to Bedside - The Children`s Hospital of Philadelphia
Transcription
to Bedside - The Children`s Hospital of Philadelphia
Bench July 2006 to Bedside R T C’ H P Hospital Breaks Ground for New Research Facility The growth of the clinical and research programs at The Children’s Hospital of Philadelphia has propelled the dramatic expansion of the institution’s physical facilities. The latest expansion plans supporting the Hospital’s flourishing research enterprise were publicly revealed in June with the ceremonial groundbreaking for an eight-story research building dedicated to translational research. Sitting upon an eight-acre parcel of land that was formerly the Philadelphia Civic Center site, the building represents the first phase of development for Children’s Hospital’s South Campus Research Complex. The ceremonial groundbreaking honored longtime board trustees Ruth M. and Tristram C. Colket Jr., in appreciation of their substantial gift that will allow the Hospital to move toward its goal of doubling the size of its existing research space. In recognition of their longstanding generosity and leadership, which has spanned more than three decades, the Hospital will name the new research building in their honor. “Ruth and Tristram Colket’s recent gift of $25 million has given an enormous boost to the advancement of research at Children’s Hospital that will help to fund our new research building on our South Campus,” said Steven M. Altschuler, M.D., the Hospital’s president and chief executive officer. “With more than 30 years of support, they have given more than $35 million to help ensure that Children’s Hospital remains the preeminent pediatric institution in this country and the world.” The philanthropy of the Colkets is evident in the Hospital’s light-filled atrium and the lobby of the Leonard and Madlyn Abramson Pediatric Research Center, both of which bear their name. In addition, the Colkets’ generosity has fostered continued research through endowed chairs in pediatric surgery and pediatric nursing. The $400 million, 558,000-square-foot future research building comprises eight stories — four new laboratory floors, administration and conference space, and a two-story ground floor housing a lobby and cafeteria. There are an additional four stories below grade consisting of infrastructure and laboratory support space. To accommodate future growth, there is potential to expand the building to 22 stories. “This state-of-the-art facility enables Children’s Hospital to recruit top-level researchers by providing the space, equipment and technology required to advance pediatric medicine,” said Chief Scientific Officer Philip R. Johnson Jr., M.D. “The Hospital will be poised to be the preeminent institution conducting translational research for the benefit of children.” The South Campus Research Complex directly across from the Hospital’s current clinical and research facilities. Once complete, the South Campus will house not only a state-of-the-art translational research facility but also a central utility plant to support the entire Children’s Hospital campus, underground parking and garage, and an ambulatory building with outpatient care, day medicine, day surgery and imaging, as well as enhanced amenities for patients, families and employees. The total facility development is estimated at $845 million and could total more than 1 million square feet. “The Children’s Hospital of Philadelphia provides us the greatest opportunity to make a difference in the lives of children,” said Ruth and Tristram Colket. “This new research building will help ensure a healthier future for the children of tomorrow.” New Deputy Scientific Director Joins Stokes Tom Curran, Ph.D., joined Children’s Hospital on July 1 as the new deputy scientific director for the Stokes Institute and professor of Pathology at the University of Pennsylvania. During his career, Dr. Curran has made numerous fundamental scientific contributions in the fields of neurobiology, signal transduction and cancer biology. “His work has had profound implications for our understanding of fundamental biological processes as well as novel medical applications,” said Philip R. Johnson Jr., M.D., chief scientific officer. He has authored more than 240 publications and holds the rare distinction of being listed as a high-impact scientist in three fields (neuroscience, molecular biology, and genetics and microbiology) by ISI HighlyCited.com, and was ranked fourth in the world in molecular biology and genetics from 1988 to 1992. In addition to these outstanding academic credentials, Dr. Curran is also known as an outstanding teacher, mentor and administrator. As deputy scientific director, Dr. Curran will oversee certain critical administrative aspects of research operations for the Stokes Institute. In addition, he will continue his academic pursuits by leading an interdisciplinary translational research center devoted to pediatric and adult brain tumors. The center will bring together investigators from across the academic campus to focus on