Early left atrial dysfunction is associated with suboptimal cardiovascular health.

AIMS: Two-dimensional speckle-tracking echocardiography can assess left atrial (LA) function by measuring atrial volumes and deformation parameters (strain, strain rate). This cross-sectional analysis explores the association between ideal CV health (CVH), LA function, and systemic biomarkers in healthy individuals from the Chilean MAUCO Cohort. METHODS: We enrolled 95 MAUCO participants with different levels of CVH (mean age: 51 ± 8 years). We categorized participants into low or high CVH groups: A: 0-2, or B: 3-6 CVH risk factors. 2D echocardiography, glucose, insulin, total cholesterol, triglycerides, proBNP, hsCRP, insulin resistance index (HOMA), and right and left atrial strain (RASs and LASs, respectively) were determined. RESULTS: LASs was lower in Group A, while systolic and diastolic blood pressure (BP), body mass index (BMI), insulin, HOMA, total cholesterol, triglycerides, and LV and RV end-diastolic volume were significantly higher in Group A than Group B (P < .01). Change in LASs was inversely correlated with insulin (P = .040), HOMA (P = .013), total cholesterol (P = .039), glycemia (P = .018), and BMI (P = .0.037). CONCLUSION: LASs during the reservoir phase was diminished in subjects with a lower level of CVH. Higher insulin, HOMA, total cholesterol, glycemia, and BMI values were associated with decreased LA deformation during the reservoir phase. Morphofunctional alterations of the LA were also identified in the group with suboptimal CVH, as well as BP values in the range of hypertension. LA dysfunction in an asymptomatic population, along with metabolic syndrome, could be an early event in the continuum of CV damage.

Haemodynamic stress-induced breaches of the arterial intima trigger inflammation and drive atherogenesis.

AIMS: Inflammatory mediators, including blood cells and their products, contribute critically to atherogenesis, but the igniting triggers of inflammation remain elusive. Atherosclerosis develops at sites of flow perturbation, where the enhanced haemodynamic stress could initiate the atherogenic inflammatory process due to the occurrence of mechanic injury. We investigated the role of haemodynamic stress-induced breaches, allowing the entry of blood cells in the arterial intima, in triggering inflammation-driven atherogenesis. METHODS AND RESULTS: Human coronary samples isolated from explanted hearts, (n = 47) displayed signs of blood entry (detected by the presence of iron, ferritin, and glycophorin A) in the subintimal space (54%) as assessed by histology, immunofluorescence, high resolution episcopic microscopy, and scanning electron microscopy. Computational flow dynamic analysis showed that intimal haemorrhagic events occurred at sites of flow disturbance. Experimental carotid arteries from Apoe deficient mice showed discrete endothelial breaches and intimal haemorrhagic events specifically occurring at the site of flow perturbation, within 3 days after the exacerbation of the local haemodynamic stress. Endothelial tearing was associated with increased VCAM-1 expression and, within 7 days, substantial Ly6G+ leucocytes accumulated at the sites of erythrocyte-derived iron and lipids droplets accumulation, pathological intimal thickening and positive oil red O staining. The formation of fatty streaks at the sites of intimal breaches was prevented by the depletion of Ly6G+ leucocytes, suggesting that the local injury driven by haemodynamic stress-induced breaches triggers atherogenic inflammation. CONCLUSION: Haemodynamic-driven breaches of the arterial intima drive atherogenic inflammation by triggering the recruitment of leucocyte at sites of disturbed arterial flow.

Flow Perturbation Mediates Neutrophil Recruitment and Potentiates Endothelial Injury via TLR2 in Mice: Implications for Superficial Erosion.

RATIONALE: Superficial erosion currently causes up to a third of acute coronary syndromes; yet, we lack understanding of its mechanisms. Thrombi because of superficial intimal erosion characteristically complicate matrix-rich atheromata in regions of flow perturbation. OBJECTIVE: This study tested in vivo the involvement of disturbed flow and of neutrophils, hyaluronan, and Toll-like receptor 2 ligation in superficial intimal injury, a process implicated in superficial erosion. METHODS AND RESULTS: In mouse carotid arteries with established intimal lesions tailored to resemble the substrate of human eroded plaques, acute flow perturbation promoted downstream endothelial cell activation, neutrophil accumulation, endothelial cell death and desquamation, and mural thrombosis. Neutrophil loss-of-function limited these findings. Toll-like receptor 2 agonism activated luminal endothelial cells, and deficiency of this innate immune receptor decreased intimal neutrophil adherence in regions of local flow disturbance, reducing endothelial cell injury and local thrombosis (P<0.05). CONCLUSIONS: These results implicate flow disturbance, neutrophils, and Toll-like receptor 2 signaling as mechanisms that contribute to superficial erosion, a cause of acute coronary syndrome of likely growing importance in the statin era.

Evaluation of two alternative ablation treatments for cervical pre-cancer against standard gas-based cryotherapy: a randomized non-inferiority study.

