High leptin levels are associated with an unfavorable cardiometabolic risk profile. A number of studies found a positive association between leptin and vascular damage, but to date, no observational ...study has evaluated a potential predictive role of leptin for arterial stiffening. Therefore, the aim of this study was to estimate the role of leptin in the incidence of arterial stiffening (pulse pressure >60 mmHg) and changes in pulse pressure in an 8-year follow-up of a sample of adult men (The Olivetti Heart Study). The analysis included 460 men without baseline arterial stiffening and antihypertensive treatment at baseline and at follow-up (age: 50.0 years, BMI: 26.5 kg/m
). At the end of the follow-up period, the incidence of arterial stiffening was 8%. Baseline leptin was significantly greater in the group that developed arterial stiffening and was significantly correlated with pulse pressure changes over time (p < 0.05). According to the median plasma leptin distribution of the whole population, the sample was stratified into two groups: one with leptin levels above the median and the other with leptin levels below the median. Those who had baseline leptin levels above the median had a greater risk of developing arterial stiffening (odds ratio: 2.5, p < 0.05) and a greater increase in pulse pressure over time (beta: 2.1, p < 0.05), also after adjustment for confounders. The results of this prospective study indicate a predictive role of circulating leptin levels for vascular damage, independent of body weight and blood pressure.
The use of human pluripotent stem cells for in vitro disease modelling and clinical applications requires protocols that convert these cells into relevant adult cell types. Here, we report the rapid ...and efficient differentiation of human pluripotent stem cells into vascular endothelial and smooth muscle cells. We found that GSK3 inhibition and BMP4 treatment rapidly committed pluripotent cells to a mesodermal fate and subsequent exposure to VEGF-A or PDGF-BB resulted in the differentiation of either endothelial or vascular smooth muscle cells, respectively. Both protocols produced mature cells with efficiencies exceeding 80% within six days. On purification to 99% via surface markers, endothelial cells maintained their identity, as assessed by marker gene expression, and showed relevant in vitro and in vivo functionality. Global transcriptional and metabolomic analyses confirmed that the cells closely resembled their in vivo counterparts. Our results suggest that these cells could be used to faithfully model human disease.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Purpose
The World Health Organization recommends reduction of salt intake to < 5 g/day and the use of iodized salt to prevent iodine deficiency states. A high prevalence of excess salt consumption ...and an inadequate iodine intake has been previously shown in an Italian pediatric population. It was appropriate, therefore, to analyse in the same population the relationship occurring between salt consumption and iodine intake.
Methods
The study population was made of 1270 children and adolescents. Estimates of salt consumption and iodine intake were obtained by measuring 24 h urinary sodium and iodine excretion.
Results
The iodine intake increased gradually across quartiles of salt consumption independently of sex, age and body weight (
p
< 0.001). Median iodine intake met the European Food Safety Authority adequacy level only in teenagers in the highest quartile of salt consumption (salt intake > 10.2 g/day). We estimated that approximately 65–73% of the total iodine intake was derived from food and 27–35% from iodized salt and that iodized salt made actually only 20% of the total salt intake.
Conclusion
In this pediatric population, in face of an elevated average salt consumption, the use of iodized salt was still insufficient to ensure an adequate iodine intake, in particular among teenagers. In the perspective of a progressive reduction of total salt intake, the health institutions should continue to support iodoprophylaxis, in the context of the national strategies for salt reduction. In order for these policies to be successful, in addition to educational campaigns, it is needed that the prescriptions contained in the current legislation on iodoprophylaxis are made compelling through specific enforcement measures for all the involved stakeholders.
The blood brain barrier (BBB) has evolved unique characteristics such as dense coverage of the endothelial cells by pericytes and interactions with astrocytes through perivascular endfeet. We study ...BBB formation in a 3-dimensional multicellular spheroid system of human primary brain endothelial cells (hpBECs), primary pericytes (hpPs) and primary astrocytes (hpAs). We show for the first time that hpBECs, hpPs and hpAs spontaneously self-organize into a defined multicellular structure which recapitulates the complex arrangement of the individual cell types in the BBB structure. Pericytes play a crucial role mediating the interaction between hpBECs and hpAs. This process is not dependent on a scaffold support demonstrating that formation and cellular architecture of the BBB is intrinsically programmed within each specific cell type. In a matrigel setup the hpBECs, hpPs and hpAs also undergo self-arrangement to form endothelial tube-like structures tightly covered by hpPs and loosely attached hpAs mainly at the junctions.
