Research News

 Return to News Page

     2014           2013         2012          2011         2010         2009         2008   
 

2014
 
 Malchenko Gene 2013

In vitro neural differentiation of human embryonic stem cells (hESCs) is an advantageous system for studying early neural development. The process of early neural differentiation in hESCs begins by initiation of primitive neuroectoderm, which is manifested by rosette formation, with consecutive differentiation into neural progenitors and early glial-like cells. In a study published in the January 2014 issue of Gene, a research team examined the involvement of early neural markers in the onset of rosette formation, during spontaneous neural differentiation. They show that the marker OTX2 is highly expressed at the onset of rosette formation, and that its expression precedes that of established markers of early neuronal differentiation.

Importantly, the rise of OTX2 expression in these cells coincides with the down-regulation of the pluripotency marker OCT4. In addition, cells derived from rosettes that emerge during spontaneous differentiation of hESCs or human induced pluripotent stem cells are capable of differentiating into dopaminergic neurons in vitro, and into mature-appearing pyramidal and serotonergic neurons weeks after being injected into the motor cortex of NOD-SCID mice.

First author Sergey Malchenko, PhD is Research Assistant Professor of Pediatrics and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University Feinberg School of Medicine, and the Cancer Biology and Epigenomics Program of Ann & Robert H. Lurie Children's Hospital of Chicago Research Center. Co-authors include members of the Developmental Biology and Neurobiology programs of the research center, divisions of Neurosurgery and Hematology, Oncology, and Stem Cell Transplantation at Ann & Robert H. Lurie Children’s Hospital of Chicago, and the Department of Molecular Pharmacology & Biological Chemistry at the Feinberg School.

This work was supported in part by the Illinois Department of Public Aid, the Dr. Ralph and Marian C. Falk Medical Research Trust, Children’s Research Fund, the Gus Foundation, the Maeve McNicholas Memorial Foundation, the Everett/ O’Connor Charitable Trust, NIH and the Northwestern University Flow Cytometry Facility.

 

Adolfo Ariza, MD, Helen Binns, MD, MPH and Ilse Salinas have published a report on the design and implementation of the Young Hearts, Strong Starts project. This study tests strategies for the rapid implementation of the National Heart, Lung, and Blood Institute (NHLBI) CV Risk Prevention Guidelines in primary care pediatric practices. The project was a collaboration of the Pediatric Practice Research Group of the research center and the East Carolina University Network (E-CARE), with 16 practices from
each network participating.

Cardiovascular disease (CVD) and the underlying atherosclerosis begin in childhood, and their presence and intensity are related to known cardiovascular disease risk factors. Attention to risk factor control in childhood has the potential to reduce subsequent risk of CVD. This study compares guideline-based quality measures for body mass index, blood pressure and tobacco using two strategies: a multifaceted, practicedirected intervention versus standard dissemination. Two primary care research networks recruited practices and provided support for the intervention and outcome evaluations. Individual practices were randomly assigned to the intervention or control groups. The intervention practices received toolkits and supported guideline implementation including academic detailing, an ongoing e-learning group. This trial will provide an opportunity to demonstrate tools and strategies to enhance CV prevention in children by guideline-based interventions.

The study is published in the January 2014 issue of Contemporary Clinical Trials and was funded by NHLBI. 

 
Santhanam Suresh 2012 At present, little information is known regarding the research education of pediatric anesthesia fellows. The main objective of an investigation by the Department of Anesthesiology at Lurie Children’s was to evaluate the status of research training in pediatric anesthesia fellowship programs in the United States. Survey responses were solicited from forty-six pediatric anesthesia fellowship directors. Questions evaluated department demographic information, the extent of faculty research activity, research resources and funding in the department, the characteristics of fellow research education and productivity, departmental support for fellow research, and perceived barriers to fellow research education. The survey found that structured research curriculum is associated with increased research productivity during pediatric anesthesia fellowship. Important barriers to fellows’ research education include high clinical demands and lack of research time for faculty. Despite acknowledging the poor research education, a small minority of fellowship directors supports the addition of an extra year exclusively dedicated to research. These findings are published in the March 2014 issue of Pediatric Anaesthesia. Senior author Santhanam Suresh, MD, FAAP is Professor of Anesthesiology and Pediatrics at the Feinberg School, chair of the Department of Anesthesiology at Lurie Children’s and a member of the Clinical and Translational Research Program of the research center. 
 

2013

 
Kathryn Farrow Pulmonary hypertension is a significant cause of morbidity and mortality in infants. Historically, there has been extensive study of the signaling pathways involved in vascular smooth muscle contraction in pulmonary arterial smooth muscle cells (PASMC) from fetal sheep. Conversely, the inability to isolate PASMC from mice was a significant limitation of that system. In the October 2013 issue of the Journal of Visualized Experiments, a team led by Kathryn Farrow, MD, PhD described the isolation of primary
cultures of mouse PASMC from neonatal mice using a variation of the previously described technique of Marshall et al. that was used to isolate rat PASMC. These murine PASMC represent a novel tool for the study of signaling pathways in the neonatal period. Smooth muscle cell identity was confirmed by immunostaining for smooth muscle myosin and desmin. Farrow is Associate Professor of Pediatrics at the Feinberg School and a member of the Clinical and Translational Research Program of the research center.
This work was supported by NIH.
 
Mark Wainwright There are limited data on the incidence of seizures and utility of brain imaging, and electroencephalogram (EEG) to predict outcome in children with acute liver failure (ALF). Members of the Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program and the Division of Gastroenterology, Hepatology and Nutrition at Lurie Children’s investigated the association between hepatic encephalopathy (HE) scores, abnormal EEG or neuroimaging and short-term outcome. Of those evaluated, patients who had an abnormal EEG on
admission were significantly more likely to die or require liver transplantation (LT). Patients with either an admission HE score ≤2, or Liver Injury Unit score <222, combined with a normal or mildly abnormal EEG were more likely to survive without LT. These findings are an initial step toward distinguishing patients with ALF who may recover spontaneously from those who will require LT. The senior author on the research, published online in the Journal of Pediatric Gastroenterology and Nutrition, is Mark Wainwright, MD, PhD, Professor of Neurology and Molecular Pharmacology & Biological Chemistry at the Feinberg School, director of the Center for Interdisciplinary Research in Pediatric Critical Illness and Injury, and a member of the Neurobiology Program of the research center. 
 
Laurie_miRNA 
miRNA profiling of human primary retinoblastomas.
Image courtesy of
Nikia Laurie, PhD
Retinoblastoma is the most common pediatric cancer of the eye. Current chemotherapeutic treatments are broad-based drugs; however, therapies targeted directly to aberrant signaling pathways may prove more effective. The Retinoblastoma Center of Excellence sought to illustrate the relationship between the expressions of miRs-449a and -449b to retinoblastoma proliferation and apoptosis. The group is the first to confirm an inhibitory effect of the miRNAs in retinoblastoma by demonstrating significantly impaired proliferation and increased apoptosis of tumor cells when the miRNAs are overexpressed. The study, published in the November 2013 Biochemical and Biophysical Research Communications, suggests that the miRNAs could serve as viable therapeutic targets for retinoblastoma treatment. This work was supported by the State of Illinois Excellence in Academic Medicine award and Research to Prevent Blindness. Lead author Nikia Laurie, PhD is Assistant Professor of Pediatrics at Northwestern University Feinberg School of Medicine, a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, a member of the Cancer Biology and Epigenomics Program of Ann & Robert H. Lurie Children's Hospital of Chicago Research Center and the Warren and Eloise Batts Research Scholar.
   
Malignant rhabdoid tumors (MRT) occur most frequently in the brain, as atypical teratoid/rhabdoid tumors (AT/RT), and as rhabdoid tumors of the kidney (RTK). MRTs at all sites are recognized as the same entity due to their similar morphology, aggressive behavior, and a common genetic abnormality. A team led by Simone Treiger Sredni, MD, PhD analyzed microRNA (miRNA) and gene expression (GE) profiles of RTK, AT/RT, and human MRT cell lines. Although GE profiles showed a significant difference between RTK and AT/RT, miRNA expression failed to identify the different tumor groups. Genes related to brain and kidney development were differentially expressed. The group hypothesizes that although MRT are the same tumor, GE differences reflect the influence of microenvironment over tumor development. The study is published in the November 2013 Child’s Nervous System, and was supported by the Rally Foundation for Childhood Cancer Research and Dr. Ralph and Marian C. Falk Medical Research Trust. Sredni is Research Assistant Professor of Neurological Surgery at the Feinberg School and a member of the Cancer Biology and Epigenomics Program of the research center. 
   
