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Competing Interests: Conflict of interest: None declared.

Background: The objective of our study was to investigate the association between body weight, clinical signs and surgical time, and the severity of elbow fractures sustained exclusively by a ground-level fall in children., Methods: Patients aged 2-11 years with elbow fracture caused exclusively by a ground-level fall were included. BMI was plotted on the sex-specific BMI-for-age percentile growth chart to obtain the BMI percentile. The elbow fractures were classified according to Gartland Classification for supracondylar fractures and the Song Classification for lateral humeral condyle fracture. Our main outcome measurement was Body Mass Index and fracture severity according Gartland or Song classifications., Results: A total of 175 patients with elbow fractures were included in this study. The mean age of total population was 5.4 years (±2.4). The majority of our patients were male (61.7%), nearly of 48% were overweight or obese patients. The ecchymosis and puckering were the clinical sign more frequent in more severe fractures., Conclusions: Our data presented did not observe a direct relation between obesity and the severity of elbow humeral fractures in the pediatric population with a ground-level fall.

Competing Interests: Conflict of interest: None declared.

Background  Obstructive sleep apnoea (OSA) has been described as a risk factor for arterial hypertension (HT). One of the proposed mechanisms linking these conditions is non dipping (ND) pattern in nocturnal blood pressure, however evidence is variable and based on specific populations with underlying conditions. Data for OSA and ND in subjects residing at high altitude are currently unavailable. Objective  Identify the prevalence and association of moderate to severe OSA with HT and ND pattern in hypertensive and non-hypertensive otherwise healthy middle-aged individuals in residing at high altitude (Bogotá:2640 mt) Methods  Adult individuals with diagnosis of moderate to severe OSA underwent 24 hour- ambulatory blood pressure monitoring (ABPM) between 2015 and 2017. Univariable and multivariable logistic regression analysis were performed to identify predictors of HT and ND pattern. Results  Ninety-three (93) individuals (male 62.4% and median age 55) were included in the final analysis. Overall, 30.1% showed a ND pattern in ABPM and 14.9% had diurnal and nocturnal hypertension. Severe OSA (higher apnea-hiponea index [AHI]) was associated with HT (p = 0.006), but not with ND patterns (p = 0.54) in multivariable regression. Smoking status and lowest oxygen saturation during respiratory events where independently associated with ND pattern (p = 0.04), whereas age (p = 0.001) was associated with HT. Conclusions  In our sample, one in three individuals with moderate to severe OSA have non dipping patterns suggesting lack of straight association between OSA and ND. Older individuals who have higher AHI are more likely to have HT, and those who smoke have a higher risk of ND. These findings add aditional information to the multiple mechanisms involved in the relationship between OSA and ND pattern, and questions the routine use of 24-hour ABPM, particullary in our region, with limited resources and healthcare acces. However, further work with more robust methodology is needed to draw conclusions., Competing Interests: Conflict of Interest None declared., (Brazilian Sleep Association. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

Introduction and Objectives: Mitral valve (MV) prolapse is highly prevalent in patients with atrial septal defect (ASD). Abnormal left ventricular geometry has been proposed as the main mechanism of MV prolapse in ASD, however, the changes in the morphology of the MV apparatus remain to be clarified. Our aim was to assess the MV geometry in patients with ASD and MV prolapse., Methods: We evaluated 99 patients (73% female, median age 40 years) with ASD who underwent a three-dimensional transesophageal echocardiogram. Three-dimensional analysis of the MV was done using dedicated automated software. Transthoracic echocardiographic parameters were assessed post ASD closure in 28 patients., Results: MV prolapse was found in 39% of patients. Although smaller left ventricular dimensions and greater interatrial shunt were found in patients with MV prolapse compared with those without prolapse, there was no difference in the subvalvular parameters. MV prolapse was associated with larger mitral anterior-posterior diameter, anterolateral-posteromedial diameter, anterior perimeter, posterior perimeter, total perimeter, and anterior leaflet area (all p < 0.05). Mitral regurgitation was more frequent in patients with MV prolapse (80 vs. 48%, p = 0.002)., Conclusions: In patients with ASD, the main mechanism of MV prolapse is the presence of an organic primary process of the MV apparatus (excessive anterior mitral leaflet tissue and mitral annular enlargement)., (© 2022 Wiley Periodicals LLC.)

