/- 3.4 kg/m2; P < 0.001). This obesity was associated with increased CRP (2.9 +/- 1.5, 0.8 +/- 1.0, and 1.2 +/- 0.9 mg/liter; P < 0.001) and IL-6 concentrations (1.5 +/- 0.7, 1.0 +/- 1.5, and 1.2 +/- 0.5 pg/ml; P = 0.014), but lower fasting serum insulin (4.7 +/- 2.3, 6.3 +/- 3.0, and 6.9 +/- 2.9 mIU/ml; P = 0.004), glucose (83 +/- 11, 90 +/- 7, and 90 +/- 7 mg/dl; P < 0.001), and leptin (10.2 +/- 6.3, 14.4 +/- 7.6, and 14.8 +/- 8.1 ng/ml; P = 0.048). Triglyceride concentrations were similar in TS and POF women and were greater than in normal controls (97 +/- 53, 97 +/- 53, and 71 +/- 27 mg/dl; P = 0.024). We conclude that women with TS have various physical and biochemical features suggestive of the metabolic/insulin resistance syndrome, but there is a discrepancy among CRP, IL-6, and leptin, with leptin and fasting insulin concentrations being lower than expected for the degree of obesity. Obesity and estrogen therapy do not fully explain these findings. Women with TS may have specific metabolic defects contributing to cardiovascular risk.

Adipose Tissue↗

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↗

PubMed2004

Inflammation-induced endothelial dysfunction involves reduced nitric oxide bioavailability and increased oxidant stress.

OBJECTIVES: Our aim was to investigate mechanisms of inflammation-induced endothelial dysfunction in humans. METHODS: Endothelial function in twenty-one healthy human volunteers was measured using forearm venous plethysmography before and 8 h after administration of typhoid vaccination to generate an inflammatory response. Basal and stimulated endothelial nitric oxide (NO) bioavailability was assessed by measurement of the responses to intra-arterial N(G)-monomethyl-l-arginine (l-NMMA) and bradykinin, respectively. The effects of supplementation with l-arginine or ascorbic acid were assessed to probe the effects of substrate deficiency and oxidative stress, respectively. Systemic effects were determined by measuring cytokine response, total anti-oxidant status (TAOS) and urinary protein excretion. RESULTS: Vaccination induced a cytokine response, a fall in total anti-oxidant status and increased urinary albumin excretion (UAE). There was a reduction in the response to bradykinin (BK, P<0.005) and l-NMMA (P<0.0001) with no effect on the response to glyceryl trinitrate (GTN) and norepinephrine (NE). Following vaccination blood flow response to BK (but not GTN) was partially returned to pre-vaccine levels by infusion of ascorbic acid (P=0.01). Supplementation with l-arginine had no effect. CONCLUSION: Inflammation causes widespread endothelial dysfunction, reduces vascular NO bioavailability and increases oxidative stress. These actions are partially reversible with local anti-oxidants. These findings suggest a role for reactive oxygen species in inflammation-induced endothelial dysfunction.

Adult↗

PubMed2004

Effect of Interleukin-6 promoter polymorphisms in survivors of myocardial infarction and matched controls in the North and South of Europe. The HIFMECH Study.

Elevated plasma IL-6 levels have been implicated in the pathogenesis of coronary heart disease. We have investigated the association of two polymorphisms in the promoter of IL-6 (-572G>C and -174G>C) with levels of inflammatory markers and risk of myocardial infarction (MI) in a European study of MI survivors and age-matched controls from two high-risk centres in the North of Europe, and two low risk centres in the South. IL-6 and CRP levels were similar in controls in both regions, but were higher in cases. For the -174G>C polymorphism the rare -174C allele showed a regional difference in allele frequency, being more common in the North European group (0.43 vs 0.28; p < 0.0005), where -174C allele carriers showed an apparent reduced risk of MI compared to -174GG homozygotes (OR 0.53, 95%CI 0.32, 0.86). No such effect was observed in the South or with the -572G>C in either group. Neither genotype was associated with a significant effect on plasma IL-6 levels in either cases or controls. Furthermore, no regional difference was observed in the frequency of the -572G>C SNP, suggesting that these polymorphisms are unlikely to be contributing to the observed increased risk of cardiovascular disease in Northern Europe.

Adult↗

PubMed2003

Stimulation of interleukin-6 release by interleukin-1beta from isolated human adipocytes.