 Rebecca Ford Paz Latino adolescents are at elevated risk for depression and suicide compared to other ethnic groups. Rebecca Ford-Paz, PhD led a study to gain insight from community leaders about depression risk factors particular to Latino adolescents and generate innovative suggestions to improve cultural relevance of prevention interventions. Focus groups of youth and youth-involved Latino community leaders yielded overarching themes crucial to a culturally tailored depression prevention intervention: utilize a multipronged and sustainable approach, raise awareness about depression in culturally meaningful ways, and promote Latino youth’s social connection and cultural enrichment activities. Findings suggest that both adaptation of existing prevention programs and development of hybrid approaches may be necessary to reduce depression/suicide disparities for Latino youth. One such hybrid program is described in the Journal of Behavioral Health Services & Research. This project was supported by the National Center for Advancing Translational Sciences. Ford-Paz is Assistant Professor of Psychiatry and Behavioral Sciences at the Feinberg School and a member of the Clinical and Translational Research Program of the research center. 
   
 anencephaly_stemcells 
Human embryonic
fluid stem cells from anencephaly affected pregnancy. Image courtesy of C.
Shekhar Mayanil, PhD
The laboratory of C. Shekhar Mayanil, PhD sought to identify novel biomarkers for early detection of neural tube defects (NTDs) in human fetuses. Amniotic fluid and serum were drawn from women in the second trimester of pregnancy, including normal pregnancies and fetuses displaying NTDs or holoprosencephaly. Amniotic fluid stem cells (AFSCs) were tested for stem cell markers, epigenetic biomarkers and histone. The levels of two markers for neural tube development were measured in amniotic fluid and serum. The scientists found that the levels of epigenetic marks in cultured AFSCs in combination with levels of key developmental proteins are potential biomarkers for early detection and identification of NTDs. The study is published in the October 2013 Journal of Neurosurgery. Pediatrics. This work was supported by the State of Illinois Excellence in Academic Medicine award, the Spastic Paralysis Research Foundation of Illinois- Eastern Iowa District of Kiwanis and the Spina Bifida Association. Mayanil is Research Associate Professor of Neurological Surgery at the Feinberg School, a member of the Developmental Biology Program of the research center, and Eleanor Clarke Research Scholar in Developmental Neurobiology. 
   
The epithelium lining the epididymis has a pivotal role in ensuring an environment that can support normal sperm maturation. Although many genes that encode proteins involved in establishing the epididymal luminal fluid are well characterized, the molecular mechanisms that coordinate expression and modulate activities are less well understood. The laboratory of Ann Harris, PhD identified epididymis-selective DNase I hypersensitive sites (DHS). They located genes with these DHS at their promoters to reveal active pathways in immature epididymis
epithelial cells. These include processes correlating with epithelial function and with specific roles in the epididymis. Peaks of epididymis-selective chromatin were seen in the androgen receptor gene and cystic fibrosis transmembrane conductance regulator gene. Epithelial transcription factors, the androgen receptor, Pax2, and Sox9 were identified as components of the transcriptional networks. The research was supported by NIH and the Cystic Fibrosis Foundation, and published in the October 2013 Biology of Reproduction. Harris is Professor of Pediatrics at the Feinberg School, director of the Human Molecular Genetics Program of the research center, and Valerie and George D. Kennedy Research Professor in Human Molecular Genetics.
   
Sookyong Koh Prolonged early-life seizures are associated with disruptions of affective and cognitive function. Postictal disturbances, temporary functional deficits that persist for hours to days after seizures, have not been thoroughly characterized. In a study published in the October 2013 Epilepsy and Behavior, the laboratory of Sookyong Koh, MD, PhD studied status epilepticus (SE) in immature rats and subsequently assessed spatial learning and memory, exploratory behavior, and the spatiotemporal distribution of cell injury. Immediately following SE the rats showed no deficit in spatial learning and memory but were hyperexploratory. In contrast, rats tested several weeks after SE exhibited markedly impaired performance in spatial learning and memory, and significantly reduced open field exploration suggestive of anxietylike behavior. The time course of behavioral deficits correlated with the presence of neuronal injury in regions of the brain involved in modulation of the hypothalamic-pituitary-adrenal stress response. This work was supported by NIH. Koh is Associate Professor of Pediatrics at the Feinberg School and a member of the Neurobiology Program of the research center. 
   
 NCS logo The National Children’s Study (NCS) examines the effects of environmental influences on child health and development in the U.S. Videovoice is a methodology that uses participatory videography and interviewing techniques to identify issues of concern, communicate knowledge, and advocate for community health. A study led by Ruchi Gupta, MD, MPH describes a videovoice project, implemented in six Illinois communities targeted by the NCS for participant recruitment. Videovoice training was conducted with NCS community outreach and engagement personnel. Evaluations and analysis identified overarching themes informing future outreach, including: high community knowledge of local health issues, low community knowledge of the NCS, and identification of barriers to participation. Two videos were created to address these barriers and educate communities about the NCS. The authors conclude that the videovoice project was effective in training NCS personnel and enhancing NCS community engagement. This project was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and published online in Health Promotion Practice. Gupta is Associate Professor of Pediatrics and the Center for Healthcare Studies at the Feinberg School and a member of the Mary Ann & J. Milburn Smith Child Health Research Program of the research center.
   
Adolfo Ariza Guidelines by organizations such as the American Academy of Pediatrics (AAP) call for pediatric practices to link patients to community services. Care for obese children should integrate health care, community resources and patient self-management. However, barriers remain. Adolfo Ariza, MD (pictured at left) and colleagues at the Illinois Chapter of AAP led the Promoting Health Project (PHP), a multi-component, practice-based pilot intervention aimed at improving care of obese children, including referrals to community services. In the May 2013 issue of Journal of Health Care for the Poor and Underserved, the authors describe the strategies the practices used. Quality improvement (QI) teams developed systems of referral specific to each site. The community connection part of PHP was implemented within practice-wide QI activities, in which providers could be trained in motivational interviewing skills to help patients achieve lifestyle changes. Community program enrollment was offered, although motivation of families to overcome barriers was perceived as a limiting factor. Clinicians reported that QI activities facilitated practice-wide implementation of care guidelines. Substantial efforts were necessary to create smoothly operating referral systems, and the effect in terms of program participation seemed not to be consistent with practice investment. Future efforts may benefit from supporting a highly motivated clinician with a practice enhancement assistant. Ariza is a Research Associate Professor of Pediatrics at Northwestern University Feinberg School of Medicine, and Associate Director of the Pediatric Practice Research Group (PPRG) of Ann & Robert H. Lurie Children's Hospital of Chicago Research Center. The member practices were Esperanza Health Centers, Kidz Health, and Town & Country Pediatrics, all of Chicago. The research was supported by the Otho S.A. Sprague Memorial Institute.
 
