High heritability of ambulatory blood pressure in families of East African descent.

We estimated the heritability of ambulatory systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) in east African families with at least 2 hypertensive siblings and living in the Seychelles islands (Indian Ocean). The sample consisted of 314 individuals (147 men and 167 women), both normotensive and hypertensive, from 76 pedigrees (mean+/-SD of 4.1+/-2.8 persons per pedigree). After a 2-week off-treatment period, daytime and nighttime ambulatory blood pressure (BP) was monitored. Office BP was measured with a standard mercury sphygmomanometer. We estimated by maximum likelihood the age- and sex-adjusted heritabilities from the additive polygenic component of the variance of the traits allowing for the presence of other familial correlations. We also adjusted for ascertainment (ie, for the fact that 2 siblings had to be hypertensive) and examined the effect of adjusting for body mass index, 24-hour urinary excretion of sodium and potassium, plasma renin activity, and plasma aldosterone concentration. Heritability estimates (+/-SE) for ambulatory SBP, DBP, and PP were, respectively, 0.37+/-0.12/0.24+/-0.12/0.54+/-0.12 for daytime and 0.34+/-0.13/ 0.37+/-0.15/0.47+/-0.12 for nighttime measurements (P<0.05 for all estimates). Heritability estimates for office SBP, DBP, and PP were, respectively, 0.20+/-0.11, 0.05+/-0.09, and 0.37+/-0.12. Heritability estimates for SBP varied markedly according to whether participants were treated for hypertension at baseline. The present data show that ambulatory BP and PP have a high heritability in families of African descent. They also demonstrate that antihypertensive treatment and the number of BP measurements have a major influence on the heritability estimates.

Selective distribution of lactate dehydrogenase isoenzymes in neurons and astrocytes of human brain.

In vertebrates, the interconversion of lactate and pyruvate is catalyzed by the enzyme lactate dehydrogenase. Two distinct subunits combine to form the five tetrameric isoenzymes of lactate dehydrogenase. The LDH-5 subunit (muscle type) has higher maximal velocity (Vmax) and is present in glycolytic tissues, favoring the formation of lactate from pyruvate. The LDH-1 subunit (heart type) is inhibited by pyruvate and therefore preferentially drives the reaction toward the production of pyruvate. There is mounting evidence indicating that during activation the brain resorts to the transient glycolytic processing of glucose. Indeed, transient lactate formation during physiological stimulation has been shown by 1H-magnetic resonance spectroscopy. However, since whole-brain arteriovenous studies under basal conditions indicate a virtually complete oxidation of glucose, the vast proportion of the lactate transiently formed during activation is likely to be oxidized. These in vivo data suggest that lactate may be formed in certain cells and oxidized in others. We therefore set out to determine whether the two isoforms of lactate dehydrogenase are localized to selective cell types in the human brain. We report here the production and characterization of two rat antisera, specific for the LDH-5 and LDH-1 subunits of lactate dehydrogenase, respectively. Immunohistochemical, immunodot, and western-blot analyses show that these antisera specifically recognize their homologous antigens. Immunohistochemistry on 10 control cases demonstrated a differential cellular distribution between both subunits in the hippocampus and occipital cortex: neurons are exclusively stained with the anti-LDH1 subunit while astrocytes are stained by both antibodies. These observations support the notion of a regulated lactate flux between astrocytes and neurons.

Selective inhibition of CTL activation by a dipalmitoyl-phospholipid that prevents the recruitment of signaling molecules to lipid rafts.

