Obese and fit adolescents have lower blood pressure levels than obese and unfit counterparts.

The aim of the study was to assess the effects of physical fitness on the relationships between body mass index (BMI) and body fat (BF) on blood pressure (BP) levels. Cross-sectional study conducted in 25 schools of Lisbon (Portugal), including 2041 boys and 1995 girls aged 10-18. BF was assessed by bioimpedance. Cardiovascular fitness was assessed by the 20-meter shuttle run and classified as fit/unfit. Obesity (BMI or BF defined) was defined according to international criteria. In both sexes, BMI was positively related with systolic and diastolic BP, while BF was only positively related with diastolic BP z-scores. No interaction was found between fitness and BMI categories regarding BP levels, while for BF a significant interaction was found. Being fit reduced the BF-induced increase in the Odds ratio (OR) of presenting with high BP: OR (95% confidence interval) 1.01 (0.73-1.40) and 0.99 (0.70-1.38) for overweight and obese fit boys, respectively, the corresponding values for unfit overweight and obese boys being 1.33 (0.94-1.90) and 1.75 (1.34-2.28), respectively. The values were 0.88 (0.57-1.35) and 1.66 (0.98-2.80) for overweight and obese fit girls, respectively, the corresponding values for unfit overweight and obese being 1.63 (1.12-2.37) and 1.90 (1.32-2.73) respectively. No interaction was found between fitness and BMI-defined overweight and obesity. Being fit reduces the negative impact of BF on BP levels and high BP status in adolescents. This protective effect was not found with BMI.

Short-term moderate hypocapnia augments detection of optimal cerebral perfusion pressure.

An autoregulation-oriented strategy has been proposed to guide neurocritical therapy toward the optimal cerebral perfusion pressure (CPPOPT). The influence of ventilation changes is, however, unclear. We sought to find out whether short-term moderate hypocapnia (HC) shifts the CPPOPT or affects its detection. Thirty patients with traumatic brain injury (TBI), who required sedation and mechanical ventilation, were studied during 20 min of normocapnia (5.1±0.4 kPa) and 30 min of moderate HC (4.4±3.0 kPa). Monitoring included bilateral transcranial Doppler of the middle cerebral arteries (MCA), invasive arterial blood pressure (ABP), and intracranial pressure (ICP). Mx -autoregulatory index provided a measure for the CPP responsiveness of MCA flow velocity. CPPOPT was assessed as the CPP at which autoregulation (Mx) was working with the maximal efficiency. During normocapnia, CPPOPT (left: 80.65±6.18; right: 79.11±5.84 mm Hg) was detectable in 12 of 30 patients. Moderate HC did not shift this CPPOPT but enabled its detection in another 17 patients (CPPOPT left: 83.94±14.82; right: 85.28±14.73 mm Hg). The detection of CPPOPT was achieved via significantly improved Mx-autoregulatory index and an increase of CPP mean. It appeared that short-term moderate HC augmented the detection of an optimum CPP, and may therefore usefully support CPP-guided therapy in patients with TBI.

Preretinal partial pressure of oxygen gradients before and after experimental pars plana vitrectomy.

PURPOSE: To evaluate preretinal partial pressure of oxygen (PO2) gradients before and after experimental pars plana vitrectomy. METHODS: Arteriolar, venous, and intervascular preretinal PO2 gradients were recorded in 7 minipigs during slow withdrawal of oxygen-sensitive microelectrodes (10-μm tip diameter) from the vitreoretinal interface to 2 mm into the vitreous cavity. Recordings were repeated after pars plana vitrectomy and balanced salt solution (BSS) intraocular perfusion. RESULTS: Arteriolar, venous, and intervascular preretinal PO2 at the vitreoretinal interface were 62.3 ± 13.8, 22.5 ± 3.3, and 17.0 ± 7.5 mmHg, respectively, before vitrectomy; 97.7 ± 19.9, 40.0 ± 21.9, and 56.3 ± 28.4 mmHg, respectively, immediately after vitrectomy; and 59.0 ± 27.4, 25.2 ± 3.0, and 21.5 ± 4.5 mmHg, respectively, 2½ hours after interruption of BSS perfusion. PO2 2 mm from the vitreoretinal interface was 28.4 ± 3.6 mmHg before vitrectomy; 151.8 ± 4.5 mmHg immediately after vitrectomy; and 34.8 ± 4.1 mmHg 2½ hours after interruption of BSS perfusion. PO2 gradients were still present after vitrectomy, with the same patterns as before vitrectomy. CONCLUSION: Preretinal PO2 gradients are not eliminated after pars plana vitrectomy. During BSS perfusion, vitreous cavity PO2 is very high. Interruption of BSS perfusion evokes progressive equilibration of vitreous cavity PO2 with concomitant progressive return of preretinal PO2 gradients to their previtrectomy patterns. This indicates that preretinal diffusion of oxygen is not altered after vitrectomy. The beneficial effect of vitrectomy in ischemic retinal diseases or macular edema may be related to other mechanisms, such as increased oxygen convection currents or removal of growth factors and cytokines secreted in the vitreous.

Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension.

Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%-2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 5' region of Uromodulin (UMOD; rs13333226, combined P value of 3.6×10(-11)). The minor G allele is associated with a lower risk of hypertension (OR [95%CI]: 0.87 [0.84-0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R. = 0.923, 95% CI 0.860-0.991; p = 0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83-0.96], p = 0.004; after eGFR adjustment: 0.89 [0.83-0.96], p = 0.003). In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk.

A comparison of methods for differential expression analysis of RNA-seq data.

BACKGROUND: Finding genes that are differentially expressed between conditions is an integral part of understanding the molecular basis of phenotypic variation. In the past decades, DNA microarrays have been used extensively to quantify the abundance of mRNA corresponding to different genes, and more recently high-throughput sequencing of cDNA (RNA-seq) has emerged as a powerful competitor. As the cost of sequencing decreases, it is conceivable that the use of RNA-seq for differential expression analysis will increase rapidly. To exploit the possibilities and address the challenges posed by this relatively new type of data, a number of software packages have been developed especially for differential expression analysis of RNA-seq data. RESULTS: We conducted an extensive comparison of eleven methods for differential expression analysis of RNA-seq data. All methods are freely available within the R framework and take as input a matrix of counts, i.e. the number of reads mapping to each genomic feature of interest in each of a number of samples. We evaluate the methods based on both simulated data and real RNA-seq data. CONCLUSIONS: Very small sample sizes, which are still common in RNA-seq experiments, impose problems for all evaluated methods and any results obtained under such conditions should be interpreted with caution. For larger sample sizes, the methods combining a variance-stabilizing transformation with the 'limma' method for differential expression analysis perform well under many different conditions, as does the nonparametric SAMseq method.

Factors associated with elevated pulmonary arterial pressure levels on the echocardiographic assessment in patients with prior pulmonary embolism.

BACKGROUND: Factors associated with the detection of raised systolic pulmonary artery pressure (sPAP) levels in patients with a prior episode of pulmonary embolism (PE) are not well known. METHODS: We used the RIETE Registry database to identify factors associated with the finding of sPAP levels ≥50 mm Hg on trans-thoracic echocardiography, in 557 patients with a prior episode of acute, symptomatic PE. RESULTS: Sixty-two patients (11.1%; 95% CI: 8.72-14.1) had sPAP levels ≥50 mm Hg. These patients were more likely women, older, and more likely had chronic lung disease, heart failure, renal insufficiency or leg varicosities than those with PAP levels <50mm Hg. During the index PE event, they more likely had recent immobility, and more likely presented with hypoxemia, increased sPAP levels, atrial fibrillation, or right bundle branch block. On multivariate analysis, women aged ≥70 years (hazard ratio [HR]: 2.0; 95% CI: 1.0-3.7), chronic heart or chronic lung disease (HR: 2.4; 95% CI: 1.3-4.4), atrial fibrillation at PE presentation (HR: 2.8; 95% CI: 1.3-6.1) or varicose veins (HR: 1.8; 95% CI: 1.0-3.3) were all associated with an increased risk to have raised sPAP levels. Chronic heart disease, varicose veins, and atrial fibrillation were independent predictors in women, while chronic heart disease, atrial fibrillation, a right bundle branch block or an S1Q3T3 pattern on the electrocardiogram were independent predictors in men. CONCLUSIONS: Women aged ≥70 years more likely had raised sPAP levels than men after a PE episode. Additional variables influencing this risk seem to differ according to gender.