Rajesh Kumar Atopy and atopic disorders such as asthma are thought to be caused by the interaction of genetic, social and environmental factors. A team of researchers from the U.S., Mexico and Puerto Rico examined risk factors for atopy within a nationwide study of U.S. Latino children with and without asthma. In baseline analyses African ancestry was associated with three times as many positive skin test responses in asthmatic participants and 3.26 times as many in control participants. Asthmatic patients of Puerto Rican and mixed ethnicity had a greater probability of positive skin test responses compared with Mexican asthmatic patients. The researchers found differences in atopy by country of origin among participants with asthma. In contrast to prior studies, genetic estimates of African ancestry were not associated with increased risk of atopy and might be proxies for local environmental factors because there are differences in patterns of immigration from Latino countries to U.S. sites. Associations vary by national origin and highlight that Latinos from different countries should be evaluated independently in studies of atopy. Rajesh Kumar, MD, Associate Professor of Pediatrics at the Feinberg School, attending physician in the Division of Allergy & Immunology at Lurie Children’s, and a member of the Mary Ann & J. Milburn Smith Child Health Research Program of the research center, led the study with Elizabeth A. Nguyen, BS of the University of California, San Francisco. The study, appearing online in Journal of Allergy and Clinical Immunology, May 2013 was supported in part by the National Heart, Lung, and Blood Institute
 
Guidelines recommend that an annual oral glucose tolerance test (OGTT) for all patients with cystic fibrosis (CF) 10 years or older is performed. A project conducted by Andrew Kern and Adrienne Prestridge, MD sought to implement an outpatient system to provide effective, evidence-based screening for cystic fibrosis-related diabetes (CFRD) at the Lurie Children’s Cystic Fibrosis Center. This included structured education, communication with families, and processes for scheduling laboratory appointments. The screening rate increased from 2 percent of eligible patients seen during the 18 weeks before the start of the initiative to 78 percent during the 18 weeks after. Screening also increased from the previous year, when only 35 percent of eligible patients received an OGTT. The overall percentage of patients without CFRD in the program who received an OGTT in the previous 12 months increased from 47 to 71 percent after implementation. The authors concluded that this approach effectively increased the rate of outpatient screening for CFRD at a pediatric CF program. The study is published in the August 2013 issue of Pediatrics. Prestridge is Assistant Professor of Pediatrics at the Feinberg School, attending physician in the Division of Pulmonary Medicine at Lurie Children’s, and a member of the Clinical and Translational Research Program of the research center. The research was funded by the Cystic Fibrosis Foundation and the Feinberg School Medical Student Summer Research Program
 
Farah Ali Acute kidney injury (AKI) carries a large burden of morbidity and mortality. Early diagnosis may lead to better strategies of clinical care. Cardiac surgery involving cardiopulmonary bypass is associated with a significant incidence of AKI. A study led by Farah N. Ali, MD, MS (pictured at left) and supported by the laboratory of Craig B. Langman, MD, a member of the Developmental Biology Program of the research center and head of the Division of Kidney Diseases at Lurie Children’s sought to determine whether pre-operative fibroblast growth factor-23 (FGF23) levels differed among pediatric patients who did or did not develop AKI following cardiac surgery. The team of researchers, including former PICU fellow Amanda Hassinger, MD and laboratory investigator Heather Price, MS, found that FGF23 levels in patients who developed AKI following cardiac surgery were elevated above normal levels, both pre-operatively and post-operatively compared with patients who did not develop AKI. They concluded that FGF23 may serve as a prognostic indicator of the development of AKI following cardiopulmonary bypass surgery in pediatric patients without chronic kidney disease. Identifying patients more likely to have AKI following surgery provides a means of achieving closer clinical management of AKI and fluid balance. The study is published in the June 2013 issue of Pediatric Nephrology. Langman is Professor of Pediatrics at the Feinberg School and the Isaac A. Abt, MD Professor of Kidney Diseases. Ali is Assistant Professor of Pediatrics at the Feinberg School and an attending physician in Kidney Diseases. 
 
Youth living with HIV/AIDS (YLH) face unique challenges to optimal adherence to antiretroviral therapy (ART). Accurate, real-time methods to assess adherence are needed to facilitate early intervention and promote viral suppression. The purpose of a study published in the July 2013 issue of Aids and Behavior was to assess the feasibility and validity of interactive text message response (ITR) as a measure of adherence among YLH. This study was part of a larger pilot intervention conducted at a community-based, LGBT-focused health center providing clinical services to YLH. Participants received personalized daily short message system reminders with a follow-up message asking whether they took medication and directing a response via text message. To determine whether ITR would be a feasible, valid measure of adherence, the researchers calculated the proportion of responses indicating medication had been taken divided by the total number of messages requesting a response and compared this rate to a self-reported adherence measure. Over the course of the intervention, participants responded to prompts approximately 61 percent of the time, with adherence rates significantly higher on weekdays. The results suggest that this method may be helpful to identify and respond to adherence patterns in real time. The research was supported by the National Institute on Drug Abuse. Senior author Robert Garofalo, MD, MPH is Associate Professor of Pediatrics and Preventive Medicine at the Feinberg School, head of the Division of Adolescent Medicine at Lurie Children’s and director of the Center for Gender, Sexuality and HIV Prevention of the research center. Lead author Nadia Dowshen, MD is an attending physician at the Children’s Hospital of Philadelphia. 
 
Simone Sredni The laboratory of Tadanori Tomita, MD, division head, Pediatric Neurosurgery and Yeager Professor in Pediatric Neurosurgery, conducted a study of atypical teratoid rhabdoid tumors (ATRTs), rare, highly malignant central nervous system tumors that occur during infancy and early childhood. Their poor outcome and resistance to conventional therapies necessitate the development of new therapeutics. Recent studies evaluating the effects of histone deacetylase inhibitors (HDACi) as a potential treatment have found that most HDACi act unselectively against histone deacetylase (HDAC) family members. The group hypothesized that specific HDAC family members are deregulated in ATRT and therefore a more selective class of HDACi would benefit patients with ATRT. They evaluated the expression levels of different HDAC family members in ATRTs and determined that only HDAC1 was significantly differentially expressed. This discovery may lead to therapeutic benefits with fewer side effects for children with ATRT. The first author on the publication in the January 2013 issue of Child’s Nervous System is Simone T. Sredni, MD, PhD (pictured at left), Research Assistant Professor in Neurological Surgery at Northwestern University Feinberg School of Medicine and a member of the Cancer Biology and Epigenomics Program. The study was supported by the Rally Foundation for Childhood Cancer Research in memory of Hailey Trainer and the Dr. Ralph & Marian C. Falk Medical Research Trust. 
   
 Ophthalmology image 2011 MicroRNAs (miRNAs) are short non-coding RNA transcripts that have the ability to regulate the expression of target genes, and that have been shown to influence the development of various tumors. A study published in the January 2013 issue of Gene sought to identify aberrantly expressed miRNAs in retinoblastoma. The Retinoblastoma Center of Excellence, including the laboratories of Nikia Laurie, PhD and Marcelo Bento Soares, PhD, Rachelle and Mark Gordon Endowed Professor in Cancer Biology and Epigenomics, identified 41 differentially expressed miRNAs in 12 retinoblastomas, as compared to expression in three normal human retinae. Further, they report the validations of five of the most downregulated miRNAs in primary human retinoblastomas and retinoblastoma cell lines. This serves as the largest and most comprehensive retinoblastoma miRNA analysis to date with corresponding clinical and pathological characteristics. The work, supported by the Illinois Department of Public Aid, Zell Family Foundation, Bear Necessities Pediatric Cancer Foundation, Research to Prevent Blindness, Maeve McNicholas Memorial Foundation and Robert H. Lurie Cancer Center of Northwestern University, is an essential step in the discovery of miRNAs associated with retinoblastoma progression, and in the identification of potential therapeutic targets. 
   
CellCycle2013coverimage Melanoma, the most serious type of skin cancer, accounts for less than 5 percent of skin cancer cases but causes a large majority of skin cancer deaths*. As the frequency of diagnosis increases, current treatment strategies struggle to significantly impact patient survival. The laboratory of Mary J.C. Hendrix, PhD studies proteins that are expressed during human development as well as in cancer. Luigi Strizzi, MD, PhD, Research Assistant Professor in the laboratory, has long been investigating the epidermal growth factor Cripto-1 (CR-1), demonstrating that it plays a critical role during early embryogenesis as well as in several human cancers, including melanoma and breast cancer. In a study published in the May 2013 issue of Cell Cycle, Strizzi and colleagues isolated cell surface CR-1-expressing human melanoma cells and grew them in vitro and in vivo in nude mice to study their growth characteristics. Says Strizzi, “Our study shows that transplantation of Cripto-1 expressing melanoma cells in nude mice can give rise to invasive tumors which also express increased levels of a protein related to multidrug resistance called MDR-1. This study highlights the fact that melanoma, like most cancers, is actually composed of heterogeneous populations of cancer cells each with unique characteristics.” The findings are significant because they indicate that efforts to treat certain cancers, such as melanoma, cannot rely on approaches that assume that all the cells will show the same response to therapy.
   
