Vitamin D supplementation and adverse skeletal and non-skeletal outcomes in individuals at increased cardiovascular risk: Results from the International Polycap Study (TIPS)-3 randomized controlled trial.

BACKGROUND AND AIMS: Vitamin D has mostly been tested in Western populations. We examined the effect of high dose vitamin D in a population drawn predominantly from outside of Western countries. METHODS AND RESULTS: This randomized trial tested vitamin D 60,000 IU monthly in 5670 participants without vascular disease but at increased CV risk. The primary outcome was fracture. The secondary outcome was the composite of CV death, myocardial infarction stroke, cancer, fracture or fall. Death was a pre-specified outcome. Mean age was 63.9 years, and 3005 (53.0%) were female. 3034 (53.5%) participants resided in South Asia, 1904 (33.6%) in South East Asia, 480 (8.5%) in South America, and 252 (4.4%) in other regions. Mean follow-up was 4.6 years. A fracture occurred in 20 participants (0.2 per 100 person years) assigned to vitamin D, and 19 (0.1 per 100 person years) assigned to placebo (HR 1.06, 95% CI 0.57-1.99, p-value = 0.86). The secondary outcome occurred in 222 participants (1.8 per 100 person years) assigned to vitamin D, and 198 (1.6 per 100 person years) assigned to placebo (HR 1.13, 95% CI 0.93-1.37, p = 0.22). 172 (1.3 per 100 person years) participants assigned to vitamin D died, compared with 135 (1.0 per 100 person years) assigned to placebo (HR 1.29, 95% CI 1.03-1.61, p = 0.03). CONCLUSION: In a population predominantly from South Asia, South East Asia and South America, high-dose vitamin D did not reduce adverse skeletal or non-skeletal outcomes. Higher mortality was observed in the vitamin D group. REGISTRATION NUMBER: NCT01646437.

Psychosocial factors and obesity in 17 high-, middle- and low-income countries: the Prospective Urban Rural Epidemiologic study.

BACKGROUND/OBJECTIVES: Psychosocial stress has been proposed to contribute to obesity, particularly abdominal, or central obesity, through chronic activation of the neuroendocrine systems. However, these putative relationships are complex and dependent on country and cultural context. We investigated the association between psychosocial factors and general and abdominal obesity in the Prospective Urban Rural Epidemiologic study. SUBJECTS/METHODS: This observational, cross-sectional study enrolled 151 966 individuals aged 35-70 years from 628 urban and rural communities in 17 high-, middle- and low-income countries. Data were collected for 125 290 individuals regarding education, anthropometrics, hypertension/diabetes, tobacco/alcohol use, diet and psychosocial factors (self-perceived stress and depression). RESULTS: After standardization for age, sex, country income and urban/rural location, the proportion with obesity (body mass index ≥30 kg m(-)(2)) increased from 15.7% in 40 831 individuals with no stress to 20.5% in 7720 individuals with permanent stress, with corresponding proportions for ethnicity- and sex-specific central obesity of 48.6% and 53.5%, respectively (P<0.0001 for both). Associations between stress and hypertension/diabetes tended to be inverse. Estimating the total effect of permanent stress with age, sex, physical activity, education and region as confounders, no relationship between stress and obesity persisted (adjusted prevalence ratio (PR) for obesity 1.04 (95% confidence interval: 0.99-1.10)). There was no relationship between ethnicity- and sex-specific central obesity (adjusted PR 1.00 (0.97-1.02)). Stratification by region yielded inconsistent associations. Depression was weakly but independently linked to obesity (PR 1.08 (1.04-1.12)), and very marginally to abdominal obesity (PR 1.01 (1.00-1.03)). CONCLUSIONS: Although individuals with permanent stress tended to be slightly more obese, there was no overall independent effect and no evidence that abdominal obesity or its consequences (hypertension, diabetes) increased with higher levels of stress or depression. This study does not support a causal link between psychosocial factors and abdominal obesity.

Angiogenic imbalance and plasma lipid alterations in women with preeclampsia from a developing country.

