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Going to the Heart: Why Research Matters 

(InTouch Fall 2010) 

A discussion of five Children's Memorial Hospital scientists who are crossing boundaries to make a difference in cardiac care.

 lewandowska300 Marzena Lewandowska, PhD 

The cystic fibrosis transmembrane conductance regulator (CFTR) gene shows a complex pattern of expression that is not accounted for solely by regulatory elements that lie within the promoter region. However, this sequence is required for gene expression. The laboratories of Ann Harris, PhD (Human Molecular Genetics Program) and Marcelo Bento Soares, PhD (Cancer Biology and Epigenomics Program) investigated the mechanism of action of the CFTR promoter in order to reveal aspects of developmental regulation of gene expression. The Harris group previously identified two upstream exons of the gene that were mutually exclusive with the normal first exon, generating an alternative splice product. In the present study, published in the September 2010 issue of the American Journal of Respiratory Cell and Molecular Biology, they demonstrated that one alternative splice product generates a stable protein, while the other inhibits translation of the protein. In a search for the promoter used by the upstream exons, they also identified a novel element that may contribute to CFTR gene expression in airway cells. Finally, they showed that the CFTR promoter is unmethylated in many cell types, irrespective of whether the gene is expressed. First author Marzena Lewandowska,
PhD is a former postdoctoral associate in the Harris laboratory who has recently returned to her native Poland.

 Nancy Young 

 Tina Tan 

Nancy Young, MD and Tina Tan, MD sought to determine the pneumococcal vaccination status of children with recent postmeningitic deafness, and to review the current approach for achieving early implantation in this population that is at significant risk for cochlear ossification. They concluded that despite the dramatic decline in invasive pneumococcal disease subsequent to widespread use of the pneumococcal vaccine in the U.S., pneumococcal meningitis as a cause of deafness has not been eliminated. Indeed, with more than 90 pneumococcal serotypes in existence, eradication is not expected even if current vaccine protocols continue to successfully limit the incidence of invasive disease. Therefore, pediatric cochlear implant programs need to remain prepared to evaluate and perform implantation in this special population. The study was published in the October 2010 issue of Archives of Otolaryngology—Head & Neck Surgery. Young is Associate professor of Otolaryngology—Head and Neck Surgery and The Lillian S. Wells Chair in Pediatric Otolaryngology at the Feinberg School. Tan is Professor of Pediatrics at the Feinberg School, attending physician in the Division of Infectious Diseases at Children’s Memorial and a member of the Clinical and Translational Research Program of the research center.
Jill Weissberg-Benchell 

The lack of a valid and reliable transplant-specific health-related quality of life (HRQOL) measure has hampered the ability to identify children at different levels of morbidity, determine the differential impact of various treatment regimens, predict which patients are at risk for emotional difficulties and/or poor regimen adherence, and identify emerging problems for long-term survivors. Such a measure would provide a more thorough understanding of the multidimensional nature of both the child’s experience and the parent’s perceptions of the child’s experience regarding the impact of solid organ transplantation. To address this critical, unmet need, a team led by Jill Weissberg-Benchell, PhD investigated the initial feasibility, reliability and validity of the Pediatric Quality of Life Inventory™ (PedsQL™) 3.0 Transplant Module in a population of children with solid organ transplants. The findings, published in the July 2010 issue of the American Journal of Transplantation, suggest that the module demonstrated excellent reliability. Transplant-specific symptoms or problems were significantly correlated with lower HRQOL, supporting construct validity. Children with solid organ transplants and their parents reported lower HRQOL than healthy children. Weissberg-Benchell is Associate professor of Psychiatry and Behavioral Sciences at the Feinberg School, pediatric psychologist in the Department of Child and Adolescent Psychiatry at Children’s Memorial, and a member of the Smith Child Health Research Program of the research center.

 

 Shekhar Mayanil  An estimated 3,000 pregnancies in the U.S. are affected by neural tube defects annually. Research shows that if all women who could become pregnant consumed recommend amounts of folic acid (FA) before and during pregnancy, the risks of neural tube defects such as spina bifida could be decreased by 70 percent. Currently, the mechanisms behind FA rescue of these defects are not well understood. Identifying the mechanism and targets is expected to provide leads for future development of novel therapeutics that could repair spina bifida and related birth defects in utero. In a study using an animal model that fails to show proper neural tube closure, resulting in spina bifida, a team led by David McLone, MD, PhD, Tadanori Tomita, MD and Chandra Shekhar Mayanil, PhD showed that FA rescued the proliferation potential of neural crest stem cells from the animals via epigenetic mechanisms. Epigenetics is the study of inherited changes in phenotype (appearance) or gene expression caused by mechanisms other than changes in the underlying DNA sequence. The study is published online in the Journal of Biological Chemistry. Senior author Mayanil is Assistant professor of Neurological Surgery at the Feinberg School, director of the Neural Tube Research Program and a member of the Developmental Biology Program of the research center. First author is Shunsuke Ichi, PhD, a member of the Mayanil laboratory and of the Department of Neurosurgery, University of Tokyo.
 
 Ben Katz 

Chronic fatigue syndrome (CFS) is a complex and controversial condition involving severe fatigue and disabling musculoskeletal and cognitive symptoms. Chronic fatigue accounts for marked functional impairment and educational disruption among adolescents. Ben Katz, MD and colleagues reported the results of a two-year prospective study of CFS after monospot-positive acute infectious mononucleosis (IM) in adolescents in the September 2010 issue of the Journal of Pediatrics. As part of their six-month evaluation, 21 adolescents diagnosed with CFS and 21 control subjects who were completely recovered from their IM participated in an exercise tolerance test; salivary cortisol also was measured before and after exercise. The group found that the adolescents with CFS have a lower degree of fitness and efficiency of exercise than recovered adolescents. Whether these abnormal findings are a cause or effect of CFS is unknown. IM can lead to both fatigue and measurable changes in exercise testing in a subset of adolescents. Katz is Professor of Pediatrics at the Feinberg School, attending physician in the Division of Infectious Diseases at Children’s Memorial and a member of the Clinical and Translational Research Program of the research center.

 

Wainwright Ralay Ranaivo 

The use of albumin as a resuscitation fluid is considered safe for most critically ill patients. However, clinical data suggest albumin may increase mortality in patients with traumatic brain injury (TBI). Albumin has been shown to activate glia, the support cells to neurons, and to play a role in the mechanisms of epileptogenesis, the sequence of events that turns a normal neuronal network into a hyperexcitable network, via the TGFß-receptor (TGFßR). The laboratory of Mark Wainwright, MD, PhD investigated the role of the TGFßR and the TGFß receptor-smad signaling pathway in astrocyte activation by albumin. In the December 2010 issue of Experimental Neurology, they show that in primary astrocyte cultures, albumin activates the TGFß-receptor-smad signaling pathway. The albumin-induced increase in the proepileptogenic cytokine IL-1ß involves the TGFßR, but is independent of smad activation. Taken together, the effects of albumin on both IL-1ß and activation of the TGFßR pathway are further evidence for a role for albumin in neurotrauma-related epileptogenesis. First author Hantamala Ralay Ranaivo, PhD is a research scientist in the Wainwright laboratory.