Isabelle De Plaen Necrotizing enterocolitis (NEC) is one of the most common gastrointestinal diseases among premature infants. Whether intestinal barrier disruption precedes or is the consequence of intestinal injury in NEC remains unknown. The laboratory of Isabelle De Plaen, MD (pictured at left) examined whether changes in intestinal permeability and specific tight junction (TJ) proteins precede NEC and asked whether the changes are prevented by administration of Bifidobacterium infantis, a probiotic known to decrease NEC incidence in humans. The family of claudin proteins plays an important role in regulating the intestinal barrier by modulating the permeability of tight junctions. A mouse model of NEC developed significantly increased intestinal permeability, occludin and claudin 4 internalization, changes in claudin expression, and increased claudin 2 protein prior to NEC onset. The researchers concluded that an increase in intestinal permeability precedes NEC and is associated with internalization of claudin 4 and occludin. Administration of B. infantis attenuated this increase, preserved claudin 4 and occludin localization at TJs, and decreased NEC incidence. These data suggest that therapeutic interventions aimed at preserving the intestinal barrier, such as probiotic therapy, may be useful in NEC prevention. The study, published in the American Journal of Pathology, is featured on the cover of the May 2013 issue. This research was supported by the National Institutes of Health, Illinois Department of Public Aid, American Gastroenterological Association and Society for Pediatric Research. De Plaen is Associate Professor of Pediatrics at the Feinberg School, a neonatologist at Ann & Robert H. Lurie Children’s Hospital of Chicago and a member of the Center for Intestinal and Liver Inflammation Research
   
About two years after implementation of pediatric rotavirus vaccination in the U.S., dramatic declines in rotavirus disease have been observed in both vaccinated and unvaccinated children. A study conducted by researchers in the Division of Infectious Diseases at Lurie Children’s and Northwestern Memorial Hospital sought to determine whether this protection extends to adults. The prevalence of rotavirus in adults declined from 4.35 percent in the prepediatric impact era (2006–2007) to 2.24 percent in the pediatric impact era (2008–2010), and was similar in both outpatients and inpatients. Pediatric rotavirus vaccination correlated with a relative decline of almost 50 percent in rotavirus identified from adults during the peak rotavirus season, suggesting that pediatric rotavirus vaccination protects adults from rotavirus. This work was supported in part by research grants from Meridian Bioscience, Inc. and the Investigator-Initiated Studies Program of Merck Sharp & Dohme Ltd. The study was published in the March 2013 issue of Clinical Infectious Diseases
 
Binns_Helen In the U.S., almost 50 percent of children take at least one medicine within any two week period and the rate of outpatient medication errors is 3 percent. Preventable adverse drug events in pediatric outpatients are most often due to errors in parental medication administration. The Pediatric Practice Research Group (PPRG) of the research center conducted a study of caregivers of primary care patients aged 0–7 years. Only three-quarters of medications recommended at a visit were accurately named by the caregiver immediately following the visit, and only about one-third of medication administration instructions were accurately recalled. This demonstration of a breakdown in effective communication between physician and caregiver endorses efforts to develop better communication that will ensure understanding. Future efforts to educate clinicians about this issue, to study communication at the medical home and pharmacy, and to study effective protocols to ensure understanding have the potential to positively impact caregiver medication administration accuracy. The senior author of the publication that appears in Patient Education and Counseling is Helen Binns, MD, MPH (pictured at left), Professor of Pediatrics and Preventive Medicine at the Feinberg School and director of the PPRG. This project was supported in part by the Northwestern University Clinical and Translational Sciences Institute (NUCATS).
   
David Walterhouse It is estimated that up to one-third of human cancers are activated by the Hedgehog (HH) signaling pathway. The glioma-associated oncogene homolog GLI1 mediates the HH signal. Inhibition of HH signaling represents a potentially important therapeutic approach for many cancers. To date, most such inhibitors in clinical trials target the smoothened (SMO) protein that functions upstream of GLI1. A growing body of evidence suggests that activation of GLI1 in some cancers is not controlled exclusively by HH signaling but also by other pathways. For example, in Ewing sarcoma, the c-MYC oncogene is thought to be involved. Given that c-MYC is constitutively expressed in Burkitt lymphoma, pediatric oncologist David Walterhouse, MD, George M. Eisenberg Research Scholar in Developmental Systems Biology, was interested in the role of GLI1 and other HH pathway components. His laboratory found that c-MYC directly up-regulates GLI1 in Burkitt lymphoma and that the HH pathway does not. The findings, published in Molecular Cancer Research, indicate that in settings such as this, inhibitors of the HH pathway that target SMO may not be effective. Walterhouse is Associate Professor of Pediatrics at the Feinberg School, attending physician in the Division of Hematology, Oncology and Stem Cell Transplant at Lurie Children’s and a member of the Developmental Biology Program
   
Zhaolin2  
 Zhaolin Zhang, PhD  

Nucleosomes are the repeating structural units of chromatin, the material that makes up chromosomes. Nucleosome positioning plays a critical role in regulating accessibility of DNA to transcription factors and chromatin modifying enzymes. Hence, detailed information on nucleosome depletion or movement at cis-acting regulatory elements has the potential to identify predicted binding sites. The Harris laboratory mapped nucleosome positions by deep sequencing across a region encompassing the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR shows tight tissue-specific regulation of expression, which is largely determined by cis-regulatory elements that lie outside the gene promoter. Although multiple elements are known, the repertoire of transcription factors that interact with these sites to activate or repress CFTR expression remains incomplete. The team showed that specific nucleosome depletion corresponds to well-characterized binding sites for known transacting factors, including hepatocyte nuclear factor 1, Forkhead box A1 and CCCTC-binding factor. Moreover, the cell-type selective nucleosome positioning effectively predicted binding sites for novel interacting factors, such as BAF155. Finally, they identified binding sites that are overrepresented in regions where nucleosomes are depleted in a cell-specific manner. This approach recognizes the glucocorticoid receptor as a novel trans-acting factor that regulates CFTR expression. This research, published online in Nucleic Acids Research, was funded by the National Institutes of Health, Cystic Fibrosis Foundation and the Cancer Research Institute. Senior author Ann Harris, PhD is Professor of Pediatrics at Northwestern University Feinberg School of Medicine and director of the Human Molecular Genetics Program of Ann & Robert H. Lurie Children's Hospital of Chicago Research Center. Jared Bischof and Zhaolin Zhang, PhD of the Harris laboratory made major contributions to the research. This work is dedicated to co-author Jonathan Widom. 

 

Breastfeeding is now widely recognized as a vital obesity prevention strategy, and hospitals play a primary role in promoting, supporting and helping mothers to initiate and maintain breastfeeding. The Baby-Friendly Hospital Initiative (BFHI) provides an evidence-based model that hospitals can use to plan and implement breastfeeding quality improvement (QI) projects. Key Chicago partners, including the Consortium to Lower Obesity in Chicago Children (CLOCC), the Chicago Department of Public Health, HealthConnect One and the American Academy of Pediatrics provided individualized support and technical assistance with breastfeeding QI projects to the 19 maternity hospitals in Chicago. A community organizing approach was taken to mobilize hospital interest, which resulted in 63 percent of the hospitals registering with Baby-Friendly USA, Inc. to pursue official Baby-Friendly designation. Key factors that fostered this success included involving all levels of hospital staff, financial incentives, and ongoing tailored technical assistance. To assist other communities in similar work, an article published online in Maternal and Child Health Journal discusses the approach taken to mobilize hospitals to improve breastfeeding support practices based on the BFHI, as well as successes and lessons learned. This project was funded by the Centers for Disease Control and Prevention’s Communities Putting Prevention to Work initiative. Lead author Samantha Schoenfelder is Health and Early Childhood Coordinator for CLOCC. 

 
JNeurophysiol2013   
Research by Michael Carroll, PhD, Center for Autonomic Medicine in Pediatrics, is featured on the cover of the January 2013 Journal of Neurophysiology. The figure shows spiking behavior of individual neurons located within the respiratory network. 
 