BACKGROUND: An imbalance between anti-angiogenic factors (e.g. soluble vascular endothelial growth factor receptor-1 (s-FLT1) and soluble endoglin (s-Eng)) and pro-angiogenic factors (e.g. placental growth factor (PlGF)) as well as increased oxidized low-density lipoprotein (ox-LDL) concentrations have been associated with preeclampsia (PE). Risk factors associated with the development of PE, however, are known to be different between developed and developing countries. The aim of the study was to determine the levels of s-FLT1, s-Eng, PIGF, and ox-LDL in women with PE from a developing country. METHODS: A multi-center case-control study was conducted. One hundred and forty three women with PE were matched by age and parity with 143 healthy pregnant women without cardiovascular or endocrine diseases. Before delivery, blood samples were taken and serum was stored until analysis. RESULTS: Women with PE had lower concentrations of PIGF (p<0.0001) and higher concentrations of s-Eng (p=0.001) than healthy pregnant women. There were no differences between the groups regarding ox-LDL or s-FLT1. Women with early onset PE had higher s-FLT1 concentrations (p=0.0004) and lower PIGF concentrations (p<0.0001) than their healthy pregnant controls. Women with late onset PE had higher concentrations of s-Eng (p=0.005). Women with severe PE had higher concentrations of s-Eng (p=0.0008) and ox-LDL (p=0.01), and lower concentrations of PIGF (p<0.0001). CONCLUSIONS: Women with PE from a developing country demonstrated an angiogenic imbalance and an increased rate of LDL oxidation. Findings from this study support the theory that PE is a multifactorial disease, and understanding differences in these subpopulations may provide a better target to approach future therapies.

Estudio neuroepidemiologico en la comunidad urbana de Piedecuesta, Santander / Neuroepidemiology study in Piedecuesta, Colombia

Introducción: las enfermedades neurológicas (EN) son una importante causa de morbilidad, mortalidad, incapacidad, deterioro en la calidad de vida y ausentismo laboral. Por ello son entidades que ocasionan una alta demanda de recursos por concepto de atención médica e invalidez. Objetivo: determinar la prevalencia de las EN más comunes en la práctica médica como son: migraña, enfermedad cerebrovascular, enfermedad extrapiramidal, neuropatía periférica, retardo mental, epilepsia, demencia y secuelas de trauma craneoencefálico. Identificar los factores de riesgo para retardo del neurodesarrollo (RND). Material y método: estudio poblacional, descriptivo de corte transversal, realizado en el municipio de Piedecuesta, ubicado a 30 minutos de la ciudad de Bucaramanga. Como instrumento se aplicó el protocolo de neuroepidemiología de la OMS modificado. El trabajo de campo se inició con un mapeo del área, sensibilización de la comunidad y aplicación de las encuestas casa a casa. Los casos sospechosos de padecer EN se evaluaron por el médico neurólogo. La información fue procesada en una base de datos en el paquete estadístico Epi Info 6,04d y se realizó un análisis de tipo descriptivo determinando prevalencias en personas por mil habitantes con sus respectivos intervalos de confianza del 95por ciento (IC). Los valores OR y p fueron calculados mediante la prueba de Mantel y Haenzel para datos pareados, se modelaron dos regresiones logísticas condicionales de efectos fijos. Resultados: de los 1.586 encuestados, 389 fueron sospechosos de padecer EN; adicionalmente, se evaluaron como control 34 sujetos no sospechosos. En 329 casos fue confirmada la sospecha de EN. Las enfermedades en orden de prevalencia por mil habitantes fueron migraña 194,2 (IC: 193,2-195,2), demencias en mayores de 50 años 42,7 (IC: 42,2-43,2), neuropatía periférica 19,6 (IC: 18,6-20,5), secuelas de trauma craneoencefálico 17,7 (IC: 16,7-18,6), retardo del neurodesarrollo 12,0 (IC: 11,0-13,0), enfermedades extrapiramidales 9,5 (IC: 8,5-10,4), epilepsia 8,8 (IC: 7,9-9,8) y enfermedad cerebrovascular 5,7 (IC: 4,7-6,7). Dentro del estudio de factores de riesgo para RND, se identificaron 17 casos, que fueron comparados con 63 controles pareados por edad; se detectó asociación con el hecho de referir el haber "nacido morado" (p=0,048); el mayor número de hermanos (p=0,079) y la menor edad materna (p=0,095) hacen como posibles factores de riesgo

Elevated C-reactive protein and pro-inflammatory cytokines in Andean women with pre-eclampsia.

OBJECTIVE: To investigate the concentration of markers of inflammation in non-pregnant women, women with normal pregnancy and women with pre-eclampsia. METHODS: Pregnant women (n=26), women with pre-eclampsia (n=25) and non-pregnant normotensive women (n=21) were included in the study. C-reactive protein was measured by latex-enhanced immunoturbidimetric assay, serum tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) by high sensitivity ELISA. Kruskal-Wallis non-parametric analysis of variance followed by the Mann-Whitney U-test were used for statistical analyses. RESULTS: Higher values (mean+/-S.E.M.) of C-reactive protein were found in pre-eclampsia (4.11+/-0.37 mg/dl) compared with normal pregnant women (2.49+/-0.26 mg/dl) and non-pregnant controls (1.33+/-0.15 mg/dl). TNF-alpha was significantly higher in women with pre-eclampsia (15.74+/-5.09 pg/ml), in relation to the control group (2.76+/-0.41 pg/ml) and women with normal pregnancy (8.31+/-1.55 pg/ml). IL-6 levels were significantly higher in pre-eclamptic women (12.91+/-1.29 pg/ml) compared with normal pregnant (5.07+/-0.423 pg/ml) and control women (1.25+/-0.13 pg/ml). CONCLUSIONS: The results of this cross-sectional study in a high-risk Andean population show that both C-reactive protein and pro-inflammatory cytokines are present in higher concentrations in women with pre-eclampsia. The study was undertaken in women with established pre-eclampsia and it is not possible to determine whether the increased concentrations of C-reactive protein and pro-inflammatory cytokines were a cause or consequence of the disease.

