DNA methylation: an epigenetic mark of cellular memory

DNA methylation is a stable epigenetic mark that can be inherited through multiple cell divisions. During development and cell differentiation, DNA methylation is dynamic, but some DNA methylation patterns may be retained as a form of epigenetic memory. DNA methylation profiles can be useful for the lineage classification and quality control of stem cells such as embryonic stem cells, induced pluripotent cells and mesenchymal stem cells. During cancer initiation and progression, genome-wide and gene-specific DNA methylation changes occur as a consequence of mutated or deregulated chromatin regulators. Early aberrant DNA methylation states occurring during transformation appear to be retained during tumor evolution. Similarly, DNA methylation differences among different regions of a tumor reflect the history of cancer cells and their response to the tumor microenvironment. Therefore, DNA methylation can be a useful molecular marker for cancer diagnosis and drug treatment.

Intracardiac tumor causing left-ventricular outflow-tract obstruction in a newborn

The following report describes the case of newborn girl with an asymptomatic systolic murmur, which on imaging revealed a nearly obstructive mass in the left-ventricular outflow tract. The mass was resected and found to be consistent with a rhabdomyoma. Here, we describe the pathologic and clinical characteristics of this tumor

Single center experience on dosing and adverse events of recombinant factor seven use for bleeding after congenital heart surgery

There are limited data on the relationship between the administered dose of recombinant factor seven [rFVIIa] and the development of adverse clinical outcomes after congenital heart surgery. This single institution case series reports on dosing, adverse events, and blood product usage after the administration of rFVIIa in the congenital heart surgery patient population. A retrospective review identified 16 consecutive pediatric patients at an academic, free-standing, children's hospital who received rFVIIa to curtail bleeding following congenital heart surgery between April 2004 and June 2012. Patients were assessed for survival to hospital discharge versus in-hospital mortality and the presence or absence of a major neurological event during inpatient hospitalization. The median age at surgery was 6.8 months [range: 3 days-42 years]. Seven patients [44%] survived to hospital discharge and nine patients [56%] died. The cause of mortality included major neurological events [44%], uncontrolled bleeding [33%], and sepsis [23%]. Eight patients [50%] required extracorporeal membrane oxygenation support following congenital heart surgery. The median cumulative rFVIIa dose administered was 97 mcg/kg, and the median cumulative amount of blood products administered was 452 ml/kg. In conclusion, this case series underscores the need to prospectively evaluate the effect that rFVIIa has on patient survival and the incidence of adverse events, including thrombotic and major neurological events, in congenital heart surgery patients. Ideally, a randomized, multicenter study would provide the sufficient numbers of patients and events to test these relationships

The Health Effects of Antenatal Multiple Micronutrient Supplementation in Nepalese Children.

Objectives: In low- and middle-income countries, prenatal multiple micronutrient supplementation has been shown in meta-analyses to increase birthweight and reduce the proportion of babies born small-for-gestational-age, but the longer term effects are unclear. We examined phenotypic and health differences between children born to mothers in a randomized controlled trial of prenatal multiple micronutrient (UNIMAPP) supplementation compared to iron and folate. Methods: The study was conducted in Dhanusha district, Nepal. We measured anthropometry, body composition using bioelectrical impedance (with population-specific isotope calibration), blood pressure, kidney dimensions by ultrasound, and spirometry. Health outcomes were recorded in questionnaires. Personal estimates of air pollution exposure (particles of less than 4 micrometers in size) were produced by microenvironment sampling. Results: We saw 841 children (80% of total), at a mean age of 8.5 years. The unadjusted mean (95%CI) difference (intervention minus control) in weight-for-age was 0.05 z-scores (-0.09,0.19), in height-for-age 0.02 z-scores (-0.10,0.15) and in BMI-for-age 0.04 z-scores (-0.09,0.18). Similar results were obtained from multi-variable regression analysis. No difference was found in body composition, kidney size, blood pressure or lung function. In addition there were no differences in health outcomes between allocation groups. Conclusions: Differences that were previously seen in phenotype and blood pressure at birth and at two years in children born to mothers who received antenatal UNIMMAP supplements were not apparent at 8.5 years of age. While not ruling out physiological differences and health benefits in adulthood, our findings do not suggest sustained effects of antenatal micronutrient supplementation.

