A one-year follow-up on the effects of raloxifene on thyroid function in postmenopausal women

OBJECTIVE: Estrogens increase serum thyroxine-binding globulin (TBG) and total thyroxine (TT4) concentrations. Serum free thyroxine (FT4) concentrations, however, remain normal. Raloxifene (RAL) is a selective estrogen receptor modulator used to treat postmenopausal osteoporosis. Data on the long-term effects of RAL on thyroid physiology are scanty. We evaluated the effects of RAL administration for 1 year on thyroid function in osteopenic, postmenopausal women. DESIGN: Fifty osteopenic, postmenopausal women were randomly assigned to receive either RAL (60 mg/day, n = 25) or placebo (PL, n = 25) for 1 year, in a double-blind study. Measurements of serum TBG, TT4, FT4, thyroid-stimulating hormone (TSH), thyroid hormone-binding ratio (THBR), FT4 index (FT4-I) and TT4/TBG ratio were carried out at baseline and after 4 and 12 months of therapy. RESULTS: Baseline values were similar in both treatment groups. Serum TBG concentrations were increased during RAL treatment from baseline values of 29.60 +/- 0.9 microg/mL to 31.45 +/- 1.33 and 32.34 +/- 1.37 microg/mL at 4 months and 1 year, respectively (P < 0.05, baseline v 1-year values) but were unchanged during PL treatment. A small, insignificant increase in TT4 and TSH concentrations occurred in the RAL group and no changes in the PL group. All other values were unchanged during either treatment. CONCLUSIONS: These results demonstrate that RAL significantly increased serum TBG levels, but the changes were small and not accompanied by changes in FT4-I, FT4, or TSH concentrations, suggesting that long-term RAL treatment is unlikely to clinically affect the thyroid status in euthyroid, postmenopausal women.     

Obese related effects of inflammatory markers and insulin resistance on increased carotid intima media thickness in pre-pubertal children

Obesity in children appears to be associated with increased risk of cardiovascular and metabolic diseases later in life. Early development of insulin resistance and impaired oxidant-antioxidant status may lead to endothelial dysfunction and increased carotid intima media thickness (IMT) even in childhood. The aim of this study was to measure IMT and the relationship between IMT, insulin resistance and oxidant status in obese pre-pubertal children. In 53 obese pre-pubertal children (27M/26F, mean age 8+/-2 years), anthropometric measurements and inflammatory markers (hs-CRP and PGF-2 alpha), were evaluated compared with 41 healthy pre-pubertal subjects (21M/20F, mean age 7+/-2 years). OGTT was performed and insulin resistance (IR) indices (HOMA-IR, WBISI, G/I and QUICKI) were calculated in all patients. High-resolution ultrasound techniques were used to evaluate IMT. Obese children had higher levels of PGF-2 alpha and hs-CRP compared to healthy subjects (p=0.001 and p=0.005). Furthermore, fasting insulin levels and HOMA-IR were higher in obese children than in controls (p=0.001 and p=0.001) while WBISI was significantly lower (p=0.002). In addition, obeses had an increased IMT (p=0.001). In obese children there was a significant correlation between IMT and indices of IR (HOMA-IR: beta=-1.233, p=0.002; WBISI: beta=-0.921, p=0.008; G/I: beta=-0.811, p=0.003) and between IMT and PGF-2 alpha (beta=0.505, p=0.004). After categorizing subjects according to tertiles of body mass index (BMI) (or=26.23 kg/m(2)) and to waist circumference (WC) (or=79.04 cm), no influence of BMI or WC on IMT were found in the three groups. In conclusion, early changes in glucose metabolism and an alteration of oxidant-antioxidant status may be present in obese pre-pubertal children; this could lead to increase IMT and early cardiovascular disease.     

Short exposure of albumin to high concentrations of malondialdehyde does not mimic physiological conditions

Malondialdehyde (MDA), a major lipid peroxidation product, spontaneously binds to, and modifies proteins. In vivo, proteins are physiologically exposed to micromolar MDA concentrations for long periods. In order to mimic this process in vitro, protein modification is often performed by short exposure to millimolar MDA concentrations, also in order to generate antigenic structures for antibody production.     

Early and late coronary deaths in the US Railroad study predicted by major coronary risk factors.