The secretion of interleukin-6 (IL-6) is modulated by immune, hormonal and metabolic stimuli in a cell-specific manner. We investigated the effect of cytokines, TNFalpha and IL-1beta, and insulin on IL-6 release from human adipocytes and peripheral blood cells (PBC). Adipocytes released IL-6 constitutively (after 5 h: 5.64 [1.61-15.30]pg ml(-1), after 10 h: 15.95 [2.34-45.59]pg ml(-1), p = 0.007), while PBC secretion did not change significantly over this period. LPS stimulated IL-6 secretion in PBC after 5 h but was without effect on adipocytes. TNFalpha and insulin induced IL-6 production from PBC, but had no effect on adipocytes. IL-1beta, however, induced a substantial increase in IL-6 release in adipocytes and PBC (all p < 0.05). Adipose tissue production of IL-1beta was assessed in vivo by measuring arterio-venous differences across the subcutaneous abdominal adipose bed. Net release of IL-1beta was not observed, suggesting that under basal conditions there is no detectable release of this cytokine into the circulation from this depot. In conclusion (1) PBC demonstrate regulated IL-6 release, while the adipocyte release has a large constitutive component; (2) immune modulators, such as LPS, TNFalpha and IL-1beta, all induce PBC IL-6 release, but only IL-1beta stimulates adipocyte release. Though IL-1beta is not an endocrine signal from adipose tissue, it is an autocrine/paracrine stimulator of IL-6 release from human adipocytes.

Adipocytes↗

PubMed2003

Plasminogen activator inhibitor-1 (PAI-1) activity post myocardial infarction: the role of acute phase reactants, insulin-like molecules and promoter (4G/5G) polymorphism in the PAI-1 gene.

High PAI-1 levels post acute myocardial infarction (AMI) are associated with a poor outcome. Concentrations of insulin-like molecules, proinflammatory cytokines and an insertion (5G)/deletion (4G) polymorphism in the promoter of the PAI-1 gene, all influence circulating PAI-1 levels. We studied the determinants of PAI-1 in 123 patients immediately following and at 6 months after AMI. Within 24 h of AMI, PAI-1 levels were related to those of proinsulin-like molecules but not to levels of cytokines (interleukin-1beta, interleukin-6 or tumour necrosis factor-alpha), to genotype, or to interactions between genotype and cytokine concentration. PAI-1 levels 6 months after AMI were related to concentrations of interleukin-1beta but not to genotype. We have found no evidence that subjects with the 4G/4G polymorphism have higher PAI-1 levels on admission or 6 months after AMI. In these patients, levels of PAI-1 are related to concentrations of proinsulin-like molecules and of proinflammatory cytokines.

Acute-Phase Proteins↗

PubMed2003

Cortisol responses to mild psychological stress are inversely associated with proinflammatory cytokines.

Glucocorticoids can down-regulate immune activity, but acute stress has been reported to increase both cortisol and levels of plasma cytokines. We investigated individual differences in cortisol responses and their associations with proinflammatory cytokines, such as interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1ra), cardiovascular activity, and mental health. Saliva samples and blood were taken from 199 healthy middle-aged participants of the Whitehall II cohort at baseline, immediately after stress and 45 min later. We defined the 40% of participants with the highest cortisol response to stress as the cortisol responder group and 40% with the lowest response as the cortisol non-responder group. Plasma IL-6 was higher and the IL-1ra response to stress was greater in the cortisol non-responder group. The cortisol non-responders showed lower heart rate variability than the cortisol responders. The cortisol responder group experienced more subjective stress during the tasks and reported more impaired mental health than the non-responders. We conclude that individual variations in neuroendocrine stress responsivity may have an impact on proinflammatory cytokines, and that both high and low cortisol stress responsiveness has potentially adverse effects.

Adaptation, Physiological↗

PubMed2003

Socioeconomic status, C-reactive protein, immune factors, and responses to acute mental stress.

Low socioeconomic status (SES) is associated with increased risk of coronary heart disease and immune-related disorders. We hypothesised that SES would be inversely associated with the acute phase reactant C-reactive protein (CRP) and with circulating lymphocyte levels, and that lymphocyte responses to acute psychological stress would also vary with SES. CRP was obtained from 226, and lymphocyte counts from 127 healthy volunteers from the Whitehall II cohort, and SES was defined primarily by grade of employment. CRP concentration was greater in lower compared with higher SES participants (1.18+/-0.75 vs. 0.75+/-0.8 mg/l,p=.002) independently of sex, age, body mass, waist/hip ratio, smoking, alcohol, and season of the year. Similar differences were evident when SES was defined by income and educational attainment. Higher SES was also associated with lower total lymphocyte (p=.023), T-lymphocyte (p=.024) and natural killer (NK) cell counts (p=.006). Total, T- and B-lymphocyte, and NK cell counts increased with stress, but immune stress reactivity did not vary with SES. Post-stress recovery was delayed in women compared with men. The results suggest that moderate inflammation and immune activation may be processes through which lower SES increases disease risk.

Adult↗

PubMed2003

Endothelial dysfunction and inflammation in asymptomatic proteinuria.