 

A Journal of Neurotrauma publication by the Wainwright group reports that TBI alters susceptibility to seizure, and that Minozac, a compound developed at Northwestern University, prevents this increased risk for seizures. The drug is in a Phase 1 clinical trial for TBI, based in large part on the work of the Wainwright laboratory. The first author is MaryAnn Chrzaszcz, a research associate. Wainwright is Associate professor of Pediatrics at the Feinberg School; a member of the Center for Molecular Innovation and Drug Discovery at Northwestern University; attending physician in the Division of Neurology at Children’s Memorial; and director of CIRPCII and a member of the Neurobiology Program of the research center.
 
Lauren Pachman   Lauren Pachman, MD and colleagues sought to determine if mycophenolate mofetil (MMF) diminished skin and muscle disease activity in children with juvenile dermatomyositis (JDM), permitting a decrease in corticosteroid dosage. JDM, a disease marked by muscle weakness and skin rash, is the most common pediatric inflammatory myopathy. Corticosteroids are the cornerstone of treatment, but their numerous side effects, as well as lack of adequate clinical response in some patients, has prompted a search for alternative therapy. The study consisted of a retrospective data review for 50 JDM children who had been given MMF for 12 months. The data suggested that its use decreases skin and muscle disease activity and is steroid sparing. MMF appears to be well tolerated, but patients should be monitored for infection. The first author on the publication in Arthritis Care and Research is Kelly Rouster-Stevens, MD of Wake Forest University Baptist Medical Center, Brenner Children’s Hospital, Winston-Salem, NC. 
 

Sheela Shrestha
Sheela Shrestha, MS 

In a separate study, Pachman and colleagues investigated the distribution of mast cells and dendritic cell subsets from untreated children with JDM. Paired muscle and skin that either had the inflammatory rash of JDM, or skin that appeared to be normal from untreated children with JDM were analyzed. Inflamed as well as normal appearing JDM skin contained many more mast cells than skin from pediatric controls. Both JDM muscle and skin showed more mature plasmacytoid dendritic cells (pDCs), which play a critical role in the induction of autoimmune disease and other skin diseases. This identification of mast cells in JDM skin indicates that they have a specific function in JDM skin pathophysiology and that they appear to work with the pDCs to initiate the inflammatory cascade. The first author on the publication in Arthritis and Rheumatism is Sheela Shrestha, MS. The article was also the subject of an editorial in the issue. Pachman is Professor of Pediatrics at Northwestern University Feinberg School of Medicine; attending physician in Rheumatology at Children’s Memorial Hospital; and director of the Chicago City-wide FOCIS Center of Excellence in Clinical Immunology of Children's Memorial Research Center.

Arun Sharma
Arun Sharma, PhD 

Arun Sharma, PhD, Earl Cheng, MD and a multidisciplinary team have been studying bladder regeneration with the hope of significantly improving techniques to recreate urinary bladder tissue for patients with neuropathic bladders. In a paper published in the August issue of Biomaterials, the team hypothesized that human mesenchymal stem cells seeded onto poly (1,8-octanediol-co-citrate) elastomeric thin films would provide a suitable milieu for partial bladder regeneration. Antibody staining, histological evaluation, quantitative morphometry, immunofluorescent imaging and mechanical stress evaluations were performed. The augmented bladders exhibited typical architecture with muscle bundle formation and the expression and retention of bladder smooth muscle contractile proteins of human derivation. Furthermore, the data demonstrated MSC seeded POCfs support partial regeneration of bladder tissue in vivo. Sharma is Research assistant professor of Urology and a member of the Institute for Bionanotechnology at the Feinberg School; and a member of the Developmental Biology Program of the research center.
In a study published in the March-April issue of Health Affairs, Maryann Mason, PhD and colleagues reviewed state and local efforts to collect childhood obesity data. Obesity-related diseases place an enormous burden on the U.S. health care system. Data collected by the Centersfor Disease Control and Prevention have been instrumental in identifying the epidemic at a national level, but local- and state-level data are essential to effectively confront childhood obesity. The group concluded that state-level models are generating innovative systems to permit detailed analysis; future efforts to plan, legislate, and implement such surveillance systems should benefit from lessons learned by states that have strived to implement them. Mason is associate director of the Child Health Data Lab and co-director of the Center for Community Partnerships and Health Promotion in the Mary Ann & J. Milburn Smith Child Health Research Program of the research center, and Research assistant professor at the Feinberg School.
JPongracic  The Inner-City Asthma Study (ICAS) was a multicenter, randomized controlled trial of environmental intervention to reduce asthma morbidity in which inner-city children with moderate to severe asthma were enrolled. A subset of ICAS participants with positive skin test responses to a fungal allergen were examined for relationships between fungal sensitization, exposure and asthma morbidity. The study found that outdoor fungal exposure is primarily associated with increased asthma symptoms and higher risk of exacerbations in this population. The first author of the article, published in the March issue of the Journal of Allergy and Clinical Immunology, is Jacqueline Pongracic, MD, head of Allergy and Immunology at Children’s Memorial, Professor of Pediatrics and Medicine at the Feinberg School, and a member of the Smith Child Health Research Program of the research center. This article was featured on the JACI Journal Club blog. 
 
Infant mortality in the U.S. is high compared to other developed nations, and the mortality rate for African-Americans is more than twice that of whites. To determine whether economic environment across generations underlies the association of maternal low birth weight (LBW) and infant LBW (including its preterm and intrauterine growth retardation (IUGR) components), James W. Collins, Jr., MD, MPH and colleagues performed analyses on an Illinois transgenerational dataset of white and African-American infants and their mothers with appended U.S. census income data. They showed that maternal LBW is a risk factor for infant LBW, preterm birth and IUGR regardless of economic environments across generations. Their finding that former non-LBW African-American mothers have a six-fold greater proportion of LBW infants attributable to generational residence in low-income neighborhoods than former non-LBW white mothers could be useful for developing programs to reduce racial disparities in birth outcomes. The research was published in the April issue of Maternal and Child Health Journal. Collins is Professor of Pediatrics at the Feinberg School, attending physician in Neonatology at Children’s Memorial, and a member of the Smith Child Health Research Program of the research center. 

Debra Weese-Mayer
Debra E. Weese-Mayer, MD 

Michael S. Carroll, Pallavi P. Patwari, MD and Debra E. Weese-Mayer, MD of the Center for Autonomic Medicine in Pediatrics (CAMP) at Children’s Memorial recently published a critical review of congenital central hypoventilation syndrome (CCHS) and rapid-onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation (ROHHAD) in the Journal of Applied Physiology. CCHS and ROHHAD exhibit great respiratory control deficits, requiring supported ventilation as a mainstay of care. The discovery of the key role of the Paired-Like Homeobox 2B (PHOX2B) gene in autonomic nervous system development, along with the identification of PHOX2B mutations causing CCHS, has led to a fruitful dialog between basic scientists and physician-scientists. This has produced an explosion of knowledge regarding genotype-phenotype correlations in this disorder as well as important animal models of chemosensory regulation deficit. Though the etiology of ROHHAD is still to be determined, recent studies have begun to carefully delineate the phenotype, suggesting that it too may provide fertile ground for research that both advances our knowledge and improves patient care.  Weese-Mayer is Professor of Pediatrics at the Feinberg School, medical director of CAMP, and a member of the Clinical and Translational Research Program of the research center.
BioEssays cover 2010 

BioEssays -- "Non-coding RNAs: Meet thy masters" 

In the July 2010 issue of BioEssaysFabrício Costa, PhD reviews the already huge, but rapidly expanding, diversity of non-coding RNAs (ncRNAs). The review describes the most recent discoveries in the ncRNA field that implicate these molecules as key players in the epigenome. Costa’s work is also featured on the cover of the journal issue. Costa is a Research scientist in the laboratory of Marcelo Bento Soares, PhDCancer Biology and Epigenomics Program.