Mitral regurgitation (MR) is a common form of valvular heart disease that is associated with significant morbidity and mortality. MR can be broadly classified into 2 different categories: primary and secondary MR. Primary MR usually is caused by leaflet abnormalities, whereas secondary MR is a chronic disease secondary to geometric distortion of both the annulus and subvalvular apparatus because of left ventricular remodeling. Without acute changes in loading conditions, myocardial blood flow, or rhythm disturbances, functional MR typically is not transient. In this E-Challenge, the authors show a transient and completely reversible acute and severe form of functional MR with the use of multimodal echocardiography., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: In patients with Ischemia and non-obstructive coronary artery stenosis (INOCA) wall motion is rarely abnormal during stress echocardiography (SE). Our aim was to determine if patients with INOCA and reduced coronary flow velocity reserve (CVFR) have altered cardiac mechanics using two-dimensional speckle-tracking echocardiography (2DSTE) during SE. Methods: In a prospective, multicenter, international study, we recruited 135 patients with INOCA. Overall, we performed high dose (0.84 mg/kg) dipyridamole SE with combined assessment of CVFR and 2DSTE. The population was divided in patients with normal CVFR (>2, group 1, n = 95) and abnormal CVFR (≤2, group 2, n = 35). Clinical and 2DSTE parameters were compared between groups. Results: Feasibility was high for CFVR (98%) and 2DSTE (97%). A total of 130 patients (mean age 63 ± 12 years, 67 women) had complete flow and strain data. The two groups showed similar 2DSTE values at rest. At peak SE, Group 1 patients showed lower global longitudinal strain ( p < 0.007), higher mechanical dispersion ( p < 0.0005), lower endocardial ( p < 0.001), and epicardial ( p < 0.0002) layer specific strain. Conclusions: In patients with INOCA, vasodilator SE with simultaneous assessment of CFVR and strain is highly feasible. Coronary microvascular dysfunction is accompanied by an impairment of global and layer-specific deformation indices during stress.

Background: WHO revised their HIV drug resistance (HIVDR) monitoring strategy in 2014, enabling countries to generate nationally representative HIVDR prevalence estimates from surveys conducted using this methodology. In 2016, we adopted this strategy in Uganda and conducted an HIVDR survey among adults initiating or reinitiating ART., Methods: A cross-sectional survey of adults aged ≥18 years initiating or reinitiating ART was conducted at 23 sites using a two-stage cluster design sampling method. Participants provided written informed consent prior to enrolment. Whole blood collected in EDTA vacutainer tubes was used for preparation of dried blood spot (DBS) specimens or plasma. Samples were shipped from the sites to the Central Public Health Laboratory (CPHL) for temporary storage before transfer to the Uganda Virus Research Institute (UVRI) for genotyping. Prevalence of HIVDR among adults initiating or reinitiating ART was determined., Results: Specimens from 491 participants (median age 32 years and 61.5% female) were collected between August and December 2016. Specimens from 351 participants were successfully genotyped. Forty-nine had drug resistance mutations, yielding an overall weighted HIVDR prevalence of 18.2% with the highest noted for NNRTIs at 14.1%., Conclusions: We observed a high HIVDR prevalence for NNRTIs among adults prior to initiating or reinitiating ART in Uganda. This is above WHO's recommended threshold of 10% when countries should consider changing from NNRTI- to dolutegravir-based first-line regimens. This recommendation was adopted in the revised Ugandan ART guidelines. Dolutegravir-containing ART regimens are preferred for first- and second-line ART regimens., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)

Habitability has been generally defined as the capability of an environment to support life. Ecologists have been using Habitat Suitability Models (HSMs) for more than four decades to study the habitability of Earth from local to global scales. Astrobiologists have been proposing different habitability models for some time, with little integration and consistency among them, being different in function to those used by ecologists. Habitability models are not only used to determine whether environments are habitable, but they also are used to characterize what key factors are responsible for the gradual transition from low to high habitability states. Here we review and compare some of the different models used by ecologists and astrobiologists and suggest how they could be integrated into new habitability standards. Such standards will help improve the comparison and characterization of potentially habitable environments, prioritize target selections, and study correlations between habitability and biosignatures. Habitability models are the foundation of planetary habitability science, and the synergy between ecologists and astrobiologists is necessary to expand our understanding of the habitability of Earth, the Solar System, and extrasolar planets.