BACKGROUND: Proteinuria is associated with vascular risk and a systemic increase in vascular permeability. Endothelial dysfunction occurs early in atherosclerosis and modulates vascular permeability. Vascular risk and chronic inflammation are associated. This study investigates whether the increased vascular permeability in proteinuria reflects systemic endothelial dysfunction and chronic inflammation. METHODS: Twenty-one patients with asymptomatic proteinuria (1.29 g/24 h; range 0.18 to 3.17) and 21 matched controls were studied. Microvascular endothelial function was assessed using acetylcholine iontophoresis. Maximum microvascular hyperemia (MMH) was assessed by flux response to local skin heating. Macrovascular endothelial function was assessed by flow-associated dilation (FAD) in the brachial artery using ultrasound. von Willebrand factor (vWF) was measured as a marker of endothelial activation. Low-grade inflammation was assessed by measurement of circulating C-reactive protein (CRP) values using a high sensitivity assay. RESULTS: FAD was impaired in proteinuric subjects (AP) compared to controls [1.8 (0.2 to 5.3) AP vs. 3.8 (1.5 to 6.2) C %; P = 0.014]. There was no significant difference between groups in MMH or in the response to acetylcholine iontophoresis. The AP group had a higher CRP [4.0 (0.5 to 39.0) AP vs. 0.2 (0.1 to 21.3) C mg/L; P < 0.001] and tendency to higher vWF [101.5 (67.0 to 197.0) AP vs. 77.5 (45.0 to 185.0) C IU/dL; P = 0.046] compared to controls. In the AP, but not control, group there was an inverse correlation between CRP and microvascular function as determined by acetylcholine iontophoresis (r = -0.509; P = 0.018). CONCLUSIONS: In AP subjects there is evidence of macrovascular endothelial dysfunction remote from the kidney and of low-grade inflammation that is associated with microvascular endothelial dysfunction.

Adult↗

PubMed2002

Inflammatory cytokines, socioeconomic status, and acute stress responsivity.

Socioeconomic status is a major determinant of coronary heart disease (CHD). Proinflammatory cytokines are implicated in the etiology of CHD, and are also sensitive to emotional stress. We hypothesised that concentration of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1 receptor antagonist (IL-1Ra) would be inversely related to socioeconomic status, and that cytokine responses to stress would be associated with SES. One hundred and twenty-five middle-aged men and 105 women from the Whitehall II epidemiological cohort were tested, and socioeconomic status was indexed by grade of employment, with participants divided into high, intermediate, and low status groups. Plasma concentrations at rest of TNF-alpha, IL-1Ra, and IL-6 (women only) were associated with socioeconomic status, with lower levels in the high status group, but the effect was non-linear. There was no relationship between socioeconomic status and cytokine responses to stress, but sex differences were observed, with men showing greater TNF-alpha, and women greater IL-6 and IL-1Ra increases. The role of inflammatory cytokines in mediating psychosocial influences on CHD is discussed.

Acute Disease↗

PubMed2002

Therapeutic potential of insulin-like growth factor-1 in patients with diabetes mellitus.

Insulin-like growth factor-1 (IGF-1) and its receptors share considerable homology with insulin and insulin receptors, and their respective signaling pathways interact at the post receptor level. While the growth hormone (GH)-IGF-1 axis principally regulates tissue growth and differentiation, insulin exerts it primary effects on fuel metabolism. However, these two endocrine systems interact at multiple levels and in diabetes mellitus the GH-IGF-1 axis is grossly disturbed, with increased secretion of GH, reduced plasma levels of IGF-1, and complex tissue-specific changes in IGF binding proteins (IGFBPs). These observations have given rise to the view that GH-IGF-1 axis dysfunction, particularly low plasma levels of circulating IGF-1, probably play a significant role in several aspects of the pathophysiology of diabetes mellitus, including insulin resistance and poor glycemic control, and may also influence the development of microvascular complications. The availability of recombinant human IGF-1 (rhIGF-1; mecasermin), used either alone or in combination with insulin, has led to experimental studies and clinical trials in humans testing these hypotheses. These studies have examined the impact of subcutaneous rhIGF-1 injections on sensitivity and metabolic parameters. In patients with type 1 and 2 diabetes mellitus, insulin sensitivity is significantly improved, insulin requirements are reduced, and glycemic control of dyslipidemia is generally improved in short-term studies. rhIGF-1 is a particularly attractive possibility in patients with type 2 diabetes mellitus, where insulin resistance is the fundamental problem. Some patients with genetic syndromes of severe insulin resistance also benefit from treatment with rhIGF-1, which can bypass blocks in the insulin signaling pathway. The common adverse effects reported for rhIGF-1 are dose-related and include edema, jaw pain, arthralgia, myalgia, hypotension, injection site pain, and less commonly, Bell's palsy and raised intracranial pressure. Although disturbance of the GH-IGF-1 axis participates in the development of diabetic complications, the functional consequences of the complex changes in IGFBP expression at the tissue level are uncertain, and it is not known whether systemic IGF-1 therapy or other manipulations of the GH-IGF-1 axis would be helpful or harmful. Experimentally, IGF-1 has a protective effect on neuropathy, and could find an application in the healing of neuropathic ulcers. The potential benefits of IGF-1 therapy in diabetes mellitus have yet to be realised.

Diabetes Mellitus, Type 1↗