Hypertension, cardiovascular risk and polymorphisms in genes controlling the cytochrome P450 pathway of arachidonic acid: A sex-specific relation?

Hypertension is a multifactorial disease in which the interplay of genetic and environmental factors that maintain blood pressure stable throughout life is altered. Cytochrome P450 (CYP)-derived metabolites of arachidonic acid such as epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid (20-HETE), active on vascular tone, endothelial function and renal sodium reapportion, have been identified as candidate mediators in the development of hypertension in several animal models, with remarkable sex-specific effect. Several SNPs, some recognized as functional, in human genes implicated in EETs/20-HETE biosynthesis and metabolism, such as CYP2J2 and CYP4A11, have been tested for association with blood pressure, hypertension and its long-term cardiovascular consequences in different populations, with conflicting results. A sex-specific effect, related to CYP4F2 polymorphisms and expression, has been observed in association studies. This finding indicates that altered 20-HETE bioactivity underlay the excess of hypertension and associated vascular events observed in men with respect to women and is consistent with the results from experimental models. Further epidemiological and mechanistic studies are required to confirm the effect of lipid mediators on blood pressure in humans and define the mechanisms of a putative sex-specific effect

D1 and D2 inhibitions of the soleus H-reflex are differentially modulated during plantarflexion force and position tasks

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Presynaptic inhibition (PSI) has been shown to modulate several neuronal pathways of functional relevance by selectively gating the connections between sensory inputs and spinal motoneurons, thereby regulating the contribution of the stretch reflex circuitry to the ongoing motor activity. In this study, we investigated whether a differential regulation of Ia afferent inflow by PSI may be associated with the performance of two types of plantarflexion sensoriomotor tasks. The subjects (in a seated position) controlled either: 1) the force level exerted by the foot against a rigid restraint (force task, FT); or 2) the angular position of the ankle when sustaining inertial loads (position task, PT) that required the same level of muscle activation observed in FT. Subjects were instructed to maintain their force/position at target levels set at similar to 10% of maximum isometric voluntary contraction for FT and 90 degrees for PT, while visual feedback of the corresponding force/position signals were provided. Unconditioned H-reflexes (i.e. control reflexes) and H-reflexes conditioned by electrical pulses applied to the common peroneal nerve with conditioning-to-test intervals of 21 ms and 100 ms (corresponding to D1 and D2 inhibitions, respectively) were evoked in a random fashion. A significant main effect for the type of the motor task (FT vs PT) (p = 0.005, eta(2)(p) = 0.603) indicated that PTs were undertaken with lower levels of Ia PSI converging onto the soleus motoneuron pool. Additionally, a significant interaction between the type of inhibition (D1 vs D2) and the type of motor task (FT vs PT) (p = 0.038, eta(2)(p) = 0.395) indicated that D1 inhibition was associated with a significant reduction in PSI levels from TF to TP (p = 0.001, eta(2)(p) = 0.731), whereas no significant difference between the tasks was observed for D2 inhibition (p = 0.078, eta(2)(p) = 0.305). These results suggest that D1 and D2 inhibitions of the soleus H-reflex are differentially modulated during the performance of plantarflexion FT and PT. The reduced level of ongoing PSI during PT suggests that, in comparison to FT, there is a larger reliance on inputs from muscle spindles primary afferents when the neuromuscular system is required to maintain position-controlled plantarflexion contractions.PPresynaptic inhibition (PSI) has been shown to modulate several neuronal pathways of functional relevance by selectively gating the connections between sensory inputs and spinal motoneurons, thereby regulating the contribution of the stretch reflex circu1011FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)FAPESP [2011/17193-0, 2011/13222-6, 2013/10433-1, 2012/09321-1, 2013/14667-7]CNPq [303313/2011-0]2011/17193-0; 2011/13222-6; 2013/10433-1; 2012/09321-1; 2013/14667-7303313/2011-

Urinary free cortisol assessment by liquid chromatography tandem mass spectrometry: a case study of ion suppression due to unacquainted administration of piperacillin

Introduction: Liquid chromatography coupled to atmospheric pressure ionization tandem mass spectrometry (LC-ESI-MS/MS) is currently considered the reference method for quantitative determination of urinary free cortisol (UFC). One of the major drawbacks of this measurement is a particular form of matrix effect, conventionally known as ion suppression. Materials and methods: We describe here the case of a 66-year-old-patient referred to the daily service of general medicine for intravenous antibiotic administration due to a generalized Staphylococcus aureus infection and for routine 24 hours UFC monitoring in the setting of glucocorticoid replacement therapy. Results: The observation of 10-fold decrease of internal standard of cortisol signal led us to hypothesize the presence of an ion suppression effect due to a co-eluting endogenous compound. Screening analysis of tandem mass spectrometry (MS/MS) spectra of the interfering molecule, along with in vitro confirmation analyses, were suggestive of the presence of high concentration of piperacillin. The problem was then easily solved with minor modifications of the chromatographic technique. Conclusions: According to our findings, antibiotic therapy with piperacillin/tazobactam should be regarded as an important interference in UFC assessment, which may potentially affect detection capability, precision and accuracy of this measurement. This case report emphasizes that accurate anamnesis and standardization of all phases of urine collection are essential aspects for preventing potential interference in laboratory testing. \ua9 Croatian Society of Medical Biochemistry and Laboratory Medicine

Succinate dehydrogenase gene mutation with cardiac paraganglioma: multimodality imaging and pathological correlation.

