Leptin Inhibits Angiotensin II-Induced Intracellular Calcium Increase and Vasoconstriction in the Rat Aorta

Besides its role in body weight control leptin may also act as a vasoactive hormone. This study was designed to investigate whether leptin modifies angiotensin II (ANG II)-induced vascular responses. The expression of functional leptin receptors (OB-Rb) was detected in vascular smooth muscle cells (VSMCs) from adult Wistar rats by RT-PCR. Immunocytochemistry and Western blot analysis further showed the expression of OB-R protein in VSMCs. The ANG II (10(-7) mol/liter)-induced increase in intracellular Ca(2+) was blocked (P < 0.01) by leptin (10(-8) mol/liter). Moreover, in calcium-free buffer leptin was able to inhibit 65% of the ANG II-induced calcium release from intracellular stores. In endothelium-denuded aortic rings from adult Wistar rats no effect of leptin on basal tension was observed. However, the ANG II-induced isometric contraction was reduced (P < 0.05) by leptin (10(-8) mol/liter). The experiments were also performed in age- and sex-matched Zucker rats, in which no effect of leptin on ANG II-induced calcium increase and vasoconstriction was observed. It is concluded that leptin blocks the vasoconstrictor action of ANG II and inhibits the ANG II-induced increase in intracellular Ca(2+) in VSMCs through OB-Rb. These findings provide new insight into the physiological effects of leptin on blood pressure regulation

Prevenciones ex ante y validaciones ex post en la selección de outputs para evaluar servicios públicos: el caso de la educación

La selección de indicadores de resultados y productividad es una cuestión de plena actualidad en el campo de la gestión y evaluación de los servicios públicos en general, y en el caso de la Educación Secundaria en particular. Para dar respuesta a este problema, en este trabajo se analizan dos aspectos complementarios. En primer lugar y como paradigma de análisis ex ante de la cuestión, detectar si se dan en la realidad en un número significativo de escuelas situaciones problemáticas que podrían sesgar la evaluación, como la especialización en determinados resultados o la aparición de estrategias. Posteriormente y como contraste ex post, se comprobará la adecuación de distintas alternativas de variables de output educativo a los casos polémicos detectados. Como datos del estudio se emplean los relativos a una muestra de 215 Institutos de Educación Secundaria públicos localizados en las CC. AA. de Asturias, Aragón y Extremadura. La metodología aplicada es el Análisis Envolvente de Datos o DEA, técnica no paramétrica de evaluación de la eficiencia productiva que se ha revelado en los últimos años como la más utilizada para la evaluación de la eficiencia productiva en los servicios públicos.eficiencia, outputs, servicios públicos, educación, DEA.

Substantial morbidity and mortality associated with pandemic A/H1N1 influenza in Mexico, winter 2013-2014: Gradual age shift and severity.