The cover image depicts the secondary structure of the long non-coding RNA HOTAIR, which is implicated in gene regulation by epigenetic mechanisms.  Image courtesy of Fabrício Costa, PhD. 
Hehuang Xie 

In 2009, Hehuang Xie, PhD and colleagues in the laboratory of Marcelo Bento Soares, PhD developed a technique to assess the methylation pattern of Alu repeat elements genome-wide. The results were published in Nucleic Acids Research. The group’s 2010 publication in the Proceedings of the National Academy of Sciences of the United States of America uses this method to understand the pattern of hypomethylation in the cancer genome. Global loss of DNA methylation is known as an epigenomic aberration associated with carcinogenesis and cancer progression. This loss affects predominantly repetitive elements, which encompass over 50% of the CpG dinucleotides present in the human genome. To precisely determine the CpG sites with methylation loss during progression of pediatric intracranial ependymomas, the group exploited a high-throughput bisulfite sequencing approach that generates methylation profiles for thousands of Alu elements and their flanking sequences. They demonstrated that methylation losses in Alu elements are insignificant in primary nonaggressive ependymomas but increase in aggressive primary tumors and further yet in relapsed ependymomas. In particular, the data suggest that the methylation status of some Alu elements may serve as prognostic factors for a subset of aggressive ependymomas. Xie is Research assistant professor in the Cancer Biology and Epigenomics Program of Children's Memorial Research Center. The study was conducted with the Falk Brain Tumor Center of Children’s Memorial Hospital.
 

Ovarian torsion is the twisting of the ovary on its vascular support. When undiagnosed, blood supply becomes compromised, resulting in tissue necrosis and loss of function. There is significant variation in the literature regarding the characteristics that are associated with pediatric ovarian torsion and its management. In the March 2010 issue of Pediatrics, Bridgette Guthrie, MD and colleagues Elizabeth Powell, MD, MPH and Mark Adler, MD sought to describe its epidemiology and the rate of oophorectomy by using nationally representative data. The researchers conducted a cohort analysis of the Healthcare Cost and Utilization Project Kids’ Inpatient Database (KID) 2000, 2003, and 2006. The analysis found 1,232 cases of ovarian torsion in KID 2006, an estimated incidence of 4.9 per 100,000. A total of 58% were treated with oophorectomy. Younger patient age, lower median household income by zip code, and presence of a benign neoplasm were associated with an increased rate of oophorectomy. Fewer than 0.5% of ovarian torsion hospitalizations were associated with malignant neoplasm. The data indicate that ovarian torsion is uncommon but occurs in all ages and is typically associated with normal ovaries or benign lesions. A growing body of literature supporting conservative management of ovarian torsion may decrease over time the rate of torsion-related oophorectomy. Powell, who is senior author on the study, is Associate professor of Pediatrics at Northwestern University's Feinberg School of Medicine, an attending physician in Emergency Medicine at Children’s Memorial and a member of the Mary Ann and J. Milburn Smith Child Health Research Program of the research center.

 
Praveen Kumar 

Praveen Kumar, MD is the lead author of two recently published American Academy of Pediatrics (AAP) statements:

Premedication for Nonemergency Endotracheal Intubation in the Neonate, AAP Committee on Fetus and Newborn, Section on Anesthesiology and Pain Medicine (Pediatrics 125(3) March 2010).
Endotracheal intubation is a common procedure in newborn care. The purpose of this clinical report is to review currently available evidence on use of premedication for intubation, identify gaps in knowledge, and provide guidance for making decisions about the use of premedication.

Hospital Stay for Healthy Term Newborns, AAP Committee on Fetus and Newborn (Pediatrics 125(2) February 2010). The hospital stay of the mother and her healthy term newborn infant should be long enough to allow identification of early problems and to ensure that the family is able and prepared to care for the infant at home. The length of stay should also accommodate the unique characteristics of each mother-infant dyad, including the health of the mother, the health and stability of the infant, the ability and confidence of the mother to care for her infant, the adequacy of support systems at home, and access to appropriate follow-up care. Input from the mother and her obstetrician should be considered before a decision to discharge a newborn is made, and all efforts should be made to keep mothers and infants together to promote simultaneous discharge.

Kumar is Associate professor of Pediatrics at the Feinberg School, Attending physician in Neonatology at Children’s Memorial and a member of the Clinical and Translational Research Program of the research center.

Frank Zelko  In a study published in the January 2010 issue of Pediatric Pulmonology, Frank Zelko, PhD and colleagues examined indices of neurocognitive functioning in children with PHOX2B mutationconfirmed neonatal onset congenital central hypoventilation syndrome (CCHS) and related them to indices of PHOX2B genotype, demographics and disease severity. Twenty patients with the syndrome who had undergone neurocognitive assessment at the Rush Children’s Hospital CCHS Center between 1990 and 2006 were studied. Neurocognitive variables of interest included Full Scale IQ (FSIQ) and Wechsler-derived marker indices of verbal comprehension, visuoperceptual reasoning, working memory, and clerical/ processing speed. The results reveal participants’ general intelligence index (FSIQ) to be lower than the general population, though the range of FSIQ observed was broad. Visuoperceptual reasoning and clerical/visuographic speed marker indices were depressed. These deficits were related to special education participation but not to PHOX2B genotype status or other demographic and clinical risk factors. In conclusion, PHOX2B mutation confirmed CCHS confers risk for adverse neurocognitive outcome, though the range of functioning observed raises questions about factors that may contribute to neurocognitive variability. PHOX2B genotype and disease severity indicators were unrelated to neurocognitive indices, possibly due to the modest sample. Increased recognition and expedited diagnosis with PHOX2B testing should allow larger studies of the relationship between neurocognitive functioning, genotype/mutation, and disease severity and management. Zelko is Assistant professor of Psychiatry and Behavioral Sciences at the Feinberg School, a pediatric neuropsychologist in the Department of Child and Adolescent Psychiatry at Children’s Memorial and a member of the Clinical and Translational Research Program of the research center.
 
Maria Dizon 

Developing Therapies for Cerebral Palsy

The benefits of combining clinical practice with laboratory research are evident in the work of Maria Dizon, MD. As a practicing neonatologist at Prentice Women’s Hospital and Children’s Memorial, Dizon encounters babies at risk for brain injury. She also is completing a Mentored Clinical Scientist Research Career Development Award from the National Institute of Neurological Disorders and Stroke. Previously in the laboratory of former research center investigator Francis Szele, PhD, Dizon now conducts research with John Kessler, MD, head of the Ken & Ruth Davee Department of Neurology at the Feinberg School. She focuses on developing novel therapies for cerebral palsy, a non-progressive disorder of motor control that can affect both full term and prematurely born babies. This disorder results from injury to white matter (myelin) in the brain. Work done in conjunction with Szele suggests that neural progenitors found within injured areas may be the appropriate targets of manipulation. Dizon has now turned her attention to these progenitors, called NG2 cells. Her work with Kessler seeks to manipulate NG2 cells to produce new oligodendrocytes, the cells that produce myelin.

