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Biomedical subjects

N Sattar

Publications and source records attributed to N Sattar.

At least 19 recordsLinked to original sources

The relationship of circulating insulin-like growth factor 1, its binding protein-3, prostate-specific antigen and C-reactive protein with disease stage in prostate cancer.

OBJECTIVE: To assess the relationships among circulating insulin-like growth factor-1 (IGF-1), IGF binding protein-3 (IGFBP-3), prostate-specific antigen (PSA) and C-reactive protein (an indicator of inflammatory systemic response) in patients with prostate disease and cancer of different stages. PATIENTS AND METHODS: Circulating IGF-1, IGFBP-3, PSA and C-reactive protein concentrations were measured in patients with BPH (17) or stages T1/T2 (15), T3/T4 (16) and metastatic prostate cancer (12 patients). RESULTS: IGF-1 and IGFBP-3 concentrations were similar between patients with BPH and those with cancer, and there was no difference between the groups with cancer. In the latter patients there was a significant correlation between age and IGFBP-3 concentrations (r = -0.400, P = 0.008) but not with IGF-1 concentrations. Controlling for age, there were significant partial correlations between C-reactive protein and IGF-1 (r = -0.412, P = 0.008) and IGFBP-3 (r = -0.277, P = 0.05). CONCLUSIONS: These results indicate that circulating IGF-1 and IGFBP-3 concentrations do not change with disease stage in prostate cancer, but that they decrease with an increase in the systemic inflammatory response.

Aged↗

Hormone replacement therapy can augment vascular relaxation in post-menopausal women with type 2 diabetes.

BACKGROUND: Diabetes is a major risk factor for coronary heart disease in women and event rates increase substantially after the menopause. Observational studies have suggested that estrogens may provide cardioprotection by regulating endothelial nitric oxide synthase. METHODS: In order to examine the effect of hormone replacement therapy (HRT) on endothelium-dependent and -independent vascular relaxation in post-menopausal women with type 2 diabetes, an open study was conducted in which gluteal biopsies were collected from 17 women before and after 6 months of transdermal 17 beta-estradiol (80 microg twice weekly) in combination with oral norethisterone (1 mg daily). Small arteries (<550 microm) were dissected from fat and mounted on a wire myograph for assessment of relaxation in response to acetylcholine (ACh), bradykinin (BK) and sodium nitroprusside (SNP). RESULTS: Maximal relaxation responses to ACh, BK and SNP in women with diabetes and non-diabetic control subjects were 52 +/- 8 versus 96 +/- 2% (P < 0.05), 76 +/- 7 versus 97 +/- 1%, (P < 0.05) and 91 +/- 2 versus 98 +/- 1% (P < 0.05) respectively. After 6 months of HRT, maximal relaxation responses to ACh, BK and SNP in women with diabetes (compared with pre-HRT) were: 88 +/- 4 (P < 0.05), 93 +/- 3 (P < 0.05) and 98 +/- 1% (P < 0.05) respectively. At baseline and after HRT, EC50 (concentration required to obtain 50% of maximum response) data exhibited similar changes. CONCLUSIONS: HRT had potentially beneficial effects on vascular relaxation. Data were consistent with improvements in endothelial function, vascular smooth muscle function, or both. Controlled studies are required to confirm and extend these findings.

Acetylcholine↗

Plasma leptin and the risk of cardiovascular disease in the west of Scotland coronary prevention study (WOSCOPS).

BACKGROUND: Leptin plays a role in fat metabolism and correlates with insulin resistance and other markers of the metabolic syndrome, independent of total adiposity. Therefore, we hypothesized that raised leptin levels may identify men at increased risk of a coronary event in the West of Scotland Coronary Prevention Study (WOSCOPS). Methods and Results- Plasma leptin levels were measured at baseline in 377 men (cases) who subsequently experienced a coronary event and in 783 men (controls) who remained free of an event during the 5-year follow-up period of the study. Controls were matched to cases on the basis of age and smoking history and were representative of the entire WOSCOPS cohort. Leptin levels were significantly higher in cases than controls (5.87+/-2.04 ng/mL versus 5.04+/-2.09 ng/mL, P<0.001). In univariate analysis, for each 1 SD increase in leptin, the relative risk (RR) of an event increased by 1.25 (95% confidence interval [CI], 1.10 to 1.43; P<0.001). There was minimal change in this RR with correction for body mass index (RR, 1.24; 95% CI, 1.06 to 1.45; P=0.006) or with further correction for classic risk factors, including age, lipids, and systolic blood pressure (RR, 1.20; 95% CI, 1.02 to 1.42; P=0.03). Leptin correlated with C-reactive protein (r=0.24, P<0.001) and, even with this variable added to the model, leptin retained significance as a predictor of coronary events (RR, 1.18; 95% CI, 1.00 to 1.39; P=0.05) at the expense of C-reactive protein. CONCLUSIONS: We show, for the first time, in a large prospective study that leptin is a novel, independent risk factor for coronary heart disease.

