Editorial: Translational research in practice

Readers will now be familiar with the notion of ‘translational research’. According to its generally acknowledged progenitor, the National Institutes of Health (NIH) in the US, this is a kind of research agenda focused on translating or applying the research findings from basic/preclinical studies to human studies and perhaps most especially treatment trials; and, the translation of clinical research findings to the community so that evidence‐based best practice is adopted.     

Human embryonic stem cells as a powerful tool for studying human embryogenesis

Human embryonic stem cells (HESC) are pluripotent stem cell lines derived from the inner cell mass (ICM) of human blastocyst-stage embryos. They are characterized by their unlimited capacity to self-renew in culture. In addition, they have a broad developmental potential, as demonstrated by their ability to form practically any cell type in vivo and in vitro. These two features have made HESC extremely important in basic and applied research. In addition, they may serve as a powerful tool for studying human development. HESC can recapitulate embryogenesis by expressing developmentally regulated genes and by activating molecular pathways as they occur in vivo. Moreover, they can be used to analyze the effect of specific mutations on particular developmental events and may enable us to identify critical factors that play a role in the processes of cell commitment, differentiation, and adult cell reprogramming. Thus, modeling human embryogenesis by the use of HESC may allow new insights into developmental processes, which would otherwise be inaccessible for research.     

Evaluation of recent research grant applications to the National Institutes of Health in the area of pediatric nephrology

To assess the National Institutes of Health extramural activity in the area of pediatric nephrology research, the rate of submission of grant applications to the National Institutes of Health and available indicators of the quality of these applications were analyzed. This was accomplished by utilizing the grant application files of the Division of Research Grants' Statistics and Analysis Branch with the help of the Reports, Analysis and Presentation Section. Applications reviewed during the period 1980-1983 (May 1980 to January 1984 Council dates) were evaluated, and data from the 10 Study Sections most frequently involved with the review of nephrology applications were tabulated. Results showed that the number of pediatric nephrology applications submitted was quite low, whereas the approval rate was good for those that were submitted.     

Why should there be an NICHD?

In its nearly 5 decades of existence, the Eunice Kennedy Shriver National Institute of Child Health and Human Development has expended $23 billion in conducting and supporting research and translating discoveries to practice. The resulting dramatic impact on peoples' lives and improved health for children and families, chronicled herein, are a testament to the benefits of having this institute at the National Institutes of Health.     

Engineered human cardiac tissue

The human heart is the first organ to develop during embryogenesis and is arguably the most essential organ for life. However, after birth, the heart has very little capacity to repair malformations such as congenital heart defects or to regenerate after an injury such as myocardial infarction. Cardiac tissue engineering addresses the need for a therapeutic biologic implant to restore cardiac structure and muscle mass. This review highlights current research in cardiac tissue engineering that uses human cardiomyocytes derived from embryonic stem cells. Other human cell sources are discussed because future human therapies will benefit from novel techniques using human-induced pluripotent stem cells and cardiomyocytes derived from direct reprogramming of somatic cells. Furthermore, this review examines the main approaches to creating engineered cardiac tissue with synthetic scaffolds, natural scaffolds, or no exogenous scaffold (i.e., “scaffold free”). The choice of scaffold and cells ultimately depends on the goals of the therapy, so the review considers how congenital heart defects define the design parameters for cardiac tissue engineering needed for surgical repair in pediatric cardiac patients.     

Developing a career in academic paediatrics

Many trainees think about research towards the end of clinical training, but at that stage, it may be too late to get the most from the limited opportunities that remain. Ideally, trainees should consider research early in their career. For some, a career in academic paediatrics may be attractive, in which case following the clinical academic pathway as outlined by the National Institutes of Health Research may be appropriate. For others, research may be part of a wider clinical training. This article discusses a variety of research opportunities available to trainees, and offers advice on a career in academic paediatrics.     

Research in Perinatal and Neonatal Medicine— A Scientific Vision for Future Decades

In this article, a brief overview is presented concerning potential opportunities for and challenges in developing a neonatal-perinatal research agenda. Over a two year period, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, in the USA developed NICHD-Scientific Vision—The Next Decade. An outline of the Vision process and some of the recommendations originating from this are also described.     