2012

 
Jill Weissberg-Benchell Adolescents with chronic health conditions are at risk for poor physical and mental health and poor behavioral outcomes. Declining diabetes management and control are common as children progress through adolescence, yet many youths with diabetes do remarkably well. There is little research that describes processes that lead to positive outcomes such as engaging in effective diabetes self-management, experiencing high quality of life, and achieving in-range glycemic control. Resilience is defined as the achievement of positive outcomes despite exposure to significant risk or adversity. Resilience theory posits that protective processes buffer the impact of risk factors on an individual’s development and functioning. In the December 2012 Current Diabetes Reports, Jill Weissberg-Benchell, PhD and colleagues from Johns Hopkins University review resilience theory in the context of type 1 diabetes management and control, and present a theoretical model of pediatric diabetes resilience. Applications to clinical care and research include the development of preventive interventions to build or strengthen protective skills and processes related to diabetes. The ultimate goal is to equip youths and their families with tools to promote both behavioral and health-related resilience. Weissberg-Benchell is Associate professor of Psychiatry and Behavioral Sciences at the Feinberg School, a psychologist in the Department of Child and Adolescent Psychiatry at Ann & Robert H. Lurie Children’s Hospital of Chicago and a member of the Mary Ann & J. Milburn Smith Child Health Research Program of the research center.

   
Wilms tumor model 2012   
Revised model for Wilms Tumor (WT) ontogeny.
Image courtesy of Samantha Gadd, PhD.
Neoplasia 2012 August; 14(8): 742-56.
 

A study of global gene expression patterns in Wilms tumors (WT) was conducted to identify and characterize distinctive subsets that may merit therapeutic stratification or respond to specific therapies. Five subsets showed differences in their pathologic and clinical features. A novel subset of epithelial WT in infants lacked WT specific mutations and nephrogenic rests and displayed a gene expression pattern of the postinduction nephron, and none recurred. Three subsets were characterized by low expression of WT1 and intralobar nephrogenic rests. These differed in their frequency of mutations, in their age, relapse rate, and expression similarities with the intermediate mesoderm versus the metanephric mesenchyme. The largest subset was characterized by biallelic methylation of the imprint control region 1, a gene expression profile of the metanephric mesenchyme, and interlunar and perilobar nephrogenic rests. These data provide an explanation for clinical and pathologic heterogeneity and enable the development of subset specific therapeutic strategies. Further, these data support a revision of the current model of WT ontogeny, which allows for an interplay between the type of initiating event and the developmental stage in which it occurs. Elizabeth Perlman, MD, professor of Pathology at the Feinberg School and head of Pathology and Laboratory Medicine at Lurie Children’s, and Arthur C. King Professor in Pathology and Laboratory Medicine, is corresponding author on the publication that appears in the August issue of Neoplasia. Samantha Gadd, PhD, research scientist in the Cancer Biology and Epigenomics Program of the research center, is first author. This work was supported by grants from the NIH.

 
PPRG Binns Robert Tanz   
Helen Binns, MD, MPH   Robert Tanz, MD

Filling a prescription is the important first step in medication adherence, but has not been studied in pediatric primary care. A study published in the October issue of Pediatrics and conducted by Rachel Zweigoron, MD, Helen Binns, MD, MPH and Robert Tanz, MD used claims data to determine the rate of unfilled prescriptions in pediatric primary care and examine factors associated with prescription filling. The data found that age of less than 1 year was significantly associated with filling prescriptions within one day, but not overall prescription filling. African American, Hispanic and male patients were more likely to have filled prescriptions. Electronic prescribing increased the likelihood that a prescription would be filled. This study demonstrates that failure to fill a prescription occurs in more than 20 percent of prescriptions given at primary care visits, and is affected by both clinical and demographic factors. Zweigoron is a former fellow in the Division of Academic General Pediatrics and Primary Care at Lurie Children’s. Tanz is professor of Pediatrics at the Feinberg School and attending physician in Academic General Pediatrics. Binns is professor of Pediatrics and Preventive Medicine at the Feinberg School, director of the Lead Evaluation Clinic and Nutrition Evaluation Clinic at Lurie Children’s, and director of the Pediatric Practice Research Group and the Center on Obesity Management and Prevention of the research center.

 

Emalee Flaherty, MD and colleagues explored how child abuse physicians (CAPs) experience the unique challenges of the emerging field of child abuse pediatrics. Practicing CAPs completed a written survey about known challenges in their field. Over 75 percent reported having experienced negative consequences as a result of their work on behalf of maltreated children, including threats to their personal safety, formal complaints to supervisors and licensing bodies, negative stories in the media and malpractice suits. A sample of CAPs participating in telephone interviews discussed strategies for coping with stresses, such as developing good balance between professional and personal life, and maintaining strong support networks and relationships. The findings highlight the stressors and challenges that may affect the ability to maintain an adequate CAP workforce. Better understanding of the challenges should help prepare physicians to practice this subspecialty. Flaherty is associate professor of Pediatrics at the Feinberg School, director of Child Abuse Pediatrics and an attending physician in Academic General Pediatrics and Primary Care at Lurie Children’s, and a member of the Smith Child Health Research Program of the research center. Her colleagues are from UMass Memorial Children’s Medical Center, Evaluation Solutions and Boston Medical Center. The Anthony E. and Christine Speiser Family Foundation supported the research. The article is published online in the September issue of Evaluation & the Health Professions.  

 
 Susanna McColley Cystic fibrosis (CF) lung disease is variable in both onset and rate of progression. There is growing evidence thatlung disease is present in the first few years of life in children with CF. A team of investigators led by Susanna McColley, MD performed an analysis of the Epidemiologic Study of Cystic Fibrosis (ESCF) to assess the average age of onset of key signs and symptoms of CF lung disease and to describe risk factors for early onset. These risk factors include pancreatic enzyme use, Pseudomonas aeruginosa infection, and prior diagnosis of asthma. A number of demographic variables that predict the onset of signs and symptoms include female sex, Medicaid insurance — a proxy for low socioeconomic status — and Hispanic race. Clinicians can use these variables to identify young children at risk of onset of persistent symptoms who could benefit from earlier intervention. Study co-authors are from the University of Rochester, Children’s Healthcare of Atlanta, University of Minnesota Amplatz Children’s Hospital, and Rainbow Babies and Children’s Hospital. The study is published in the October issue of Pediatric Pulmonology, and was supported by Genentech, Inc. McColley is professor of Pediatrics at the Feinberg School, head of the Division of Pulmonary Medicine and director of the Cystic Fibrosis Center at Lurie Children’s and a member of the Clinical and Translational Research Program of the research center. 

   
Mary Beth Madonna

Neuroblastoma is the most common extracranial solid tumor of childhood and accounts for 15 percent of cancer-related deaths in children. While infants and the youngest children often do well, older children may have a poor prognosis. Acquired resistance to chemotherapeutic agents remains a primary barrier to successful treatment. Histone deacetylase (HDAC) inhibitors have shown promise in the treatment of resistant and refractory tumors including neuroblastoma. A study by the laboratory of Mary Beth Madonna, MD is the first to demonstrate that class III HDAC inhibition with cambinol may be at least as efficacious as class I and II HDAC inhibition with vorinostat. Further studies are needed to determine if triple therapy with vorinostat, cambinol, and doxorubicin can be tolerated without risk of toxicity, and whether this combination has any therapeutic advantage. The article is published in the June 2012 issue of the Journal of Pediatric Surgery. First author Timothy Lautz, MD is a former fellow in Pediatric Surgery at the Feinberg School. Madonna is assistant professor of Surgery at the Feinberg School, attending physician in Pediatric Surgery at Lurie Children’s and a member of the Cancer Biology and Epigenomics Program of the research center.

   
Lauren Pachman    
Lauren Pachman, MD  
A collaboration between the Cancer Biology and Epigenomics Program and the Cure JM Juvenile Myositis Research Program of Excellence of the research center undertook to determine the methylation alteration in inflamed muscles from children with juvenile dermatomyositis (JDM) and other idiopathic inflammatory myopathies (IIM). Comparison of genome-wide DNA methylation profiling between JDM and normal controls revealed that Wilms Tumor gene 1 (WT1) and several homeobox genes were significantly hypo- or hypermethylated. WT1 protein was increased in JDM muscle but was undetectable in normal muscle. Alterations in homeobox genes have been viewed as evidence of a “self-renewal” signature in stem cells, while a key function of WT1 in mature tissues is to maintain the pluripotency of progenitor/stem cells. The results suggest that affected muscles of children with JDM and IIM have the capacity to repair, and that homeobox and WT1 genes are epigenetically marked to facilitate this process. The study is published in the June 2012 online issue of Arthritis and Rheumatism. First author Min Wang, PhD is research assistant professor of Pediatrics at the Feinberg School and a member of the Soares laboratory. Corresponding author Lauren Pachman, MD is professor of Pediatrics at the Feinberg School and director of the Cure JM Program. 

