Secuenciación de siguiente generación en mujeres afectadas por falla ovárica prematura no sindrómica para la identificación de nuevos genes etiológicos de la enfermedad y estudio funcional de la mutación p.thr943ile en adamts19

La infertilidad afecta en la actualidad a aproximadamente 1 de cada 7 parejas a nivel mundial. La falla ovárica prematura (FOP) es una condición común en la población femenina, afectando al 1% de mujeres menores de 40 años. La etiología de la FOP es idiopática entre el 50% y el 80% de los casos, lo que sugiere causas genéticas, epigenéticas y ambientales aún desconocidas. A pesar de los avances en las técnicas de cartografía genética y de sistematización de la técnica de Sanger, pocos genes etiológicos de FOP fueron identificados en los últimos 20 años. Este fracaso relativo se asoció principalmente a que cientos de genes, que abarcan grandes regiones del genoma, son candidatos pero la técnica de secuenciación directa sólo permite el análisis de unas 700bp en cada reacción. En el presente trabajo se empleó la secuenciación de siguiente generación (NGS) para la búsqueda de mutaciones en 70 genes candidatos que potencialmente contribuyen con el desarrollo de la patología. Se identificaron mutaciones en 3 de 12 pacientes. La paciente POF-7 presentaba una mutación no sinónima en el gen ADAMTS19 (c.2828C>T, p.Thr943Ile). La proteína ADAMTS19 se clasifica dentro de la familia ADAMTS como huérfana ya que no se ha identificado su sustrato. Mediante el sistema de doble hibrido en levaduras se buscó identificar las potenciales proteínas que interactúan con ADAMTS19. Permitió identificar, a partir de las versiones murinas, la interacción de Adamts19 y Col6a2. Para comprobar la interacción entre las proteínas ADAMTS19 y COL6A2 humanas se empleó el sistema de doble hibrido en células eucariotas. Los hallazgos no permitieron replicar los resultados obtenidos previamente. En síntesis de identificó una mutación potencialmente causal de FOP en un gen nuevo y una muy probable interacción entre ADAMTS19 y COL6A2.

Bugaboo the wicked witch.

Esta es la historia de una bruja que es tan estúpida que en realidad es inofensiva. Pero, después de un golpe en la cabeza se vuelve una bruja buena. Incluye actividades al final del texto, para que también participen amigos y familiares.

Integración de las TIC en la docencia universitaria : situación actual y retos en el EEES.

Resumen basado en el de la publicación

Os efeitos do treinamento de força e do treinamento em circuito na ativação e na força muscular, no consumo máximo de oxigênio e na densidade mineral óssea de mulheres pós-menopáusicas com perda óssea

O objetivo geral desse estudo foi analisar os efeitos de dois treinamentos de força diferenciados, em volume e intensidade, em algumas variáveis relacionadas à saúde da população idosa, tais como, força isométrica (FI) e dinâmica de membros superiores (FMS) e inferiores (FMI), ativação muscular do quadríceps (EMG), consumo máximo de oxigênio (VO2máx.), tempo de exaustão em esteira (TE) e densidade mineral óssea (DMO). Vinte e oito mulheres pós-menopáusicas, com perda óssea (osteoporose ou osteopenia), com e sem reposição hormonal, foram divididas em três grupos experimentais: (1) treinamento de força (GF - n=9) com intensidades entre 35 e 80% de 1RM, (2) treinamento em circuito (GC - n=10) com intensidades entre 35 e 60% de 1RM , e (3) um grupo controle (GCON - n=9). Os grupos GF e GC treinaram 3 vezes por semana durante 24 semanas, enquanto o GCON não realizou nenhum tipo de exercício físico sistemático. Em todos os grupos (GF, GC e GCON), as variáveis analisadas foram comparadas através de análise de variância (ANOVA) para medidas repetidas e, em caso de diferenças significativas, foi utilizado o teste Post-Hoc de Bonferroni. Em todas as análises, o nível de significância de p<0,05 foi considerado. Após as 24 semanas de treinamento foram observados aumentos significativos nas variáveis analisadas, somente em GF e GC. No entanto, enquanto o GF teve as variáveis FI (112 ± 18,4Nm vs. 149,8 ± 23,4Nm), FMS (7,3 ± 0,75kg vs. 9,4 ± 0,96kg), FMI (46,7 ± 5,5kg vs. 65,2 ± 8,9kg), EMG (138 ± 35µV vs. 208 ± 51µV), VO2máx. (21,7 ± 2,7ml.kg-1.min-1 vs. 26,6 ± 2,2 ml.kg-1.min-1) e TE (562,6 ± 98,3s vs. 671,7 ± 72,7s), modificadas; o GC apresentou modificações apenas nas variáveis FI (124,1 ± 23,2Nm vs. 146,7 ± 22,3Nm), FMS (6,8 ± 1,3kg e 8,5 ± 1,2kg); FMI (41,4 ± 7,8kg para 60,1 ± 9,5kg), VO2máx. (22,1 ± 2,3 ml.kg-1.min-1 vs. 26,2 ± 2,3 ml.kg-1.min-1) e TE (573,2 ± 66,5s, pós: 669 ± 75,3s). A DMO não foi modificada em nenhum grupo experimental. No GCON não houve qualquer modificação das variáveis analisadas. Esses resultados sugerem que tanto o treinamento de força como o treinamento em circuito interferem positivamente na força e ativação muscular, e no condicionamento cardiorespiratório de mulheres pós-menopáusicas. No entanto a DMO parece não ser alterada com esses tipos de treinamento, em um período de 24 semanas.