this important scientific and clinical problem. Before joining the Hospital, Dr. Curran was with St. Jude Children’s Research Hospital in Memphis, where he served as chairman of the Department of Developmental Neurobiology and was a member of the senior leadership. New Research Employees (June 2006) We welcome the following new research employees: High-resolution Genomic Microarrays Allow Rapid Diagnosis of Birth Defects Adolescent Case Manager For years, many children with multiple congenital problems, such as developmental delays, heart defects and facial abnormalities, have gone undiagnosed because they may not have an easily recognizable syndrome. samples from two patients with known chromosomal rearrangements and wellcharacterized genetic diseases. In a blinded analysis, the experiment found the correct location of the abnormal regions. More refined laboratory technology, however, has made it possible for Children’s Hospital investigators to detect many of these small rearrangements in chromosomes and find the abnormal gene or genes that give rise to a disorder. The researchers then studied samples from 10 patients with multiple congenital anomalies, identifying novel submicroscopic deletions in two patients. These deletions were not detected in the patients’ parents, providing strong evidence that the deletions were the underlying cause of the multiple defects seen in the children. Jennifer Rasco Administrative Director Robert Skraban Animal Caretaker T.D. Montgomery Chaplain Mirabai Galashan Clinical Research Assistant Christine Leas Director, Technology Transfer Joseph DiDonato Program Coordinator Stephen LaMonica Research Assistant Kelly Lannutti Research Associates Andrew Eckert Cecilia Kim Research Technicians Joseph Glessner Janeflora Kanya Johanna Murray Rebecca Schray Svetoslav Stratiev Rati Venkatesh Resource Coordinator Diana Stratigakis Statistical Technician Laura Lawrence Using commercially available gene chips, molecular geneticist Tamim H. Shaikh, Ph.D., led a team of investigators that scrutinized all of a patient’s chromosomes to identify small defects that cause genetic diseases. Because current genetic tests usually cannot detect these abnormalities, the new research may lead to more accurate diagnosis of congenital diseases, including puzzling disorders that lead to mental retardation. Conditions that originate in alterations of chromosome architecture have been called “genomic diseases.” The smallest of these structural defects are microdeletions, a loss of a small amount of genetic material, or microduplications, an excess of genetic material. Individually, many genomic diseases are rare, but collectively, they may occur in one in 1,000 live births. Frequently, the gene aberrations harm multiple organ systems. For example, patients with chromosome 22q11.2 deletion syndrome may have heart defects, impaired immunity and developmental delays. Deletions of several genes in Prader-Willi syndrome may cause obesity and mental retardation. To seek out miniscule rearrangements in chromosomes, Dr. Shaikh and his team employed the types of gene chips, or microarrays, originally designed to identify genes involved in common, complex diseases like diabetes and hypertension. Children’s Hospital's study is one of the first to report using these microarrays in a clinical setting to detect constitutional rearrangements that lead to severe birth defects. The results of their study, published in the May 2006 issue of Human Mutation, validated the microarray by using it to test Bench to Bedside Dr. Shaikh’s laboratory has subsequently used the microarray to analyze DNA samples from more than 60 patients, and have detected novel microdeletions and microduplications in 25 percent of the cases. He also has received a grant to investigate chromosomal rearrangements in bipolar disease, a complex disorder thought to involve interactions among multiple genes. Dr. Shaikh is currently collaborating with other Hospital researchers, particularly Elaine H. Zackai, M.D., director of Clinical Genetics, and Hakon Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics, to evaluate other higherdensity gene chips that provide greater resolution. His team is also developing better computational tools to evaluate data from these chips. “Our ability to detect even smaller rearrangements will only get better as there are improvements in the resolution of the microarrays and the computational tools required to analyze and mine the data generated,” said Dr. Shaikh. The National Institutes of Health supported this research, as did the Ethel Brown Foerderer Fund at Children’s Hospital. Dr. Shaikh’s co-authors were Jeffrey E. Ming, M.D., Elizabeth Geiger, Alison C. James, Karen L. Ciprero, Manjunath Nimmakayalu, Ph.D., Yi Zhang, Andrew Huang, Madhavi Vaddi, Eric Rappaport, Ph.D., and Elaine H. Zackai, M.D. Study Confirms Safety Seats and Boosters Provide a Safety Advantage Improper positioning of the lap or shoulder portion of seat belts place children at risk for ejection from the belt and from the