INTRODUCTION: Gas-based cryotherapy is the conventional ablative treatment for cervical pre-cancer in low-income settings, but the use of gas poses significant challenges. We compared the depth of necrosis induced by gas-based cryotherapy with two gas-free alternatives: cryotherapy using CryoPen,and thermoablation. METHODS: We conducted a five-arm randomized non-inferiority trial: double-freeze carbon dioxide (CO2) cryotherapy (referent), single-freeze CO2 cryotherapy, double-freeze CryoPen, single-freeze CryoPen, and thermoablation. Subjects were 130 women scheduled for hysterectomy for indications other than cervical pathology, and thus with healthy cervical tissue available for histological evaluation of depth of necrosis post-surgery. The null hypothesis was rejected (ie, conclude non-inferiority) if the upper bound of the 90% confidence interval (90% CI) for the difference in mean depth of necrosis (referent minus each experimental method) was <1.14 mm. Patient pain during treatment was reported on a scale of 0 (no pain) to 10 (worst pain). RESULTS: A total of 133 patients were enrolled in the study. The slides from three women were deemed unreadable. One patient was excluded because her hysterectomy was postponed for reasons unrelated to the study, and two patients were excluded because treatment application did not follow the established protocol. For the remaining 127 women, mean depth of necrosis for double-freeze CO2 (referent) was 6.0±1.6 mm. Differences between this and other methods were: single-freeze CO2 = 0.4 mm (90% CI -0.4 to 1.2 mm), double-freeze CryoPen= 0.7 mm (90% CI 0.04 to 1.4 mm), single-freeze CryoPen= 0.5 mm (90% CI -0.2 to 1.2 mm), and thermoablation = 2.6 mm (90% CI 2.0 to 3.1 mm). Mean pain levels were 2.2±1.0 (double-freeze CO2 cryotherapy), 1.8±0.8 (single-freeze CO2 cryotherapy), 2.5±1.4 (double-freeze CryoPen), 2.6±1.4 (single-freeze CryoPen), and 4.1±2.3 (thermoablation). DISCUSSION: Compared with the referent, non-inferiority could not be concluded for other methods. Mean pain scores were low for all treatments. Depth of necrosis is a surrogate for treatment efficacy, but a randomized clinical trial is necessary to establish true cure rates.

Left Cardiac Remodelling Assessed by Echocardiography Is Associated with Rho-Kinase Activation in Long-Distance Runners.

This single-blind and cross-sectional study evaluated the role of Rho-kinase (ROCK) as a biomarker of the cardiovascular remodelling process assessed by echocardiography in competitive long-distance runners (LDRs) during the training period before a marathon race. Thirty-six healthy male LDRs (37.0 ± 5.3 years; 174.0 ± 7.0 height; BMI: 23.8 ± 2.8; V˙ O2-peak: 56.5 ± 7.3 mL·kg-1·min-1) were separated into two groups according to previous training level: high-training (HT, n = 16) ≥ 100 km·week-1 and low-training (LT, n = 20) ≥ 70 and < 100 km·week-1. Also, twenty-one healthy nonactive subjects were included as a control group (CTR). A transthoracic echocardiography was performed and ROCK activity levels in circulating leukocytes were measured at rest (48 h without exercising) the week before the race. The HT group showed a higher left ventricular mass index (LVMi) and left atrial volume index (LAVi) than other groups (p < 0.05, for both); also, higher levels of ROCK activity were found in LDRs (HT = 6.17 ± 1.41 vs. CTR = 1.64 ± 0.66 (p < 0.01); vs. LT = 2.74 ± 0.84; (p < 0.05)). In LDRs a direct correlation between ROCK activity levels and LVMi (r = 0.83; p < 0.001), and LAVi (r = 0.70; p < 0.001) were found. In conclusion, in male competitive long-distance runners, the load of exercise implicated in marathon training is associated with ROCK activity levels and the left cardiac remodelling process assessed by echocardiography.

Circulating Vascular Cell Adhesion Molecule-1 (sVCAM-1) Is Associated With Left Atrial Remodeling in Long-Distance Runners.

Introduction: An increased risk of atrial fibrillation (AF) has been demonstrated in high-performance athletes. Soluble vascular adhesion molecule-1 (sVCAM-1), a biomarker involved in inflammation and cardiac remodeling, is associated with the development of AF in the general population. However, the relationship between sVCAM-1 and left atrial (LA) remodeling has been poorly investigated in long-distance runners (LDR). Aim: To determine the association between LA remodeling and sVCAM-1 levels in LDR during the training period before a marathon race. Methods: Thirty-six healthy male LDR (37.0 ± 5.3 years; 174.0 ± 7.0 height; BMI: 23.8 ± 2.8; V°O2-peak: 56.5 ± 7.3 mL·kg-1·min-1) were evaluated in this single-blind and cross-sectional study. The LDR were separated into two groups according to previous training levels: high-training (HT) (n = 18) ≥100 km·week-1 and low-training (LT) (n = 18) ≥70 and <100 km·week-1. Also, 18 healthy non-active subjects were included as a control group (CTR). In all participants, transthoracic echocardiography was performed. sVCAM-1 blood levels were measured baseline and immediately finished the marathon race in LDR. Results: HT showed increased basal levels of sVCAM-1 (651 ± 350 vs. 440 ± 98 ng·mL-1 CTR, p = 0.002; and vs. 533 ± 133 ng·mL-1 LT; p = 0.003) and a post-marathon increase (ΔsVCAM-1) (651 ± 350 to 905 ± 373 ng·mL-1; p = 0.002), that did not occur in LT (533 ± 133 to 651 ± 138 ng·mL-1; p = 0.117). In LDR was a moderate correlation between LA volume and sVCAM-1 level (rho = 0.510; p = 0.001). Conclusions: In male long-distance runners, sVCAM-1 levels are directly associated with LA remodeling. Also, the training level is associated with basal sVCAM-1 levels and changes after an intense and prolonged exercise (42.2 km). Whether sVCAM-1 levels predict the risk of AF in runners remains to be established.