Anthracycline-mediated cardiomyopathy: Basic molecular knowledge for the cardiologist / Miocardiopatía inducida por antraciclinas: conocimientos moleculares básicos para el cardiólogo

Anthracyclines are cytostatic antibiotics discovered almost half a century ago exerting their action through inhibition of topoisomerase II. The two most representative drugs are doxorubicin and daunorubicin and they have been proven as useful antineoplastics and are widely prescribed in daily oncology practice; unfortunately, cardiotoxicity has been a limiting factor when it comes to their use. Diverse mechanisms have been involved in anthracycline cardiotoxicity, none of which are capable of causing the whole clinical picture by itself. Traditionally, reactive oxygen species (ROS) have received more attention, although recently basic research has proven other factors to be as important as ROS. These factors mainly involve sarcomeric structure disruption, toxic accumulation of metabolites, iron metabolism, energetic alterations and inflammation. The role of genetics has been studied by some groups, although a clear genotype-response relationship is yet to be elucidated. With the improved survival from different oncologic diseases we are witnessing more cases of chemotherapy-induced cardiotoxicity and the advent of new anticancer drugs poses several challenges for the cardiologist, highlighting the importance of a deep knowledge of the main mechanisms inducing this toxicity.

Hace casi medio siglo se descubrieron las antraciclinas; estas son antibióticos citostáticos inhibidores de la topoisomerasa II. Los 2 fármacos más representativos de este grupo son la doxorrubicina y la daunorrubicina. Estos fármacos han demostrado ser eficaces antineoplásicos y han sido ampliamente utilizados en la práctica oncológica. Desafortunadamente, la cardiotoxicidad sigue siendo un elemento limitante para su uso. Los mecanismos mediante los cuales estos fármacos ocasionan cardiotoxicidad son múltiples pero ninguno de ellos de forma individual es capaz de explicar el cuadro clínico por completo. Casi siempre se ha considerado que la formación de especies reactivas de oxígeno era responsable de gran parte de la toxicidad, sin embargo la experimentación básica reciente ha demostrado que hay otros factores, entre los que destacan las alteraciones en la estructura sarcomérica, la acumulación de metabolitos tóxicos, las alteraciones del metabolismo del hierro o de los mecanismos energéticos, y la liberación de mediadores de inflamación. Por otra parte, diversos grupos han investigado la intervención que la genética podría tener en el desarrollo de esta enfermedad, si bien no se puede definir aún una clara correlación genotipo-respuesta. Con el aumento de la supervivencia por el tratamiento de diversas enfermedades oncológicas, se están detectando más casos de cardiotoxicidad mediada por quimioterapia; y con la aparición de nuevos fármacos quimioterápicos se añaden nuevos retos, con lo que se demuestra la importancia del estudio profundo de los mecanismos causales.

Endoscopic Imaging in Barrett's Oesophagus: Applications in Routine Clinical Practice and Future Outlook

The practice for endoscopic surveillance of Barrett's oesophagus has evolved from "blind" or random 4 quadrant biopsies (Seattle protocol) to a more "intelligent" targeted biopsy approach. This evolution has been possible due to the rapid advances in endoscopic imaging technology and expertise in the last decade. Previous endoscopes had relatively poor image resolution that often did not allow the subtle mucosal changes associated with dysplastic Barrett's mucosa to be identified. Newer endoscopic imaging techniques available today may allow endoscopists to identify areas of dysplasia or malignancy and target biopsies accordingly. These modalities which include narrow band imaging, chromoendoscopy, autofluorescence imaging, and confocal endomicroscopy as well as a few novel imaging modalities on the horizon will be discussed further.

MaiMwana Women's Groups: a Community Mobilisation Intervention to Improve Mother and Child Health and Reduce Mortality in Rural Malawi

This article presents a detailed description of a community mobilization intervention involving women's groups in Mchinji District; Malawi. The intervention was implemented between 2005 and 2010. The intervention aims to build the capacities of communities to take control of the mother and child health issues that affect them. To achieve this it comprises trained local female facilitators establishing groups and using a manual; participatory rural appraisal tools and picture cards to guide them through a community action cycle to identify and implement solutions to mother and child health problems. Significant resource inputs include salaries for facilitators and supervisors; and training; equipment and materials to support their work with groups. It is hypothesized that the groups will catalyse community collective action to address mother and child health issues and improve the health and reduce the mortality of mothers and children. Their impact; implementation and cost-effectiveness have been rigorously evaluated through a randomized controlled trial design. The results of these evaluations will be reported in 2011

Therapeutic Hypothermia for Neonatal Encephalopathy Implications for Neonatal Units in India.