Age Factors↗

Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study.

BACKGROUND: We examined the development of new diabetes mellitus in men aged 45 to 64 years during the West of Scotland Coronary Prevention Study. METHODS AND RESULTS: Our definition of diabetes mellitus was based on the American Diabetic Association threshold of a blood glucose level of >/=7.0 mmol/L. Subjects who self-reported diabetes at baseline or had a baseline glucose level of >/=7.0 mmol/L were excluded from the analyses. A total of 5974 of the 6595 randomized subjects were included in the analysis, and 139 subjects became diabetic during the study. The baseline predictors of the transition from normal glucose control to diabetes were studied. In the univariate model, body mass index, log triglyceride, log white blood cell count, systolic blood pressure, total and HDL cholesterol, glucose, and randomized treatment assignment to pravastatin were significant predictors. In a multivariate model, body mass index, log triglyceride, glucose, and pravastatin therapy were retained as predictors of diabetes in this cohort. CONCLUSIONS: We concluded that the assignment to pravastatin therapy resulted in a 30% reduction (P:=0.042) in the hazard of becoming diabetic. By lowering plasma triglyceride levels, pravastatin therapy may favorably influence the development of diabetes, but other explanations, such as the anti-inflammatory properties of this drug in combination with its endothelial effects, cannot be excluded with these analyses.

Anticholesteremic Agents↗

Antenatal waist circumference and hypertension risk.

OBJECTIVE: To assess whether waist circumference at the first antenatal visit predicts risk of developing hypertension later in pregnancy. METHODS: Pregnant women with singleton pregnancies (n = 1142, median age 29 years, interquartile range 25-32 years, 387 primigravidas) were recruited at their first antenatal visits. Using standardized methods, midwives determined the weights, heights (for calculation of body mass index [BMI]), and waist circumferences of all women. Eighty-two women developed pregnancy-induced hypertension, and 21 developed preeclampsia (hypertension with proteinuria). RESULTS: The median waist circumference between 6 and 16 weeks' gestation was 79 cm (interquartile range 72-84 cm), and there was no significant relationship between waist circumference and gestational age. Greater waist circumference was noted in subjects who subsequently developed pregnancy-induced hypertension (median 81 versus 77 cm, Mann-Whitney U test, P =.002) or preeclampsia (median 80 versus 77 cm, P =.02). The conventional, nonpregnant waist circumference action level of 80 cm gave a Mantel-Haenszel odds ratio (OR) for pregnancy-induced hypertension of 1.8 (95% confidence interval [CI] 1.1, 2.9) and for preeclampsia of 2.7 (95% CI 1.1, 6.8), compared with waists of less than 80 cm. Body mass index values were higher in women who developed pregnancy-induced hypertension (median 26 versus 24, P =.001) or preeclampsia (median 26 versus 24, P =.02). The conventional action limit for a BMI of 25 had an OR for pregnancy-induced hypertension of 2.0 (95% CI 1.2, 3.4) and for preeclampsia of 1.9 (95% CI 0.7, 4.8). Results were similar when the analysis was restricted to data from primigravidas. CONCLUSION: We conclude that waist circumference up to 16 weeks' gestation can predict pregnancy-induced hypertension and preeclampsia. Therefore, waist circumference could form the basis for health promotion involving raising awareness of the importance of or urging weight reduction for women planning pregnancies.

Adult↗

Attenuation of endothelin-1 induced vasoconstriction by 17beta estradiol is not sustained during long-term therapy in postmenopausal women with coronary heart disease.