 
Yongchao Ma

The biological substrate of human mental capability, the neocortex, is comprised of six neuronal layers that are generated in a defined temporal sequence. While certain cues are known to regulate the sequential production of neocortical neurons, how these factors coordinate is poorly understood. A group from the University of Calgary, Ottawa Hospital Research Institute and the research center examined how the proneural gene Neurog2 function is temporally controlled during mouse neocortical development. Neurog2 activity declines in late corticogenesis, correlating with its phosphorylation by GSK3 kinase. The researchers show that GSK3 suppresses Neurog2 activity by influencing the molecules with which it combines (dimerization), promoting heterodimeric over homodimer interactions, which occur when GSK3 activity is low. The research suggests that temporal regulation of heterodimerization is a central component of the “clock” that coordinates neocortical neurogenesis in the mouse. Yong-Chao Ma, PhD, assistant professor of Pediatrics, Physiology and Ken and Ruth Davee Department of Neurology at the Feinberg School, and a member of the Developmental Biology Program of the research center, is a co-author on the publication which appears in the June 2012 issue of the Journal of Neuroscience

   
Anthony Chin

Acute pancreatitis accounts for more than 5,000 pediatric admissions to hospitals per year in the U.S.  The need for a reliable system to stratify children for risk of complications is underscored by the increasing number of hospitalizations and high rate of major complications. The computed tomography severity index (CTSI), or Balthazar score, which is based on the appearance of the pancreas and extent of necrosis has been reported to be superior to other systems in adults but has not been studied in children. The departments of Surgery and Medical Imaging at Lurie Children’s assessed the utility of the CTSI in the pediatric population by reviewing 64 children with acute pancreatitis who underwent contrast-enhanced CT at presentation. The results demonstrate that the CTSI is a clinically useful tool for predicting which patients will develop major complications. The study is published in the June 2012 issue of the Journal of Pediatric Surgery. Corresponding author Anthony Chin, MD is assistant professor of Surgery at the Feinberg School, attending physician in Pediatric Surgery at Lurie Children’s and a member of the Clinical and Translational Research Program of the research center. Timothy Lautz, MD is first author. 

   
Pediatrics image 2011 CAMP   
   

Familial dysautonomia (FD) is a profound sensory and autonomic nervous system disorder associated with an increased risk for sudden death. While bradycardia has been hypothesized to play a role, extended inhome monitoring has failed to find evidence of low heart rates in children with FD. Twenty-five affected children and matched controls were studied with in-home technology by the Center for Autonomic Medicine in Pediatrics (CAMP) at Lurie Children’s and the Center for Integrative Brain Research at Seattle Children’s Research Institute. The data indicate that children with FD exhibit systemic cardiorespiratory dysregulation, poor respiratory control, high average heart rates during the night, and reduced heart rate variability in day and night recordings. Measures of cardiorespiratory coupling and autonomic tone also support pervasive autonomic dysregulation. FD represents an important model for explicating disease processes in kindred autonomic and respiratory disorders, and for understanding basic mechanisms of homeostatic cardiorespiratory regulation. The study is published in the July 2012 issue of Pediatric Pulmonology. Corresponding author Debra Weese-Mayer, MD is professor of Pediatrics at the Feinberg School and director of CAMP. The first author is Michael Carroll, PhD, computational neuroscientist in CAMP. 

(Figure) Cardiorespiratory dysregulation in familial dysautonomia (FD). Image courtesy of Michael S. Carroll, PhD, Center for Autonomic Medicine in Pediatrics. Pediatric Pulmonology, 2012 July;47(7):682-91.

 
 Ann Harris

Non-fibrillar collagen XV is a chondroitin sulfate modified glycoprotein that is associated with the basement membrane zone in many tissues and plays a critical role in the structural integrity of the extracellular matrix. Loss of collagen XV from the basement membrane zone precedes invasion of a number of tumor types. The laboratory of Ann Harris, PhD previously reported that collagen XV functions as a dose-dependent suppressor of tumorigenicity in cervical carcinoma cells. In the June 2012 issue of Matrix Biology, they show that this is not due to the part of the protein that has homology with endostatin, a known inhibitor of angiogenesis. This important finding demonstrates a novel mechanism for the action of collagen XV in tumor suppression. Moreover, they show that expression of collagen XV enhances the adhesion of cervical carcinoma cells to collagen I in vitro as does the N-terminus and collagenous regions of collagen XV. Destruction of a cysteine residue in the collagenous region that is critical for intermolecular interactions of collagen XV abolishes the enhanced adhesion to collagen I. Harris is Valerie and George D. Kennedy Endowed Chair in Human Molecular Genetics and professor of Pediatrics at the Feinberg School, and director of the Human Molecular Genetics Program of the research center. First author Michael Mutolo, MS is the manager of the Harris laboratory. 

   
Kelly Michelson

Kelly Michelson, MD, MPH and colleagues conducted In depth, semi-structured focus groups and one-on-one interviews with eighteen parents of children who died in the pediatric intensive care unit (PICU) and 48 PICU healthcare professionals (HCPs) -- physicians, nurses, social workers, child-life specialists, chaplains, and case managers -- to explore experiences in end-of-life care decision making. They identified medical and nonmedical end-of-life care decisions that parents face toward the end of a child’s life. They went on to identify seven roles HCPs play in end-of-life care decisions: family supporter, family advocate, information giver, general care coordinator, decision maker, end-of-life care coordinator and point person. The results, to appear in Pediatric Critical Care Medicine, describe a framework for HCPs’ roles in parental end-of-life care decision making in the PICU that includes directive, value-neutral and organizational roles. Actively ensuring attention to these roles during the decision-making process could improve parents’ experiences at the end of a child’s life. Michelson is associate professor of Pediatrics and the Buehler Center on Aging, Health & Society at the Feinberg School, an attending physician in the Division of Critical Care at Lurie Children’s, and a member of the Mary Ann & J. Milburn Smith Child Health Research Program of the research center. 

   
Maryann Mason A team from Northwestern University and Lurie Children’s conducted the first research study describing perceptions of weight and the health effects of weight in South Asian Americans. The prevalence of overweight and obesity among participants was high, and underestimation of weight status and the consequences of being overweight were common. Although study participants frequently cited physical weight-related problems, few associated their weight with the risk for developing chronic diseases. Lack of a perceived connection between one’s weight and chronic disease risk has been reported among other populations, but it may be a particular problem for South Asian Americans, who develop insulin resistance (and thus diabetes and cardiovascular disease) at a lower BMI than do other racial/ethnic groups. The study, which is published in the May 2012 issue of Preventing Chronic Disease, suggests that interventions to promote weight loss among South Asian Americans should focus on reforming perceptions of normal weight, establishing the connection between overweight and the development of chronic diseases, and strengthening the perceptions of personal risk. Co-author Maryann Mason, PhD is research assistant professor of Pediatrics and Preventive Medicine at the Feinberg School, director of research and evaluation for the Consortium to Lower Obesity in Chicago Children (CLOCC), and associate director of the Child Health Data Lab (CHDL) of the research center. 
   