Diabetic cardiomyopathy is a complication of type 2 diabetes, with known contributions of lifestyle and genetics. We develop environmentally and genetically driven in vitro models of the condition ...using human-induced-pluripotent-stem-cell-derived cardiomyocytes. First, we mimic diabetic clinical chemistry to induce a phenotypic surrogate of diabetic cardiomyopathy, observing structural and functional disarray. Next, we consider genetic effects by deriving cardiomyocytes from two diabetic patients with variable disease progression. The cardiomyopathic phenotype is recapitulated in the patient-specific cells basally, with a severity dependent on their original clinical status. These models are incorporated into successive levels of a screening platform, identifying drugs that preserve cardiomyocyte phenotype in vitro during diabetic stress. In this work, we present a patient-specific induced pluripotent stem cell (iPSC) model of a complex metabolic condition, showing the power of this technique for discovery and testing of therapeutic strategies for a disease with ever-increasing clinical significance.
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•Diabetic cardiomyopathy can be induced in vitro by environmental or genetic means•Diabetic patient-specific cardiomyocytes show baseline cardiomyopathy•The extent of patient-specific cardiomyopathy is clinically correlated•Phenotypic screening identifies drugs that rescue the disease phenotype
Diabetes causes pathological remodeling of cardiac muscle, which impairs heart function. Drawnel et al. use induced-pluripotent-stem-cell-derived cardiomyocytes to develop environmental and patient-specific in vitro models recapitulating the condition. These models are harnessed in a phenotypic screening assay that identifies candidate protective molecules.
A short G1 phase is a characteristic feature of mouse embryonic stem cells (ESCs). To determine if there is a causal relationship between G1 phase restriction and pluripotency, we made use of the ...Fluorescence Ubiquitination Cell Cycle Indicator (FUCCI) reporter system to FACS-sort ESCs in the different cell cycle phases. Hence, the G1 phase cells appeared to be more susceptible to differentiation, particularly when ESCs self-renewed in the naïve state of pluripotency. Transitions from ground to naïve, then from naïve to primed states of pluripotency were associated with increased durations of the G1 phase, and cyclin E-mediated alteration of the G1/S transition altered the balance between self-renewal and differentiation. LIF withdrawal resulted in a lengthening of the G1 phase in naïve ESCs, which occurred prior to the appearance of early lineage-specific markers, and could be reversed upon LIF supplementation. We concluded that the short G1 phase observed in murine ESCs was a determinant of naïve pluripotency and was partially under the control of LIF signaling.
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► We engineered mouse ES cells for live cell imaging of cell cycle progression. ► mESCs in the G1 phase have an increased susceptibility to differentiation. ► G1 phase duration varies according to the pluripotency state. ► LIF regulates the kinetics of G1 phase progression in naïve ES cells.
The right amount and quality of amino acids (AAs) supplied to patients on parenteral nutrition (PN) reduces muscle mass loss, may preserve or even increase it, with significant clinical benefits. ...Several industrial PN mixtures are available so that nutrition specialists can choose the product closest to the patient's needs. In selected cases, there is the possibility of personalizing compounded mixtures in a hospital pharmacy that completely meets the individual nutritional needs of PN patients. This narrative review deals with the AA solutions used in PN mixtures. The physiology, the methods to calculate the AA needs, and the AA and energy requirements suggested by scientific guidelines for each patient type are also reported.
Metabolic syndrome (MS) and its components are associated with greater cardiovascular risk. A number of studies found a positive association between MS and vascular damage, but few observational ...studies evaluated the predictive role of MS on arterial stiffening (AS). Therefore, the aim of this study was to estimate the ability of MS and its components to predict the risk of AS in an 8-year follow-up of a sample of adult men (Olivetti Heart Study).
The analysis included 778 men without AS (pulse pressure >60 mmHg) at baseline. A positive diagnosis of MS was made by recognized criteria, if at least three components were present.
At the end of the follow-up period, there was an incidence of 11% in AS. The percentage of participants that developed AS was greater in the MS group than those without MS, also after adjustment for main confounders (odds ratio: 2.5, 95% confidence interval: 1.3-4.9). The risk of AS also increased with increase in the numbers of MS elements (p for trend <.01). In addition, the analysis of the predictive role of the single MS component showed that high blood pressure (HBP) was the strongest predictor.