Cost-effectiveness analysis of VECTOS software for the control of diseases transmitted by Aedes aegypti in two Colombian municipalities / [Análisis de costo-efectividad del uso del programa VECTOS en el control rutinario de enfermedades transmitidas por Aedes aegypti en dos municipios de Santander, Colombia].

Introduction: Diseases transmitted by Aedes aegypti are considered a public health problem. VECTOS is a novel software for the integration of vector control strategies. Objective: To assess the cost-effectiveness of the use of VECTOS in the routine control programs of diseases transmitted by A. aegypti in the municipality of San Juan de Girón (Santander). Materials and methods: We conducted a cost-effectiveness analysis using a decision analysis model from the perspective of the local health authorities. We considered the use of the VECTOS software in the routine control activities in the municipality of San Juan de Girón during 2016 as the treatment group while the routine control in the municipality of Floridablanca, where VECTOS is not implemented, was considered as the comparator. We calculated the incremental cost-effectiveness ratio (ICER) taking as effectiveness measure the disability-adjusted life years (DALY). Results: VECTOS was cost-effective at a rate of USD$ 660,4 savings per each DALY avoided compared to the routine control in Floridablanca. The probabilistic model showed that the system was cost-effective in 70% of the 10.000 iterations for a threshold between 1 to 3 GDP per capita. Conclusions: VECTOS software as implemented in the municipality of San Juan de Girón is highly cost-effective and could be used in other municipalities in the country where diseases transmitted by A. aegypti are endemic.

Introducción. Las enfermedades transmitidas por Aedes aegypti son un problema de salud pública. VECTOS es un programa novedoso de integración de estrategias de control de vectores. Objetivo. Evaluar el costo-efectividad del uso del VECTOS en los programas de control rutinario de enfermedades transmitidas por el vector Aedes aegypti en el municipio de San Juan de Girón (Santander). Materiales y métodos. Se evaluó el costo-efectividad del programa empleando un modelo de análisis de decisiones desde la perspectiva de las autoridades locales de salud. Se estudió la integración de las estrategias de control de vectores mediante el programa VECTOS utilizado en el municipio de San Juan de Girón durante el 2016, con el control rutinario llevado a cabo sin VECTOS en el municipio de Floridablanca. Se calculó la razón incremental del costo-efectividad (RICE), usando como medida de efectividad los años de vida ajustados por discapacidad (AVAD). Resultados. El uso del programa VECTOS fue rentable a una tasa de ahorro de USD$660,4 por cada AVAD evitado en comparación con el control de rutina en Floridablanca. El modelo probabilístico indicó que el sistema fue costo-efectivo en el 70 % de las 10.000 iteraciones para un umbral entre 1 y 3 PIB per cápita. Conclusiones. El programa VECTOS fue muy costo-efectivo en el municipio de San Juan de Girón. Su uso puede adoptarse en otros municipios del país donde las enfermedades transmitidas por A. aegypti son endémicas.

Clinical study and some molecular features of Mexican patients with syndromic craniosynostosis.

BACKGROUND: Craniosynostosis is one of the major genetic disorders affecting 1 in 2,100-2,500 live newborn children. Environmental and genetic factors are involved in the manifestation of this disease. The suggested genetic causes of craniosynostosis are pathogenic variants in FGFR1, FGFR2, FGFR3, and TWIST1 genes. METHODS: In order to describe their major clinical characteristics and the presence of pathogenic variants, a sample of 36 Mexican patients with craniosynostosis diagnosed as: Crouzon (OMIM 123,500), Pfeiffer (OMIM 101,600), Apert (OMIM 101,200), Saethre-Chotzen (OMIM 101,400), and Muenke (OMIM 602,849) was analyzed. RESULTS: In addition to craniosynostosis, most of the patients presented hypertelorism, midface hypoplasia, and abnormalities in hands and feet. To detect the pathogenic variants p.Pro252Arg FGFR1 (OMIM 136,350), p.Ser252Trp, p.Pro253Arg FGFR2 (OMIM 176,943), p.Pro250Arg, FGFR3 (OMIM 134,934), and p.Gln119Pro TWIST1 (OMIM 601,622), PCR amplification and restriction enzyme digestion were performed. Four and two patients with Apert presented the pathogenic variants p.Ser252Trp and p.Pro253Arg in FGFR2, respectively (with a frequency of 11.1% and 5.5%). The p.Pro250Arg pathogenic variant of FGFR3 was found in a patient with Muenke (with a frequency of 2.8%). The above percentages were calculated with the total number of patients. CONCLUSION: The contribution of this work is discreet, since only 4 genes were analyzed and sample size is small. However, this strategy could be improved by sequencing the FGFR1, FGFR2, FGFR3, and TWIST1 genes, to determine different pathogenic variants. On the other hand, it would be important to include other genes, such as TCF12 (OMIM 600,480), MSX2 (OMIM 123,101), RAB23 (OMIM 606,144), and EFNB1 (OMIM 300,035), to determine their participation in craniosynostosis in the Mexican population.