BACKGROUND: A recrudescent wave of pandemic influenza A/H1N1 is underway in Mexico in winter 2013-14, following a mild 2012-13 A/H3N2 influenza season. Mexico previously experienced several waves of pandemic A/H1N1 activity in spring, summer and fall 2009 and winter 2011-2012, with a gradual shift of influenza-related hospitalizations and deaths towards older ages. Here we describe changes in the epidemiology of the 2013-14 A/H1N1 influenza outbreak, relative to previous seasons dominated by the A/H1N1 pandemic virus. The analysis is intended to guide public health intervention strategies in near real time. METHODS: We analyzed demographic and geographic data on hospitalizations with severe acute respiratory infection (SARI), laboratory-confirmed A/H1N1 influenza hospitalizations, and inpatient deaths, from a large prospective surveillance system maintained by the Mexican Social Security medical system during 01-October 2013 to 31-Jan 2014. We characterized the age and regional patterns of influenza activity relative to the preceding 2011-2012 A/H1N1 influenza epidemic. We also estimated the reproduction number (R) based on the growth rate of daily case incidence by date of symptoms onset. RESULTS: A total of 7,886 SARI hospitalizations and 529 inpatient-deaths (3.2%) were reported between 01-October 2013 and 31-January 2014 (resulting in 3.2 laboratory-confirmed A/H1N1 hospitalizations per 100,00 and 0.52 laboratory-confirmed A/H1N1-positive deaths per 100,000). The progression of daily SARI hospitalizations in 2013-14 exceeded that observed during the 2011-2012 A/H1N1 epidemic. The mean age of laboratory-confirmed A/H1N1 patients in 2013-14 was 41.1 y (SD=20.3) for hospitalizations and 49.2 y (SD=16.7) for deaths. Rates of laboratory-confirmed A/H1N1 hospitalizations and deaths were significantly higher among individuals aged 30-59 y and lower among younger age groups for the ongoing 2013-2014 epidemic, compared to the 2011-12 A/H1N1 epidemic (Chi-square test, P\u3c0.001). The reproduction number of the winter 2013-14 wave in central Mexico was estimated at 1.3-1.4 which is slightly higher than that reported for the 2011-2012 A/H1N1 epidemic. CONCLUSIONS: We have documented a substantial and ongoing increase in the number of A/H1N1-related hospitalizations and deaths during the period October 2013-January 2014 and a proportionate shift of severe disease to middle aged adults, relative to the preceding A/H1N1 2011-2012 epidemic in Mexico. In the absence of clear antigenic drift in globally circulating A/H1N1 viruses in the post-pandemic period, the gradual change in the age distribution of A/H1N1 infections observed in Mexico suggests a slow build-up of immunity among younger populations, reminiscent of the age profile of past pandemics

Safety, feasibility, and hemodynamic response of regadenoson for stress perfusion CMR

Owing to its pharmacodynamics and posology, the use of regadenoson for stress cardiac magnetic resonance (CMR) has potential advantages over other vasodilators. We sought to evaluate the safety, hemodynamic response and diagnostic performance of regadenoson stress-CMR in routine clinical practice. All regadenoson stress-CMR examinations performed between May 2017 and July 2020 at our institution were retrospectively reviewed. A total of 698 studies were included for the final analysis. A conventional stress/rest protocol was performed using a 1.5T MRI scanner (Magnetom Aera, Siemens Healthineers, Erlangen, Germany). Adverse events, clinical symptoms, and hemodynamic response were assessed. Diagnostic accuracy of the test was evaluated in patients who underwent invasive coronary angiography. Nearly half of patients (48.5%) remained asymptomatic. Most common clinical symptoms included dyspnea (137, 19.6%), chest pain (116, 16.6%) and flushing (44, 6.3%). Two patients (0.28%) could not complete the examination due to severe hypotension or unbearable chest pain. Overall, an increase in heart rate (HR) response (36.2% [IQR: 22.5–50.9]) and a decrease in systolic and diastolic blood pressure (BP) (median systolic BP response of -5% [IQR: -11.5-0.6]; median diastolic BP response of -6.3 mmHg [IQR: -13.4-0]) was observed. Patients with symptoms induced by regadenoson showed higher HR response (40.3%, IQR: 26.4–56.1 vs. 32.4%, IQR: 19-45.6, p<0.001), whereas a blunted HR response was observed in diabetic (29.6%, IQR: 18.4–42 p<0.001), obese (31.7%, IQR: 20.7–46.2 p=0.005) and patients aged 70 years or older (32.9%, IQR: 22.6–43.1 p<0.001). Overall, regadenoson stress-CMR showed 95.65% (IQ 91.49–99.81) sensitivity, 54.84% (IQ 35.71–73.97) specificity, 86.99% (IQ 82.74–94.68) positive predictive value, and 77.27% (IQ 57.49–97.06) negative predictive value for detecting significant coronary stenosis as compared with invasive coronary angiography. Regadenoson is a well-tolerated vasodilator that can be safely employed for stress perfusion CMR, with high diagnostic performanc

