A phase I study of hydralazine to demethylate and reactivate the expression of tumor suppressor genes

BACKGROUND: The antihypertensive compound hydralazine is a known demethylating agent. This phase I study evaluated the tolerability and its effects upon DNA methylation and gene reactivation in patients with untreated cervical cancer. METHODS: Hydralazine was administered to cohorts of 4 patients at the following dose levels: I) 50 mg/day, II) 75 mg/day, III) 100 mg/day and IV) 150 mg/day. Tumor biopsies and peripheral blood samples were taken the day before and after treatment. The genes APC, MGMT; ER, GSTP1, DAPK, RARβ, FHIT and p16 were evaluated pre and post-treatment for DNA promoter methylation and gene expression by MSP (Methylation-Specific PCR) and RT-PCR respectively in each of the tumor samples. Methylation of the imprinted H19 gene and the "normally methylated" sequence clone 1.2 was also analyzed. Global DNA methylation was analyzed by capillary electrophoresis and cytosine extension assay. Toxicity was evaluated using the NCI Common Toxicity Criteria. RESULTS: Hydralazine was well tolerated. Toxicities were mild being the most common nausea, dizziness, fatigue, headache and palpitations. Overall, 70% of the pretreatment samples and all the patients had at least one methylated gene. Rates of demethylation at the different dose levels were as follows: 50 mg/day, 40%; 75 mg/day, 52%, 100 mg/day, 43%, and 150 mg/day, 32%. Gene expression analysis showed only 12 informative cases, of these 9 (75%) re-expressed the gene. There was neither change in the methylation status of H19 and clone 1.2 nor changes in global DNA methylation. CONCLUSION: Hydralazine at doses between 50 and 150 mg/day is well tolerated and effective to demethylate and reactivate the expression of tumor suppressor genes without affecting global DNA methylatio

Respiratory failure and death in vulnerable premature children with lower respiratory tract illness

Background. Efforts to better understand the risk factors associated with respiratory failure (RF) and fatal lower respiratory tract infection (LRTI) in premature children in developing countries are necessary to elaborate evidenced-based preventive interventions. We aim to characterize the burden of respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) LRTI in premature children and determine risk factors for RF and fatal illness in a vulnerable population. Methods. This is a prospective, population-based, cross-sectional study. Subjects with severe LRTI were enrolled during respiratory season. Risk factors for RF and death in premature infants were investigated. Results. A total of 664 premature children participated. Infant's hospitalization rate due to LRTI was 82.6/1000 (95% confidence interval [CI], 68.6-96.7/1000). Infant's RSV and hMPV rates were 40.9/1000 (95% CI, 36.3-45.6/1000) and 6.6/1000 (95% CI, 3.9- 9.2/1000), respectively. The RF rate was 8.2/1000 (95% CI, 4.9-11.5/1000). The LRTI mortality was 2.2/1000 (95% CI, 0.7-3.7/1000); for RSV, the rate was 0.8/1000 (95% CI, 0-1.7/1000) with a case-fatality ratio of 1.8%. Never breastfeeding, malnutrition, younger than 6 months, congenital heart disease, and lower hematocrit were risk factors for RF. Experiencing pneumonia, pneumothorax, sepsis, or apnea were clinical determinants of poor outcomes. Conclusions. Premature children under 2 years old in vulnerable environments experience RF and death more often than term counterparts. Modifiable risk factors associated with poor outcomes should prompt evidence-based interventions.Fil: Ofman, Gaston. Fundacion de Endocrinologia Infantil.; ArgentinaFil: Pradarelli, Brad. Fundacion de Endocrinologia Infantil.; ArgentinaFil: Caballero, Mauricio Tomás. Fundacion de Endocrinologia Infantil.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bianchi, Alejandra. Fundacion de Endocrinologia Infantil.; ArgentinaFil: Grimaldi, Luciano Alva. Gobierno de la Provincia de Buenos Aires. Hospital Zonal General de Agudos Doctor Lucio Melendez.; ArgentinaFil: Sancilio, Andrea. Gobierno de la Provincia de Buenos Aires. Hospital Interzonal de Agudos Evita; ArgentinaFil: Duenas, Karina. Gobierno de la Provincia de Buenos Aires. Hospital Interzonal de Agudos Evita; ArgentinaFil: Rodriguez, Andrea. Gobierno de la Provincia de Buenos Aires. Hospital Provincial Evita Pueblo.; ArgentinaFil: Ferrero, Fernando. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños Pedro Elizalde (ex Casa Cuna); ArgentinaFil: Ferretti, Adrian. Fundacion de Endocrinologia Infantil.; ArgentinaFil: Coviello, Silvina Andrea. Fundacion de Endocrinologia Infantil.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ferolla, Fausto Martín. Fundacion de Endocrinologia Infantil.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Acosta, Patricio Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundacion de Endocrinologia Infantil.; ArgentinaFil: Bergel, Eduardo. Fundacion de Endocrinologia Infantil.; ArgentinaFil: Libster, Romina Paula. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundacion de Endocrinologia Infantil.; ArgentinaFil: Polack, Fernando Pedro. Fundacion de Endocrinologia Infantil.; Argentin