Factor de crecimiento análogo a insulina-1 y cardiotrofina-1 inducido por ejercicio y su relación con hipertrofia miocárdica en maratonistas / Cardiotrophin-1 and Insulin like growth factor induced by exercise are associated to cardiac hypertrophy in marathon runners

Antecedentes: El ejercicio de alta intensidad induce hipertrofia miocárdica necesaria para adaptar al corazón a la mayor demanda de trabajo. Se desconoce si correr una maratón induce de forma aguda factores humorales asociados al desarrollo de hipertrofia miocárdica en atletas. Objetivo: Evaluar cardiotrofina-1 (CT1) y el factor de crecimiento análogo a insulina-1 (IGF-1), conocidos inductores de hipertrofia, en maratonistas previo y justo después de correr una maratón y su relación con hipertrofia cardíaca. Métodos: Estudio prospectivo ciego simple de atletas hombres que corrieron la maratón de Santiago. Se incluyó un grupo control sedentario. En todos los sujetos se realizó un ecocardiograma transtorácico estándar. Los niveles de CT1 e IGF-1 se determinaron en plasma obtenidos antes (basal) y justo después de haber terminado (antes de 15 minutos) la maratón, usando test de ELISA. Resultados: Los atletas tenían frecuencias cardíacas menores que los controles, asociado con una mayor hipertrofia miocárdica, determinado por el grosor del septo y pared posterior del corazón, y volúmenes del ventrículo y aurícula izquierda. Los niveles basales de CT1 e IGF-1 fueron similares entre atletas y controles sedentarios. El correr la maratón aumentó los niveles de estas dos hormonas en un subgrupo de atletas. Solo los atletas que incrementaron los niveles de IGF-1, pero no de CT1, tenían volúmenes de ventrículo izquierdo y derecho más grandes que los otros atletas. Conclusiones: IGF-1 que se incrementa de forma aguda por el ejercicio, pero no CT1, estaría asociado con el aumento de los volúmenes ventriculares observado en los atletas.

Background: High intensity exercise induces the development of myocardial hypertrophy necessary to adapt the heart to the increased work demand. Whether running a marathon is associated with acutely induced humoral factors responsible for the development of myocardial hypertrophy observed in athletes is not known. Objective: To evaluate the levels of cardiotrophin-1 (CT1) and insulin-like growth factor-1 (IGF-1), known hypertrophy inducers, in marathon runners before and just after running a marathon and their relationship with cardiac hypertrophy. Methodology: Single-blind prospective study of male athletes who ran the Santiago's marathon. A sedentary control group was included. All subjects underwent a standard transthoracic echocardiogram. CT1 and IGF-1 levels were determined in plasma obtained before (basal) and just after finishing (within 15 min) the marathon using ELISA assays. Results: Athletes had lower heart rates than controls, associated with greater myocardial hypertrophy, as determined by thickness of the heart's septum and posterior wall, and left atrial and ventricular volumes. Basal CT1 and IGF-1 levels were similar between athletes and sedentary controls. Marathon running increased the levels of these two hormones in a subgroup of athletes. Only the athletes who increased IGF-1 levels, but not CT1, had larger left and right ventricular volumes. Conclusion: IGF-1 acutely increased by exercise, but not CT1, was associated with the augmented ventricular volumes observed in athletes.

A "sweet-spot" for fluid-induced oscillations in the conditioning of stem cell-based engineered heart valve tissues.

Fluid-induced shear stresses are involved in the development of cardiovascular tissues. In a tissue engineering framework, this stimulus has also been considered as a mechanical regulator of stem cell differentiation. We recently demonstrated that the fluid-oscillating effect in combination with a physiologically-relevant shear stress magnitude contributes to the formation of stem cell-derived de novo heart valve tissues. However, the range of oscillations necessary to induce favorable gene expression and engineered tissue formation is unknown. In this study, we took a computational approach to establish a range of oscillatory shear stresses that may optimize in vitro valvular tissue growth. Taking a biomimetic approach, three physiologically-relevant flow waveforms from the human: (i) aorta, (ii) pulmonary artery and (iii) superior vena cava were utilized to simulate pulsatile flow conditions within a bioreactor that housed 3 tissue specimens. Results were compared to non-physiological pulsatile flow (NPPF) and cyclic flexure-steady flow (Flex-Flow) conditions. The oscillatory shear index (OSI) was used to quantify the fluid-induced oscillations occurring on the specimen surfaces. The range of mean OSI under the physiological conditions investigated was found to be 0.18 ≤ OSI ≤ 0.23. On the other hand, NPPF and Flex-Flow environments yielded a mean OSI of 0.37 and 0.11 respectively, which were 46% higher and 45% lower than physiological conditions. Moreover, we subsequently conducted OSI-based human bone marrow stem cell (HBMSC) culture experiments which resulted in preferential valvular gene expression and phenotype (significant upregulation of BMP, KLF2A, CD31 and α-SMA using an OSI of 0.23 in comparison to a lower OSI of 0.10 or a higher OSI of 0.38; p < .05). These findings suggest that a distinct range or a "sweet-spot" for physiological OSI exists in the mechanical conditioning of tissue engineered heart valves grown from stem cell sources. We conclude that in vitro heart valve matrix development could be further enhanced by simultaneous exposure of the engineered tissues to physiologically-relevant magnitudes of both fluid-induced oscillations and shear stresses.