Antigen-specific T-cell activation implicates a redistribution of plasma membrane-bound molecules in lipid rafts, such as the coreceptors CD8 and CD4, the Src kinases Lek and Fyn, and the linker for activation of T cells (LAT), that results in the formation of signaling complexes. These molecules partition in lipid rafts because of palmitoylation of cytoplasmic, membrane proximal cysteines, which is essential for their functional integrity in T-cell activation. Here, we show that exogenous dipalmitoyl-phosphatidylethanolamine (DPPE), but not the related unsaturated dioleoyl-phosphatidylethanolamine (DOPE), partitions in lipid rafts. DPPE inhibits activation of CD8(+) T lymphocytes by sensitized syngeneic antigen-presenting cells or specific major histocompatibility complex (MHC) peptide tetramers, as indicated by esterase release and intracellular calcium mobilization. Cytotoxic, T lymphocyte (CTL)-target cell conjugate formation is not affected by DPPE, indicating that engagement of the T-cell receptor by its cognate ligand is intact in lipid-treated cells. In contrast to other agents known to block raft-dependent signaling, DPPE efficiently inhibits the MHC peptide-induced recruitment of palmitoylated signaling molecules to lipid rafts and CTL activation without affecting cell viability or lipid raft integrity.

Effect of weight reduction in moderately overweight patients on recorded ambulatory blood pressure and free cytosolic platelet calcium.

Although platelet cytosolic calcium has been shown to decrease during pharmacological treatment of hypertension, there is no evidence that cytosolic calcium also falls during a nonpharmacological reduction in blood pressure. To provide such evidence, we examined prospectively the relation between platelet cytosolic calcium and ambulatory blood pressure during weight reduction in moderately overweight (body mass index [BMI] greater than 25), mildly hypertensive individuals. The experimental group (responders: BMI reduction greater than 5%) consisted of 19 patients who lost 8.5 +/- 2.9 kg (mean +/- SD, p less than 0.05) during a 10-week hypocaloric diet, whereas the control group (nonresponders: BMI reduction less than 5%) consisted of 12 patients who showed no relevant change in body weight (-2.0 +/- 1.3 kg) during the same period of time. The moderate weight loss of the responders decreased blood pressure by 14/5 mm Hg (p less than 0.05), as measured by ambulatory monitoring, which renders a placebo effect unlikely. This nonpharmacological reduction in blood pressure was accompanied by a proportional 11% decrease (p less than 0.05) in platelet cytosolic calcium and also by significant (p less than 0.05) decreases in plasma catecholamines and serum cholesterol. These findings establish the concept of a nonpharmacological reduction in free cytosolic platelet calcium in humans and add further evidence suggesting a link between intracellular calcium homeostasis and blood pressure regulation.

Functional analysis of Ectodysplasin-A mutations causing selective tooth agenesis.

Mutations of the Ectodysplasin-A (EDA) gene are generally associated with the syndrome hypohidrotic ectodermal dysplasia (MIM 305100), but they can also manifest as selective, non-syndromic tooth agenesis (MIM300606). We have performed an in vitro functional analysis of six selective tooth agenesis-causing EDA mutations (one novel and five known) that are located in the C-terminal tumor necrosis factor homology domain of the protein. Our study reveals that expression, receptor binding or signaling capability of the mutant EDA1 proteins is only impaired in contrast to syndrome-causing mutations, which we have previously shown to abolish EDA1 expression, receptor binding or signaling. Our results support a model in which the development of the human dentition, especially of anterior teeth, requires the highest level of EDA-receptor signaling, whereas other ectodermal appendages, including posterior teeth, have less stringent requirements and form normally in response to EDA mutations with reduced activity.

Fitness, sport et pression artérielle [Fitness, sports and blood pressure].

Blood pressure is lowered for a few hours after aerobic exercise, but also after resistance exercise, although for a shorter period of time. An exercise program can significantly lower resting and ambulatory BP measurements. Multiple mechanisms interact for the BP lowering effect, such as decreased total peripheral resistance, enhanced endothelial function, diminished sympathetic or rennin plasmatic activity, structural vascular modifications and baroreceptor reflex modulation. New exercises like eccentric or isometric (handgrip) contractions are promising. Resistance activities have long been considered dangerous for blood vessels because of increased arterial stiffness, but if the intensity remains moderate and aerobic exercises are integrated, then the effects are altogether beneficial.