History of pediatric stem cell transplantation

Abstract:  During the past 50 yr, intensive studies into the use of hematopoietic cell transplantation (HCT) for therapy of cancer and non-malignant hematologic diseases have changed this treatment modality from one that was thought to be plagued by insurmountable complications to one that is now standard therapy for some diseases. Continued research by transplant teams worldwide is likely to allow continued progress toward developing novel and improved treatment modalities and even wider application of the use of pluripotent hematopoietic stem cells in the treatment of human diseases.     

Collection of sibling donor cord blood for children with thalassemia

Bone marrow transplantation has curative potential for patients with thalassemia major who have a matched sibling marrow donor, but usefulness of alternative stem cell sources is undergoing investigation. Cord blood (CB) from a sibling has different characteristics from marrow and has potential advantages and disadvantages as a stem cell source. Whereas many families caring for a child with thalassemia major (or other transplant-treatable condition) experience an additional pregnancy, most give birth at hospitals without the infrastructure needed to collect and process the new infant's CB. To address this, and with funding from the National Institutes of Health, we have developed the first noncommercial CB program, operating across the United States, designed specifically to facilitate medically indicated CB collections from sibling donors. Using a case-management model, we have collected CB for 25 thalassemia families in eight states. Three of these CB units have now been used for transplantation; two others are human leukocyte antigen-identical and contain adequate nucleated cell dose to perform transplantation in their intended recipient. We conclude that a CB bank focused on sibling donations may be a useful stem cell resource and that families with specific medical need, such as a child with thalassemia, should consider preserving CB from siblings.     

24-hour ambulatory ECGs in the detection and management of cardiac dysrhythmias in infants and children

Summary Sixty-four 24-hour ambulatory ECGs (cardioscans) were recorded in 47 patients, 5 days to 24 years of age, using a new commercially available miniature tape recorder and analysis system to evaluate known or suspected dysrhythmias. Only two of the 64 cardioscans were inadequate for interpretation, and the study was based on the 62 that could be interpreted. A dysrhythmia was found in 84% (52/62) and in 48% (30/62) a dysrhythmia was detected on the cardioscan, which had not been present on the previous standard 15-lead ECG.Of 25 cardioscans done to determine the cause of symptoms, symptoms coincided with dysrhythmia in only three; in 13 the symptoms did not occur during the cardioscan although dysrhythmia was recorded; in nine the symptoms did occur but no dysrhythmia was recorded, excluding dysrhythmia as their cause.Twenty-five of 44 cardioscans done to judge the adequacy of medical therapy for a dysrhythmia suggested that the therapy was suboptimal. Changes in therapy based on the cardioscan resulted in improvement in 21 patients and partial or no improvement in four patients.Useful information was detected in five of 13 postoperative cardioscans and in one of three cardioscans performed on children with artificial pacemakers.Of 25 cardioscans showing potentially life-threatening dysrhythmias, 12 showed an increase during sleep of frequency or duration of dysrhythmic episodes, five showed no change during sleep, and eight showed a decrease during sleep.The 24-hour cardioscan is a useful means of detecting and managing dysrhythmias in the pediatric age group.Supported in part by grant HL-07190 from the National Institutes of Health and by Public Health Service grant RR-00188 from the General Clinical Research Branch, National Institutes of Health. Dr. Gillette is recipient of a National Institutes of Health Research Career Development Award HL00571.Presented in part at the 26th Annual Scientific Session of the American College of Cardiology, Las Vegas, Nevada, March 1977     

Unusual roentgenographic presentation of a congenital cystic malformation of the lung

We describe here an infant with a large, solitary, fluid-filled lung cyst and hyperinflation of adjacent lung tissue in the same lobe. The combination of a fluid-filled cyst and ectatic emphysema in the same lobe suggests bronchial collapse and airway obstruction as a contributory mechanism for this unusual roentgenographic presentation of a congenital cystic malformation of the lung.This investigation was supported in part by a grant (RR-81) from the General Clinical Research Centers Program of the Division of Research Resources, National Institutes of Health and by Grant HD-00049 from the National Institutes of Health     