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Hypertension, uncontrolled hypertension and resistant hypertension: prevalence, comorbidities and prescribed medications in 228,406 adults resident in urban areas. A population-based observational study

Although hypertension is the leading cause of cardiovascular disease and premature death worldwide, it remains difficult to control. The prevalence of uncontrolled and resistant hypertension (RH) may be underestimated and can reach up to 50% of all hypertensive patients. The aim of this observational study was to analyze the prevalence of hypertension, uncontrolled hypertension and RH, and their associations with risk factors or diseases in a large cohort of patients referred to primary care physician. In a population of 228406 adults, we only collected data from people with a diagnosis of arterial hypertension for a total of 43,526 patients. For this purpose, we used the MySQL database, run by Azalea.NET, built on the medical records of 150 General Practitioners (GPs). Patient data included sex, age, blood pressure (BP) values, number of antihypertensive drugs and presence of major cardiovascular comorbidities. We classified patients with RH as those treated with 3 different antihypertensive agents, with recorded BP & GE; 140/90 mmHg, or patients taking & GE; 4 medications. The prevalence of hypertension was 19.06%, that of resistant hypertension was 2.46% of the whole population and 20.85% of the hypertensive group. Thirteen thousand hundred, forty-six patients (30.20% of the hypertensive group) had uncontrolled BP (& GE; 140/90 mmHg), whereas 16,577 patients did not have BP measurements done in the last 2 years (38.09% of the hypertensive group). Patients with uncontrolled BP were mainly female, used less drugs and showed a lower prevalence of all major cardiovascular comorbidities, except for diabetes. Instead, patients with RH had a significantly higher prevalence of all considered comorbidities compared to those without RH. Our results evidence that a broad number of patients with hypertension, especially those without comorbidities or with a low number of antihypertensive drugs, do not achieve adequate BP control. To improve the clinical management of these patients it is very important to increase the collaboration between GPs and clinical specialists of hypertension

The Renalase Asp37Glu polymorphism is not associated with hypertension and cardiovascular events in an urban-based prospective cohort: the Malmo Diet and cancer study

Background: Renalase (gene name RNLS), a recently discovered enzyme with monoamine oxidase activity, is implicated in the degradation of catecholamines. Recent studies delineate a possible role of this enzyme in blood pressure (BP) maintenance and cardiac protection and two single nucleotide polymorphisms, RNLS rs2576178 A > G and rs2296545 C > G have been associated with hypertension. The latter SNP leads to a non synonymous Asp to Glu substitution deleting a flavin adenine dinucleotide (FAD) binding site with possible impaired functionality. We tested the hypothesis that these polymorphisms could affect BP levels, hypertension prevalence, and risk of incident cardiovascular events in middle-aged Swedes. Methods: The polymorphisms were genotyped in 5696 participants of the population-based Cardiovascular Cohort of the "Malmo Diet and Cancer" (MDC-CC). The incidence of cardiovascular events (coronary events [n = 408], strokes [n = 330], heart failure [n = 190] and atrial fibrillation/flutter [n = 406]) was monitored for an average of approximately 15 years of follow-up. Results: Both before and after adjustment for sex, age and BMI the polymorphisms did not show any effect on BP level and hypertension prevalence. Before and after adjustment for major cardiovascular risk factors, the hazard ratio for cardiac and cerebrovascular events was not significantly different in carriers of different genotypes. A significant interaction was found between the rs2296545 C > G and age with respect to BP/hypertension. Conclusions: Our data do not support a major role for these RNLS polymorphisms in determining BP level and incident events at population level. The positive interaction with age suggest that the effect of the rs2296545 C > G polymorphism, if any, could vary between different ages

Plasma bile acid profile in patients with and without Type 2 Diabetes

A paucity of information currently exists on plasma bile acid (BA) profiles in patients with and without type 2 diabetes mellitus (T2DM). We assayed 14 plasma BA species in 224 patients with T2DM and in 102 nondiabetic individuals with metabolic syndrome. Plasma BA levels were measured with ultra-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) technique. Multivariable linear regression analyses were undertaken to assess associations between measured plasma BA species and T2DM status after adjustment for confounding factors. The presence of T2DM was significantly associated with higher plasma concentrations of both primary BAs (adjusted-standardized beta coefficient: 0.279, p = 0.005) and secondary BAs (standardized beta coefficient: 0.508, p < 0.001) after adjustment for age, sex, adiposity measures, serum alanine aminotransferase and use of statins or metformin. More specifically, the presence of T2DM was significantly associated with higher levels of plasma taurochenodeoxycholic acid, taurodeoxycholic acid, glycochenodeoxycholic acid, hyodeoxycholic acid, glycodeoxycholic acid, glycolithocholic acid, deoxycholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, glycochenodeoxycholic acid and glycodeoxycholic acid (adjusted-standardized beta coefficients ranging from 0.315 to 0.600; p < 0.01 or less), as well as with lower plasma levels of cholic acid (adjusted-standardized beta coefficient: -0.250, p = 0.013) and taurocholic acid (adjusted-standardized beta coefficient: -0.309, p = 0.001). This study shows that there are marked differences in plasma BA profiles between patients with and without T2DM. Further research will be needed to better understand how these differences in plasma BA profiles may interplay with the pathophysiology of T2DM

Prediction of Blood Pressure Changes Over Time and Incidence of Hypertension by a Genetic Risk Score in Swedes.