vehicles, as well as for serious injuries to the head, neck, abdomen and spinal cord. Child restraints, such as child safety seats and belt-positioning booster seats, are designed to keep children safe until they are old enough for the adult seat belt — designed to protect an average adult-sized male. Researchers led by Dennis Durbin, M.D., M.S.C.E., and Flaura Winston, M.D., Ph.D., co-directors of the Center for Injury Research and Prevention, found that children who used child restraints were 28 percent less likely to be killed in a crash than children who were wearing seat belts alone. Including in the analysis gross misuse of a child restraint — a restraint that was not attached to the vehicle seat or a child who was not wearing the seat’s harness — children were 21 percent less likely to be killed than children using seat belts alone. The investigators studied records of nearly 9,000 children aged 2 through 6 involved in serious motor-vehicle crashes occurring between 1998 and 2003. This data represents vehicles and child restraint designs in use by today’s families, previous analyses of child-crash fatalities and restraint types involved crashes dating back to 1975. To avoid potential biases seen in past analyses that looked only at fatal crashes, the data was collected from two national crash databases that include data from fatal and non-fatal crashes: the U.S. Department of Transportation’s Fatality Analysis Reporting System (FARS) and the National Automotive Sampling System. “Our research to date has focused primarily on preventing serious injury, because we felt this is where we could have the greatest effect,” said Dr. Durbin. “Now we can assure parents that, while rear seating and seat belts are better than no restraint at all, child restraints are significantly more effective at preventing both injuries and death for children younger than 7 years old.” The study was supported by State Farm Mutual Insurance Company through a research partnership called Partners for Passenger Safety, and the findings were published in the Archives of Pediatric and Adolescent Medicine. Study Reveals New Findings on Ventricular Fibrillation in Children Ventricular fibrillation (VF), a life-threatening heart-rhythm disorder that may accompany full cardiac arrest, is one of the most common causes of cardiac arrest in adults but thought to be much less common in children. Hospital investigators Vinay Nadkarni, M.D., and Peter A. Meaney, M.D., M.P.H., found that VF occurs more frequently in children than commonly believed. Abnormal rhythms during cardiac arrests in children were thought to occur in fewer than 10 percent of the cases, but investigators found the occurrence to be 27 percent. The study — by far the largest ever considered for outcomes from VF in children — analyzed records from 1,005 children who suffered in-hospital cardiac arrest. More than one in four (272 patients) had documented VF or tachycardia — rapid heart beats — that required shocks at some point during the arrest. In 104 of those patients, VF or tachycardia occurred initially. In 49 patients, it occurred subsequently during the arrest. Investigators found VF is more likely to be fatal if it is not the initial heart rhythm detected at the start of cardiac arrest, but instead develops later during the arrest, typically during resuscitation. Of the children with initial abnormal rhythms, 35 percent survived to hospital discharge, compared with 11 percent of children with subsequent abnormal rhythms. The largest group of patients with cardiac arrest, 733 children, had no documented VF or tachycardia. Of this group, a majority (602 patients) were known to have asystole — no heart contractions — or no pulse at the start of cardiac arrest. This group had intermediate outcomes and 27 percent survived to hospital discharge. Investigators were surprised that this group had better outcomes than children with subsequent VF. Researchers plan to conduct additional research on why survival outcomes from subsequent VF were so low. Possible explanations may be that children with subsequent VF have more severe underlying heart disease or that clinicians are less aware of the possibility of subsequent VF and may not diagnose and treat it until it is recognized late in resuscitation efforts. The authors explain that although outcomes vary, the majority of children with cardiac arrest do not survive to hospital discharge; however, CPR and advanced life support are certainly not futile, even among the group with the worst outcomes. “Our findings reinforce the concept that CPR with early recognition of shockable rhythms remains a most important aspect of successful cardiac resuscitation,” said Dr. Nadkarni. “We need to continue to develop, teach and implement better strategies using registries and networks that help us to discern key aspects of cardiac arrest.” This study was published in the June issue of the New England Journal of Medicine. Support was granted by the Emergency Cardiovascular Care Committee of the American Heart Association and