Introduction: Without a prompt diagnosis, developmental dysplasia of the hip (DDH) in infants can lead to severe sequelae. Current screening strategies emphasize the use of Ortolani and Barlow physical examination manoeuvres, yet they exhibit low sensitivity. The purpose of this study is to evaluate the performance of a new physical examination tool (the pronation manoeuvre) as a screening tool for DDH., Methods: To evaluate the new manoeuvre, a cross-sectional and analytic study was performed with a nonprobabilistic sampling method. Patients with either a positive Ortolani or Barlow manoeuver were evaluated with the new manoeuvre and hip ultrasound. Controls were infants with negative Ortolani, Barlow and pronation manoeuvres and also had ultrasound performed., Results: DDH was confirmed in 83 of 130 cases (64%) and 2 of 130 controls (2%). The new pronation manoeuvre had a sensitivity of 76% and a specificity of 94% as compared to the Ortolani and Barlow manoeuvres (sensitivity 31 to 32%, specificity 93 to 100%) (P<0.05)., Conclusion: This new physical examination manoeuvre could serve as another clinical tool for the initial screening of DDH in newborns. Its promising results against traditional screening procedures might potentially impact diagnosis and prognosis for patients with DDH., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Canadian Paediatric Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: The aim of this study was to analyze whether right ventricular free wall longitudinal strain (RVFWSL) could be a predictor of low-cardiac-output syndrome (LCOS) after surgical aortic valve replacement (SAVR) in patients with left ventricular ejection fraction ≥40%., Design: Prospective, observational study., Setting: The study was conducted at a third level university hospital., Participants: The study comprised 75 patients with severe aortic stenosis and LVEF ≥40% who underwent SAVR. The primary outcome was the occurrence of LCOS, and secondary outcomes were in-hospital mortality, hospital stay, or vasoplegic syndrome., Interventions: Patients were divided into two groups (LCOS and no LCOS), and RVFWSL was analyzed to determine whether it is a predictor for LCOS. In addition, a receiver operating characteristic curve also was constructed, and the best cutoff value to predict LCOS was found. Furthermore, the reproducibility of RVFWSL measurements was evaluated., Measurement and Main Results: The incidence of LCOS was 20% in the present study's cohort. After multivariate analysis, cross-clamp time (odds ratio 1.06, 95% confidence interval 1.02-1.11; p = 0.002) and RVFWSL (odds ratio 1.41, 95% confidence interval 1.07-1.87; p = 0.015) were the only predictors of LCOS. However, RVFWSL did not show association with secondary outcomes (p > 0.05 for all). The area under the curve of RVFWSL to predict LCOS was 0.75, and the best cutoff value was -17.3%, with a sensitivity of 86.7% and specificity of 61.7%., Conclusions: RVFWSL seems to be a predictor of LCOS in patients with severe aortic stenosis and LVEF ≥40% undergoing SAVR. RVFWSL less than -17.3% may identify patients at increased risk for LCOS., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The Fontan operation was introduced in 1968 as a palliative treatment for patients with univentricular heart physiology. Natural history and outcomes are poor. By 10 years after Fontan operation, most patients will develop any complication such as tachyarrhythmias, any spectrum of Fontan-associated liver disease, protein-losing enteropathy, heart failure, thrombosis, and infective endocarditis among others. Echocardiography and magnetic resonance imaging (MRI) are the first-line diagnostic tools for detecting such complications. Clinical and imaging follow-up are a mainstay for the evaluation of this patients., (© 2020 Wiley Periodicals LLC.)

We present the case of an 18-year-old man with aborted sudden cardiac death. His initial echocardiogram suggested an anomalous origin of the left coronary artery from the pulmonary artery. Diagnosis was confirmed with coronary angiography. He underwent Takeuchi procedure and fully recovered. A two-year follow-up echocardiogram showed a moderate supravalvular pulmonary stenosis related to the transpulmonary baffle. The presence of extensive collateral circulation should raise suspicion of ALCAPA. Postoperative surveillance in this group of patients needs to be oriented in finding complications such as supravalvular pulmonary stenosis, aortic and pulmonary valve insufficiency, and baffle obstruction and leaks., (© 2020 Wiley Periodicals LLC.)

Background: Ebstein's anomaly (EA) is a myopathy of the right ventricle that causes a variable spectrum of tricuspid valve delamination failure with diverse clinical and anatomical presentation. We reviewed our data of EA to establish an association between clinical and echocardiographic findings with mortality., Methods: We divided patients in infants, Children/adolescents (Ch/A), and adults, according to age of presentation. Clinical and echocardiographic parameters were compared among groups. Multivariate analysis was performed for mortality. Survival analysis was plotted using Kaplan Meier curves., Results: Cyanosis, severe forms of AE and heart failure were more frequent among infants, arrhythmias in Ch/A and stroke among adults. Surgery was performed in 71 patients; infants had higher mortality and early complications. We found that the predicted mortality at 40 years of age in the three groups was significantly different (log rank test, p <0.0001): Infants: 38%, Ch/A 16 and 4% in adults. Multivariate model in surgical group showed that progressive drop of right ventricular fractional shortening (RVFS) predicts a higher mortality risk. In the non-surgical group, low RVFS and cyanosis were significantly associated with mortality., Conclusion: EA in infants is linked to higher morbidity and mortality, while arrhythmias predominate in Ch/A and stroke in adults. In general, stroke is frequent in patients with EA, some prevention alternative must be implemented. Right ventricular dysfunction is very important in EA and is associated with high mortality. It must be subject of discussion the planning of the type of surgery or even in the decision of to preclude surgical treatment., (Copyright © 2020 IMSS. Published by Elsevier Inc. All rights reserved.)