Recent Genome-Wide Association Studies (GWAS) have pinpointed different single nucleotide polymorphisms consistently associated with blood pressure (BP) and hypertension prevalence. However, little data exist regarding single nucleotide polymorphisms predicting BP variation over time and hypertension incidence. The aim of this study was to confirm the association of a genetic risk score (GRS), based on 29 independent single nucleotide polymorphisms, with cross-sectional BP and hypertension prevalence and to challenge its prediction of BP change over time and hypertension incidence in >17 000 middle-aged Swedes participating in a prospective study, the Malmö Preventive Project, investigated at baseline and over a 23-year average period of follow-up. The GRS was associated with higher systolic and diastolic BP values both at baseline (β±SEM, 0.968±0.102 mm Hg and 0.585±0.064 mm Hg; P<1E-19 for both) and at reinvestigation (β±SEM, 1.333±0.161 mm Hg and 0.724±0.086 mm Hg; P<1E-15 for both) and with increased hypertension prevalence (odds ratio [95% CI], 1.192 [1.140-1.245] and 1.144 [1.107-1.183]; P<1E-15 for both). The GRS was positively associated with change (Δ) in BP (β±SEM, 0.033±0.008 mm Hg/y and 0.023±0.004 mm Hg/y; P<1E-04 for both) and hypertension incidence (odds ratio [95% CI], 1.110 [1.065-1.156]; P=6.7 E-07), independently from traditional risk factors. The relative weight of the GRS was lower in magnitude than obesity or prehypertension, but comparable with diabetes mellitus or a positive family history of hypertension. A C-statistics analysis does not show any improvement in the prediction of incident hypertension on top of traditional risk factors. Our data from a large cohort study show that a GRS is independently associated with BP increase and incidence of hypertension

Comparison of Performance in the Six-Minute Walk Test (6MWT) between Overweight/Obese and Normal-Weight Children and Association with Haemodynamic Parameters: A Cross-Sectional Study in Four Primary Schools

Physical activity plays a pivotal role in preventing obesity and cardiovascular risks. The six-minute walk test (6MWT) is a tool to assess functional capacity and predict cardiovascular events. The aim of this cross-sectional study was to compare the performance and haemodynamic parameters before and after a 6MWT between obese/overweight vs. normal-weight children (average age 8.7 +/- 0.7 years) participating in a project involving four primary schools in South Verona (Italy). Validated questionnaires for physical activity and diet, as well as blood drops, were collected. Overweight or obese children (OW &amp; OB; n = 100) covered a shorter 6MWT distance compared to normal-weight children (NW, n = 194). At the test's conclusion, the OW&amp;OB group exhibited a higher Rate Pulse Product (RPP = Systolic Blood Pressure x Heart Rate) as compared to the NW. Body Mass Index, waist-to-height ratio, fat mass by electrical impedance, and trans fatty acids showed direct correlations with pre and post-test haemodynamic parameters, such as RPP, and inverse correlations with oxygen saturation. OW&amp;OB children demonstrated lower performance in this low-intensity exercise test, along with an elevated haemodynamic response. Excess fat in childhood can be considered a risk factor for haemodynamic stress, with potential deleterious consequences later in life. Efforts should be initiated early to break this cycle

Snoring in a cohort of obese children: association with palate position and nocturnal desaturations

Purpose of the study: Frequency of habitual snoring is significantly higher in obese than in normal-weight subjects. Obesity and adeno-tonsillar size are risk factors of snoring. Other factors, such as fat distribution and upper airway collapsibility, could explain the relationship between obesity, snoring and obtructive sleep apneas. The aim of the study was to investigate clinical and instrumental significance of snoring in exogenous obese children referred to our department.Methodology: This preliminary study takes part of a larger prospective respiratory sleep study. In 36 consecutive obese children (18 males), bodymass index (BMI), BMI Z score and neck circumference were calculated according to age and sex. Nasal patency, tonsil size, palate position scoring were also recorded. An overnight polygraphy was performed using a portable ambulatory device. Statistical analysis was done using SPSS® Statistics 19.0 software for Windows®.Main findings: Snoring, objectively measured by polygraphy, was associated with palate position and with oxygen desaturation index (ODI). The correlation between snoring and ODI completely disappeared when adjusting for palate position scoring.Key conclusions: Low palate position can be identified as an adjunctive, although not unique, factor that can contribute to making snoring and increased desaturation events possibly related to increased risk of upper airway collapsibility during sleep in obese childre