The results of this prospective study indicate a predictive role of MS on AS, independently of main confounders. In addition, HBP seems the strongest predictor of AS among MS components.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hypertension is the leading cause of death in developed countries and reduction of salt intake is recommended as a key preventive measure.
To assess the dietary sodium and potassium intakes in a ...national sample of Italian children and adolescents and to examine their relationships with BMI and blood pressure (BP) in the framework of the MINISAL survey, a program supported by the Italian Ministry of Health.
The study population included 1424 healthy subjects (766 boys, 658 girls) aged 6-18 years (mean age: 10.1±2.9) who were consecutively recruited in participating National Health Service centers in 10 Italian regions. Electrolyte intake was estimated from 24 hour urine collections tested for completeness by the concomitant measurement of creatinine content. Anthropometric indices and BP were measured with standardized procedures.
The average estimated sodium intake was 129 mmol (7.4 g of salt) per day among boys and 117 mmol (6.7 g of salt) among girls. Ninety-three percent of the boys and 89% of the girls had a consumption higher than the recommended age-specific standard dietary target. The estimated average daily potassium intakes were 39 mmol (1.53 g) and 36 mmol (1.40 g), respectively, over 96% of the boys and 98% of the girls having a potassium intake lower than the recommended adequate intake. The mean sodium/potassium ratio was similar among boys and girls (3.5 and 3.4, respectively) and over 3-fold greater than the desirable level. Sodium intake was directly related to age, body mass and BP in the whole population.
The Italian pediatric population is characterized by excessive sodium and deficient potassium intake. These data suggest that future campaigns should focus on children and adolescents as a major target in the framework of a population strategy of cardiovascular prevention.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Serum uric acid levels in humans are influenced by diet, cellular breakdown, and renal elimination, and correlate with blood pressure, metabolic syndrome, diabetes, gout, and cardiovascular disease. ...Recent genome-wide association scans have found common genetic variants of SLC2A9 to be associated with increased serum urate level and gout. The SLC2A9 gene encodes a facilitative glucose transporter, and it has two splice variants that are highly expressed in the proximal nephron, a key site for urate handling in the kidney. We investigated whether SLC2A9 is a functional urate transporter that contributes to the longstanding association between urate and blood pressure in man.
We expressed both SLC2A9 splice variants in Xenopus laevis oocytes and found both isoforms mediate rapid urate fluxes at concentration ranges similar to physiological serum levels (200-500 microM). Because SLC2A9 is a known facilitative glucose transporter, we also tested whether glucose or fructose influenced urate transport. We found that urate is transported by SLC2A9 at rates 45- to 60-fold faster than glucose, and demonstrated that SLC2A9-mediated urate transport is facilitated by glucose and, to a lesser extent, fructose. In addition, transport is inhibited by the uricosuric benzbromarone in a dose-dependent manner (Ki = 27 microM). Furthermore, we found urate uptake was at least 2-fold greater in human embryonic kidney (HEK) cells overexpressing SLC2A9 splice variants than nontransfected kidney cells. To confirm that our findings were due to SLC2A9, and not another urate transporter, we showed that urate transport was diminished by SLC2A9-targeted siRNA in a second mammalian cell line. In a cohort of men we showed that genetic variants of SLC2A9 are associated with reduced urinary urate clearance, which fits with common variation at SLC2A9 leading to increased serum urate. We found no evidence of association with hypertension (odds ratio 0.98, 95% confidence interval CI 0.9 to 1.05, p > 0.33) by meta-analysis of an SLC2A9 variant in six case-control studies including 11,897 participants. In a separate meta-analysis of four population studies including 11,629 participants we found no association of SLC2A9 with systolic (effect size -0.12 mm Hg, 95% CI -0.68 to 0.43, p = 0.664) or diastolic blood pressure (effect size -0.03 mm Hg, 95% CI -0.39 to 0.31, p = 0.82).
This study provides evidence that SLC2A9 splice variants act as high-capacity urate transporters and is one of the first functional characterisations of findings from genome-wide association scans. We did not find an association of the SLC2A9 gene with blood pressure in this study. Our findings suggest potential pathogenic mechanisms that could offer a new drug target for gout.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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