Bob Dettman 2011

Perturbation of the development of the epicardium, a layer that eventually covers the heart, results in cardiac abnormalities. In a study published in the June 2012 issue of Developmental Biology, an international group of researchers focused on the contribution of epicardially derived cells (EPDCs) to developing atrioventricular (AV) valves, which ensure unidirectional flow of blood from atria to ventricles. Using a mouse model, the scientists studied the contribution of EPDCs to the developing heart. In concordance with previous reports, they found that EPDCs contribute to the majority, if not all, of the interstitial fibroblasts found in the embryonic myocardium. Migration of EPDCs through the AV myocardium and into the endocardially derived lateral AV cushions begins around embryonic day (ED) 12. As development progresses the epicardially derived fibroblasts eventually become the predominant cell type in the leaflets that derive from these lateral cushions. Importantly, the contribution of EPDCs to the leaflets derived from the major AV cushions is very limited. This new paradigm in valve development has significant pragmatic consequences for experimental studies and the interpretation of experimental results. More importantly, this insight may lead to the development of testable hypotheses regarding the pathogenesis of cardiac abnormalities and diseases that preferentially affect individual leaflets of the AV valvuloseptal complex. Robert Dettman, PhD, research assistant professor of Pediatrics at the Feinberg School and a member of the Developmental Biology Program of the research center, is a co-author on the publication. Andy Wessels, Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina is first author. Contributors include researchers from the Academic Medical Centre of Amsterdam, the Children’s Hospital of Philadelphia, the University of Málaga, Spain and the Fox Chase Cancer Center, Philadelphia.

   
Arun Sharma The need for a consistent therapeutic approach to tendon injury repair is long overdue. Patients with tendon microtears or full ruptures are eligible for a wide range of invasive and non invasive interventions, often subjectively decided by the physician. Surgery produces the best outcomes, and while studies have been conducted to optimize graft constructs and to track outcomes, the data from these studies have been inconclusive on the whole. What has been established is a clear understanding of healthy tendon architecture and the inherent process of healing. With this knowledge, tissue regeneration efforts have achieved immense progress in scaffold design, cell line selection, and, more recently, the appropriate use of cytokines and growth factors. A review paper by Hatim Thaker and Arun Sharma, PhD evaluates the plasticity of bone-marrow-derived stem cells and the elasticity of recently developed biomaterials towards tendon regeneration efforts. Mesenchymal stem cells (MSCs), hematopoietic progenitor cells, and poly(1,8-octanediol co-citrate) scaffolds (POC) are discussed in the context of established grafting strategies. With POC scaffolds to cradle the growth of MSCs and hematopoietic progenitor cells, developing a fibroelastic network guided by cytokines and growth factors may contribute towards consistent graft constructs, enhanced functionality, and better patient outcomes. Sharma is research assistant professor of Urology at the Feinberg School, director of Pediatric Urological Regenerative Medicine at Lurie Children's Division of Pediatric Urology and a member of the Developmental Biology Program of the research center.
   
Seth Corey

Chronic myeloid leukemia (CML) is relatively uncommon in children, making evidence-based recommendations difficult. The drug imatinib has revolutionized treatment for adult CML by eliminating stem cell transplantation (SCT) for many patients. Imatinib and successive tyrosine kinase inhibitors (TKI) have also been shown effective in pediatric CML, but because SCT is tolerated in children and adolescents, the decision to treat by either TKI or transplantation is controversial. In the February 2012 issue of Blood, Jeffrey Andolina of Golisano Children’s Hospital, Steven Neudorf of Children’s Hospital of Orange County and Seth Corey of Children’s Memorial present a case of a 12-month old boy to highlight the controversies. They review pediatric SCT outcomes as well as experience with imatinib and other TKIs, including side effects and costs. They recommend frontline therapy for pediatric CML in chronic phase as TKI without transplantation. Patients in accelerated or blast crisis or who fail to reach landmarks on TKIs should pursue SCT. Although they recommend adopting adult clinical experience to guide therapeutic decision making, they caution that some issues specific to children merit investigation. Corey is professor of Pediatrics and Cell and Molecular Biology and Sharon B. Murphy, MD and Steven T. Rosen, MD Endowed Chair in Cancer Biology Research at Northwestern University Feinberg School of Medicine; director of Oncology Research and attending physician, Children’s Memorial Center for Cancer and Blood Disorders; a member of the Cancer Biology and Epigenomics Program; and director of the Pediatric Drug Development Center of Children's Memorial Research Center.

   
John Lavigne
While American Academy of Pediatrics guidelines recommend obtaining symptom reports from both parents and teachers when treating children with attention-deficit/hyperactivity disorder (ADHD), information from parents is easier to obtain and practitioners may prefer to rely solely on parent report when managing medications. There are, however, few empirical data on the relationship between parent and teacher reports during medication management of ADHD. John Lavigne, PhD and colleagues examined the relationship between parent and teacher reports of symptoms of ADHD during a clinical trial involving 24 pediatric practices with 270 children. The research showed that agreement between parent and teacher ratings of symptoms of ADHD is too low for clinicians to rely on parent reports. Teacher reports are still needed to ensure optimal management. Published in the May 2012 issue of Journal of Developmental and Behavioral Pediatrics, this study was a collaboration among the Department of Child and Adolescent Psychiatry and the Division of Academic General Pediatrics and Primary Care at Children’s Memorial, the Mary Ann and J. Milburn Smith Child Health Research Program of the research center, the Practice Based Research Program, Community Engaged Research Center of Northwestern University Clinical and Translational Sciences Institute and the Department of Pediatrics of the Feinberg School. Lavigne is professor of Psychiatry and Behavioral Sciences and Pediatrics of the Feinberg School, chief psychologist at Children's Memorial and a member of the Smith Child Health Research Program.
   
Risk factors for chronic anemia in the post-transplant period have not been clearly delineated in pediatric liver transplant recipients. Robert Liem, MD and colleagues analyzed data from children with at least two consecutive hemoglobin values from follow-up between six months and five year post-transplant. Of 1,026 children, 23.6 percent were found to have chronic anemia. GI bleeding, presence of leukopenia, use of cyclosporine and corticosteroids, and cGFR <90 mL/min/1.73 m(2) represented the most significant risk factors for chronic anemia. Use of antihypertensive medications was also significantly associated with a higher risk. In summary, chronic anemia is common in children following liver transplant. The findings, published in the March 2012 issue of Pediatric Transplantation, underscore the need to define the mechanisms by which these risk factors, some of which are modifiable, result in chronic anemia in pediatric liver transplant recipients. Liem is an attending physician in Children's Memorial Center for Cancer and Blood Disorders and assistant professor of Pediatrics at the Feinberg School. The EMMES Corporation and the Division of Gastroenterology, Hepatology and Nutrition at Children's Memorial participated in the study.
 
 Douglas Nordli

Deficits in cognitive proficiency (CP) are a defining characteristic of pediatric epilepsy and serve as an important marker of neurocognitive status. CP, the combination of working memory and processing speed, is not typically viewed in relation to focal cerebral function. A group from the Department of Child and Adolescent Psychiatry and the Neurology Division at Children’s Memorial examined CP and its relationship to general intellectual ability and seizure focus in patients with pediatric epilepsy. CP was significantly lower than general ability (GA) in the overall sample. The data indicate that CP is selectively compromised by epileptogenic activity, especially in individuals with seizures originating from the right hemisphere or frontal lobe. The discrepancy between CP and GA varied with participants’ overall intelligence, being more pronounced in individuals of lower ability. The study is published in the February 2012 issue of Epilepsy and Behavior. Douglas Nordli, Jr., MD, the lead author, is Lorna S. and James P. Langdon Chair in Pediatric Neurology, director of the Epilepsy Center at Children’s Memorial, professor of Pediatrics and Neurology at the Feinberg School and a member of the Clinical and Translational Research Program of the research center.

   
FASEB Journal 2012
During forelimb regeneration in the newt, the dynamic expression of a transitional matrix controls muscle cell behavior. However, the influence of extracellular matrix (ECM) remodeling on tissue stiffness and the cellular response to mechanical variations during regeneration is unknown. To determine how ECM and stiffness combine to affect skeletal muscle fragmentation, migration and fusion, Sarah Calve, PhD, a former postdoctoral associate in the laboratory of Hans-Georg Simon, PhD coated substrates with matrices representative of transitional and differentiated environments. She provides for the first time evidence that a newly made regenerationspecific ECM, which is rich in tenascin-C (figure, in green) also results in changes of local tissue stiffness. Moreover, in controlled in vitro cultures with defined ECM components Calve demonstrates that variations in ECM composition and the stiffness of the cell substrate cooperate to control muscle cell behavior towards regenerative growth. The findings are published in the FASEB Journal, March 2012. Simon is Bernard L. Mirkin Research Scholar, associate professor of Pediatrics at the Feinberg School, director of the Children’s Memorial Research Training Program and a member of the Developmental Biology Program of the research center.
   