Blood pressure changes in acute ischemic stroke and outcome with respect to stroke etiology.

OBJECTIVE: Previous research suggested that proper blood pressure (BP) management in acute stroke may need to take into account the underlying etiology. METHODS: All patients with acute ischemic stroke registered in the ASTRAL registry between 2003 and 2009 were analyzed. Unfavorable outcome was defined as modified Rankin Scale score >2. A local polynomial surface algorithm was used to assess the effect of baseline and 24- to 48-hour systolic BP (SBP) and mean arterial pressure (MAP) on outcome in patients with lacunar, atherosclerotic, and cardioembolic stroke. RESULTS: A total of 791 patients were included in the analysis. For lacunar and atherosclerotic strokes, there was no difference in the predicted probability of unfavorable outcome between patients with an admission BP of <140 mm Hg, 140-160 mm Hg, or >160 mm Hg (15.3 vs 12.1% vs 20.8%, respectively, for lacunar, p = 015; 41.0% vs 41.5% vs 45.5%, respectively, for atherosclerotic, p = 075), or between patients with BP increase vs decrease at 24-48 hours (18.7% vs 18.0%, respectively, for lacunar, p = 0.84; 43.4% vs 43.6%, respectively, for atherosclerotic, p = 0.88). For cardioembolic strokes, increase of BP at 24-48 hours was associated with higher probability of unfavorable outcome compared to BP reduction (53.4% vs 42.2%, respectively, p = 0.037). Also, the predicted probability of unfavorable outcome was significantly different between patients with an admission BP of <140 mm Hg, 140-160 mm Hg, and >160 mm Hg (34.8% vs 42.3% vs 52.4%, respectively, p < 0.01). CONCLUSIONS: This study provides evidence to support that BP management in acute stroke may have to be tailored with respect to the underlying etiopathogenetic mechanism.

The association of aldosterone with obesity-related hypertension and the metabolic syndrome.

Overweight and obesity are associated with arterial hypertension. Given the large increase in the obesity prevalence worldwide, the number of obese patients with hypertension is likely to increase substantially in the near future. Overweight and obese patients are exposed to an important metabolic and cardiovascular risk. The understanding of the mechanisms linking obesity to hypertension is important for specific prevention and therapy in this population. There is some evidence that obesity is associated with an increased aldosterone level. To date, 2 mechanisms may explain the interaction of fat tissue with the renin-angiotensin-aldosterone system, and therefore explain, in part, obesity-related hypertension. First, human adipose tissue produces several components of the renin-angiotensin-aldosterone system, mainly adipose tissue-derived angiotensinogen. Second, increased fatty acid production in the obese patient, especially nonesterified fatty acids, might stimulate aldosterone production, independent of renin. A better understanding of these mechanisms might have implications for the management of hypertension in overweight and obese patients. Because aldosterone also is associated with blood glucose and blood lipids, selective aldosterone blockade may represent a particularly attractive therapeutic strategy in obese patients with a clustering of cardiovascular risk factors.

Vasopressin dilates the rat carotid artery by stimulating V1 receptors.

The acute effects of various vasopressor agents on the diameter of the common carotid artery were studied in halothane-anesthetized normotensive rats. The animals were infused intravenously for 60 min with equipressor doses of angiotensin II (10 ng/min), the alpha1-stimulant methoxamine (5 microg/min), lysine vasopressin (5 mU/min), or vehicle. The arterial diameter was measured by using a high-resolution ultrasonic echo-tracking device. The three vasoconstrictors increased the carotid artery diameter, but this effect was significantly more pronounced with lysine vasopressin. Even a nonpressor dose of lysine vasopressin (1 mU/min) caused a significant increase in the arterial diameter. The lysine vasopressin-induced vasodilatation could be prevented by the administration of d(CH2)5Tyr(Me)AVP (10 microg, i.v.), a selective V1-vasopressinergic receptor antagonist. These data therefore suggest that a short-term increase in blood pressure induces in rats a distention of the carotid artery. The increase in arterial diameter seems to involve an active mechanism with lysine vasopressin caused by the stimulation of V1-vasopressinergic receptors.