Dexmedetomidine versus standard care sedation with propofol or midazolam in intensive care: an economic evaluation.

INTRODUCTION Dexmedetomidine was shown in two European randomized double-blind double-dummy trials (PRODEX and MIDEX) to be non-inferior to propofol and midazolam in maintaining target sedation levels in mechanically ventilated intensive care unit (ICU) patients. Additionally, dexmedetomidine shortened the time to extubation versus both standard sedatives, suggesting that it may reduce ICU resource needs and thus lower ICU costs. Considering resource utilization data from these two trials, we performed a secondary, cost-minimization analysis assessing the economics of dexmedetomidine versus standard care sedation. METHODS The total ICU costs associated with each study sedative were calculated on the basis of total study sedative consumption and the number of days patients remained intubated, required non-invasive ventilation, or required ICU care without mechanical ventilation. The daily unit costs for these three consecutive ICU periods were set to decline toward discharge, reflecting the observed reduction in mean daily Therapeutic Intervention Scoring System (TISS) points between the periods. A number of additional sensitivity analyses were performed, including one in which the total ICU costs were based on the cumulative sum of daily TISS points over the ICU period, and two further scenarios, with declining direct variable daily costs only. RESULTS Based on pooled data from both trials, sedation with dexmedetomidine resulted in lower total ICU costs than using the standard sedatives, with a difference of €2,656 in the median (interquartile range) total ICU costs-€11,864 (€7,070 to €23,457) versus €14,520 (€7,871 to €26,254)-and €1,649 in the mean total ICU costs. The median (mean) total ICU costs with dexmedetomidine compared with those of propofol or midazolam were €1,292 (€747) and €3,573 (€2,536) lower, respectively. The result was robust, indicating lower costs with dexmedetomidine in all sensitivity analyses, including those in which only direct variable ICU costs were considered. The likelihood of dexmedetomidine resulting in lower total ICU costs compared with pooled standard care was 91.0% (72.4% versus propofol and 98.0% versus midazolam). CONCLUSIONS From an economic point of view, dexmedetomidine appears to be a preferable option compared with standard sedatives for providing light to moderate ICU sedation exceeding 24 hours. The savings potential results primarily from shorter time to extubation. TRIAL REGISTRATION ClinicalTrials.gov NCT00479661 (PRODEX), NCT00481312 (MIDEX).

Application of Monte Carlo simulations to identify an appropriate dosage strategy for patients receiving a continuous intravenous infusion of enoxaparin

Aim: To identify an appropriate dosage strategy for patients receiving enoxaparin by continuous intravenous infusion (CII). Methods: Monte Carlo simulations were performed in NONMEM, (200 replicates of 1000 patients) to predict steady state anti-Xa concentrations (Css) for patients receiving a CII of enoxaparin. The covariate distribution model was simulated based on covariate demographics in the CII study population. The impact of patient weight, renal function (creatinine clearance (CrCL)) and patient location (intensive care unit (ICU)) were evaluated. A population pharmacokinetic model was used as the input-output model (1-compartment first order output model with mixed residual error structure). Success of a dosing regimen was based on the percent of Css that is between the therapeutic range of 0.5 IU/ml to 1.2 IU/ml. Results: The best dose for patients in the ICU was 4.2IU/kg/h (success mean 64.8% and 90% prediction interval (PI): 60.1–69.8%) if CrCL60ml/min, the best dose was 8.3IU/kg/h (success mean 65.4%, 90% PI: 58.5–73.2%). Simulations suggest that there was a 50% improvement in the success of the CII if the dose rate for ICU patients with CrCL

Socioeconomic Differences in Preferences and Willingness-to-Pay for Insulin Delivery Systems in Type 1 and Type 2 Diabetes