BACKGROUND: The purpose of this study was to explore the duration of the association of major coronary risk factors measured on a single occasion with coronary heart disease (CHD) deaths during 40 years in a population sample of middle-aged men. DESIGN: Measurement of age, systolic blood pressure, serum total cholesterol, and cigarette smoking was made on a single occasion in 2376 cardiovascular disease free men, aged 40-59, belonging to the US Railroad cohort of the Seven Countries Study enrolled in the late 1950s. During 40 years of follow up 627 men died from typical CHD (sudden death coronary death or definite myocardial infarction). METHODS: Eight partitioned proportional hazards models were solved, one for each independent 5-year block of follow up, to predict the risk of CHD death. Eight 5-year partitioned hazard scores, derived from the coefficients, were cumulated for each risk factor. RESULTS: The resulting curves showed a regularly increasing time trend in risk for coronary deaths as a function of serum cholesterol, systolic blood pressure and cigarette smoking, for the first 30-35 years of follow up followed by a loss of predictive power thereafter. The curves fit straight lines, with large squared correlation coefficients ranging from 0.96 to 0.99. There was a relatively constant strength in the association of risk factors levels with events, which are predicted irrespective of the distance from risk factor measurements. CONCLUSIONS: Measurement of major coronary risk factors taken on a single occasion in middle-aged men maintained a regular and almost monotonic relationship with the subsequent occurrence of CHD deaths for at least 30-35 years of follow up.     

Short and long term association of a single serum cholesterol measurement in middle-aged men in prediction of fatal coronary and other cardiovascular events: A cross-cultural comparison through Europe

Aims: The purpose was to study the association of a single serum cholesterol measurement with early and late coronary and other cardiovascular deaths during 35 years of follow-up in samples of men aged 40–59 years in five European countries. Methods and results: A single serum total cholesterol measurement was considered in samples from Finland (N = 1563), the Netherlands (N = 811), Italy (N = 1642), Serbia (N = 1537) and Greece (N = 1158) (total = 6711). Seven partitioned proportional hazards models were solved, one for each of seven independent 5-year blocks, to predict coronary, stroke, cardiovascular disease and all-cause mortality risk. Partitioned hazard scores were cumulated. The resulting curves showed a relatively constant strength in risk for coronary deaths as a function of baseline serum cholesterol levels, although a strong relationship during the first 10-year period was followed by a weaker relationship later on. The pooled estimates for the five countries gave a relative risk for 1 mmol/l of serum cholesterol (95% confidence intervals) of 1.44 (1.23–1.68) for the first period; 1.52 (1.31–1.76) for the second period; and 1.16 (1.02–1.32) for the third period; 1.18 (1.05–1.32) for the forth period; 1.17 (1.05–1.31) for the fifth period; 1.22 (1.10–1.35) for the sixth period; 1.18 (1.05–1.32) for the seventh 5-year period of follow-up. No significant relationship were found between serum cholesterol and stroke and all-cause mortality, while intermediate findings were obtained for cardiovascular diseases. Conclusion: A single serum cholesterol measurement in middle aged-men maintains a strong relationship with the occurrence of coronary heart disease (CHD) deaths during 35 years of follow-up.     

IL-6 regulates MCP-1, ICAM-1 and IL-6 expression in human myoblasts

The inflammatory reaction in autoimmune polymyositis and rejection of transplanted myoblasts is characterized by mononuclear cell infiltration. In other settings monocytes are locally recruited by an IL-6-induced IL-8-to-MCP-1 switch. IL-6, upon binding to soluble gp80 (sIL-6R), can interact with membrane-bound ubiquitously expressed gp130 and activate virtually all cells (transsignaling). We found that human myoblasts could use transsignaling to produce IL-6, MCP-1 and ICAM-1; the addition of sIL-6R, binding to IL-1beta-induced IL-6, greatly increases IL-6 production. These in vitro data support the hypothesis that locally secreted IL-6 can target monocyte chemotaxis and leukocytes trafficking through an IL-6, MCP-1 and ICAM-1 modulation.     