The ERICE-score: the new native cardiovascular score for the low-risk and aged mediterranean population of Spain

[Abstract] Introduction and objectives. In Spain, data based on large population-based cohorts adequate to provide an accurate prediction of cardiovascular risk have been scarce. Thus, calibration of the EuroSCORE and Framingham scores has been proposed and done for our population. The aim was to develop a native risk prediction score to accurately estimate the individual cardiovascular risk in the Spanish population. Methods. Seven Spanish population-based cohorts including middle-aged and elderly participants were assembled. There were 11 800 people (6387 women) representing 107 915 person-years of follow-up. A total of 1214 cardiovascular events were identified, of which 633 were fatal. Cox regression analyses were conducted to examine the contributions of the different variables to the 10-year total cardiovascular risk. Results. Age was the strongest cardiovascular risk factor. High systolic blood pressure, diabetes mellitus and smoking were strong predictive factors. The contribution of serum total cholesterol was small. Antihypertensive treatment also had a significant impact on cardiovascular risk, greater in men than in women. The model showed a good discriminative power (C-statistic = 0.789 in men and C = 0.816 in women). Ten-year risk estimations are displayed graphically in risk charts separately for men and women. Conclusions. The ERICE is a new native cardiovascular risk score for the Spanish population derived from the background and contemporaneous risk of several Spanish cohorts. The ERICE score offers the direct and reliable estimation of total cardiovascular risk, taking in consideration the effect of diabetes mellitus and cardiovascular risk factor management. The ERICE score is a practical and useful tool for clinicians to estimate the total individual cardiovascular risk in Spain.[Resumen] Introducción y objetivos. En España no existen unas cohortes poblacionales suficientemente grandes para hacer predicciones precisas del riesgo cardiovascular. Las ecuaciones de Framingham y EuroSCORE calibradas son las más utilizadas en España. El objetivo es desarrollar la primera ecuación de predicción autóctona para estimar con precisión el riesgo cardiovascular individual en España. Métodos. Análisis conjunto de siete cohortes españolas de población de mediana edad y anciana. La población del estudio —11.800 personas (6.387 mujeres)— aportó un total de 107.915 personas-año de seguimiento y 1.214 eventos cardiovasculares (633 de ellos, mortales). Se efectuó un análisis de regresión de Cox para examinar la contribución de los diferentes factores al riesgo de cualquier evento cardiovascular (mortal y no mortal). Resultados. La edad fue el principal factor de riesgo de eventos cardiovasculares. La presión arterial sistólica, la diabetes mellitus, el tabaquismo y el tratamiento antihipertensivo fueron factores predictivos fuertemente asociados con el riesgo cardiovascular. En cambio, la contribución del colesterol total sérico fue pequeña, especialmente en los mayores de 70 años. El modelo final de riesgo mostró un buen poder discriminatorio (estadístico C = 0,789 en varones y C = 0,816 en mujeres). Conclusiones. ERICE es una nueva ecuación de riesgo cardiovascular genuinamente española obtenida a partir del riesgo concurrente individual de los participantes en varias cohortes. La ecuación ERICE ofrece una estimación directa y fiable del riesgo cardiovascular total teniendo en cuenta factores como la diabetes mellitus y el tratamiento farmacológico de los factores de riesgo cardiovascular, habitualmente no incluidos en otras ecuaciones.Instituto de Salud Carlos III; G03/065Instituto de Salud Carlos III; PI05/1464Instituto de Salud Carlos III; RD06/0014/001

Torasemide inhibits angiotensin II-induced vasoconstriction and intracellular calcium increase in the aorta of spontaneously hypertensive rats