Background: An evaluation of patients' preferences is necessary to understand the demand for different insulin delivery systems. The aim of this study was to investigate the association between socioeconomic status (SES) and patients' preferences and willingness to pay (WTP) for various attributes of insulin administration for diabetes management. Methods: We conducted a discrete choice experiment (DCE) to determine patients' preferences and their WTP for hypothetical insulin treatments. Both self-reported annual household income and education completed were used to explore differences in treatment preferences and WTP for different attributes of treatment across different levels of SES. Results: The DCE questionnaire was successfully completed by 274 patients. Overall, glucose control was the most valued attribute by all socioeconomic groups, while route of insulin delivery was not as important. Patients with higher incomes were willing to pay significantly more for better glucose control and to avoid adverse events compared to lower income groups. In addition, they were willing to pay more for an oral short-acting insulin ($Can 71.65 [95% confidence interval, $40.68, $102.62]) compared to the low income group ($Can 9.85 [95% confidence interval, 14.86, 34.56; P < 0.01]). Conversely, there were no differences in preferences when the sample was stratified by level of education. Conclusions: This study revealed that preferences and WTP for insulin therapy are influenced by income but not by level of education. Specifically, the higher the income, the greater desire for an oral insulin delivery system, whereas an inhaled route becomes less important for patients.

Analgesic and Anti-Inflammatory Activities of Salicylaldehyde 2-Chlorobenzoyl Hydrazone (H(2)LASSBio-466), Salicylaldehyde 4-Chlorobenzoyl Hydrazone (H(2)LASSBio-1064) and Their Zinc(II) Complexes

Salicylaldehyde 2-chlorobenzoyl hydrazone (H(2)LASSBio-466), salicylaldehyde 4-chlorobenzoyl hydrazone (H(2)LASSBio-1064) and their complexes [Zn(LASSBio-466) H(2)O](2) (1) and [Zn(HLASSBio-1064) Cl](2) (2) were evaluated in animal models of peripheral and central nociception, and acute inflammation. All studied compounds significantly inhibited acetic acid-induced writhing response. Upon coordination the anti-nociceptive activity was favored in the complex 1. H(2)LASSBio-466 inhibited only the first phase of the formalin test, while 1 was active in the second phase, like indomethacin, indicating its ability to inhibit nociception associated with the inflammatory response. Hence coordination to zinc(II) altered the pharmacological profile of H(2)LASSBio-466. H(2)LASSBio-1064 inhibited both phases but this effect was not improved by coordination. The studied compounds did not increase the latency of response in the hot plate model, indicating their lack of central anti-nociceptive activity. All compounds showed levels of inhibition of zymosan-induced peritonitis comparable or superior to indomethacin, indicating an expressive anti-inflammatory profile.

Antioxidant Capacity of 2-(3,5-diaryl-4,5-dihydro-1H-pyrazol-1-yl)-4-phenylthiazoles

The antioxidant capacity of 2-(3,5-diaryl-4,5-dihydro-1H-pyrazol-1-yl)-4-phenylthiazoles was evaluated. The values of antioxidant capacities of compounds 2d and 2e were found to be, respectively, 2,700 +/- 150 and 3,135 +/- 230 TE by the ORAC method, corresponding to a significant antioxidant capacity.

Evidências de validade da versão brasileira do Exercise Motivation Inventory-2 em contexto de academia e personal training

Este estudo teve como objetivos verificar a validade fatorial e a validade interna da versão brasileira do Exercise Motivation Inventory-2 (EMI-2) e comparar os principais motivos para prática de exercício tendo em conta os contextos de academia e personal training. Um total de 588 praticantes de exercício da cidade de Pelotas/RS/Brasil (405 de academia e 183 de personal training) preencheram o EMI-2, o qual é constituído por 51 itens, agrupados em 14 motivos (fatores) para prática de exercício físico. A validade fatorial do EMI-2 foi testada através da realização de análises fatoriais confirmatórias e a validade interna através do alfa de Cronbach. Para a verificar o efeito do contexto nos motivos foi utilizada a MANOVA e calculado o tamanho do efeito. Os resultados obtidos dão suporte à estrutura original do EMI-2 com 14 fatores, nesta amostra. Verificou-se um efeito multivariado significativo do contexto sobre os motivos de prática [Wilks’ λ = 0.912, F (14, 573.000) = 3.9, p < 0.001, η² = 0.088]. Os motivos de “Prazer”, “Força e resistência”, “Desafio”, “Socialização”, “Competição” e “Reconhecimento Social” foram significativamente superiores no contexto de academia e os motivos de “Agilidade” e “Prevenção de Doenças” foram significativamente superiores no contexto de personal training.