To investigate the role of right ventricular free wall strain (RVFWSL) to predict low functional capacity in repaired tetralogy of Fallot (rTOF). We prospectively enrolled 33 patients with rTOF with moderate to severe PR who underwent rest and peak exercise echocardiography on a semisupine cycloergometer. Conventional function and strain imaging parameters of both ventricles were measured. Patients performing < 7 METS were defined to have low functional capacity. Logistic regression was used to identify parameters associated with low functional capacity. Eleven patients (33.3%) had low functional capacity. These patients were shorter (height 155 ± 7 vs 163 ± 9 cm, p = 0.023), more frequently female (27.3 vs 72.7%, p = 0.024) and had history of Blalock-Taussig shunt (45.5 vs 9.1%, p = 0.027). On multivariate analysis RVFWSL was the only predictor of low functional capacity OR 1.39 (CI 95%, 1.06-1.83., p = 0.018) per % change. A RVFWSL < 17% (absolute value) had an AUC of 0.785, sensitivity of 81.8% and specificity of 77.3% to predict low functional capacity. Right ventricular free wall strain is an independent predictor of low functional capacity in repaired tetralogy of Fallot with moderate to severe PR. A value < 17% might be useful in deciding when to perform pulmonary valve replacement, when functional capacity cannot be objectively measured.

Background Blood pressure is determined by the interactions between the heart and arterial properties, and subjects with identical blood pressure may have substantially different hemodynamic determinants. Whether arterial hemodynamic indices quantified by impedance cardiography ( ICG ), a simple operator-independent office procedure, independently predict all-cause mortality in adults from the general population, and specifically among those who do not meet criteria for American College of Cardiology/American Heart Association stage 2 hypertension, is currently unknown. Methods and Results We studied 1639 adults aged 18 to 80 years from the general population. We used ICG to measure hemodynamic parameters and metrics of cardiac function. We assessed the relationship between hemodynamic parameters measured at baseline and all-cause mortality over a mean follow-up of 10.9 years. Several ICG parameters predicted death. The strongest predictors were total arterial compliance index (standardized hazard ratio=0.38; 95% confidence interval=0.31-0.46; P<0.0001) and indices of cardiac contractility: velocity index (standardized hazard ratio=0.45; 95% confidence interval=0.37-0.55; P<0.0001) and acceleration index (standardized hazard ratio=0.44; 95% confidence interval=0.35-0.55; P<0.0001). These remained independently predictive of death after adjustment for multiple confounders, as well as systolic and diastolic blood pressure. Among subjects without stage 2 hypertension (n=1563), indices of cardiac contractility were independently predictive of death and identified a subpopulation (25% of non-stage-2 hypertensives) that demonstrated a high 10-year mortality risk, equivalent to that of stage 2 hypertensives. Conclusions Hemodynamic patterns identified by ICG independently predict mortality in the general population. The predictive value of ICG applies even in the absence of American College of Cardiology/American Heart Association stage 2 hypertension and identifies higher-risk individuals who are in earlier stages of the hypertension continuum.

Aims: Ischaemic mitral regurgitation (IMR) is consequence of left ventricular (LV) remodelling after myocardial infarction. In some cases, the mitral valve enlarges to compensate for LV remodelling and tenting, improving its coaptation; a process termed 'plasticity'. We sought to identify clinical and echocardiographic factors associated with plasticity in patients with chronic inferior myocardial infarction (CII)., Methods and Results: This study included 91 revascularized CII patients and 46 controls. Plasticity and IMR severity were evaluated by 2D transthoracic echocardiography. Compared with controls, CII patients were older (59 vs. 25 years) and mostly men (80% vs. 46%), both P < 0.001. Chronic inferior myocardial infarction patients also had significant LV remodelling: larger LV volumes, larger mitral tenting areas, larger coaptation depths, longer mitral leaflets and chords, and worse mitral regurgitation (all P ≤ 0.03). Of 91 CII patients, 60 had mitral plasticity (longer anterior and posterior leaflets and longer posterior chords, all P < 0.001), despite not exhibiting significantly larger LV volumes, tenting area or coaptation depth, when compared with patients with no plasticity. Contralateral (anterior) papillary muscle-to-annulus length tended to be increased in CII plasticity patients (P = 0.05). Also they had less moderate and severe IMR (both P < 0.04) compared with non-plasticity CII patients. Multivariate analysis demonstrated independent associations between plasticity and smoking [odds ratio (OR) 0.03, 0.002-0.57; P = 0.019], duration of type-2 diabetes (OR 1.19, 1.007-1.42; P = 0.04) and haemoglobin (OR 2.17, 1.25-3.76; P = 0.005)., Conclusion: Mitral plasticity results in less moderate and severe IMR. Longer time-duration of diabetes mellitus and higher haemoglobin level are independently associated with mitral plasticity, while smoking independently associates with no plasticity. Increased anterior papillary muscle-to-annulus length in CII patients with plasticity suggests complex LV remodelling mechanisms are involved in plasticity.