Brain Tissue Hypoxia is a Strong Predictor of Outcome after Severe Traumatic Brain Injury Independent from Elevated Intracranial Pressure

Introduction: Low brain tissue oxygen pressure (PbtO2) is associated with worse outcome in patients with severe traumatic brain injury (TBI). However, it is unclear whether brain tissue hypoxia is merely a marker of injury severity or a predictor of prognosis, independent from intracranial pressure (ICP) and injury severity. Hypothesis: We hypothesized that brain tissue hypoxia was an independent predictor of outcome in patients wih severe TBI, irrespective of elevated ICP and of the severity of cerebral and systemic injury. Methods: This observational study was conducted at the Neurological ICU, Hospital of the University of Pennsylvania, an academic level I trauma center. Patients admitted with severe TBI who had PbtO2 and ICP monitoring were included in the study. PbtO2, ICP, mean arterial pressure (MAP) and cerebral perfusion pressure (CPP = MAP-ICP) were monitored continuously and recorded prospectively every 30 min. Using linear interpolation, duration and cumulative dose (area under the curve, AUC) of brain tissue hypoxia (PbtO2 < 15 mm Hg), elevated ICP >20 mm Hg and low CPP <60 mm Hg were calculated, and the association with outcome at hospital discharge, dichotomized as good (Glasgow Outcome Score [GOS] 4-5) vs. poor (GOS 1-3), was analyzed. Results: A total of 103 consecutive patients, monitored for an average of 5 days, was studied. Brain tissue hypoxia was observed in 66 (64%) patients despite ICP was < 20 mm Hg and CPP > 60 mm Hg (72 +/- 39% and 49 +/- 41% of brain hypoxic time, respectively). Compared with patients with good outcome, those with poor outcome had a longer duration of brain hypoxia (1.7 +/- 3.7 vs. 8.3 +/- 15.9 hrs, P<0.01), as well as a longer duration (11.5 +/- 16.5 vs. 21.6 +/- 29.6 hrs, P=0.03) and a greater cumulative dose (56 +/- 93 vs. 143 +/- 218 mm Hg*hrs, P<0.01) of elevated ICP. By multivariable logistic regression, admission Glasgow Coma Scale (OR, 0.83, 95% CI: 0.70-0.99, P=0.04), Marshall CT score (OR 2.42, 95% CI: 1.42-4.11, P<0.01), APACHE II (OR 1.20, 95% CI: 1.03-1.43, P=0.03), and the duration of brain tissue hypoxia (OR 1.13; 95% CI: 1.01-1.27; P=0.04) were all significantly associated with poor outcome. No independent association was found between the AUC for elevated ICP and outcome (OR 1.01, 95% CI 0.97-1.02, P=0.11) in our prospective cohort. Conclusions: In patients with severe TBI, brain tissue hypoxia is frequent, despite normal ICP and CPP, and is associated with poor outcome, independent of intracranial hypertension and the severity of cerebral and systemic injury. Our findings indicate that PbtO2 is a strong physiologic prognostic marker after TBI. Further study is warranted to examine whether PbtO2-directed therapy improves outcome in severely head-injured patients .

Genome-wide association analysis of blood-pressure traits in African-ancestry individuals reveals common associated genes in African and non-African populations.

High blood pressure (BP) is more prevalent and contributes to more severe manifestations of cardiovascular disease (CVD) in African Americans than in any other United States ethnic group. Several small African-ancestry (AA) BP genome-wide association studies (GWASs) have been published, but their findings have failed to replicate to date. We report on a large AA BP GWAS meta-analysis that includes 29,378 individuals from 19 discovery cohorts and subsequent replication in additional samples of AA (n = 10,386), European ancestry (EA) (n = 69,395), and East Asian ancestry (n = 19,601). Five loci (EVX1-HOXA, ULK4, RSPO3, PLEKHG1, and SOX6) reached genome-wide significance (p < 1.0 × 10(-8)) for either systolic or diastolic BP in a transethnic meta-analysis after correction for multiple testing. Three of these BP loci (EVX1-HOXA, RSPO3, and PLEKHG1) lack previous associations with BP. We also identified one independent signal in a known BP locus (SOX6) and provide evidence for fine mapping in four additional validated BP loci. We also demonstrate that validated EA BP GWAS loci, considered jointly, show significant effects in AA samples. Consequently, these findings suggest that BP loci might have universal effects across studied populations, demonstrating that multiethnic samples are an essential component in identifying, fine mapping, and understanding their trait variability.