OBJECTIVES: The goal of this study was to determine the long-term effects of estrogen replacement therapy on the response to endothelin-1 (ET-1) in postmenopausal women with coronary heart disease. BACKGROUND: It is thought that the vasoconstrictor ET-1 is involved in the development and progression of atherosclerosis. Estrogen replacement may slow the development of atherosclerosis in postmenopausal women. METHODS: Nineteen of 20 postmenopausal women randomized to either three months of 2 mg oral estradiol or placebo completed the double-blind placebo-controlled protocol. Change in forearm blood flow (FBF) in response to a 60 min brachial arterial infusion of ET-1 (5 pmol/min) was measured before randomization, after one month of randomized therapy and after three months of therapy using venous occlusion plethysmography. RESULTS: Estrogen treatment had no effect on baseline FBF. Systolic and diastolic blood pressure and heart rate did not change in response to estrogen therapy or ET-1. Before randomization, in response to ET-1, FBF was reduced by -21.9% (mean response over 60 min) in the placebo group and -19.0% in the estradiol group (p = 0.67). After one month of therapy, the response was attenuated in the estrogen group, -10.0%, compared with the placebo group, -23.6 (difference in means 13.6%, 95% confidence interval [0.7%, 26.6%], p = 0.041). After three months of therapy, there was no difference in response between the placebo group, -27.0%, and estrogen group, -30.2% (p = 0.65). CONCLUSIONS: In postmenopausal women with coronary heart disease, estrogen therapy inhibits the vasoconstrictor response to ET-1 after one month of therapy. This effect is lost after three months of therapy, suggesting that tachyphylaxis to one potentially beneficial action of estradiol develops during chronic treatment.

Aged↗

Fatty acid status of women of reproductive age.

OBJECTIVE: Healthy foetal and infant development is dependent on an adequate maternal supply of essential and polyunsaturated fatty acids (PUFA). While there are published data on the fatty acid status of pregnant women, there are few on the status of non-pregnant women of reproductive age. The aims of this study were to test the hypotheses that the fatty acid status of non-pregnant women is affected by socio-economic status and anthropometric, behavioural and obstetric factors. DESIGN: Observational study METHODS: One-hundred and thirty-five women of child-bearing age (mean 29.8 y, s.d. 6.92) were invited to provide a blood sample and to answer a questionnaire, of whom 114 were included in the study. Plasma and red cell total fatty acids were measured as their methyl esters by gas chromatography mass spectrometry. RESULTS: On multivariate analyses, use of hormonal contraception was independently associated with lower plasma polyunsaturated fatty acids (difference between means -2.76, 95% confidence interval (-4.64, -0.88), P=0.0034), whereas cigarette smoking was associated with higher red cell oleic acid (0.74 (0.18, 1.29), P=0.0094). Fish intake was associated with higher red cell total n-3 fatty acids (0.62 (0.27, 0.85), P=0.0014). CONCLUSIONS: We have reported data on the range of the fatty acids of plasma and red blood cells (RBC) total lipids of 114 healthy women of reproductive age. These data provide further information on how socio-economic, anthropometric, behavioural and obstetric factors may be relevant to female and nutrition and health. SPONSORSHIP: University of Glasgow.

Adult↗

Relation of C-reactive protein to body fat distribution and features of the metabolic syndrome in Europeans and South Asians.