Coexisting bicuspid aortic and pulmonary valves is an extremely rare condition, and there have been few published cases. Diagnosis of bicuspid aortic valve is straightforward with 2D echocardiography; however, analysis of the morphology of the pulmonary valve is challenging. In this study, we report on a case of a 32-year-old man with bicuspid aortic and pulmonary valves diagnosed by 2D and 3D transthoracic echocardiography. The enlarged pulmonary artery without any obvious etiology led us to suspect a pulmonary valve anomaly; thus, we comprehensively evaluated it with 2D and 3D echocardiography, which confirmed the diagnosis of bicuspid pulmonary valve., (© 2018, Wiley Periodicals, Inc.)

Low cardiac output syndrome (LCOS) after surgical aortic valve replacement (SAVR) is related to increased mortality and treatment related costs. We aimed to evaluate whether echocardiography-derived left ventricular global longitudinal strain (LV-GLS) relates to the occurrence of postoperative LCOS in patients undergoing SAVR. We prospectively enrolled 75 patients with symptomatic severe aortic stenosis, left ventricular ejection fraction (LVEF) >40%, NYHA Class 

Background: In Ebstein's anomaly (EA) current surgical criteria may not translate into better long-term survival. The aim of this study was therefore to determine if surgical treatment for EA increases survival, and to analyze factors associated with mortality.Methods and Results:A retrospective study was carried out involving 103 patients with surgical indication using current criteria, comparing operated (n=49; 47.5%) and non-operated patients (n=54; 52.4%); the severity of disease was similar in all cases. Overall follow-up was 12 years (range, 1-49 years). There were no differences in mortality: in the surgical and non-surgical groups, survival at 10 years was 92.8% vs. 90.7%; 20 years, 85.7% vs. 81.0%; and 30 years, 78.5% vs. 72.2%, respectively. On multivariate analysis right ventricular fractional shortening (RVFS) was associated with mortality in both groups. Decreasing RVFS was associated with worse survival according to severity: when RVFS was <20%, survival at 20, 40 and 60 years was 58%, 39%, and 12.5%, respectively (P<0.0013). Left ventricular ejection fraction also correlated with survival (P<0.0013)., Conclusions: Surgery did not translate into benefit in terms of survival, and this was clearly associated with RV function; therefore this should be a key factor in the surgical decision making.

Background: Severe aortic stenosis (AS), leads to pathological left ventricular remodeling that may worsen with concomitant overweight and obesity (OW/O)., Methods: We aimed to prospectively analyze the impact of OW/O on ventricular remodeling in severe AS, by evaluating the percentage of intraendomyocardial fibrosis (PIEF) and the percentage of infiltrating intraendocardial lipid vacuoles (PIELV) and its relationship to global longitudinal strain (GLS) in patients with OW/O., Results: 44 patients with severe AS were included, 13 non-obese (29%) and 31 OW/O (71%), all of them with left ventricular ejection fraction ≥ 55%. GLS was evaluated with 2D speckle tracking. During valve replacement, an endocardial biopsy was obtained, where PIEF and PIELV were analyzed. Patients with higher PIEF and PIELV had greater body mass index ( p < 0.0001) and worse GLS ( p < 0.0053). A GLS cut-off point < -14% had a sensitivity of 75%, and a specificity of 92.8% to detect important PIEF (AUC: 0.928, 95% confidence interval: 0.798-1.00). On multivariate analysis, OW/O and PIELV were independently associated to the PIEF, and OW/O and PIEF were independently associated to GLS. A high correlation between the amount of PIELV and PIEF were found., Conclusion: Patients with severe AS and OW/O have greater PIEF and PIELV, suggesting more pathological remodeling. GLS is useful to detect subclinical myocardial injury and is potentially useful for endomyocardial fibrosis detection. The presence of higher PIELF may be a trigger factor for the development of intraendomyocardial fibrosis.

Our identification of dysregulation of the AKT pathway in ovarian cancer as a platinum resistance specific event led to a comprehensive analysis of in vitro, in vivo and clinical behaviour of the AKT inhibitor GSK2141795. Proteomic biomarker signatures correlating with effects of GSK2141795 were developed using in vitro and in vivo models, well characterised for related molecular, phenotypic and imaging endpoints. Signatures were validated in temporally paired biopsies from patients treated with GSK2141795 in a clinical study. GSK2141795 caused growth-arrest as single agent in vitro, enhanced cisplatin-induced apoptosis in vitro and reduced tumour volume in combination with platinum in vivo. GSK2141795 treatment in vitro and in vivo resulted in ~50-90% decrease in phospho-PRAS40 and 20-80% decrease in fluoro-deoxyglucose (FDG) uptake. Proteomic analysis of GSK2141795 in vitro and in vivo identified a signature of pathway inhibition including changes in AKT and p38 phosphorylation and total Bim, IGF1R, AR and YB1 levels. In patient biopsies, prior to treatment with GSK2141795 in a phase 1 clinical trial, this signature was predictive of post-treatment changes in the response marker CA125. Development of this signature represents an opportunity to demonstrate the clinical importance of AKT inhibition for re-sensitisation of platinum resistant ovarian cancer to platinum.