Dizon is completing work showing that downregulation of bone morphogenetic proteins results in protection and even increased production of myelin after hypoxia-ischemia. This finding is relevant to an important clinical problem in which white matter is lost in the preterm baby. Dizon has demonstrated rescue of both neurons and neuronal function. Experiments are under way to further elucidate the mechanism underlying this protection. Dizon will present her work at the Hershey Conference on Developmental Brain Injury in June. Dizon is Assistant professor of Pediatrics at the Feinberg School and a member of the Neurobiology Program of the research center.

Max Maizels 

CEVL for Health Care

For over a century, medical residency training programs have utilized the Halstedian apprenticeship method (i.e., “see one, do one, teach one”) as the standard of surgical education. Recent changes in the landscape of health care training necessitate changing how residents are trained to assure skill proficiency in residency graduates. Attending physician teachers increasingly need to utilize operating room time efficiently, document resident skill performance, and provide training for both open and endoscopic surgery; while resident learners are experiencing more restricted time in the operating room. A web-based curriculum that includes multimedia as written text, two- and three-dimensional visuals as annotated pictures and movie clips, and interactive animations, along with a method for feedback and remediation would comprise strategies designed to implement such change and improve skill proficiency. CEVL (Computer Enhanced Visual Learning) provides the necessary web-accessible curriculum and a method for feedback and remediation of skill performance. CEVL presents curriculum with hierarchical steps, visuals, readiness, feedback and remediation. Further, it appeals to inter-institutional training, provides reports that are ACGME-(Accreditation Council for Graduate Medical Education) compatible and documents level of resident skill proficiency.

Over the past year, the CEVL team has presented and won honors at professional meetings, received research grants, and published on the concept of CEVL and its outcomes in specific training situations. Team leader Max Maizels, MD is Professor of Urology at the Feinberg School, director of Perinatal Urology and co-medical director of the Institute for Fetal Health at Children’s Memorial and a member of the Developmental Biology Program of the research center.
 

Aleksandra Glavaski  A New Therapy for Parkinson’s Disease?

In the September 2009 Cell Transplantation, scientists in the laboratory of Martha C. Bohn, PhD, director of the research center’s Neurobiology Program, reported on a potential use of bone marrow derived neuroprogenitor cells for the treatment of Parkinson’s disease (PD). PD is a neurodegenerative disease characterized by the extensive loss of dopaminergic (DA) neurons in the midbrain, resulting in debilitating movement disorders. Following collection of bone marrow from healthy human adult volunteers, mesenchymal stem cells (MSC) were genetically modified to create SB623 cells. These cells express genes characteristic of neuroprogenitor cells derived from brain. Micro-deposits of SB623 cells were surgically placed into the rat brain near the terminals of DA neurons that had previously been damaged. In rats that received these cells, dense rejuvenated host DA axons were observed. These results suggest that MSC could be developed as a novel therapy for ameliorating the degeneration of DA neurons in PD patients. This study was done in collaboration with a stem cell biotechnology company, SanBio Inc. The remarkable effect of SB623 cells on DA neurons was featured on the cover of the issue. The first co-authors of the study are Aleksandra Glavaski-Joksimovic, PhD, a Research assistant professor of Pediatrics at the Feinberg School; and Tamas Virag, PhD, a former postdoctoral fellow in the Bohn laboratory.
Sookyong Koh  In the December 2009 Journal of Neuroinflammation, scientists at the Children’s Memorial Epilepsy Center and colleagues quantified cell death, astrocyte proliferation, microglial activation and cytokine release in brain tissue from patients who underwent epilepsy surgery. They found that neuroinflammation and ongoing cell injury were extensive in patients with intractable epilepsy. The results suggest that active neuroinflammation and marked cellular injury may play a common pathogenic role, or be the result of childhood epilepsy of diverse etiologies. Their findings support the concept that immunomodulation that targets activated microglia and astrocytes may be a novel therapeutic strategy to reduce neurological morbidity and prevent intractable epilepsy. Sookyong Koh, MD, PhD, corresponding author, is an attending physician in Neurology at Children’s Memorial Hospital; Assistant professor of Pediatrics at the Feinberg School; and a member of the Neurobiology Program of the research center.
Simone Sredni  Wilms tumor is a rare kidney cancer that primarily affects children. Recent studies suggest that children younger than 24 months of age with very low risk Wilms tumors (VLRWT) have an excellent prognosis when treated with nephrectomy, without adjuvant chemotherapy. The identification of risk categories within VLRWT may enable optimization of therapy. Simone T. Sredni, PhD and colleagues conducted global gene expression analysis and subsequent validation studies on 39 VLRWT. They identified two distinctive clusters comprising a total of 56% of VLRWT that have pathogenetic and molecular differences and apparent differences in risk for relapse. If these predictors can be prospectively validated, refinement of clinical stratification could be enabled. The study was published in the November 2009 Clinical Cancer Research. Sredni is a Research scientist in the laboratory of Marcelo Bento Soares, PhD, director of the Cancer Biology and Epigenomics Program of the research center.
Christopher Hamm  Abnormal patterns of DNA methylation are observed in several types of human cancer. However, the effect that genome-wide loss of methylation has on tumorigenesis is not completely known. To examine this, the laboratory of Marcelo Bento Soares, PhD induced DNA demethylation in a rat model of human chondrosarcoma. Loss of methylation was accompanied by increases in invasiveness of the cells in vitro and of tumor growth in vivo. Subsequent microarray analysis provided insight into the gene expression changes that resulted. Two genes that may function in tumorigenesis were expressed at low levels in control cells but upon treatment became overexpressed. Promoter region DNA analysis revealed that these genes were methylated in control cells but became demethylated following treatment. After withdrawal of treatment, the chondrosarcoma cells reestablished global DNA methylation levels that were comparable to those of control cells. Concurrently, invasiveness decreased to a level indistinguishable to that of control cells. These experiments demonstrate that global DNA hypomethylation may promote specific aspects of tumorigenesis in rat chondrosarcoma cells. The results were published in the December 2009 PLoS One. The first author, Christopher Hamm, PhD, is a research associate in the Soares laboratory.

 
Joel Frader  In the Fall 2009 Journal of Law, Medicine and Ethics, Rebecca Dresser and Joel Frader examined current federal policies and ethical standards governing off-label prescribing, and policy reforms to promote patient and public interests in evidence-based off-label prescribing. Under U.S. law, physicians may prescribe drugs and devices in situations not covered on the label approved by the Food and Drug Administration. Patients benefit from off-label prescribing that is supported by sound scientific and medical evidence. In the absence of such evidence, patients can be exposed to risky and ineffective treatments. The authors concluded that the medical community must determine whether available evidence justifies specific uses and has a duty to promote information gathering when the evidence is inadequate. Physicians should discuss with patients the uncertainties accompanying off-label uses. Federal authorities should closely monitor the effects and adopt measures to reduce harm and enhance benefits produced by this practice. Joel Frader, MD is the A. Todd Davis Professor of General Academic Pediatrics and Medical Humanities and Bioethics at the Feinberg School; head of General Academic Pediatrics and Associate director of The Bridges Program - Pediatric Palliative and End-of-Life Care at Children’s Memorial; and a member of the Mary Ann and J. Milburn Smith Child Health Research Program of the research center.