OBJECTIVE: To investigate the association between circulating C-reactive protein (CRP) concentrations and indices of body fat distribution and the insulin resistance syndrome in South Asians and Europeans. DESIGN: : Cross-sectional study. SUBJECTS: A total of 113 healthy South Asian and European men and women in West London (age 40-55 y, body mass index (BMI) 17-34 kg/m(2)). MEASUREMENTS: Fatness and fat distribution parameters (by anthropometry, dual-energy X-ray absorptiometry and abdominal CT scan); oral glucose tolerance test with insulin response; modified fat tolerance test; and CRP concentration by sensitive ELISA. RESULTS: Median CRP level in South Asian women was nearly double that in European women (1.35 vs 0.70 mg/1, P=0.05). Measures of obesity and CRP concentration were significantly associated in both ethnic groups. The correlation to CRP was especially strong among South Asians (P<0.01) for measures of central obesity (waist girth and visceral fat area), whereas BMI and percentage fat were more significantly associated with CRP in Europeans (P<0.05). In South Asians the associations of CRP with visceral fat area and waist girth persisted after adjustment for either BMI or percent fat (all, P<0.05). In age-, sex- and smoking-adjusted regression analyses CRP concentrations were significantly associated with fasting and 2 h insulin and lipid levels in both ethnic groups (P<0.05). When further statistical adjustment was made for visceral fat area these associations were abolished (P>0.15). CONCLUSION: We suggest that adiposity and in particular visceral adipose tissue is a key promoter of low-grade chronic inflammation. This observation may in part account for the association of CRP with markers of the metabolic syndrome. Future studies should confirm whether CRP concentrations are elevated in South Asians and whether losing weight by exercise or diet, or reduction in visceral fat mass, is associated with reduction in plasma CRP concentrations.

Adipose Tissue↗

Lipids and lipoprotein subfractions in women with PCOS: relationship to metabolic and endocrine parameters.

OBJECTIVE: Women with polycystic ovary syndrome (PCOS) exhibit an abnormal lipoprotein profile, characterized by raised concentrations of plasma triglyceride, marginally elevated low density lipoprotein (LDL)-cholesterol, and reduced high density lipoprotein (HDL)-cholesterol. However, a normal LDL-cholesterol level may be misleading since LDL exists as subpopulations of particles differing in size and atherogenic potential. Smaller LDL particles are more atherogenic and high concentrations often occur in association with elevated circulating triglyceride concentrations (but frequently normal total LDL-cholesterol), increased hepatic lipase activity (HL) and insulin resistance. Information on LDL subclasses and HL activity in women with PCOS is sparse. The aim of this study was to determine the concentrations of small, dense LDL (LDL-III) in women with PCOS relative to body mass index (BMI)-matched controls. We also examined the association of lipoprotein subfraction concentrations with endogenous sex hormone concentrations, since existing literature suggested that androgens up-regulate and oestrogens down-regulate HL activity, a key determinant of LDL subfraction distribution. DESIGN: Cross sectional study. PATIENTS: Fifty-two women with oligomenorrhoea and polycystic ovaries determined by ultrasound and BMI matched women with normal menstrual rhythm (NMR) and normal ovarian appearances (n = 14) were recruited from gynaecology clinics. Anthropometric data and fasting blood samples were obtained for metabolic, hormonal and LDL subfraction estimation and a heparin provocation test was used to estimate HL activity. RESULTS: Subjects with PCOS demonstrated higher waist:hip ratio (WHR), testosterone, triglyceride, VLDL-cholesterol concentrations, and HL activity (P < 0.05), whereas SHBG concentrations were significantly lower than controls. PCOS women had higher concentrations (38.0 vs. 25.0 mg/l; P = 0.026) and proportions (12.8 vs. 8.2%; P = 0.006) of small, dense LDL (LDL III), relative to controls. Within the PCOS group, plasma triglyceride and HL activity were the strongest univariate predictors of LDL III mass. They remained as independent predictors in multivariate analysis, and together accounted for 37% of its variability (P = 0.0002). Independent predictors of plasma triglyceride and HL in turn, were measures of fat distribution (waist circumference or WHR) and fasting insulin concentration. Serum testosterone concentration was not associated either in univariate or multivariate analysis with any of the measured lipid, lipoprotein or subfraction parameters, nor with HL activity in the women with PCOS. CONCLUSION: We conclude that women with polycystic ovary syndrome have increased hepatic lipase activity and mass and percentage of small, dense low density lipoprotein relative to body mass index-matched controls with normal menstrual rhythm and normal ovaries. Further, these metabolic perturbances appear related more closely to adiposity/insulin metabolism than to circulating androgen levels.

Adult↗

Measurement of the systemic inflammatory response predicts cancer-specific and non-cancer survival in patients with cancer.