The role of a baseline casual blood pressure measurement and of blood pressure changes in middle age in prediction of cardiovascular and all-cause mortality occurring late in life: a cross-cultural comparison among the European cohorts of the Seven Countries Study

OBJECTIVE: The first objective was to study the long-term association of a casual measurement of systolic blood pressure (SBP) with cardiovascular deaths (CVD) and all causes of death (ALL) occurring during 35 years of follow-up in different population samples of men aged 40-59 years in five European countries. The second objective was to study the predictive power of early change in SBP levels (years 0-10) in relation to late fatal events (years 10-35). DESIGN, SETTING AND PARTICIPANTS: A single measurement of SBP was considered in cohorts in Finland, The Netherlands, Italy, Serbia and Greece for a total of 6507 men. Three partitioned proportional hazards models were solved, one for each independent and subsequent time block of 10 years, after excluding data from the first 5 years, to predict the risk of cardiovascular disease deaths of atherosclerotic origin (CVD) and all cause mortality (ALL). Independently, the predictive power of SBP changes (Delta-SBP) occurred during the first 10 years of follow-up was explored as a possible additional risk factor in relation to CVD and ALL deaths occurring between year 10 and year 35 of follow-up. RESULTS: Partitioned hazard scores derived from the three partitioned functions were cumulated. The resulting curves showed a continuous and significant association of baseline SBP with CVD and ALL deaths during three decades, although the strength of association declined significantly from the first to the third decade. The relative risk for 20 mmHg of SBP (and its 95% confidence intervals) in predicting CVD deaths was 1.65 (1.54-1.77) for the first 10-year block; 1.33 (1.24-1.42) for the second block; and 1.22 (1.13-1.31) for the last 10-year block. The corresponding levels of ALL deaths were 1.41 (1.34-1.49), 1.26 (1.19-1.32) and 1.11 (1.05-1.17). Changes in SBP during 10 years (Delta-SBP) added predictive power to baseline measurements in a direct and significant way, with a relative risk for a change of 10 mmHg of 1.14 (1.10-1.17) for CVD deaths and 1.11 (1.09-1.13) for ALL deaths. CONCLUSION: A single measurement of systolic blood pressure in middle-aged men maintains a strong relationship with fatal CVD and ALL deaths during the next 35 years, although for late events the strength of the association definitely declines. Changes in systolic blood pressure levels during the first 10 years of follow-up add predictive power, while baseline measurements retain their predictive power.     

Ambulatory blood pressure monitoring in obese children: role of insulin resistance

OBJECTIVES: To investigate the relationship between ambulatory blood pressure (ABPM) parameters and insulin resistance in obese children. METHODS: A population of 56 obese prepubertal children was recruited for the study. They underwent ABPM, an oral glucose tolerance test and complete physical examination, including adiposity indexes such as body mass index (BMI), skinfolds, waist-to-hip ratio (WHR) and fat mass. RESULTS: The standard deviation score for BMI was significantly correlated with 24-h systolic blood pressure (SBP) (r = 0.30; P = 0.02) and diastolic blood pressure (DBP) (r = 0.29; P = 0.03), daytime SBP and DBP (r = 0.28; P = 0.04 and r = 0.32; P = 0.02), night-time SBP and DBP (r = 0.32; P = 0.01 and r = 0.27; P = 0.04). Fat mass was correlated with 24-h SBP (r = 0.46; P = 0.005), daytime SBP (r = 0.40; P = 0.01) and night-time SBP (r = 0.49; P = 0.03). No correlations were found between ABPM parameters and WHR. Furthermore, significant correlations were found between insulin resistance indexes, such as the homeostasis model assessment of insulin resistance and quantitative insulin-sensitivity check index, and 24-h DBP (r = 0.34; P = 0.01 and r = -0.29; P = 0.03), daytime DBP (r = 0.35; P = 0.009 and r = -0.34; P = 0.01) and daytime SBP (r = 0.32; P = 0.02 and r = -0.27; P = 0.04). Only 24-h and daytime DBP remained correlated with insulin resistance after adjustment for obesity. The analysis of the circadian rhythm of blood pressure revealed that 24 out the 56 children were non-dippers. CONCLUSIONS: The results of the present study indicate that adiposity and insulin resistance have an important role in influencing blood pressure in obese children, and also show a high prevalence of non-dipping phenomenon. This is of particular relevance because blood pressure tracks from childhood into adulthood and an already early-life high blood pressure is associated with an increased cardiovascular risk.