Torasemide is a loop diuretic that is effective at low once-daily doses in the treatment of arterial hypertension. Because its antihypertensive mechanism of action may not be based entirely on the elimination of salt and water from the body, a vasodilator effect of this drug can be considered. In the present study, the ability of different concentrations of torasemide to modify angiotensin II (Ang II)-induced vascular responses was examined, with the use of an organ bath system, in endothelium-denuded aortic rings from spontaneously hypertensive rats. Ang II-induced increases of intracellular free calcium concentration ([Ca(2+)](i)) were also examined by image analysis in cultured vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats. A dose-response curve to Ang II was plotted for cumulative concentrations (from 10(-9) to 10(-6) mol/L) in endothelium-denuded aortic rings (pD(2)=7.5+/-0.3). Isometric contraction induced by a submaximal concentration of Ang II (10(-7) mol/L) was reduced in a dose-dependent way by torasemide (IC(50)=0.5+/-0.04 micromol/L). Incubation of VSMCs with different concentrations of Ang II (from 10(-10) to 10(-6) mol/L) resulted in a dose-dependent rise of [Ca(2+)](i) (pD(2)=7.5+/-0.3). The stimulatory effect of [Ca(2+)](i) induced by a submaximal concentration of Ang II (10(-7) mol/L) was blocked by torasemide (IC(50)=0.5+/-0.3 nmol/L). Our findings suggest that torasemide blocks the vasoconstrictor action of Ang II in vitro. This action can be related to the ability of torasemide to block the increase of [Ca(2+)](i) induced by Ang II in VSMCs. It is proposed that these actions might be involved in the antihypertensive effect of torasemide observed in vivo

Pedunculopontine arousal system physiology—Effects of psychostimulant abuse

This review describes the interactions between the pedunculopontine nucleus (PPN), the ventral tegmental area (VTA), and the thalamocortical system. Experiments using modulators of cholinergic receptors in the PPN clarified its role on psychostimulant-induced locomotion. PPN activation was found to be involved in the animal?s voluntary search for psychostimulants. Every PPN neuron is known to generate gamma band oscillations. Voltage-gated calcium channels are key elements in the generation and maintenance of gamma band activity of PPN neurons. Calcium channels are also key elements mediating psychostimulant-induced alterations in the thalamic targets of PPN output. Thus, the PPN is a key substrate for maintaining arousal and REM sleep, but also in modulating psychostimulant self-administrationFil: Urbano Suarez, Francisco Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Bisagno, Veronica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas (i); ArgentinaFil: Gonzalez, Betina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas (i); ArgentinaFil: Rivero Echeto, Maria Celeste Solange. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Muñiz, Javier A.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas (i); ArgentinaFil: Luster, Brennon. University Of Arkansas For Medical Sciences; Estados UnidosFil: D'onofrio, Stasia. University Of Arkansas For Medical Sciences; Estados UnidosFil: Mahaffey, Susan. University Of Arkansas For Medical Sciences; Estados UnidosFil: Garcia Rill, E. University Of Arkansas For Medical Sciences; Estados Unido

Toward a clinical practice guide in pharmacogenomics testing for functional polymorphisms of drug-metabolizing enzymes. Gene/drug pairs and barriers perceived in Spain

The development of clinica lpractice recommendations or guidelines for the clinical use of biomarkers is an issue of great importance withr regard to adverse drug reactions.The poten-tial of pharmacogenomicbiomarkers has been extensively investigated in recent years.However,several barriers to implementing the use of pharmacogenomics testing exist.We conducted a survey among members of the Spanish Societies of Pharmacology and Clinical Pharmacology to obtain information about the perception of such barriers and to compare the perceptions of participants about the relative importance of majorgene/drug pairs.Of 11 potential barriers,the highest importance was attributed to lack of institutional support for pharmacogenomic stesting,and to the issues related to the lack of guidelines.Of the proposed gene/drug pairs the highest importance was assigned to HLA-B/abacavir, UGT1A1/irinotecan, and CYP2D6/tamoxifen.In this perspective article,we compare the relative importance of 29 gene/drugpairs in the Spanish study with that of the same pairs in the American Society for Clinical Pharmacology and Therapeutic sstudy,and we provide suggestions and areas of focus to develop a guide for clinical practice in pharmacogenomics testingThe work in the author’s laboratory is financed by Grants PS09/00943, PS09/00469, RETICS RIRAAF RD07/0064/0016, and CIBERehd from Instituto de Salud CarlosIII,Madrid, Spain, and by Grants GR10068 from Junta de Extremadura, Spain. Financed in part with FEDER funds from the European Unio