The assessment of prognosis in patients with advanced cancer remains problematical. The value of C-reactive protein concentration in this context has not been clearly defined. Patients with a diagnosis of colorectal (n = 182), gastric (n = 87), breast (n = 99), or bronchogenic (n = 404) cancer and who had measurements of C-reactive protein and albumin were identified. Median survival, from the time of sampling, ranged from 478 days in the colorectal cancer patients to 60 days in patients with bronchogenic cancer. On univariate analysis, there was, in each tumor type, a significant relationship between the duration of survival and both log10 C-reactive protein and albumin concentrations (P < or = 0.0002). On multivariate analysis, in each tumor type, log10 C-reactive protein remained a significant independent predictor of survival (P < or = 0.0002). When all four groups of cancer patients were analyzed (n = 772), the hazard ratio for a 10-fold increase in C-reactive protein concentration in cancer-specific survival was 2.21 (95% confidence interval = 1.92-2.56, P < 0.0001) and the corresponding hazard ratio for non-cancer survival was 5.48 (95% confidence interval = 3.55-8.46, P < 0.0001). The results of the present study indicate that in advanced cancer patients the presence of a systemic inflammatory response and the magnitude of that response predict the duration of cancer-specific and non-cancer survival.

Adult↗

The effects of transdermal estradiol in combination with oral norethisterone on lipoproteins, coagulation, and endothelial markers in postmenopausal women with type 2 diabetes: a randomized, placebo-controlled study.

People with type 2 diabetes have a substantially increased risk of coronary heart disease (CHD). Short-term studies with unopposed oral estradiol in women with diabetes have suggested potentially beneficial effects on lipids, thrombotic factors, and insulin sensitivity. However, most (nonhysterectomized) postmenopausal women require combined estrogen-progesterone preparations. We randomized 43 women with type 2 diabetes either to continuous transdermal estradiol (80-microg patches) in combination with oral norethisterone (1 mg daily) or to identical placebos. Blood samples were taken before and after 6 months for measurement of lipoproteins, coagulation factors, and endothelial markers. Total cholesterol and triglyceride concentrations decreased by 8% and 22%, respectively, in those receiving hormone replacement therapy (P < 0.05 relative to change in placebo group after adjustment for baseline concentrations). There was a trend toward a reduction in high density lipoprotein cholesterol concentration (P = 0.06). Factor VII activity decreased by 16% (P < 0.001), and von Willebrand factor antigen decreased by 7% (P = 0.014) with active treatment. Levels of fibrinogen, tissue plasminogen activator, fibrin D dimer, very low density lipoprotein cholesterol, low density lipoprotein cholesterol, lipoprotein(a), and leptin were not significantly altered. No change in glycemic control was detected. Overall, lipid changes may be considered slightly beneficial with respect to CHD risk. The significant decrease in factor VII activity in this study is notable, because elevated factor VII activity has been associated with an increased risk of coronary thrombosis and normally increases with administration of oral estrogen-containing preparations. In addition, a reduction in von Willebrand factor antigen is consistent with an improvement in endothelial function. We suggest that the regimen used in this study may have the potential to reduce CHD risk in women with type 2 diabetes.

Administration, Cutaneous↗

Low grade chronic inflammation in women with polycystic ovarian syndrome.

Low grade chronic inflammation as reflected by increased C-reactive protein (CRP) concentrations independently predicts those at risk for coronary heart disease (CHD) and type 2 diabetes. Women with polycystic ovarian syndrome (PCOS) are insulin resistant and have increased risk for CHD and type 2 diabetes, but currently there are no data on markers of inflammation in women with PCOS. Seventeen women with PCOS (defined on the basis of elevated testosterone and oligomenorrhea) and 15 healthy women matched as a group for body mass index were recruited. Measurement of CRP concentrations was made using a highly sensitive assay. Insulin resistance was assessed using the hyperinsulinemic euglycemic clamp technique. The women with PCOS had significantly elevated CRP concentrations relative to controls (geometric means, 2.12 and 0.67 mg/L, respectively; P = 0.016). Log CRP correlated with body mass index in both PCOS and controls (r = 0.58; P < 0.05 and r = 0.78; P < 0.01, respectively) and inversely with insulin sensitivity (r = -0.57; P < 0.05 and r = -0.69; P < 0.01). Total testosterone did not correlate with log CRP in either group. On adjustment for body mass index and age, there remained a significant difference in log CRP between PCOS and controls (t = 2.13; P < 0.05). On further adjustment for insulin sensitivity, log CRP was no longer significantly different between groups (t = 1.51; P = 0.14). We conclude that women with PCOS have significantly increased CRP concentrations relative to women with normal menstrual rhythm and normal androgen levels. We propose low grade chronic inflammation as a novel mechanism contributing to increased risk of CHD and type 2 diabetes in these women.