Background: Arterial wave reflections are important determinants of central pressure pulsatility and left ventricular afterload. The augmentation index (AIx) is the most widely used surrogate of arterial wave reflections. Despite multiple cross-sectional studies assessing the correlates of AIx, little prospective data exist regarding changes in AIx over time. We aimed to assess the predictors of changes in AIx over time in adults from the general population., Methods: We performed radial arterial tonometry assessments a median of 3.18 ± 0.4 years apart on 143 nondiabetic adult participants in the population-based PREVENCION study. Central AIx was obtained using the generalized transfer function of the Sphygmocor device., Results: Predictors of the change in AIx over time were investigated. Among men (n = 67), the change in AIx was predicted by abdominal obesity (standardized β for waist circumference = 0.34; P = 0.002), impaired fasting glucose (standardized β = 0.24; P = 0.009), and the change in heart rate (standardized β = -0.78; P < 0.001). Among women (n = 76), the change in AIx was predicted by non-high-density lipoprotein cholesterol (standardized β = 0.33; P = 0.001), C-reactive protein levels (standardized β = 0.24; P = 0.02), change in mean arterial pressure (standardized β = 0.33; P = 0.001), and change in heart rate (standardized β = -0.52; P < 0.001)., Conclusions: Metabolic and inflammatory factors predicted changes in AIx over time, with important sex differences. Metabolic factors, such as abdominal obesity and impaired fasting glucose, predicted changes in AIx in men, whereas C-reactive protein and non-high-density lipoprotein cholesterol levels predicted changes in women. Our findings highlight the impact of sex on arterial properties and may guide the design of interventions to favorably impact changes in late systolic pressure augmentation., (© American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Due to numerous technical developments, in vivo imaging is suitable for pharmacokinetic and metabolism studies of new chemical entities as well as for evaluating their pharmacological or biological effects. MRI, nuclear medicine, X-Ray, ultrasound and optical imaging are available for both clinical and experimental imaging with even higher performance. For all these imaging modalities, diagnostic agents are useful to improve contrast and specificity. Specific targeting of biological events is addressed by molecular imaging. From a pharmacodynamic perspective, radiolabeling of a new chemical entity allows in vivo visualization quantitative measure of its biodistribution, its elimination and its specific molecular binding. Non-invasive imaging methods are useful for longitudinal investigations of biological changes. Based on nanotechnologies, specificity of drug delivery can be monitored by imaging. New developments in hybrid imaging technologies as well as multimodal contrast agents reinforce in vivo experimental and clinical proof of mechanism of new chemical entities., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Chronic inflammation is an important contributor to the insulin resistance observed in type 2 diabetes (T2D). We evaluated the expression and function of the P2X(7) receptor and CD39/Entpd1, molecules involved in the cellular regulation of inflammation, in peripheral blood mononuclear cells from T2D patients, and their correlation with the concentration of HbA1c in blood. T2D patients with deficient metabolic control (DC) showed increased proportion of P2X(7)(+) cells compared with healthy individuals; T2D-DC subjects also displayed higher proportion of CD14(+), CD4(+) and CD19(+) subpopulations of P2X(7)(+) cells when compared with T2D patients with acceptable metabolic control. A significant association was observed between the proportion of P2X(7)(+)CD14(+) cells and blood concentration of LDL-c. In addition, the percentages of CD39(+) cells and CD39(+)CD19(+) cells were significantly associated with HbA1c and fasting plasma glucose levels. No changes were observed in the function of P2X(7)(+) cells from T2D patients; however, enhanced CD39/Entpd1 enzyme activity and low serum levels of IL-17 were detected. Therefore, CD39(+) cells could have a balancing regulatory role in the inflammatory process observed in patients with T2D., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Different imaging modalities can provide complementary information on biological processes at the cellular or molecular level in vitro and in vivo. However, specific molecular probes suitable for a comparison of different imaging modalities are often not readily accessible because their preparation is usually accomplished by individually developed and optimized syntheses. Herein, we present a general, modular synthetic approach that provides access to multiple probes derived from a single precursor by application of the same, efficient functionalization strategy, the Cu(I)-catalyzed cycloaddition of terminal alkynes and azides (click chemistry). To demonstrate the viability and efficiency of this approach, folic acid (FA) was selected as a targeting vector because the preparation of FA-based imaging probes used for SPECT, PET, MRI, and NIRF by reported synthetic strategies is usually difficult to achieve and often results in low overall yields. We prepared a versatile γ-azido-FA precursor as well as a set of alkyne functionalized probes and precursors including ligand systems suitable for the chelation of various (radio)metals, an NIR dye and (18)F- and (19)F-derivatives, which enabled the parallel development of new FA-imaging probes. The Cu(I)-mediated coupling of the alkynes with the γ-azido-FA precursor was accomplished in high yields and with minimal use of protective groups. The various probes were fully characterized spectroscopically as well as in vitro and in vivo. In vitro, all new FA-derivatives exhibited high affinity toward the folic acid receptor (FR) and/or were specifically internalized into FR-overexpressing KB cells. In vivo experiments with nude mice showed that all probes (except the MRI probes which have not been tested yet) accumulated specifically in FR-positive organs and human KB-cell xenografts. However, in vivo imaging revealed significant differences between the various FA-derivatives with respect to unspecific, off-target localization. In general, the comparison of different probes proved the superiority of the more hydrophilic, radiometal-based imaging agents, a result which will guide future efforts for the development of FA-based imaging probes and therapeutic agents. In addition, the strategy presented herein should be readily applicable to other molecules of interest for imaging and therapeutic purposes and thus represents a valuable alternative to other synthetic approaches.