The selective migration of young graduates : which of them return to their rural home region and which do not?

This paper addresses the migration behaviours of young university graduates from a rural region in Switzerland. Based on a questionnaire survey, it compares graduates' current place of residence (i.e. whether or not they returned to their home region) with characteristics related to their socio-familial, migration and professional trajectories. The propensity to return varies not only according to labour market variables (employment opportunities), but also to other factors, some of which have even more influence than job opportunities. The graduates' life course position (kind of household), their partners' characteristics (level of education and home region) and their family background (socio-economic status and history of migration) all play a central role. On the whole, results show that migration appears as a selective and complex process embedded in the life course of graduates.

Assessing heterogeneity of effects on blood pressure in a meta-analysis of pharmacist interventions trials

Background: Recent reviews of randomized control trials have shown that pharmacist interventions improve cardiovascular diseases (CVD) risk factors in outpatients. Various interventions were evaluated in different settings, and a substantial heterogeneity was observed in the effect estimates. To better express uncertainties in the effect estimates, prediction intervals (PI) have been proposed but are, however, rarely reported. Objective: Pooling data from two systematic reviews, we estimated the effect of pharmacist interventions on systolic blood pressure (BP), computed PI, and evaluated potential causes of heterogeneity. Methods: Data were pooled from systematic reviews assessing the effect of pharmacist interventions on CVD risk factors in patients with or without diabetes, respectively. Effects were estimated using random effect models. Results: Systolic BP was the outcome in 31 trials including 12 373 patients. Pharmacist interventions included patient educational interventions, patient-reminder systems, measurement of BP, medication management and feedback to physician, or educational intervention to health care professionals. Pharmacist interventions were associated with a large reduction in systolic BP (-7.5 mmHg; 95% CI: -9.0 to -5.9). There was a substantial heterogeneity (I2: 66%). The 95% PI ranged from -13.9 to -1.0 mmHg. The effect tended to be larger if the intervention was conducted in a community pharmacy and if the pharmacist intervened at least monthly. Conclusion: On average, the effect of pharmacist interventions on BP was substantial. However, the wide PI suggests that the effect differed between interventions, with some having modest effects and others very large effects on BP. Part of the heterogeneity could be due to differences in the setting and in the frequency of the interventions.

Selective expression of the V beta 14 T cell receptor on Leishmania guyanensis--specific CD8+ T cells during human infection.

Peripheral blood mononuclear cells from subjects never exposed to Leishmania were stimulated with Leishmania guyanensis. We demonstrated that L. guyanensis-stimulated CD8(+) T cells produced interferon (IFN)- gamma and preferentially expressed the V beta 14 T cell receptor (TCR) gene family. In addition, these cells expressed cutaneous lymphocyte antigen and CCR4 surface molecules, suggesting that they could migrate to the skin. Results obtained from the lesions of patients with localized cutaneous leishmaniaisis (LCL) showed that V beta 14 TCR expression was increased in most lesions (63.5%) and that expression of only a small number of V beta gene families (V beta 1, V beta 6, V beta 9, V beta 14, and V beta 24) was increased. The presence of V beta 14 T cells in tissue confirmed the migration of these cells to the lesion site. Thus, we propose the following sequence of events during infection with L. guyanensis. After initial exposure to L. guyanensis, CD8(+) T cells preferentially expressing the V beta 14 TCR and secreting IFN- gamma develop and circulate in the periphery. During the infection, these cells migrate to the skin at the site of the parasitic infection. The role of these V beta 14 CD8(+) T cells in resistance to infection remains to be determined conclusively.