Psychometric Properties of the Resilience Inventory for Pregnant Mexican Women

  Resilience has been related to mental health during perinatal period.  However, to our knowledge, there are no instruments of resilience that have been validated in this population. The purpose of this study was to examine the psychometric properties of the Resilience Inventory in a sample of Mexican pregnant women.  A sample of 280 women was evaluated using the Resilience Inventory, Patient Health Questionnaire and a stressful life events questionnaire.  The reliability coefficient of Resilience Inventory was 0.88 for the complete scale. Exploratory factor analysis resulted in a three-factor structure of resilience (personal competence, religiosity and positive attitude) for pregnant women. Concurrent validity was supported by negative correlations with prenatal depressive symptoms and stressful life events. The Resilience Inventory could be a potentially a valid and reliable measure. It is necessary to continue exploring the role of resilience in the perinatal period and identify the factors that shape it

La vida en la frontera: protocol for a prospective study exploring stress and health resiliencies among Mexican-origin individuals living in a US-Mexico border community

Abstract Background Mexican-origin adults living near the U.S.-Mexico border experience unique and pervasive social and ecological stressors, including poverty, perceived discrimination, and environmental hazards, potentially contributing to the high burden of chronic disease. However, there is also evidence that residents in high-density Mexican-origin neighborhoods exhibit lower prevalence rates of disease and related mortality than those living in other areas. Understanding the factors that contribute to health resiliencies at the community scale is essential to informing the effective design of health promotion strategies. Methods La Vida en la Frontera is a mixed-methods participatory study linking a multi-disciplinary University of Arizona research team with Campesinos Sin Fronteras, a community-based organization founded by community health workers in San Luis, Arizona. This paper describes the current protocol for aims 2 and 3 of this multi-faceted investigation. In aim 2 a cohort of N≈300 will be recruited using door-to-door sampling of neighborhoods in San Luis and Somerton, AZ. Participants will be surveyed and undergo biomarker assessments for indicators of health and chronic stress at three time points across a year length. A subset of this cohort will be invited to participate in aim 3 where they will be interviewed to further understand mechanisms of resilience and wellbeing. Discussion This study examines objective and subjective mechanisms of the relationship between stress and health in an ecologically diverse rural community over an extended timeframe and illuminates health disparities affecting residents of this medically underserved community. Findings from this investigation directly impact the participants and community through deepening our understanding of the linkages between individual and community level stress and chronic disease risk. This innovative study utilizes a comprehensive methodology to investigate pathways of stress and chronic disease risk present at individual and community levels. We address multiple public health issues including chronic disease and mental illness risk, health related disparities among Mexican-origin people, and health protective mechanisms and behaviors