 
Hans-Georg  Tbx5, a transcription factor that controls developmental pathways, is involved in congenital heart disease. However, the mechanisms leading to organ malformation are largely unknown. Using a zebrafish model, the laboratory of Hans-Georg Simon, PhD showed an essential role of the Tbx5 binding protein Pdlim7 in controlling nuclear/cytoplasmic shuttling and function of the transcription factor, and in regulating cardiac formation. Molecular and histological analysis showed that loss of Pdlim7 function causes no valve tissue to develop while lack of Tbx5 results in increased valve tissue. These opposing defects are the result of distinct gene misregulation during specification of the atrio-ventricular (AV) boundary. Pdlim7/Tbx5 interactions affect the expression of two Tbx5 target genes at the AV boundary, and their domains of misexpression correlate with the identified defects. These studies were published in the January 2010 Developmental BiologySimon is Associate professor of Pediatrics at the Feinberg School; a member of the Developmental Biology Program; and director of the Children’s Memorial Research Center Training Program.
Kelly Michelson  A study conducted by Kelly Michelson, MD, MPH and colleagues explored factors described by parents of patients in the pediatric intensive care unit as important/influential if they were to consider withdrawing life-sustaining therapies. In interviews, over half of parents said they could imagine a situation in which they would consider withdrawing life-sustaining therapies. Specific factors that might influence their decision making included: if their child were suffering, quality-of life considerations, physician-estimated prognosis, and financial burden. Qualitative analysis of their comments identified nine factors: quality of life, suffering, ineffective treatments, faith, time, financial considerations, general rejection of withdrawing life-sustaining therapies, mistrust/doubt toward physicians, and reliance on self/intuition. The study was published in the November 2009 Archives of Pediatrics and Adolescent Medicine. Michelson is Assistant professor of Pediatrics and Associate physician at the Buehler Center on Aging, Health and Society at the Feinberg School; attending physician in the Division of Pediatric Critical Care Medicine at Children’s Memorial; and a member of the Smith Child Health Research Program of the research center.
 
In a paper published in the October 2009 issue of the Journal of Urology, Arun K. Sharma, PhD and colleagues sought to evaluate the potential uses of autologous sources of bone marrow mesenchymal stem cells and endothelial progenitor cells as alternatives to cells currently used for bladder tissue regeneration. To evaluate the potential uses of these cells, the team determined whether mesenchymal stem cells have contractile protein profiles and physiological functions similar to those of normal bladder smooth muscle cells, and determined the angiogenic potential of endothelial progenitor cells. Preliminary data suggest that bone marrow mesenchymal stem cells provide a robust source of cells that may be substituted for the smooth muscle cell component in the bladder, based on in vitro functional testing. Also, as proof of concept, endothelial progenitor cells showed the potential to provide vascularization for developing tissue. Further examination of bone marrow stem and progenitor cells may provide evidence about the usefulness of these cells for bladder regeneration. Says Sharma: “Selecting appropriate cell types for bladder tissue regeneration is imperative for overall graft growth and development.” Sharma is Research assistant professor of Urology and a member of the Institute for Bionanotechnology at the Feinberg School; and a member of the Developmental Biology Program of the research center.
 

Hospital policies on donation 

Although authoritative bodies have promulgated guidelines for donation after cardiac death (DCD) and the Joint Commission requires hospitals to address DCD, little is known about actual hospital policies. In a study published in the May 13, 2009 issue of JAMA, Joel Frader, MD and colleagues characterized DCD policies in children's hospitals and evaluated variation among policies. They conducted a mixed-methods analysis of policies collected between November 2007 and January 2008 from hospitals in the United States, Puerto Rico, and Canada in 2 membership categories of the National Association of Children's Hospitals and Related Institutions. The authors concluded that most children's hospitals have developed or are developing DCD policies.  However, these policies vary considerably from one institution to another and to the degree to which they conform to recommendations or requirements from national authorities and regulatory agencies.  In addition, the policies do not always clarify the ethical basis for the institutional actions they specify.

Health professionals and conscientious objection 

Frader and Charles L. Bosk, a medical sociologist, write in the February 2009 issue of the American Journal of Medical Genetics. Part C, Seminars in Medical Genetics that staff members’ conscientious objection (CO) to recommending or providing genetic testing raises serious questions about what it means to be a health-care professional (HCP). Most of the discussion about CO has focused on the logic of moral arguments for and against aspects of CO and has ignored the social context in which CO occurs. Invoking CO to deny services to patients violates both the professional's duty to respect the patient's autonomy and also the community standards that determine legitimate treatment options. The HCP exercising the right of CO may make it impossible for the patient to exercise constitutionally guaranteed rights to self-determination around reproduction. This creates a decision-making imbalance between the HCP and the patient that amounts to an abuse of professional power. To prevent such abuses, professionals who wish to refrain from participating have an obligation to warn prospective patients of their objections prior to establishing a professional-patient relationship or, if a relationship already exists, to arrange for alternative care expeditiously.

Joel Frader, MD is Professor of Pediatrics and Medical Humanities and Bioethics and A Todd Davis Professor of Academic Medicine at the Feinberg School; Head of the Division of General Academic Pediatrics and Associate director of The Bridges Program - Pediatric Palliative and End-of-Life Care at Children’s Memorial; and a member of the  Mary Ann & J. Milburn Smith Child Health Research Program  of the research center.
 

Infectious mononucleosis linked to chronic fatigue syndrome in teens 

July 14, 2009 (Reuters Health Medical News) – The results of a study published in the July 2009 issue of Pediatrics suggest that infectious mononucleosis may be a risk factor for chronic fatigue syndrome in adolescents. Previous studies suggest that 9% to 12% of adults with acute infectious mononucleosis go on to develop chronic fatigue syndrome, Ben Z. Katz, MD and colleagues write. However, there have been no comparable prospective studies with teens and no studies with teens have monitored post-infectious mononucleosis for longer than 6 months. The researchers prospectively monitored 301 adolescents with infectious mononucleosis. Six months after the mononucleosis diagnosis, 70 patients (24%) had not made a full recovery. These subjects underwent clinical evaluations at 6, 12, and 24 months and established pediatric criteria were used to diagnose chronic fatigue syndrome. A clinical evaluation was performed at 6 months on 53 of the 70 teens who had not recovered. Thirty-nine of these subjects were diagnosed with chronic fatigue syndrome, reflecting 13% of the original group of 301. At 12-month follow-up, 7% had chronic fatigue syndrome and at 24 months, chronic fatigue syndrome persisted in 4%. "As part of our study, we also followed a group of adolescents who completely recovered from their mononucleosis," Katz said in an email interview with Reuters Health. "We are now in the process of trying to figure out what differentiates adolescents who recover from those who don't," he said. "Objective criteria that could differentiate these two groups would have obvious implications for prognosis and for targeting potential future therapeutic interventions."

Ben Z. Katz, MD is Professor of Pediatrics at the Feinberg School; Attending physician in the Division of Infectious Disease, Medical director of the International Travel Immunizations Program and Co-Medical director of the International Adoptee Program at Children’s Memorial; and a member of the  Clinical and Translational Research Program  of the research center.