the Children’s Hospital of Philadelphia Endowed Chair in Anethesiology and Critical Care Medicine. R at The Children’s Hospital of Philadelphia New Human Subjects/HIPAA and Animal Care and Use Training Coming As part of Stokes’ commitment to delivering high-quality, effective education and training, the Department of Research Education will launch two nationally recognized training programs this summer: the Collaborative Institutional Training Initiative (CITI) Course in the Protection of Human Research Subjects and the AALAS Learning Library (ALL) for Animal Care and Use. Both the CITI and AALAS programs are online courseware packages used by many institutions across the country. The Hospital’s adoption of these programs reflects the increased federal oversight governing research and national trends emphasizing the need for a more comprehensive and pertinent training curriculum. The CITI program will replace the existing five-module Institutional Review Board training and the HIPAA for research booklets. The Web-based modules from ALL will replace the Hospital’s current video presentations used for general training for animal care and use. In addition, efforts are underway to finalize an agreement with the University of Pennsylvania to reduce duplicative training requirements for researchers collaborating across institutions. CITI offers customizable training tracks for biomedical, social/behavioral, data/ specimen users and research administration. Hospital investigative team members and administrative staff who support research will complete the appropriate CITI track, which includes reviewing the required modules and passing each corresponding quiz with a minimum score of 80 percent. The ALL initiative involves new speciesspecific training for animal care and use. This online training will supplement the existing requirement for species-specific, hands-on training, which presents Hospital policies and procedures for the care and use of animals and a guided tour of the animal facility. In addition, a Web-based module addressing occupational health and safety and the special hazards facing investigators working with animals will be added. New clinical researchers or administrators supporting research must complete the appropriate CITI track before engaging in human subject research. In addition, new primary and co-investigators, trainees or lab personnel working with animals must complete the ALL course curriculum and hands-on training before they begin their research. Existing researchers are being asked to complete the appropriate CITI track and/or ALL course curricula by the end of the calendar year. As of Jan. 1, 2007, the IRB and IACUC will not approve any new or continuing review submission until all investigative team members and animal users have completed the appropriate training. Recertification of CITI and ALL training will be required every three years. Questions about the training programs may be directed to Research Education at researcheducation@email.chop.edu. Registration Required for New Clinical Research Studies Investigators about to start a new clinical research study that will generate either professional or technical bills to be paid through a research account must register the study to become part of the Clinical Research Business Project (CRBP). The CRBP is part of a Hospital-wide strategic initiative designed to ensure compliance and improve subject, investigator and other stakeholder experiences with the clinical research business process. The CRBP, a compliance initiative and an important contributor to the ideal patient experience, provides for accurate billing based on registrations that ensure separation of stand and of care from research-only charges. The CRBP affects all clinical research systems and processes, including subject preregistration, scheduling, registration, budgeting, billing and reconciliation. For more information, visit the CRBP Web site at http://stokes.chop.edu/intranet/CRBP/ index.html. Investigators may register their studies and select a training date through the site. Study Finds Medication, Behavior Changes May Aid Weight Loss When combined with behavior therapy, the weight loss medication sibutramine — sold under the brand name Meridia — may help obese adolescents lose weight, according to a Children’s Hospital study. Robert I. Berkowitz, M.D. Psychiatrist-in-cheif and chief of Child and Adolescent Psychiatry, led the first large multicenter trial of the weight loss medication sibutramine for obese adolescents. The study enrolled 498 severely obese adolescents, ages 12 to 16, in 33 outpatient clinics throughout the United States from 2000 to 2002. The patients were randomized into two double-blinded groups, one receiving sibutramine and one receiving a placebo, while both groups received behavior therapy. The research team found that patients who received the medicine lost an average of 14 pounds over a year, while patients who received a placebo gained four pounds over the year. At the end of a year of treatment, body mass