Relative Effects of Fluid Oscillations and Nutrient Transport in the In Vitro Growth of Valvular Tissues.

Engineered valvular tissues are cultured dynamically, and involve specimen movement. We previously demonstrated that oscillatory shear stresses (OSS) under combined steady flow and specimen cyclic flexure (flex-flow) promote tissue formation. However, localized efficiency of specimen mass transport is also important in the context of cell viability within the growing tissues. Here, we investigated the delivery of two essential species for cell survival, glucose and oxygen, to 3-dimensional (3D) engineered valvular tissues. We applied a convective-diffusive model to characterize glucose and oxygen mass transport with and without valve-like specimen flexural movement. We found the mass transport effects for glucose and oxygen to be negligible for scaffold porosities typically present during in vitro experiments and non-essential unless the porosity was unusually low (<40%). For more typical scaffold porosities (75%) however, we found negligible variation in the specimen mass fraction of glucose and oxygen in both non-moving and moving constructs (p > 0.05). Based on this result, we conducted an experiment using bone marrow stem cell (BMSC)-seeded scaffolds under Pulsatile flow-alone states to permit OSS without any specimen movement. BMSC-seeded specimen collagen from the pulsatile flow and flex-flow environments were subsequently found to be comparable (p > 0.05) and exhibited some gene expression similarities. We conclude that a critical magnitude of fluid-induced, OSS created by either pulsatile flow or flex-flow conditions, particularly when the oscillations are physiologically-relevant, is the direct, principal stimulus that promotes engineered valvular tissues and its phenotype, whereas mass transport benefits derived from specimen movement are minimal.

Immunological and Functional Characterization of RhoGDI3 and Its Molecular Targets RhoG and RhoB in Human Pancreatic Cancerous and Normal Cells.

RhoGDI proteins have been implicated in several human cancers; changes in their expression levels have shown pro- or anti-tumorigenic effects. Pancreatic Ductal Adenocarcinoma (PDAC) is a complex pathology, with poor prognosis, and most patients die shortly after diagnosis. Efforts have been focused on understanding the role of RhoGDI's in PDAC, specially, RhoGDI1 and RhoGDI2. However, the role of RhoGDI3 has not been studied in relation to cancer or to PDAC. Here, we characterized the expression and functionality of RhoGDI3 and its target GTPases, RhoG and RhoB in pancreatic cell lines from both normal pancreatic tissue and tissue in late stages of PDAC, and compared them to human biopsies. Through immunofluorescences, pulldown assays and subcellular fractionation, we found a reduction in RhoGDI3 expression in the late stages of PDAC, and this reduction correlates with tumor progression and aggressiveness. Despite the reduction in the expression of RhoGDI3 in PDAC, we found that RhoB was underexpressed while RhoG was overexpressed, suggesting that cancerous cells preserve their capacity to activate this pathway, thus these cells may be more eager to response to the stimuli needed to proliferate and become invasive unlike normal cells. Surprisingly, we found nuclear localization of RhoGDI3 in non-cancerous pancreatic cell line and normal pancreatic tissue biopsies, which could open the possibility of novel nuclear functions for this protein, impacting gene expression regulation and cellular homeostasis.

Neuroticism and cortisol: The importance of checking for sex differences.

Existent research documents an unclear and contradictory pattern between cortisol and personality variables, especially neuroticism. Specifically, no effect, positive correlations and negative correlations have all been reported to exist between cortisol and neuroticism. The current study tested whether males and females have a fundamentally different relationship between HPA activation and neuroticism and if this might partially account for some of the discrepancy in findings. Saliva samples (n=183) for cortisol were collected three times across a 90min period. Neuroticism was measured via the NEO-FFI. For men, neuroticism was positively correlated with cortisol level (r=.29). For women it was negatively correlated. The negative correlation between neuroticism and cortisol level remained when oral contraceptive use was statistically controlled, and the statistical significance actually increased (partial r=-.20). This suggests a slight suppressor effect, explainable by prior research on correlates of oral contraceptive use. Overall, these findings may offer some explanation for the discrepant results that have been reported in the existing literature regarding neuroticism and cortisol measures.

Marrow stem cell differentiation for valvulogenesis via oscillatory flow and nicotine agonists: unusual suspects?