Preeclampsia: from epidemiological observations to molecular mechanisms

Preeclampsia is the main cause of maternal mortality and is associated with a five-fold increase in perinatal mortality in developing countries. In spite of this, the etiology of preeclampsia is unknown. The present article analyzes the contradictory results of the use of calcium supplementation in the prevention of preeclampsia, and tries to give an explanation of these results. The proposal of an integrative model to explain the clinical manifestations of preeclampsia is discussed. In this proposal we suggest that preeclampsia is caused by nutritional, environmental and genetic factors that lead to the creation of an imbalance between the free radicals nitric oxide, superoxide and peroxynitrate in the vascular endothelium. The adequate interpretation of this model would allow us to understand that the best way of preventing preeclampsia is the establishment of an adequate prenatal control system involving adequate antioxidant vitamin and mineral supplementation, adequate diagnosis and early treatment of asymptomatic urinary and vaginal infections. The role of infection in the genesis of preeclampsia needs to be studied in depth because it may involve a fundamental change in the prevention and treatment of preeclampsia

Colombian study to assess the use of noninvasive determination of endothelium-mediated vasodilatation (CANDEV). Normal values and factors associated.

The endothelium plays a critical role in vascular homeostasis. Recently, a noninvasive method has been developed to assess flow mediated vasodilatation of the brachial artery (FMD). This test is remarkably stable overtime but no clear set of normal values has been developed. The purposes of our study were to evaluate the accuracy and reproducibility and to identify a set of normal values of FMD. We included 253 normotensive healthy volunteers from three Colombian cities (mean age: 38.2 years; 33% were women). All subjects underwent ultrasound evaluation of endothelial and smooth muscle function. Flow mediated vessel diameter change was measured by two independent observers. The interobserver Lin's concordance correlation coefficient was 0.88% (95% CI: 0.82, 0.94) and there was no evidence of systematic difference between the two measurements (mean difference of -0.30% with limits of agreement of -4.48 to 3.87). Mean %FMD was 11.98% (95% CI: 11.36, 12.61), 13.32% (95% CI: 12.39, 14.25) in women and 11.32% (95% CI: 10.52, 12.13) in men. Subjects with no cardiovascular risk factors had a mean %FMD of 13.74% (95% CI: 13.14, 14.35), in contrast to a mean of only 7.40% (95% CI: 4.33, 9.91) in those with at least one risk factor. A %FMD cut point of 10.4 had a sensitivity of 71.2% and an specificity of 77.2% to identify subjects with at least one cardiovascular risk factor. Using this cut point, endothelial dysfunction was 3.13 times more frequent in subjects with than in subjects without cardiovascular risk factors (95% CI: 2.30, 4.25). In addition, obesity, smoking and hypercholesterolemia were the modifiable risk factors with largest independent significant reduction effects on %FMD. FMD measurements can be made with high accuracy and precision, and a cut point of 10.4% is useful to discriminate between subjects with and without cardiovascular risk factors, and can be recommended as a screening test for the detection of patients at risk of CVD.

Improvement in functions of the central nervous system by estrogen replacement therapy might be related with an increased nitric oxide production.

Estrogen promotes neurons growth, prevents neuronal cell atrophy and regulates synaptic plasticity. Administration of estrogen protects neurons against oxidative stress, excitotoxins, and beta-amyloid-induced toxicity in cell culture. It has been shown that estrogen treatment reduces the serum monoamino oxidase levels and might regulate learning and memory. Nitric oxide (NO) is a retrograde messenger and long-term potentiation can be block using NO-synthase inhibitors or can be prevent with NO-scavengers. NO synthase is widespread in the central nervous system and acts as neurotransmitter/neuromodulator. The actions of serotonin, bradykinin, endothelin, acetylcholine and noradrenaline might be linked to NO formation. Estrogen induces activity of constitutive NO synthase and estrogen replacement therapy in postmenopausal women increases significantly circulating nitrite plus nitrate levels. The effect of estrogen on NO synthesis is rapid and is maintained with repeated administration. We demonstrated the effects of estrogen replacement therapy in Andean postmenopausal women were associated with a significantly increase in plasma levels of nitrite plus nitrate. Our hypothesis is that beneficial effect of estrogen replacement therapy on involutive depression in postmenopausal women is mediated by increase in NO production by central nervous system.