Introduction: [18F]-(E)-3-((6-Fluoropyridin-2-yl)ethynyl)cyclohex-2-enone O-methyl oxime ([18F]-FPECMO) is a novel derivative of [11C]-ABP688. [18F]-FPECMO was characterized as a PET imaging agent for the metabotropic glutamate receptor subtype 5 (mGluR5)., Methods: [18F]-FPECMO was synthesized in a one-step reaction sequence by reacting [(18)F]-KF-K(222) complex with (E)-3-((6-bromopyridin-2-yl)ethynyl)cyclohex-2-enone O-methyl oxime in dry DMSO. The in vitro affinity of FPECMO was determined by displacement assays using rat whole brain homogenates (without cerebellum) and the mGluR5-specific radioligand [(3)H]-M-MPEP. Further in vitro characterization involved metabolite studies, lipophilicity determination and autoradiographical analyses of brain slices. In vivo evaluation was performed by postmortem biodistribution studies and PET experiments using Sprague-Dawley rats., Results: The radiochemical yield after semipreparative HPLC was 35+/-7% and specific activity was >240 GBq/micromol. [(18)F]-FPECMO exhibited optimal lipophilicity (logD=2.1) and high metabolic stability in vitro. Displacement studies revealed a K(i) value of 3.6+/-0.7 nM for FPECMO. Biodistribution studies and ex vivo autoradiography showed highest radioactivity accumulation in mGluR5-rich brain regions such as the striatum and hippocampus. Co-injection of [18F]-FPECMO and ABP688 (1 mg/kg body weight), an mGluR5 antagonist, showed 40% specific binding in the striatum, hippocampus and cortex, regions known to contain high densities of the mGluR5. PET imaging, however, did not allow the visualization of mGluR5-rich brain regions in the rat brain due to a fast washout of [18F]-FPECMO from mGluR5-expressing tissues and rapid defluorination., Conclusions: [18F]-FPECMO showed significant potential for the detection of mGluR5 in vitro; however, its in vivo characteristics are not optimal for a clear-cut visualization of the mGluR5 in rats.

Data regarding the prevalence of metabolic syndrome (MTS) in Andean populations are limited. We evaluated the prevalence of MTS according to American Heart Association/National Heart, Lung and Blood Institute criteria among 1878 subjects in the PREVENCION study in Peru. In women, the most common component was low HDL cholesterol (60.9%) followed by abdominal obesity (36.9%). In men, the most common component was elevated triglycerides (52.0%) followed by low HDL cholesterol (32.5%), whereas the prevalence of abdominal obesity was 14%. Abnormal fasting glucose was the least common component in men (5.4%) and women (5.0%). The prevalence of MTS was significantly higher in women compared to men (23.2% versus 14.3%) and increased steeply with age, particularly in women (p<0.0001). Using body mass index (BMI>or=30kg/m2) instead of waist circumference as a component of the MTS lead to equivalent prevalence estimates of MTS in men but significantly underestimated the prevalence in women. The MTS is highly prevalent among Peruvian Andeans, particularly in older women. The pattern of MTS components in this Andean population is characterized by a high prevalence of dyslipidemia and a relatively low prevalence of elevated fasting glucose. Further studies are required to characterize genetic and environmental determinants of these patterns.

Aim: To use radioreceptor analysis for evaluating whether vasoactive intestinal peptide (VIP) receptors are present in chronic periapical lesions and to determine whether differences in its expression are found according to the size of the lesions., Methodology: Twelve periapical lesions were obtained from teeth diagnosed with chronic apical periodontitis and indicated for endodontic surgery; they were classified according to the size of the lesion in two groups of six samples (lesion size greater or smaller than 5 mm), and then processed and labelled with (125)I-VIP. Binding sites were identified by (125)I-VIP and standard VIP competition assays. Mann-Whitney's test was used to establish statistically significant differences in the VIP receptor expression between groups., Results: Vasoactive intestinal peptide receptor expression was found in all periapical lesion samples. There was a statistically significantly higher expression in periapical lesions <5 mm (P < 0.001)., Conclusion: Vasoactive intestinal peptide receptors were expressed in chronic periapical lesions with levels inversely proportional to lesion size.