Therapeutic hypothermia has recently emerged from bench to bedside. Three large multicenter trials from industrialized countries and three independent meta-analyses have shown its efficacy in reducing death and disability following neonatal encephalopathy due a perinatal hypoxic event. Many neonatal units in well-resourced settings now offer hypothermia as standard care in neonatal encephalopathy. However, these results cannot be extrapolated to low resource settings due to differences in population, risk benefits and high cost. Use of therapeutic hypothermia in low resource settings should be considered experimental and should therefore be restricted to well equipped level 2 and 3 neonatal units. The safety and efficacy of hypothermia using novel low technology methods need to be examined in rigorously controlled multicenter randomized controlled trials in these neonatal units before it can be offered as a standard care, as the risks may outweigh the benefits. The current practice of maintaining normothermia should continue, until such evidence is available.

Recuperación de la contracción auricular luego de la cirugía de MAZE III izquierdo / Atrial Contraction Recovery After Left MAZE III Surgery

Introducción La cirugía de MAZE III izquierdo demostró una efectividad elevada en la restauración a ritmo sinusal. Sin embargo, la efectividad en la restauración de la sístole auricular en poblaciones con cardiopatía estructural y el predominio de enfermedad reumática resultan áreas de incertidumbre. Objetivo Evaluar la efectividad de la cirugía de MAZE en la restauración de la sístole auricular en pacientes con cardiopatía estructural. Material y métodos Estudio prospectivo, consecutivo de 27 pacientes portadores de fibrilación auricular crónica persistente con indicación de cirugía cardiovascular y en los que se realizó la técnica de MAZE como tratamiento de la arritmia. La presencia de sístole auricular se evaluó mediante Doppler tisular del anillo mitral lateral. Resultados En una población caracterizada por predominancia de cardiopatía reumática (41%) y tiempo prolongado de evolución de la arritmia (61 meses promedio), al final del seguimiento el 87% se encontraba en ritmo sinusal en el 80% de los casos con actividad mecánica. El antecedente de cardiopatía reumática, una duración de la arritmia mayor de 5,5 años, el sexo femenino y el reemplazo de válvula mitral fueron variables estadísticamente significativas en cuanto a la ausencia de sístole auricular. No tuvieron significación la edad, la fracción de eyección del ventrículo izquierdo y el tamaño de la aurícula izquierda. Conclusiones En esta población es significativa la falta de correspondencia entre ritmo sinusal y sístole auricular. El Doppler tisular es un método útil para identificar a aquellos pacientes sin contracción auricular. El impacto clínico de este hallazgo está vinculado con la decisión en la continuidad del tratamiento anticoagulante.

Introduction Left MAZE III surgery has proven a high level of effectiveness in restoring the sinus rhythm. However, the effectiveness in restoring the atrial systole in individuals with structural cardiopathy and the prevalence of rheumatic disease are still uncertain areas. Objective To assess the effectiveness of the MAZE surgery in restoring the atrial systole in patients with structural cardiopathy. Material and Methods Prospective, consecutive study in 27 patients with persistent or chronic atrial fibrillation and recommendation for cardiovascular surgery, who underwent the MAZE technique for treating the arrhythmia. The presence of atrial systole was assessed by lateral mitral annular tisular Doppler. Results In a population characterized by rheumatic cardiopathy predominance (41%) and long arrhythmia evolution (61 months on average), 87% individuals had sinus rhythm and 80% of them had mechanical activity at the end of the follow- up. A history of rheumatic cardiopathy, an arrhythmia lasting more than 5.5 years, the fact of being female, and the mitral valve replacement were statistically significant variables, considering the absence of atrial systole. Factors like age, left ventricle ejection fraction, and left atrial size were not significant. Conclusions In this population, the absence of correlation between the sinus rhythm and the atrial systole is significant. The tisular Doppler is a useful method to identify those patients with no atrial contraction. The clinical impact of this finding is related to the decision on continuing the anticoagulant therapy.

Ethical challenges in cluster randomized controlled trials: experiences from public health interventions in Africa and Asia

Public health interventions usually operate at the level of groups rather than individuals, and cluster randomized controlled trials (RCTs) are one means of evaluating their effectiveness. Using examples from six such trials in Bangladesh, India, Malawi and Nepal, we discuss our experience of the ethical issues that arise in their conduct. We set cluster RCTs in the broader context of public health research, highlighting debates about the need to reconcile individual autonomy with the common good and about the ethics of public health research in low-income settings in general. After a brief introduction to cluster RCTs, we discuss particular challenges we have faced. These include the nature of ­ and responsibility for ­ group consent, and the need for consent by individuals within groups to intervention and data collection. We discuss the timing of consent in relation to the implementation of public health strategies, and the problem of securing ethical review and approval in a complex domain. Finally, we consider the debate about benefits to control groups and the standard of care that they should receive, and the issue of post-trial adoption of the intervention under test.