Fluid-induced oscillatory shear stress (OSS) and nicotine are known antagonists in cardiovascular disease. However, from a regenerative medicine standpoint, we hypothesized that these parameters may support the cell differentiation of bone marrow mesenchymal stem cells (BMMSCs) for engineering heart valves. In this study, OSS and nicotine (10-6M) were applied individually to BMMSCs in monolayer culture. In both cases, a significantly higher expression of CD31 was detected compared to corresponding controls (p<0.05). We interpret our findings to indicate that both OSS and nicotine independently support mesenchymal to endothelial transformation; however, the underlying mechanism for this transformation in terms of the cell cytoskeletal structure was entirely different between the two stimulants. In the case of OSS, F-actin filaments exhibited a stretching response and formed a preferential alignment with each other. However, in the nicotine-treated group, a clear increase was observed in the number of actin filaments present, which led to the maximum expression of CD31 in comparison to the OSS and control groups. From our findings, we speculate that while nicotine may stimulate an increase in the differentiation of BMMSCs to endothelial cells, OSS may play a greater role in cellular distribution and the eventual creation of a tissue engineered heart valve (TEHV) endothelium.

Differentiation and Distribution of Marrow Stem Cells in Flex-Flow Environments Demonstrate Support of the Valvular Phenotype.

For treatment of critical heart valve diseases, prosthetic valves perform fairly well in most adults; however, for pediatric patients, there is the added requirement that the replacement valve grows with the child, thus extremely limiting current treatment options. Tissue engineered heart valves (TEHV), such as those derived from autologous bone marrow stem cells (BMSCs), have the potential to recapitulate native valve architecture and accommodate somatic growth. However, a fundamental pre-cursor in promoting directed integration with native tissues rather than random, uncontrolled growth requires an understanding of BMSC mechanobiological responses to valve-relevant mechanical environments. Here, we report on the responses of human BMSC-seeded polymer constructs to the valve-relevant stress states of: (i) steady flow alone, (ii) cyclic flexure alone, and (iii) the combination of cyclic flexure and steady flow (flex-flow). BMSCs were seeded onto a PGA: PLLA polymer scaffold and cultured in static culture for 8 days. Subsequently, the aforementioned mechanical conditions, (groups consisting of steady flow alone-850ml/min, cyclic flexure alone-1 Hz, and flex-flow-850ml/min and 1 Hz) were applied for an additional two weeks. We found samples from the flex-flow group exhibited a valve-like distribution of cells that expressed endothelial (preference to the surfaces) and myofibroblast (preference to the intermediate region) phenotypes. We interpret that this was likely due to the presence of both appreciable fluid-induced shear stress magnitudes and oscillatory shear stresses, which were concomitantly imparted onto the samples. These results indicate that flex-flow mechanical environments support directed in vitro differentiation of BMSCs uniquely towards a heart valve phenotype, as evident by cellular distribution and expression of specific gene markers. A priori guidance of BMSC-derived, engineered tissue growth under flex-flow conditions may serve to subsequently promote controlled, engineered to native tissue integration processes in vivo necessary for successful long-term valve remodeling.

Análisis de costo-efectividad del uso del programa VECTOS en el control rutinario de enfermedades transmitidas por Aedes aegypti en dos municipios de Santander, Colombia / Cost-effectiveness analysis of VECTOS software for the control of diseases transmitted by Aedes aegypti in two Colombian municipalities

Introducción. Las enfermedades transmitidas por Aedes aegypti son un problema de salud pública. VECTOS es un programa novedoso de integración de estrategias de control de vectores. Objetivo. Evaluar el costo-efectividad del uso del VECTOS en los programas de control rutinario de enfermedades transmitidas por el vector Aedes aegypti en el municipio de San Juan de Girón (Santander). Materiales y métodos. Se evaluó el costo-efectividad del programa empleando un modelo de análisis de decisiones desde la perspectiva de las autoridades locales de salud. Se estudió la integración de las estrategias de control de vectores mediante el programa VECTOS utilizado en el municipio de San Juan de Girón durante el 2016, con el control rutinario llevado a cabo sin VECTOS en el municipio de Floridablanca. Se calculó la razón incremental del costo-efectividad (RICE), usando como medida de efectividad los años de vida ajustados por discapacidad (AVAD). Resultados. El uso del programa VECTOS fue rentable a una tasa de ahorro de USD$ 660,4 por cada AVAD evitado en comparación con el control de rutina en Floridablanca. El modelo probabilístico indicó que el sistema fue costo-efectivo en el 70 % de las 10.000 iteraciones para un umbral entre 1 y 3 PIB per cápita. Conclusiones. El programa VECTOS fue muy costo-efectivo en el municipio de San Juan de Girón. Su uso puede adoptarse en otros municipios del país donde las enfermedades transmitidas por A. aegypti son endémicas.