Diastolic dysfunction following anthracycline-based chemotherapy in breast cancer patients: incidence and predictors

[Abstract] INTRODUCTION: Cardiotoxicity represents a major limitation for the use of anthracyclines or trastuzumab in breast cancer patients. Data from longitudinal studies of diastolic dysfunction (DD) in this group of patients are scarce. The objective of the present study was to assess the incidence, evolution, and predictors of DD in patients with breast cancer treated with anthracyclines. METHODS: This analytical, observational cohort study comprised 100 consecutive patients receiving anthracycline-based chemotherapy (CHT) for breast cancer. All patients underwent clinical evaluation, echocardiogram, and measurement of cardiac biomarkers at baseline, end of anthracycline-based CHT, and at 3 months and 9 months after anthracycline-based CHT was completed. Fifteen patients receiving trastuzumab were followed with two additional visits at 6 and 12 months after the last dose of anthracycline-based CHT. A multivariate analysis was performed to find variables related to the development of DD. Fifteen of the 100 patients had baseline DD and were excluded from this analysis. RESULTS: At the end of follow-up (median: 12 months, interquartile range: 11.1-12.8), 49 patients (57.6%) developed DD. DD was persistent in 36 (73%) but reversible in the remaining 13 patients (27%). Four patients developed cardiotoxicity (three patients had left ventricular systolic dysfunction and one suffered a sudden cardiac death). None of the patients with normal diastolic function developed systolic dysfunction during follow-up. In the logistic regression model, body mass index (BMI) and age were independently related to the development of DD, with the following odds ratio values: BMI: 1.19 (95% confidence interval [CI]: 1.04-1.36), and age: 1.12 (95% CI: 1.03-1.19). Neither cardiac biomarkers nor remaining clinical variables were predictors of DD. CONCLUSION: Development of diastolic dysfunction after treatment with anthracycline or anthracycline- plus trastuzumab chemotherapy is common. BMI and age were independently associated with DD following anthracycline chemotherapy.Instituto de Salud Carlos III; RD06/0014/002Instituto de Salud Carlos III; RD12/0042/006

Risk factors associated with moderate-to-severe renal dysfunction among heart transplant patients: results from the CAPRI study

[Abstract] The longer survival of patients with heart transplantation (HT) favors calcineurin inhibitor–related chronic kidney disease (CKD). It behoves to identify risk factors. At 14 Spanish centers, data on 1062 adult patients with HT (age 59.2 ± 12.3 yr, 82.5% men) were collected at routine follow-up examinations. Glomerular filtration rate, GFR, was estimated using the four-variable MDRD equation, and moderate-or-severe renal dysfunction (MSRD) was defined as K/DOQI stage 3 CKD or worse. Time since transplant ranged from one month to 22 yr (mean 6.7 yr). At assessment, 26.6% of patients were diabetic and 63.9% hypertensive; 53.9% were taking cyclosporine and 33.1% tacrolimus; and 61.4% had MSRD. Among patients on cyclosporine or tacrolimus at assessment, multivariate logistic regression identified male sex (OR 0.44), pre- and post-HT creatinine (2.73 and 3.13 per mg/dL), age at transplant (1.06 per yr), time since transplant (1.05 per yr), and tacrolimus (0.65) as independent positive or negative predictors of MSRD. It is concluded that female sex, pre- and one-month post-HT serum creatinine, age at transplant, time since transplant, and immunosuppression with cyclosporine rather than tacrolimus may all be risk factors for development of CKD ≥ stage 3 by patients with HT