Outcomes after robot-assisted laparoscopic radical prostatectomy / 亚洲男科学杂志(英文版)

Robot-assisted laparoscopic radical prostatectomy (RALRP) using the da Vinci surgical system is now in widespread use in many countries where economic conditions allow the installation of this expensive technology. Controversy has surrounded the procedure since it was first performed in 2000, with many critics highlighting the lack of evidence to support its use. However, despite the lack of level I evidence, many large studies of patients have confirmed that the procedure is feasible and safe, with low morbidity. Available longer-term oncological data seem to show that outcomes from the robotic approach at least match those of traditional open radical prostatectomy. Functional outcomes also seem satisfactory, although randomized controlled trials are lacking. This paper reviews the current status of RALRP with respect to perioperative data and complications and oncologic and functional outcomes.

Laboratory investigation of fungal infections of the central nervous system.

While fungal infections of the central nervous system (CNS) are relatively rare, fungal pathogens are increasingly being recognized as an important etiology of CNS infections, particularly amongst the growing immunocompromized population. In this paper we aim to provide a practical approach to the diagnosis of fungal infections of the CNS, review some of the diagnostic methods currently available and discuss diagnosis of certain pathogens of particular interest to the practicing neurologist.

Maternal and newborn-care practices during pregnancy, childbirth, and the postnatal period: a comparison in three rural districts in Bangladesh.

The aim of this study was to examine the prevalence of maternal and newborn-care practices among women reporting a birth in the previous year in three districts in different divisions of Bangladesh. In 2003, 6,785 women, who had delivered a newborn infant in the previous year, across three districts in Bangladesh, were interviewed. Overall, less than half of the women received any antenatal care, and 11% received a minimum of four check-ups. Only 18% took iron tablets for at least four months during pregnancy. Over 90% of the 6,785 deliveries took place at home, and only 11% were attended either by a doctor or by a nurse. The mothers reported three key hygienic practices in 54% of deliveries: attendants washing their hands with soap and boiling cord-tie and blade for cutting the cord. Forty-four percent of the 6,785 infants were bathed immediately after delivery, and 42% were given colostrum as their first food. The results suggest that maternal and newborn-care remains a cause of concern in rural Bangladesh. Short-term policies to promote healthy behaviour in the home are needed, in addition to the long-term goal of skilled birth attendance.

Prevalence of childhood and adolescent disabilities in rural Nepal.

The study aimed to determine the number of children and young people reported as having a disability by family members, and to classify impairments leading to disability. A Cross-sectional census was conducted of all households in 24 rural geopolitical units of Makwanpur district, Nepal. Heads of household were asked about family members under the age of 20 with disability. Such members were resident in 733 of 28,376 households, a household prevalence of 2.58%. 829 people under the age of 20 were reported as having a disability, a population prevalence of 0.95%. The commonest functional impairments reported were motor and the commonest anatomical impairments involved the limbs. More males with disability were identified than females.

Adolescent nutrition in a rural community in Bangladesh.

The objective of this study was to assess the nutritional status of adolescent boys and girls in a rural community in Bangladesh. Between December 1996 and January 1997, a cross-sectional survey was carried out in 803 households, each containing at least one adolescent, sampled consecutively from four purposely-selected villages in Rupganj Thana, Narayanganj district. Initially, the guardians of 1483 healthy and unmarried 10-17 year old adolescents (51% boys and 49% girls) were interviewed about family structure and socio-economic status. Out of these children, 906 (47% boys and 53% girls) from 597 households were weighed, had their height and MUAC measured and were clinically examined. Blood was then collected from 861 adolescents for haemoglobin estimation. The median monthly income per person in these 597 families was approximately Taka 554 (US $12). Twenty seven per cent of the household heads were labourers, 21% were solvent farmers, 14% ran small scale businesses and 6% were unemployed. Sixty seven per cent of adolescents were thin (defined as BMI < 5th centile of WHO recommended reference) with 75% boys and 59% girls being affected. The percentage of thin adolescents fell from 95% at age 10 years to 12% at age 17 years. The prevalence of stunting (height for age < 3rd centile NCHS/WHO) was 48% for both boys and girls and rose from 34% at age 10 to 65% at age 17. On clinical examination angular stomatitis was present in 46%, 27% had glossitis, 38% had pallor, 11% had dental caries, 3.2% had an conspicuously enlarged thyroid and 2.1% had eye changes of vitamin A deficiency. According to INACG (International Nutritional Anaemia Consultative Group, 1985) cut-off values, 94% of the boys and 98% of the girls were anaemic. We conclude that rural Bangladesh adolescents suffer from high rates of malnutrition and almost universal anaemia. Nutritional interventions to target this population are urgently required.