Transseptal left heart catheterization: Experience with a new technique in 520 pediatric and adult patients

Summary A new technique for transseptal left heart catheterization utilizing the Transseptal Introducer Set® in 520 patients is described in detail. The age range of these patients was 3 months to 40 years with 30% of the patients less than 2 years old and 28% less than 10 kilograms in weight. The safety and advantages of the technique are emphasized. The introducer set and new technique make transseptal left heart catheterization a safe, versatile, and dependable approach to all areas of the left heart, particularly in infants and children with complex congenital heart lesions.Supported in part by grant HL-07190 from the National Institutes of Health, United States Public Health Service and by grant RR-00188 from General Clinical Research Branch, National Institutes of Health.Presented in part at 52nd Scientific Session of American Heart Association, November 12–15, 1979.     

Alternative medicine: herbal preparations

An extraordinary escalation has occurred in the number of individuals who use herbal preparations or essential oils, either alone or in combination with other alternative medicine practices, over the last decade in the United States. Currently, there is no regulation of the safety or efficacy of these products, but the National Institutes of Health is supporting research in this area. This report reviews 20 popular herbs and essential oils, with emphasis on their potential toxicity and interactions.     

Prospects and challenges of reprogrammed cells in hematology and oncology

Induced pluripotent stem cells (iPSCs) have emerged as a promising basis for modeling pediatric genetic disorders, allowing the derivation, study, and genetic correction of disease and patient-specific cell lines in vitro. Similar to embryonic stem cells (ESCs), iPSCs are capable of unlimited in vitro expansion and derivation of many cell types, including hematopoietic stem cells (HSCs). These may not only allow large scale screenings to develop therapeutic compounds, but also help to overcome cross-species barriers of genetically engineered animal models, which do not adequately recapitulate the associated human phenotype. Here, we review the current state and emerging developments of iPSC research, which can be exploited as a tool in modeling pediatric hematopoietic disorders and could lead to new clinical applications in gene and cell therapies.     

Psychotropic medication use in pediatric patients with cancer

BACKGROUND: Use of psychotropic medication in medically ill adults, in particular, patients with cancer, is common. While increased use of psychotropic medications in children and adolescents in the general population has been reported, little is known about the prescribing practices for these medications in medically ill children. OBJECTIVE: To examine the frequency and types of psychotropic medications used in a population of children and adolescents with cancer. DESIGN: Retrospective review of the National Institutes of Health Medical Information System. SETTING: Pediatric Oncology Branch of the National Cancer Institute, National Institutes of Health. PARTICIPANTS: Three hundred forty-seven patients aged 1 to 21 years who were enrolled in clinical research trials at the Pediatric Oncology Branch between January 2000 and December 2003. MAIN OUTCOME MEASURES: Psychotropic medication use was analyzed according to cancer diagnosis and patient age. RESULTS: Fourteen percent of identified patients had been prescribed at least 1 psychotropic medication at the time of National Cancer Institute clinical trial enrollment. The most commonly used medications were anticonvulsant agents (8%) and antidepressant medications (7%), in particular, selective serotonin reuptake inhibitors. Anxiolytic medications could not be accurately assessed because of their frequent use as antiemetic agents in many chemotherapy regimens. Psychostimulant use was rare. CONCLUSIONS: This study suggests that psychotropic medications are commonly prescribed to children and adolescents with cancer. Clinical safety and efficacy trials are needed in medically ill children at high risk for mood and anxiety symptoms.     