Differential sensitivity of GLUT1- and GLUT2-expressing beta cells to streptozotocin.

Streptozotocin injection in animals destroys pancreatic beta cells, leading to insulinopenic diabetes. Here, we evaluated the toxic effect of streptozotocin (STZ) in GLUT2(-/-) mice reexpressing either GLUT1 or GLUT2 in their beta cells under the rat insulin promoter (RIPG1 x G2(-/-) and RIPG2 x G2(-/-) mice, respectively). We demonstrated that injection of STZ into RIPG2 x G2(-/-) mice induced hyperglycemia (&gt;20 mM) and an approximately 80% reduction in pancreatic insulin content. In vitro, the viability of RIPG2 x G2(-/-) islets was also strongly reduced. In contrast, STZ did not induce hyperglycemia in RIPG1 x G2(-/-) mice and did not reduce pancreatic insulin content. The viability of in vitro cultured RIPG1 x G2(-/-) islets was also unaffected by STZ. As islets from each type of transgenic mice were functionally indistinguishable, these data strongly support the notion that STZ toxicity toward beta cells depends on the expression of GLUT2.

Markedly reduced blood pressure responsiveness in endotoxemic rats; reversal by neuropeptide Y.

This study in conscious normotensive rats was performed to assess the effect of the vasoconstrictor peptide, neuropeptide Y (NPY), on blood pressure responsiveness to exogenous norepinephrine in endotoxaemia. NPY and endotoxin were infused at doses which had no effect on blood pressure, whether given alone or in combination. Endotoxin markedly reduced the pressor responses to bolus injections of norepinephrine. However, blood pressure responsiveness could be enhanced by infusing NPY simultaneously with the endotoxin. It is suggested that low dose NPY infusions may be clinically useful in reversing the reduced vascular responsiveness to pressor amines in shock.

Acetaminophen increases blood pressure in patients with coronary artery disease.

BACKGROUND: Because traditional nonsteroidal antiinflammatory drugs are associated with increased risk for acute cardiovascular events, current guidelines recommend acetaminophen as the first-line analgesic of choice on the assumption of its greater cardiovascular safety. Data from randomized clinical trials prospectively addressing cardiovascular safety of acetaminophen, however, are still lacking, particularly in patients at increased cardiovascular risk. Hence, the aim of this study was to evaluate the safety of acetaminophen in patients with coronary artery disease. METHODS AND RESULTS: The 33 patients with coronary artery disease included in this randomized, double-blind, placebo-controlled, crossover study received acetaminophen (1 g TID) on top of standard cardiovascular therapy for 2 weeks. Ambulatory blood pressure, heart rate, endothelium-dependent and -independent vasodilatation, platelet function, endothelial progenitor cells, markers of the renin-angiotensin system, inflammation, and oxidative stress were determined at baseline and after each treatment period. Treatment with acetaminophen resulted in a significant increase in mean systolic (from 122.4±11.9 to 125.3±12.0 mm Hg P=0.02 versus placebo) and diastolic (from 73.2±6.9 to 75.4±7.9 mm Hg P=0.02 versus placebo) ambulatory blood pressures. On the other hand, heart rate, endothelial function, early endothelial progenitor cells, and platelet function did not change. CONCLUSIONS: This study demonstrates for the first time that acetaminophen induces a significant increase in ambulatory blood pressure in patients with coronary artery disease. Thus, the use of acetaminophen should be evaluated as rigorously as traditional nonsteroidal antiinflammatory drugs and cyclooxygenase-2 inhibitors, particularly in patients at increased cardiovascular risk. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00534651.