Adult↗

Circulating leptin concentrations and ovarian function in polycystic ovary syndrome.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is characterized by ovarian dysfunction. Although the role of leptin in the control of reproduction is unclear, it may be involved in the control of ovulation. The aim of this cross-sectional study was to determine the relationship between circulating leptin concentrations, and anthropometric, metabolic and endocrine variables as well as to examine a possible role of leptin in ovarian dysfunction associated with PCOS. DESIGN: Prospective observational study. METHODS: Seventy-one subjects with PCOS and 23 body mass index (BMI)-matched control subjects were recruited from infertility clinics. The association between serum leptin concentrations and the above variables was measured outwith the luteal phase. A subgroup of 24 PCOS subjects underwent more frequent blood sampling to monitor follicular growth and ovulation. The association between variables was measured by univariate, multivariate and partial correlation analyses. RESULTS: Serum leptin concentrations were not different in subjects with PCOS and controls, and were strongly associated with BMI in both groups. Twelve patients ovulated during the study period. There was no significant difference in serum leptin concentrations between ovulatory and anovulatory subjects. The relationship between BMI and leptin was similar in both groups. CONCLUSION: The results indicated that circulating leptin concentrations relate principally to total body fat in subjects with PCOS and controls, and that this is not associated with the facility for follicular development and ovulation in these patients.

Adult↗

The Glasgow Outcome, APCR and Lipid (GOAL) Pregnancy Study: significance of pregnancy associated activated protein C resistance.

Activated protein C (APC) resistance secondary to Factor V Leiden (FVL) is associated with pregnancy failure and pre-eclampsia (PET). In non-pregnant subjects, the degree of resistance to APC relates to venous thrombosis risk. In pregnancy, resistance to APC occurs in the absence of FVL. We investigated, in an unselected prospective longitudinal study of 1,671 pregnant, non-FVL subjects, the relationship of the APC sensitivity ratio (APC:SR) with demographic variables and pregnancy outcome. Lower APC:SR values at 7-16 weeks gestation were observed in subjects who subsequently developed PET (median APC:SR 2.55, IQR 2.29-2.70 vs 2.69, IQR 2.48-2.93, Mann-Whitney U-test p = 0.003) in the current pregnancy. An APC:SR < the median (2.69) at 7-16 weeks was associated with a 2.95-fold increased risk (CI95 1.2-7.4) of PET in the current pregnancy. No relationship between the APC:SR, at any gestation, and fetal loss was observed. An inverse correlation between the APC:SR and birth weight was noted. Higher APC:SRs were observed in blood group O subjects and smokers. An inverse relationship of the APC:SR with age, diastolic blood pressure and total serum cholesterol was observed.

Abortion, Spontaneous↗

The co-ordinated cytokine/hormone response to acute injury incorporates leptin.

Recent studies have implicated leptin as a "stress" hormone and highlighted its association with increases in inflammatory cytokines, C-reactive protein and cortisol. In order to investigate the exact temporal leptin response to stress we undertook a detailed longitudinal study of circulating leptin concentrations during the well defined surgical injury of cholecystectomy. Circulating concentrations of cortisol, free fatty acids, leptin and C-reactive protein were measured at 3, 6, 9, 12, 18, 24, 48 and 72 h from the start of surgery in nine patients. There was a significant correlation between baseline concentrations of leptin and BMI (r=0. 893, P<0.001). Over the 72 h from the start of surgery there were significant (P<0.05) increases in the concentrations of all analytes (peak median concentrations); cortisol (6 h), free fatty acids (9 h), leptin (18 h) and C-reactive protein (48 h). Interestingly the timing of the leptin peak at approximately 18 h after an acute inflammatory stimulus is exactly the same as previously reported for interleukin 6. These data support the suggestion that the relationship between cortisol and leptin mirrors that of cortisol and another cytokine, interleukin 6, i.e. stimulatory in acute and suppressive in chronic situations. They also imply a physiological role for leptin in acute injury.

C-Reactive Protein↗