Introduction: Diseases transmitted by Aedes aegypti are considered a public health problem. VECTOS is a novel software for the integration of vector control strategies. Objective: To assess the cost-effectiveness of the use of VECTOS in the routine control programs of diseases transmitted by A. aegypti in the municipality of San Juan de Girón (Santander). Materials and methods: We conducted a cost-effectiveness analysis using a decision analysis model from the perspective of the local health authorities. We considered the use of the VECTOS software in the routine control activities in the municipality of San Juan de Girón during 2016 as the treatment group while the routine control in the municipality of Floridablanca, where VECTOS is not implemented, was considered as the comparator. We calculated the incremental cost-effectiveness ratio (ICER) taking as effectiveness measure the disability-adjusted life years (DALY). Results: VECTOS was cost-effective at a rate of USD$ 660,4 savings per each DALY avoided compared to the routine control in Floridablanca. The probabilistic model showed that the system was cost-effective in 70% of the 10.000 iterations for a threshold between 1 to 3 GDP per capita. Conclusions: VECTOS software as implemented in the municipality of San Juan de Girón is highly cost-effective and could be used in other municipalities in the country where diseases transmitted by A. aegypti are endemic.

Trends in mortality due to motor vehicle traffic accident injuries between 1987 and 2011 in a Spanish region (Comunitat Valenciana).

OBJECTIVE: To analyse the time evolution of the rates of mortality due to motor vehicle traffic accidents (MVTA) injuries that occurred among the general population of Comunitat Valenciana between 1987 and 2011, as well as to identify trend changes by sex and age group. METHODS: An observational study of annual mortality trends between 1987 and 2011. We studied all deaths due to MVTA injuries that occurred during this period of time among the non-institutionalised population residing in Comunitat Valenciana (a Spanish Mediterranean region that had a population of 5,117,190 inhabitants in 2011). The rates of mortality due to MVTA injuries were calculated for each sex and year studied. These rates were standardised by age for the total population and for specific age groups using the direct method (age-standardised rate - ASR). Joinpoint regression models were used in order to detect significant trend changes. Additionally, the annual percentage change (APC) of the ASRs was calculated for each trend segment, which is reflected in statistically significant joinpoints. RESULTS: For all ages, ASRs decrease greatly in both men and women (70% decrease between 1990 and 2011). In 1990 and 2011, men have rates of 36.5 and 5.2 per 100,000 men/year, respectively. In the same years, women have rates of 8.0 and 0.9 per 100,000 women/year, respectively. This decrease reaches up to 90% in the age group 15-34 years in both men and women. ASR ratios for men and women increased over time for all ages: this ratio was 3.9 in 1987; 4.6 in 1990; and 5.8 in 2011. For both men and women, there is a first significant segment (p<0.05) with an increasing trend between 1987 and 1989-1990. After 1990, there are 3 segments with a significant decreasing APC (1990-1993, 1993-2005 and 2005-2011, in the case of men; and 1989-1996, 1999-2007 and 2007-2011, in the case of women). CONCLUSION: The risk of death due to motor vehicle traffic accidents injuries has decreased significantly, especially in the case of women, for the last 25 years in Comunitat Valenciana, mainly as of 2006. This may be a consequence of the road-safety measures that have been implemented in Spain and in Comunitat Valenciana since 2004. The economic crisis that this country has undergone since 2008 may have also been a contributing factor to this decrease. Despite the decrease, ASR ratios for men and women increased over time and it is still a high-risk cause of death among young men. It is thus important that the measures that helped decrease the risk of death are maintained and improved over time.

Computational simulations predict a key role for oscillatory fluid shear stress in de novo valvular tissue formation.

Previous efforts in heart valve tissue engineering demonstrated that the combined effect of cyclic flexure and steady flow on bone marrow derived stem cell-seeded scaffolds resulted in significant increases in engineered collagen formation [Engelmayr et al. Cyclic flexure and laminar flow synergistically accelerate mesenchymal stem cell-mediated engineered tissue formation: Implications for engineered heart valve tissues. Biomaterials 2006; 27(36): 6083-95]. Here, we provide a new interpretation for the underlying reason for this observed effect. In addition, another related investigation demonstrated the impact of fluid flow on DNA content and quantified the fluid-induced shear stresses on the engineered heart valve tissue specimens [Engelmayr et al. A Novel Flex-Stretch-Flow Bioreactor for the Study of Engineered Heart Valve Tissue Mechanobiology]. Annals of Biomedical Engineering 2008, 36, 1-13]. In this study, we performed more advanced CFD analysis with an emphasis on oscillatory wall shear stresses imparted on specimens when mechanically conditioned by a combination of cyclic flexure and steady flow. Specifically, we hypothesized that the dominant stimulatory regulator of the bone marrow stem cells is fluid-induced and depends on both the magnitude and temporal directionality of surface stresses, i.e., oscillatory shear stresses (OSS) acting on the developing tissues. Therefore, we computationally quantified the (i) magnitude of fluid-induced shear stresses as well as (ii) the extent of temporal fluid oscillations in the flow field using the oscillatory shear index (OSI) parameter. Noting that sample cyclic flexure induces a high degree of OSS, we incorporated moving boundary computational fluid dynamic simulations of samples housed within a bioreactor to consider the effects of: (1) No Flow, No Flexure (control group), (2) Steady Flow-alone, (3) Cyclic Flexure-alone and (4) Combined Steady flow and Cyclic Flexure environments. Indeed we found that the coexistence of both OSS and appreciable shear stress magnitudes explained the high levels of engineered collagen previously observed from combining cyclic flexure and steady flow states. On the other hand, each of these metrics on its own showed no association. This finding suggests that cyclic flexure and steady flow synergistically promote engineered heart valve tissue production via OSS, so long as the oscillations are accompanied by a critical magnitude of shear stress.