 

Isabelle De PlaenNF-kappaB, shock and acute bowel injury

Platelet-activating factor (PAF), an endogenous proinflammatory phospholipid, when injected intravascularly to rats and mice, causes shock and acute bowel injury that resembles necrotizing enterocolitis (NEC), a disease affecting premature infant. Therefore, this has been used as an animal model to study acute bowel injury and NEC. PAF i.v. induces the rapid activation of a major regulator of inflammation, transcription factor Nuclear Factor-kappaB (NF-kappaB) p50-p50 and an increase in the production of the chemokine CXCL2. CXCL2 has been shown to mediate PAF-induced acute bowel injury. In a study published in the July 2009 issue of the American Journal of Physiology. Gastrointestinal and Liver Physiology, the laboratory of Isabelle De Plaen, MD investigated the mechanism of NF-kappaB activation and the role of the NF-kappaB p50 subunit in PAF-induced shock and acute bowel injury. They found that PAF induced the processing of NF-kappaB p105 into p50 and that NF-kappaB p50-deficient mice were protected against PAF-induced mortality, shock, intestinal hypoperfusion, and injury compared with wild-type animals. They also found that p50-deficient mice had decreased gene expression of CXCL2 and TNF and a decrease in CXCL2 protein production compared with wild-type mice. The study suggests that p50 plays a role in the PAF-induced systemic inflammatory response and acute bowel injury. 

 Isabelle De Plaen, MD is Associate professor of Pediatrics at the Feinberg School; an attending physician in the Division of Neonatology at Children's Memorial; and a member of the Center for Digestive Diseases and Immunobiology and the Clinical and Translational Research Program of the research center.

Palliative care training needs

The American Academy of Pediatrics recommends that pediatricians become knowledgeable in and comfortable with providing palliative care. A study conducted by Kelly Michelson and colleagues aimed to determine the extent of training, knowledge, experience, comfort and competence in palliative care communication and symptom management of pediatric residents and fellows; obtained residents' and fellows' views on key palliative care concepts; identified topics and methods for palliative care education; and identified differences in responses between residents and fellows. Pediatrics residents and fellows completed a survey, and described none to moderate levels of training, experience, knowledge, competence and comfort in palliative care. Most respondents said they would benefit from more formal palliative care training. Respondents identified discussing prognosis, delivering bad news, and pain control as the three most important areas of needed education. Learning about supporting families spiritually and emotional support for physicians were among the least important educational areas identified. Respondents recommended delivering education via observation, bedside teaching, and participation in multidisciplinary groups. The authors concluded that efforts to improve education in pediatric palliative care are needed. A palliative care team could facilitate palliative care education through engaging trainees in "real-life" interactions. The role of physicians in providing spiritual support and the need for educating physicians in obtaining emotional support for themselves merit further investigation. The study was published in the May 2009 issue of the Journal of Palliative Medicine.

Kelly N. Michelson, MD is Assistant professor of Pediatrics and Associate physician at the Buehler Center on Aging, Health and Society at the Feinberg School; attending physician in the Division of Pediatric Critical Care Medicine at Children’s Memorial; and a member of the Smith Child Health Research Program of the research center.

Research on juvenile dermatomyositis

The laboratory of Lauren Pachman, MD, sought to determine the presence of small integrin-binding ligand N-linked glycoprotein (SIBLING) and bone components in juvenile dermatomyositis (DM) dystrophic calcifications, one of the most troubling consequences of chronic inflammation in children with JDM. Calcifications were removed from 4 girls with juvenile DM symptoms more than 3 years and they were stained for SIBLING proteins. The disorganized juvenile DM calcifications differ in structure, composition, and protein content from bone, as well as the lack of deposition of hydroxyapatite on collagen, suggesting that they may not form through an osteogenic pathway. Osteoclasts at the deposit surface represent an attempt to initiate its resolution.  The findings were published in the April 2009 issue of Arthritis and Rheumatism and an illustration from the paper was featured on the cover.

Interferon-alpha (IFNalpha) has been implicated in the pathogenesis of juvenile dermatomyositis (DM). The aim of a study co-authored by Pachman and published in the June 2009 issue of Arthritis and Rheumatism was to examine serum IFNalpha activity in a cohort of children with juvenile DM to determine relationships between IFNalpha and indicators of disease activity and severity. Thirty-nine children with definite/probable juvenile DM were included in the study. Serum samples were obtained at the time of diagnosis from 18 untreated patients with juvenile DM. Second samples from 11 of these patients were obtained at 24 months, while they were receiving treatment, and third samples were obtained from 7 of these patients at 36 months. The remaining 21 children were studied 36 months after their initial diagnosis. Serum IFNalpha activity was measured using a functional reporter cell assay. Patients with juvenile DM had higher serum IFNalpha activity than both pediatric and adult healthy control subjects. In untreated patients, serum IFNalpha activity was positively correlated with serum muscle enzyme levels and inversely correlated with the duration of untreated disease. The tumor necrosis factor alpha -308A allele was associated with higher serum IFNalpha levels only in untreated patients. At 36 months, serum IFNalpha levels were inversely correlated with muscle enzyme levels in those patients still requiring therapy and with the skin Disease Activity Score in those patients who had completed therapy. The authors concluded that serum IFNalpha activity was associated with higher serum levels of muscle-derived enzymes and a shorter duration of untreated disease in patients with newly diagnosed juvenile DM and was inversely correlated with measures of chronic disease activity at 36 months postdiagnosis. These data suggest that IFNalpha could play a role in disease initiation in juvenile DM. 

Lauren M. Pachman, MD is Professor of Pediatrics at the Feinberg School; attending physician in the Division of Rheumatology/Immunology at Children’s Memorial; and Director of the Chicago City-wide FOCIS (Federation of Clinical Immunology Societies) Center of Excellence of the research center.

Mark WainwrightEarly-life seizures and neurologic injury

Early-life seizures result in increased susceptibility to seizures and greater neurologic injury with a second insult in adulthood. The mechanisms that link seizures in early-life to increased susceptibility to neurologic injury following a 'second hit' are not known. In a paper published in the June 2009 online issue of Brain Research, the laboratory of Mark Wainwright, MD, PhD examined the contribution of microglial activation and increased proinflammatory cytokine production to the subsequent increase in susceptibility to neurologic injury using a kainic acid (KA)-induced, established 'two-hit' seizure model in rats. Postnatal day (P)15 rats were administered intraperitoneal KA (early-life seizures) or saline, followed on P45 with either a 'second hit' of KA, a first exposure to KA (adult seizures), or saline. The levels of proinflammatory cytokines (IL-1beta, TNF-alpha, and S100B), the chemokine CCL2, microglial activation, seizure susceptibility and neuronal outcomes were measured in adult rats 12 hours and 10 days after the second hit on P45. The 'two-hit' group exposed to KA on both P15 and P45 had higher levels of cytokines, greater microglial activation, and increased susceptibility to seizures and neurologic injury compared to the adult seizures group. Treatment after early-life seizures with Minozac, a small molecule experimental therapeutic that targets upregulated proinflammatory cytokine production, attenuated the enhanced microglial and cytokine responses, the increased susceptibility to seizures, and the greater neuronal injury in the 'two-hit' group. These results implicate microglial activation as one mechanism by which early-life seizures contribute to increased vulnerability to neurologic insults in adulthood, and indicate the potential longer term benefits of early-life intervention with therapies that target up-regulation of proinflammatory cytokines. The paper will also be featured on the cover of Brain Research.