Cardiovascular disease is emerging as a leading cause of morbidity and mortality in Latin America. Population-based data regarding the prevalence of hypertension and hypertension subtypes in Andean Hispanic populations are scarce. The authors performed a population-based study that included 1878 Peruvian Andean adults to determine: (1) the prevalence, awareness, and control of hypertension and (2) the relative frequency of hypertension subtypes (systolic vs. diastolic). The prevalence of hypertension was 15.7% (95% confidence interval [CI], 14.0%-17.4%), did not differ by gender, and increased steeply with age, particularly in women. Awareness, treatment, and control rates were 47.9%, 39.5%, and 14%, respectively. Diastolic blood pressure increased until age 50 years and reached a plateau thereafter, whereas mean arterial pressure continued to increase with age even after age 50 years. Furthermore, in sharp contrast with the United States population, the predominant type of hypertension was systodiastolic (41.7%; 95% CI, 35.1%-48.5%). Isolated systolic hypertension accounted for only 29.3% of cases (95% CI, 23.9%-35.4%) and was responsible for a minority of cases in all age groups before age 70 years. Hypertension subtypes in this Andean population seem to differ significantly from those present in the United States population, with a much larger proportion of systodiastolic and diastolic hypertension even with advanced age. These differences result from interactions between hemodynamic and structural factors, and further studies aimed at characterizing their genetic and environmental determinants and implications in end-organ damage and prognosis in this population may contribute to understanding the pathophysiology of hypertension.

It has been previously reported that the metabolism of reduced glutathione (GSH) by gamma-glutamyltranspeptidase (GGT) in the presence of chelated metals leads to free radical generation and lipid peroxidation (LPO). The present study demonstrates for the first time that an established cell line expressing GGT-rel, a human GGT-related enzyme, metabolizes extracellular GSH to cysteinylglycine (CysGly) in a time-dependent manner when cells were incubated in a medium containing 2.5 mM GSH and 25 mM glycylglycine. Supplementation with 150-165 microM Fe(3+)-EDTA resulted in a reactive oxygen species (ROS) generation process. The resulting data showed a significantly higher level (7.6-fold) of ROS production in the GGT-rel positive cells in comparison with the GGT-rel negative control cells. CysGly and Cys, but not GSH, were responsible for the observed ROS production, as we confirmed by measuring the same process in the presence of Fe(3+)-EDTA and different thiols. A higher iron reduction and an increased LPO level determined by malondialdehyde HPLC measurement were also found in GGT-rel-overexpressing cells compared to GGT-rel negative cells. Our data clearly indicate that in the presence of iron, not only GGT, but also GGT-rel has a pro-oxidant function by generation of a reactive metabolite (CysGly) and must be taken into account as a potential physiopathological oxidation system.

A liquid chromatography (LC) method for the simultaneous measurement of the main low molecular mass thiols (i.e., cysteine, cysteinylglycine, homocysteine, and glutathione) in human plasma is described. The sample treatment consists of the reduction of disulfide bounds with tri-n-butylphosphine and protein precipitation with trichloroacetic acid followed by precolumn derivatization with a thiol-selective fluorogenic reagent (7-fluoro-2,1,3-benzoxadiazole-4-sulfonamide). The structure of thiol derivatives is assessed using electrospray ionization-mass spectrometry (MS). The stability of resulting adducts in acidic medium (24 h at 10 degrees C) allows the automation of the technique and a high throughput of samples (approximately 50 per day). Separation is complete within 12 min using isocratic reversed-phase mode, and detection is operated by spectrofluorimetry (lambda ex = 385 nm and lambda em = 515 nm). Quantitation is performed by an internal standardization mode using thioglycolic acid. The LC method is fully validated, and homocysteine concentrations obtained in plasma samples are compared with values measured using either fluorescence polarization immunoassay or capillary gas chromatography-MS; a good correlation is observed between LC and both methods. The method has been applied in daily use to a large-scale study in a human healthy population, and some resulting data are discussed.

We report on 7 patients (6 M, 1 F) with Coffin-Lowry syndrome who have a sensorineural hearing deficit in addition to developmental delay and characteristic facial changes. One of the patients also had a history of premature exfoliation of primary teeth. These are previously unappreciated clinical signs that may aid in the early diagnosis of Coffin-Lowry syndrome. Early diagnosis and recognition of a hearing deficit in the patient can lead to the use of hearing aids to help the patient achieve his or her full potential. These "new" clinical manifestations expand the phenotype of Coffin-Lowry syndrome and constitute an additional indication of pleiotropy.

We describe a case of a 79-year-old woman who developed pain and pitting edema of the upper right extremity due to total venous obstruction following the implantation of an atrioventricular sequential pacemaker. She was treated by arm elevation and anticoagulation after which the pain and edema subsided. To our knowledge, this is the first reported case of this complication occurring following implantation of a dual-chamber pacing system. We recommend that venographic studies be done after implantation if apparent arm swelling occurs, and that anticoagulant therapy be instituted if thrombosis is present.