index decreased by 9.4 percent in the treatment group compared to 1.2 percent in the control group. One-third of the adolescents who received medication were no longer severely overweight, and one out of six dropped below the standard definition of being overweight at the end of the study. In addition to reductions in body mass index and weight, the treated adolescents had improvements in disease risk factors related to obesity such as triglycerides, high-density lipoprotein cholesterol and insulin levels. Further investigations are needed to analyze long-term weight management and health outcomes for adolescents with obesity and to focus on possible long-term risks of medication versus risks of continued weight gain. “Although much research remains to be done, our findings are encouraging for clinicians, and may offer treatment options for obese adolescents for whom behavioral therapies alone are not successful,” said Dr. Berkowitz. The study’s findings were published in the July issue of the Annals of Internal Medicine. Support for the study was provided by Knoll Pharmaceutical Company, now Abbott Laboratories, which manufactures sibutramine. Award Focuses on a Protein’s Structure and Interactions Atherosclerosis — hardening of the arteries — generally is not considered a pediatric condition, but the formation of fatty streaks that contribute to the condition starts in utero and builds up over decades. Although children usually have low cholesterol concentrations, by the age of 12 to 14 years approximately 70 percent of children have fatty streak lesions that may eventually contribute to atherosclerosis. Obtaining information at the molecular level about this process may lead to the understanding of early pathophysiological events in atherosclerosis. Serum lipoproteins — complexes of fats and proteins present in the blood — play a role in lipid and cholesterol transport and in the development of atherosclerosis. One of the structural proteins of lipoproteins, called apolipoprotein (apo) E, is involved in the metabolism of cholesterol and triglycerides. ApoE prevents plaque buildup by interacting with lipids and molecules on a cell’s surface like low-density lipoprotein receptors (LDLR) and glycosaminoglycans. However, the structural basis for these interactions is not fully understood. ApoE is also part of lipoproteins in the central nervous system where it mediates neuronal repair, remodeling and protection against dementia and Alzheimer’s disease. There are three major forms of apoE, some of which can increase the risk of developing atherosclerosis and Alzheimer’s disease. With support from the National Institutes of Health, Sissel Lund-Katz, Ph.D., of the Lipid Research Group in the Division of Gastroenterology, Hepatology and Nutrition, is leading a study on the molecular features that control apoE’s binding to lipids, lipoprotein particles and cell surface receptors. As part of the $1.6 million, four-year award, Dr. Lund-Katz and her colleagues will also investigate how the receptor binding domain for apoE controls its binding to glycosaminoglycans as compared to members of the LDLR family. The team will also characterize how apoE interacts with cells to create high-density lipoprotein particles, which protect against harmful deposition of cholesterol in tissues. Understanding the molecular basis for apoE’s different activities may lead to the design of treatments or preventative strategies for atherosclerosis and other conditions. FYI TraumaLink Changes Name: TraumaLink has changed its name to the Center for Injury Research and Prevention at The Children’s Hospital of Philadelphia to more accurately reflect its mission of conducting and disseminating research on the causes of childhood injury and developing interventions to prevent injury. As part of the name change, the Center has updated its Web site (http://www.chop.edu/traumalink) to make it easier for healthcare professionals, educators and government officials to locate, order and download educational and advocacy materials, including videos, reports, images and fact sheets on child passenger safety and pediatric traumatic stress. New LAF Director: Rebecca Wiltshire, D.V.M., joined Children’s Hospital as the new director of the Laboratory Animal Facility (LAF). In this role she will be responsible for the institution’s animal care and use programs, providing veterinary care, surgery and animal husbandry, and will work closely with investigators to design and implement experiments involving animals. She will also manage the ongoing development of the LAF, including animal management, veterinary research services, population management, and the design and commissioning of new or renovated animal facilities. The Center for Injury Research and Prevention is the umbrella organization for Partners for Child Passenger Safety and other programs. Stokes Recruits Associate OCTR Director Lisa Speicher, Ph.D., joined Children’s Hospital on July 10 as the associate director for the Office of Clinical and Translational Research (OCTR). Drawing upon her more than 15 years of experience in translational research and development, Dr. Speicher will support the OCTR’s mission by helping to facilitate research collaborations between investigators, sponsors and academic institutions; matching investigators to funding opportunities; and developing procedures to enhance clinical and translational research experience across the institution. She will also take a leading role in the Clinical Trials Office, which supports the Hospital’s clinical and translational investigators by providing study coordinators, assisting with submissions to the Institutional Review Board, developing budgets for clinical research, and preparing Investigational New Drug and Investigational Device Exemption applications. Immediately before joining the Hospital, Dr. Speicher served as the director of Translational Research at Wyeth Research. She also served as the associate director for the Clinical Trials Unit at the University of Pennsylvania Health System. Faculty Awards/Honors A study by Charles Stanley, M.D., chief, Division of Endocrinology, and his colleagues was featured as the “Paper of the Week” in the Journal of Biological Chemistry, a journal of the American Society for Biochemistry and Molecular Biology. The study confirmed that mutations in an enzyme called glutamate dehydrogenase can cause congenital hyperinsulinism. The results of the study on congenital hyperinsulinism, which can cause hypoglycemia in infants and children, have potential for many therapeutic and diagnostic applications. Specifically, the results may provide targets for developing new drugs that inhibit the glutamate dehydrogenase enzyme. The results also support the use of genetic mutation analysis of glutamate dehydrogenase to diagnose children with hypoglycemia and suggest that the enzymes could ultimately serve as targets for drugs to treat diabetes. An internationally recognized expert in the after-effects of children’s cancer, Dr. Meadows and her colleagues were the first to investigate the late effects of childhood cancer. Their studies, which began in the 1970s, showed that radiation then used to treat leukemia damaged the children’s cognitive development and increased the risk of later brain cancer. The findings prompted a change in medical practice, with physicians eliminating or reducing the doses of radiation to the head. Since 1993, Dr. Meadows has served as a prominent investigator in the Childhood Cancer Survivor Study, a National Cancer Institutesponsored long-term national study of 15,000 cancer survivors. She also directs the Hospital’s Cancer Survivorship Program and leads both the Cancer Survivorship Research Program and the Lance Armstrong Foundation Living Well After Cancer Program at the University of Pennsylvania. The American Society of Clinical Oncology awarded Anna T. Meadows, M.D., with its 2006 Pediatric Oncology Award, which is presented to those who have contributed outstanding scientific work to the future of pediatric oncology. Research Education Develops Materials to Facilitate Postdoc Mentoring Mentoring is critical for the future success of postdoctoral fellows, but the quality of mentoring can be compromised for international postdocs. Unlike postdocs supported by federal training grants, their training needs are not addressed by NIH policy and U.S. mentors are often illequipped to deal with potential barriers to the advancement of foreign postdocs such as immigration problems, language difficulties and cultural biases. With the support of a grant from the Office of Research Integrity (ORI), the Department of Research Education at Children’s Hospital developed video vignettes with a supplemental guidebook to facilitate mentoring between mentors and their international postdocs. The video vignettes and comprehensive guidebook are available to mentors nationwide through ORI’s Web site at: http://ori.dhhs.gov/ as well as on Research Education’s site at http://stokes.chop.edu/intranet/ departments/education/edu10.html. DVDs and hard copies of the guidebook are also available from Research Education. HAVE NEWS? The video vignettes and guidebook can: help to identify and create awareness and sensitivity to specific issues improve mentor skills and competencies in problem areas ● define mentor and postdoc roles and responsibilities ● illustrate positive mentoring practices and different styles and approaches to resolving conflict. ● ● The topics addressed include hiring practices, mentor expectations, immigration issues, mentor/trainee trust, trainee expectations, communication, performance assessment, career guidance, cultural bias, ethnic stereotypes, working environment, abuse of power and cultural barriers. Contact Jennifer Long at ext. 4-2105 or by e-mail at longj@email.chop.edu. Read this and previous versions of Bench to Bedside online at http://stokes.chop.edu/intranet/pubs/ Produced by the Joseph Stokes Jr. Research Institute for The Children’s Hospital of Philadelphia. Copyright © 2006 by The Children’s Hospital of Philadelphia.