Mark Wainwright, MD, PhD is Associate professor of Pediatrics at the Feinberg School; a member of the Center for Drug Discovery and Chemical Biology at Northwestern University; Attending physician in the Division of Neurology at Children's Memorial; and Director of the Center for Interdisciplinary Research in Pediatric Critical Illness and Injury and a member of the Neurobiology Program of the research center.

 William Tse 

Researchers at Children's Memorial Hospital propose a new model of stem cell memory and plasticity

April 7, 2009 — How does a human cell remember its past and decide its future? Working with human bone marrow stem cells that can turn into bone or muscle, researchers at Children's Memorial Research Center have recently demonstrated how these cells juggle decision-making processes that determine their fate. The research was published in the April 6, 2009 online issue of the Proceedings of the National Academy of Sciences of the United States of America. Team leader William T. Tse, MD, PhD, is an assistant professor of Pediatrics at Northwestern University’s Feinberg School of Medicine. Read more. 

 Naira Margaryan 

Health threats from malignant melanoma targeted

Naira V. Margaryan, DVM, PhD, Research scientist in the laboratory of Mary J.C. Hendrix, PhDCancer Biology and Epigenomics Program of the research center, is first author on a paper published in the February 2009 issue of Cancer Biology and Therapy. The paper’s title is also featured on the cover of the issue. The greatest health threat from malignant melanoma is death due to metastatic disease. Consequently, the identification of markers predictive of metastatic disease is essential for developing new therapeutic targets. EphA2, a receptor commonly expressed in epithelial cells, has been found to be overexpressed in melanoma tumor cells having a metastatic phenotype. The researchers analyzed a panel of human melanoma tumor cell lines derived from patient tissues classified as primary and/or metastatic for the expression of EphA2, and found a correlation between increased EphA2 expression and metastatic potential. Experiments using the most metastatic of the human melanoma cell lines demonstrated that downregulation of EphA2 results in a significant decrease in invasion, proliferation, clonogenicity and vasculogenic mimicry in vitro, in addition to suppressed tumorigenicity in an orthotopic mouse model. These results provide the first direct in vivo evidence demonstrating a role for EphA2 in promoting melanoma tumorigenicity and suggest EphA2 as a significant molecular target for the therapeutic intervention of malignant melanoma.

 

Racial disparities in birth outcomes

In the United States, African-American infants have significantly worse outcomes than white infants. In a review published in the March 2009 issue of Clinics in Perinatology, James W. Collins, Jr., MD, MPH and Richard J. David, MD, looked beyond traditional risk factors and explored the social context of race in this country in an effort to understand African-American women’s longstanding pregnancy outcome disadvantage. In the process, new insights were highlighted concerning likely causes for the poor birth outcomes of white infants in this country compared with infants in most other industrialized nations. An extensive body of literature strongly suggests that closing the racial gap in prenatal care use cannot singularly lead to closure of the gap in the incidence of low birth weight. An expanding literature shows that aberrant early life (i.e., fetal) programming and cumulative wear and tear (i.e., weathering) underlie African-American women’s reproductive outcome disadvantage. Eliminating the racial gap in birth outcomes takes a life-course approach, addressing early life disadvantages in addition to lifelong exposure to neighborhood poverty, interpersonal racial discrimination, and job strain. Collins is Professor of Pediatrics at the Feinberg School, a member of the Division of Neonatology at Children’s Memorial Hospital, and the Mary Ann & J. Milburn Smith Child Health Research Program of the research center.

 Sara Ahlgren 

 

Effects of ethanol on embryos

The phenotype of embryos exposed to ethanol is complex and likely due to multiple alterations in developmental pathways. Among the conditions found in children with fetal alcohol exposure is a persistent short stature relative to unexposed peers and family members, as well as defects in musculature. The laboratory of Sara Ahlgren, PhD used zebrafish embryos to examine the effects of ethanol on development of the trunk. In this study they describe defects in early embryonic cell movements that lead to a reduction in the length of the trunk of exposed embryos. Defects in muscle cell development are also seen in exposed embryos. Many of these defects are similar to those in embryos exposed to specific drugs that inhibit the developmental signaling molecule, Sonic hedgehog (Shh). Increasing Shh in zebrafish embryos exposed to ethanol reverses most of these defects associated with trunk development. The study was published in the June 2009 issue of Birth Defects Research. Part A, Clinical and Molecular Teratology. Ahlgren is Assistant professor of Pediatrics at the Feinberg School and a member of the Developmental Biology Program of the research center. She is also the Crown Family Research Scholar in Developmental Biology.

 Cheng lab 

In vitro study

Children suffering from neural tube defects such as spina bifida encounter a myriad of physiological problems that may include hydrocephalus, varying degrees of paralysis, and dysfunctional bowel and bladder tissues. A current goal of regenerative medicine therapies includes the isolation of autologous sources of cells that may be used in combination with synthetic matrices in a manner that would be conducive to urinary bladder regeneration. In order to conduct such studies, these appropriate cell types must be delineated and characterized prior to any in vivo manipulation. In an important in vitro study published in the February 2009 online issue of the World Journal of Urology, Arun Sharma, PhD and colleagues have determined that “standard procedures” utilized routinely to isolate the smooth muscle cells that make up the bladder wall that comprise the basis for a bladder graft have resulted in a mixed population of cells. The ramifications of these findings suggest that contaminating cells in these preparations may hinder cell-to-scaffold interactions, and negatively affect the porosity of cell seeded synthetic scaffolds used for urinary bladder tissue engineering. More importantly, mixed populations of cells utilizing the “standard procedure” do not resemble the native bladder tissue from a physiological and functional perspective. Further studies by Sharma will try to elucidate schemes that allow for the isolation of purified populations of these cell types along with the identification of unique, autologous cell sources for urinary bladder regeneration. Sharma is a member of the Division of Pediatric Urology at Children’s Memorial Hospital, Department of Urology at the Feinberg School, the Institute for BioNanotechnology in Medicine at Northwestern University, and the Developmental Biology Program of the research center.

 

Cynthia LaBella 

Research team helps get female athletes back on the field

Sports-related knee pain is a common complaint among female adolescent athletes and frequently limits sports participation. A research team led by Cynthia R. LaBella, MD tested the hypothesis that preseason neuromuscular training would reduce sports-related knee pain and improve self-rated athletic performance. The results suggest that this is the case, and support the development of curricula to train coaches in incorporating neuromuscular exercises into their preseason routines. The study is published in Clinical Pediatrics. LaBella is medical director of the Children’s Memorial Institute for Sports Medicine and Assistant professor of Pediatrics at the Feinberg School. Co-authors are Michael R. Huxford, MEd, Tracie L. Smith, MPH and Jenifer Cartland, PhD. Smith and Cartland are members of the Mary Ann and J. Milburn Smith Child Health Research Program of the research center. Read about the Knee Injury Prevention Program (KIPPTM) at Children’s Memorial.

Neil Blackledge
Neil Blackledge, PhD 

Ann Harris, PhD, Professor of Pediatrics at the Feinberg School, director of the Human Molecular Genetics Program and the Valerie and George D. Kennedy Research Professor in Human and Molecular Genetics of the research center, and colleagues, have published two papers on elements that interact with the cystic fibrosis transmembrane conductance regulator (CFTR). The first, entitled “An insulator element 3’ to the CFTR gene binds CTCF and reveals an active chromatin hub in primary cells” was published in Nucleic Acids Research in January 2009. The first author is Neil Blackledge, PhD, a former graduate student and postdoctoral fellow in the Harris laboratory. The data suggest that the CFTR locus exists in a looped conformation, characteristic of an active chromatin hub.