Comparison of the cardiovascular action of isoproterenol,dopamine, and dobutamine in the neonatal and mature dog

Summary To determine if there are age-related differences of cardiovascular responses to isoproterenol, dopamine hydrochloride, and dobutamine hydrochloride, we recorded cardiac output, renal artery blood flow, central aortic blood pressure, and heart rate in 11 anesthetized puppies ranging in age from 0 to 10 days and in five adult dogs during incremental infusion of isoproterenol (0.05 to 1.25μg/kg/min), dopamine (2 to 50μg/kg/min), and dobutamine (2 to 50μg/kg/min). Isoproterenol decreased systemic arterial mean blood pressure and renal blood flow more in adult dogs than in puppies. Cardiac output was increased in both age groups, but the increase was more marked in adults than in puppies. Heart rate increased similarly in puppies and adults. Dopamine increased systemic arterial mean blood pressure, heart rate, renal blood flow, and cardiac output in both puppies and adult dogs, but the increase of cardiac output was more marked in adult dogs than in puppies. Dobutamine significantly increased systemic arterial mean blood pressure, cardiac output, and renal blood flow in adult dogs but not in puppies. Heart rate increased in both groups of dogs. This study demonstrates age-related differences in the response of the cardiovascular system of anesthetized dogs to isoproterenol, dopamine, and dobutamine. This material was developed by the Section of Myocardial Biology of the National Heart and Blood Vessel Research and Demonstration Center, Baylor College of Medicine, a grant-supported research project of the National Heart, Lung, and Blood Institute, National Institutes of Health, grant HL 17269 and contract HV-52998. Supported in part by grant HL-5756 from the National Institutes of Health. Dr. Driscoll is recipient of Young Investigator's Award 1-R23 H622309-01 from the National Heart, Lung, and Blood Institute. Dr. Gillette is recipient of National Institutes of Health Research Career Development Award HL00571. Presented at the Scientific Sessions of the American Academy of Pediatrics, Section of Cardiology, New York, New York, November 1977     

Stem cells in pediatric cardiology

The ability to reprogram virtually any cell of human origin to behave like embryonic or pluripotent stem cells is a major breakthrough in stem cell biology. Human induced pluripotent stem cells (iPSC) provide a unique opportunity to study “disease in a dish” within a defined genetic and environmental background. Patient-derived iPSCs have been successfully used to model cardiomyopathies, rhythm disorders and vascular disorders. They also provide an exciting opportunity for drug discovery and drug repurposing for disorders with a known molecular basis including childhood onset heart disease, particularly cardiac genetic disorders. The review will discuss their use in drug discovery, efficacy and toxicity studies with emphasis on challenges in pediatric-focused drug discovery. Issues that will need to be addressed in the coming years include development of maturation protocols for iPSC-derived cardiac lineages, use of iPSCs to study not just cardiac but extra-cardiac phenotypes in the same patient, scaling up of stem cell platforms for high-throughput drug screens, translating drug testing results to clinical applications in the paradigm of personalized medicine, and improving both the efficiency and the safety of iPSC-derived lineages for future stem cell therapies.     

Study of the conduction system in a population of patients with sudden infant death syndrome

Summary The conduction system of 23 infant hearts, 15 of sudden infant death syndrome (SIDS) and eight of those dying from known cause, was serially sectioned. A left-sided His bundle was found more commonly in (SIDS) (eight of 15) than in the controls (two of eight). Taking into account a previous study in which a left-sided His bundle was found in only four of 32 hearts from all age groups, this is statistically significant and may be a factor promoting SIDS.This research was aided by grant HL-30558-02 from the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.     

Current status and future prospects of human gene therapy

Gene therapy is defined as the treatment of diseases by the transfer of genes into patients. Clinical trials of gene therapy became feasible as a result of the development of retroviral mediated gene transfer techniques. The first trial was begun in September 1990 at the National Institutes of Health when a four year old girl was treated for adenosine deaminase deficiency. Currently, more than 500 patients are being treated by this innovative therapeutic strategy. In the present review article, the basic concepts and present status of human gene therapy are summarized.     

Pediatric oncology at Hospital Infantil de Mexico: fifty-five years of accomplishment

The Department of Oncology at Hospital Infantil de México Federico Gómez (HIMFG) was the first unit in our country, and one of the first in Latin America, to specialize in the management of children with cancer. The HIMFG is part of the National Institutes of Health of Mexico, and is a reference hospital with research, educative, and tertiary care medical function. To date, the HIMFG and the Instituto Nacional de Pediatria are the principal medical centers in which children with cancer receive comprehensive care.