Prevention of preeclampsia with calcium supplementation and its relation with L-arginine: citric oxide pathway

Pregnancy-induced hypertension (PIH) remains a common cause of maternal and fetal morbidity and mortality. During the past 7 years, some progress has been made in the prevention of PIH. Specifically, clinical studies have shown that supplementation with calcium can significantly reduce the frequency of PIH, especially in populations with a low calcium intake. We have suggested that, in such a population, calcium supplementation is a safe and effective measure for reducing the incidence of PIH. Calcium supplementation reduces the risk of PIH by maintaining the serum ionized calcium level which is crucial for the production of endothelial nitric oxide, the increased generation of which maintains the vasodilatation that is characteristic of normal pregnancy. In PIH there is an impaired nitric oxide synthesis and cyclic GMP production.

Systemic effects of S-nitroso-glutathione in the human following intravenous infusion.

Nitric oxide (NO) is a potent vasodilator and inhibitor of platelet aggregation. At present the clinical use of NO donors as inhibitors of platelet activation is limited by their concomitant hypotensive effect. The new NO donor S-nitroso-glutathione (GSNO) has a significant antiplatelet effect at doses that cause only a small decrease in blood pressure in rats. We have examined the antiplatelet and vasodilator properties of this nitrosothiol following systemic intravenous infusion in the human. GSNO was administered intravenously to 10 normal females of reproductive age noting changes in blood pressure, pulse and reported side effects. Ex vivo platelet aggregation to ADP was then performed in a platelet-ionized calcium lumiaggregometer on blood samples taken both before and after the infusions. Side effects such as headache or palpitations occurred only in two subjects at the highest infusion rate of 250 micrograms min-1. Blood pressure and pulse did not vary significantly during the study. Ex vivo platelet aggregation in response to ADP was significantly reduced by the infusion. These results suggest that GSNO is a more potent inhibitor of platelet activation than it is a vasodilator and therefore potentially represents a more clinically useful NO donor than has so far been available where an anti-thrombotic effect is required.

[Nitric oxide: from endogenous vasodilator to biologic mediator]. / El óxido nítrico: de vasodilatador endógeno a mediador biológico.

This paper review the actual knowledges about the physiological role of nitric oxide, sintetized from amino acid L-arginine. The nitric oxide sintetized in the vascular endothelium has a fundamental role in vascular tone, blood flow and arterial pressure control, acting stimulating guanylate cyclase on vascular smooth muscle. Nitric oxide could be considered the endogenous nitrovasodilator. Its action on the cardiovascular system are imitated by nitroglycerine, sodium nitroprusside and related compounds. Probably the disturbance in the synthesis or release of nitric oxide may be involved in the pathophysiology of hypertension, vasospasm and atherosclerosis. Recently has been shown that nitric oxide synthesis from L-arginine also occurs in other different cells like macrophages, central nervous system, liver, neutrophils, adrenal glands, playing different biological effects. Changes in nitric oxide synthesis or action in those systems, could be related to different pathological disorders as inflammation, atherosclerosis and cancer. The found of a substance as simple as nitric oxide, let suppose that we are in the presence of a biological mediator with a very early evolutionary origin, probably widespread in all the animal kingdom, and which represents the universal transduction system for activation of the soluble guanylate cyclase enzyme.

Effect of gonadal steroids on hypothalamus and anterior pituitary endo-oligopeptidase B (proline-endopeptidase) activity in castrated female rats.

In the present study we investigated the possible participation of endo-oligopeptidase B (poline-endopeptidase) in the control of gonadotrophin secretion through the control of LH-RH inactivation. This enzyme selectively hydrolyzes the Pro9-Gly10-NH2 peptide bond of LH-RH, thereby inactivating this substance. The enzyme activity was evaluated using a specific colorimetric substrate, i.e., Z-Gly-Pro-SM. Female adult Wistar rats were submitted to castration, experimental situations that are known to produce changes in gonadotrophin secretion. Hypothalamic and pituitary endo-oligopeptidase B activity was shown to be present predominantly in the soluble fraction of the enzyme preparations. The results also indicated that endo-oligopeptidase B activity adult female rat pituitary decreased after castration and increased after administration of estradiol and progesterone to castrated animals. The present results lead us to suggest that anterior pituitary endo-oligopeptidase B may be related to the control gonadotrophin secretion in female rats.