Chris Ott
Chris Ott  

A second paper published by the Harris lab, entitled “A complex intronic enhancer regulates expression of the CFTR gene by direct interaction with the promoter” was published in the Journal of Cellular and Molecular Medicine in March 2009. The first author is Christopher Ott, a current graduate student in the laboratory. The data provide the first insight into the 3D structure of the CFTR locus and confirm the contribution of intronic cis-acting elements to the regulation of CFTR gene expression.

 

XenoBase Graphic 

XenoBase update

The goal of XenoBase in brain tumor study is to assist in the discovery of alterations and processes associated with brain tumor initiation and progression. Because of the heterogeneity and special locations of brain tumors, development of non-invasive diagnostic and prognostic methods is highly desired. The infrastructure provided by XenoBase will enable the integration of molecular data with clinical information, and facilitate the identification of potential markers for better patient stratification as well as drug resistance prediction. XenoBase will implement three levels of queries for brain tumor study: supervised queries that will allow the study of associations of two or more observations; unsupervised queries in which the causal effects of latent variables are examined; and network-based unsupervised queries that allow biological processes and networks to be taken into account.

Currently, XenoBase has successfully interfaced with an in-house brain tumor database system. The previous gene-centric XenoBase model was adapted into region-centric, in order to host a variety of research data from such data types as gene expression, methylation, and structural alterations. Gene expression data analysis has been used as a proof of concept of this adaptation. Methylation data generated in the Soares laboratory have been added to XenoBase, where certain association studies can be performed. Various queries enabled by XenoBase will allow researchers to gain insight into the large-scale datasets generated in the laboratory.

 

Seconds for Care: Evaluation of Five Health Supervision Visit Topics Using a New Method

This study was conducted to gain understanding of the time it takes and some of the actions that occur to address key preventive topics during pediatric health supervision visits of children between the ages of two and ten years. The authors developed a new method and a tool to help conduct the assessments of five preventive health topics. Read more. 

 

 GLI1 pathway 

Defining a developmental pathway for medulloblastoma

In the January 2009 issue of the International Journal of Cancer, Joon Won Yoon, PhD, David Walterhouse, MD, and colleagues studied changes in gene expression profiles in cells transformed by a gene that has been shown to be overactive in a subset of medulloblastomas. Read more.  

 

IMBFT model for family therapy

The integrative, module-based family treatment model (IMBFT) developed by Karen R. Gouze, PhD, and Richard Wendel, DMin, provides a formalized series of steps that clinicians can use in their case planning and implementation. It is based on nine clinically relevant modules for assessment and intervention that are consistent with current best practices and empirically supported treatments. Read more. 

Novel technique for studying cell cultures

Zoe N. Demou, PhD, has published a study in the journal Biotechnology and Bioengineering describing a novel technique for studying morphological and molecular dynamics in differentiating 3D cell cultures. A custom-built chamber expands the Veritas laser capture microdissection (LCM) system by enabling time-lapse image acquisition for morphological and topographical mapping of cell cultures. Read more.  

Family-based HIV prevention study of young men who have sex with men

Is it it time for HIV prevention programs for young men who have sex with men to involve families and parents - similar to approaches used for other adolescent/young adult populations? This is the question asked by a team of investigators at Children's Memorial Hospital, Howard Brown Health Center and the University of Illinois at Chicago. HIV surveillance data suggest that in the U.S., the majority of HIV-infected adolescent males and young adult men are infected through having sex with other men. However, there are few intervention efforts targeting this vulnerable population, and no family-based approaches, despite the fact that these approaches have shown promise with other groups of young people. Read more.  

Link between prematurity and wheezing revealed

April 15, 2008 — Rajesh Kumar, MD, and colleagues at Children's Memorial have identified a potential link between respiratory problems and premature birth.  Read more. 

Pax3 as regulator

Chandra S.K. Mayanil, PhD, and colleagues have published a study in the journal Developmental Biology that investigates whether the paired-box gene transcription factor, Pax3, plays a role in regulating certain key transcription factors…Read more.  

 Epicardial cells 

Research on early epicardial development

Robert Dettman, PhD, and colleagues have found that the integrin alpha4beta1 controls many aspects of early epicardial development in the chick heart. It does so in part by regulating other integrins in epicardial cells that are important for cell adhesion and migration. Read more.  

Therapies for ODD

John V. Lavigne, PhD, and colleagues tested two types of therapies for Oppositional Defiant Disorder, the most common psychiatric disorder among preschool children. "The findings raise the possibility of developing brief but effective interventions for ODD that can be used by a large number of families, with more intensive treatment being reserved for situations in which the brief treatment is insufficient," Lavigne said. Read more.  

Differences in drug administration may affect disease outcome in patients with Juvenile Dermatomyositis

April 5, 2008 — Lauren M. Pachman, MD, and colleagues have published a study that shows a difference in absorption of a drug administered to juvenile dermatomyositis (JDM) patients when given orally as opposed to intravenously. Read more.  

Protein in human embryonic stem cells controls malignant tumor cells

Groundbreaking work by the Mary J.C. Hendrix laboratory and colleagues is elucidating how a protein that governs development of human embryonic stem cells (hESCs) also inhibits the growth and spread of malignant melanoma, the deadliest skin cancer.

Discovering cancer's "molecular switches"

Developmental biologist David Walterhouse, MD, is featured in an article in Children’s Memorial Foundation’s quarterly e-newsletter, Online Update, spotlighting his research on how normal cells receive “signals” that cause them to turn into cancer cells.

Wainwright and colleagues identify gene for cerebral palsy

CHICAGO --- Apolipoprotein E (APOE), a gene associated with heightened risk for Alzheimer's disease in adults, can also increase the likelihood that brain-injured newborns will develop cerebral palsy, researchers at Children's Memorial Research Center have discovered. This is the first identification of a gene that increases susceptibility to cerebral palsy. Results of the study, published in the February 2007 issue of the journal Pediatrics, may enable early identification of children who are at risk for poor neuro-developmental outcome after brain injury as newborns and thus target those children for early therapeutic intervention. The lead scientist on the study was Mark S. Wainwright, MD, PhD, assistant professor of Pediatrics (Neurology) and Molecular Pharmacology and Biological Chemistry at Northwestern University's Feinberg School of Medicine and the Children's Memorial Research Center. Wainwright is also a researcher in the Center for Drug Discovery and Chemical Biology at Feinberg. Read more.  

Anne Rowley
Anne H. Rowley, MD 

 

Zeroing in on a cause for Kawasaki disease

In an important discovery in infectious disease research, a team of scientists from Children’s Memorial Research Center and Northwestern University’s Feinberg School of Medicine has identified a possible viral cause of Kawasaki disease, the most common cause of acquired heart disease in children in developed nations.

Kawasaki disease is a serious pediatric illness that causes inflammation of the blood vessels and can cause damage to coronary arteries. Investigators have suspected an infectious cause, but, until now, none has been identified. Results of the new study suggest a single viral cause that enters through the respiratory system and infects the bronchi of children.

The research group was led by Anne H. Rowley, MD, attending physician in Children’s Memorial Hospital’s Division of Infectious Disease, and professor of pediatrics and of microbiology/immunology at Northwestern University’s Feinberg School of Medicine.

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