Estructura factorial del Cuestionario de Experiencias Relacionadas con Internet en universitarios chilenos / Factorial structure of the Questionnaire of Experiences Related with Internet on Chilean university students

Resumen El uso de Internet está masificado en casi todo el mundo. Existe evidencia de que su uso excesivo tiene consecuencias negativas, por lo que es necesario contar con instrumentos que evalúen su uso. El Cuestionario de Experiencias Relacionadas con Internet (CERI) es un instrumento de dos factores que evalúan conflictos (intrapersonales e interpersonales) asociados a su uso excesivo. Estudios realizados en distintas partes del mundo han utilizado este instrumento sin analizar sus propiedades psicométricas con la suficiente profundidad y han privilegiado el uso del puntaje total en lugar del puntaje de los dos factores. Por esta razón, en este artículo se evalúan las propiedades psicométricas del instrumento en población chilena. Se realizaron dos estudios en los que participaron un total de 626 estudiantes universitarios (180 en el estudio 1 y 446 en el estudio 2) que respondieron el CERI y un cuestionario de abuso del teléfono móvil. En el estudio 1 se realizó un análisis factorial exploratorio que sugirió seleccionar la estructura unifactorial en lugar de la estructura bifactorial original, aunque ambas presentaban adecuada validez convergente (relaciones directas con el abuso del teléfono móvil). En el estudio 2 se realizó un análisis factorial confirmatorio y ambas estructuras factoriales presentaron buen ajuste, pero la consistencia interna del factor único fue mayor que la de los dos factores originales. Es necesario continuar evaluando la estructura factorial del CERI en orden a determinar cuál es la mejor alternativa factorial, mientras tanto la estructura unifactorial parece entregar mayores garantías psicométricas.

Abstract A large proportion of the world's population has access to the Internet. On the one hand this has brought undeniable benefits to society by facilitating access to information. But on the other hand, the excessive use of the Internet has also brought with it a series of new problems ranging from physical injuries (for example: tendinitis), psychological pathologies (for example: Internet addiction) to new forms of crime (for example: online sexual abuse). For this reason, it is necessary to have reliable and valid instruments that evaluate the use and abuse of the Internet. The Internet Related Experiences Questionnaire (CERI) has two factors that evaluate conflicts (intrapersonal factor, with 6 items and interpersonal factor, with 4 items) associated with excessive use of the Internet. Studies in different parts of the world (Spain, Chile and other Latin American countries) have used this instrument without analyzing its psychometric properties with sufficient depth. These studies have mostly used the total CERI score (10 items) instead of the two-factor structure, but they have not justified this choice. For this reason, this paper intends to analyze the factorial structure of the instrument, its convergent validity and its internal consistency in the Chilean population. We conducted two researches in which participated a total of 626 university students (180 in the study 1, and 446 in the study 2). The participants responded to the CERI and a questionnaire of abuse of the mobile phone (CERM). In the study 1, the results of exploratory factor analyzes suggest to use a unifactorial structure which included the 10 items, instead of the original bifactorial structure. In particular, in the bifactorial structure item 1 was not included in any factor (factorial loads less than .2), two items (items 5 and 10) presented similar factor loads in both factors and other two items (items 8 and 9) were included in the factor that it did not correspond. The single factor was greater internal consistency than that of the original intrapersonal and interpersonal factors (Cronbach´s alpha of .78, .68 and .56, respectively). Although both alternatives have adequate convergent validity (direct relations with mobile phone abuse). In study 2, a confirmatory factorial analysis was carried out in order to compare the unifactorial structure obtained in study 1 with the bifactorial structure of the original study. The results show that both factorial structures presented good fit, but again the internal consistency of the single factor was greater than that of the original intrapersonal factor and interpersonal factor (Cronbach´s alpha of .74, .61 and .51 respectively). The low reliability of interpersonal and intrapersonal factors may be due to the few number of items grouped in them (4 and 6 respectively). It is necessary to continue evaluating the factorial structure of the CERI in order to determine which is the best factorial alternative or if it is necessary to increase the number of items of interpersonal and intrapersonal factors. Although the results are not conclusive, for the moment, it seems advisable to use the one factor structure as it seems to give further psychometric guarantees.

Oscillatory shear stress created by fluid pulsatility versus flexed specimen configurations.

Oscillatory shear stress (OSS), caused by time-varying flow environments, may play a critical role in the production of engineered tissue by bone marrow-derived stem cells. This is particularly relevant in heart valve tissue engineering (HVTE), owing to the intense haemodynamic environments that surround native valves. In this study, we examined and quantified the role that (i) physiologically relevant scales of pulsatility and (ii) changes in geometry as a function of specimen flexure have in creating OSS conditions. A U-shaped bioreactor capable of producing flow, stretch and flexure was modelled with housed specimens, and computational fluid dynamic simulations were performed. We found that physiologically relevant OSS can be maximised by the application of pulsatile flow to straight, non-moving specimens in a uniform manner. This finding reduces a substantial layer of complexity in dynamic HVTE protocols in which traditionally, time-varying flow has been promoted through specimen movement in custom-made bioreactors.