 
EJHG 2012     
Figure from Kluppel M et al; Forced expression
of C4ST-1 can rescue the elastogenesis
defects in Costello syndrome fibroblasts.
Reprinted by permission from Macmillan
Publishers Ltd: European Journal of Human
Genetics
, advance online publication, 8 February
2012 (doi: 10.1038/ EGHG.2012.12)
 
   
Costello syndrome is a pediatric genetic disorder caused by mutations in the HRAS gene, and characterized by multiple developmental abnormalities and predisposition to malignancies. Michael Klüppel, PhD and colleagues explored a functional involvement of the glycosaminoglycan chondroitin sulfate (C4S) biosynthesis gene, CHST11/C4ST-1, as well as an impaired chondroitin sulfation balance, as a mediator of oncogenic HRAS. They demonstrated a loss of C4S and reduction in C4ST-1 mRNA and protein expression in primary fibroblasts from patients. They showed that expression of oncogenic HRAS in normal fibroblasts can repress C4ST-1 expression, interference with oncogenic HRAS signaling in Costello syndrome fibroblasts elevates C4ST-1 expression, and forced expression of C4ST-1 could rescue the defects associated with oncogenic HRAS signaling. These findings might be exploited to treat Costello syndrome, other RASopathies, and cancers associated with RAS mutations. Klüppel is a member of the Human Molecular Genetics Program of the research center, assistant professor of Pediatrics and a member of The Robert H. Lurie Comprehensive Cancer Center of Northwestern University. This study is published online in the February 2012 European Journal of Human Genetics in collaboration with scientists at Mount Sinai Hospital and The Hospital for Sick Children, Toronto. 
   
 Elfriede Pahl  Elfriede Pahl, MD led a study by the Pediatric Cardiomyopathy Registry (PCMR) Investigators to establish the incidence of and risk factors for sudden cardiac death (SCD) in pediatric dilated cardiomyopathy (DCM). In a cohort of 1,803 children with a diagnosis of DCM from 1990 to 2009, 280 deaths occurred. Of these, 35 were SCD, and the cause was unknown for 56. The five-year incidence rate for SCD incorporating a subset of the unknown deaths is 3 percent. Patients receiving antiarrhythmic medication were at higher risk of SCD. Thirty of 35 SCDs occurred in patients younger than 14.3 years at diagnosis with left ventricular (LV) end-systolic dimension z-score greater than 2.6, and LV posterior wall thickness to end-diastolic dimension ratio less than 0.14. Patients who meet the criteria should be considered for implantable cardioverter-defibrillator placement. The study is published in the February 2012 issue of the Journal of the American College of Cardiology. Pahl is medical director of the Heart Transplant Program at Children’s Memorial; Marvin E. Wodika Professor of Cardiology; professor of Pediatrics at the Feinberg School, and a member of the Human Molecular Genetics Program of the research center.
 

States develop specific protocols for cystic fibrosis (CF) newborn screening to reflect the population served. Kimberly Watts, MD in the Division of Pulmonary Medicine and colleagues hypothesized that mutation distribution and detection rates would differ between Hispanic and non-Hispanic CF patients diagnosed by Illinois newborn screen with more Hispanic infants carrying mutations not detected by the state panel. Data from CF cases diagnosed via newborn screen in Illinois between 2008 and 2010 showed that more Hispanic infants had one or more undefined mutations after screening, in comparison to non-Hispanic Caucasian patients. The researchers caution that health care providers must be aware of the limitations of CF newborn screening to ensure appropriate counseling and prompt referral for a positive newborn screen, even when zero or one mutations are identified. The results are published online in February 2012 in the Journal of Genetic Counseling. Watts is assistant professor of Pediatrics at the Feinberg School and a member of the Human Molecular Genetics Program of the research center.

In the March 2012 issue of Paediatric Respiratory Reviews, Watts writes, “Identifying that health inequalities exist is not enough; nor does the knowledge that a patient has a high-risk genotype or comes from a higher risk socioeconomic background, by itself, help the patient.” To thoroughly examine the origins of health disparities, a broad view of environmental and molecular influences must be included. As factors are identified, it is important to focus on interventions that can change outcomes for patients. Tools for education, community involvement, literacy and environmental safety need to be developed, tested and disseminated. The basic science of health disparities must move forward in a coordinated fashion by structuring research that is integrated between basic sciences and clinical medicine, and includes all traditionally underserved communities. These collaborations can help to eliminate health inequalities in the future.
 

Bohnjpg
Martha C. Bohn, PhD 

Corticospinal motor neurons (CSMN) are the cortical component of motor neuron circuitry, which controls voluntary movement and degenerates in diseases such as amyotrophic lateral sclerosis (ALS). The laboratory of Pembe Hande Ozdinler, PhD used a novel AAV-mediated retrograde transduction approach to reveal an intrinsic mechanism for early stages of CSMN vulnerability. The data indicate lack of cortical connectivity and circuitry modulation of CSMN as a potential cause of neuronal susceptibility and degeneration in ALS. In addition, the findings offer retrograde transduction as a tool for future targeted gene therapy, especially valuable for modulating intrinsic factors responsible for CSMN vulnerability. Martha C. Bohn, PhD, director of the Neurobiology Program of the research center, is a coauthor on the publication, in the April 2012 online issue of Neurobiology of Disease. Bohn is Medical Research Institute Council Professor in Neurobiology, and professor of Pediatrics and Molecular Pharmacology and Biological Chemistry at the Feinberg School.

   

In an update to bladder regeneration research being conducted by Arun Sharma, PhD and colleagues in the Urology Division at Children’s Memorial and the Institute for BioNanotechnology in Medicine at Northwestern University, the research team modified an elastomeric scaffold previously shown to enhance urinary bladder regeneration. By adding proangiogenic factors that are released from the scaffold, including vascular endothelial growth factor, fibroblast growth factor 2 and insulin-like growth factor 1, the group demonstrated a threefold increase in vessel growth compared to controls over a 30-day time course in vitro. Subcutaneous implantation into animals yielded increased vascular growth. The results, published in the Journal of Biomedical Materials Research. Part A, show that elastomeric films can be chemically modified and possess the ability to promote angiogenesis in vivo. Sharma is research assistant professor in Urology at Northwestern University Feinberg School of Medicine, director of Pediatric Urological Regenerative Medicine at Children’s Memorial, and a member of the Developmental Biology Program of the research center.

 

Scientists from the research center, Duke University, the University of North Carolina at Chapel Hill and Case Western Reserve University collaborated to identify and locate the regulatory elements that control gene expression in the airway epithelium. They used DNase I hypersensitivity mapping followed by deep sequencing to generate a map of open chromatin in primary human tracheal epithelial cells. Bioinformatic approaches were used to characterize the distribution of these sites within the genome and with respect to gene promoters, intronic and intergenic regions. These data are of direct relevance to elucidating the molecular basis of normal lung function and lung disease. Ann Harris, PhD, professor of Pediatrics and the Valerie and George D. Kennedy Research Professor in Human and Molecular Genetics at the Feinberg School, and director of the Human Molecular Genetics Program of the research center, was corresponding author on the publication, which appeared in the January 4, 2012 online issue of Thorax. Jared Bischof, MS, a bioinformaticist in the Harris laboratory, was first author.

 
Mark Wainwright, MD, PhD is a co-author on the first update of the pediatric traumatic brain injury (TBI) management guidelines since their first edition in 2003. “Guidelines for the acute medical management of severe traumatic brain injury in infants, children, and adolescents”, the January 2012 supplemental issue of Pediatric Critical Care Medicine, is available for free. The authors write: “Given the importance of severe TBI to the overall burden of childhood morbidity and mortality, we hope that these new guidelines aid caregivers and stimulate the pediatric TBI community to generate additional answers.” Wainwright, Bernard L. Mirkin Research Scholar in Pediatric Neurology, is associate professor of Pediatrics at the Feinberg School, attending physician in Neurology and Critical Care Medicine at Children’s Memorial, director of the Center for Interdisciplinary Research in Pediatric Critical Illness and Injury, and a member of the Neurobiology Program of the research center.

 

2011

 
 Neuromuscular team    

Northwestern selected as neuroscience clinical trials site 
Children's Memorial will lead up SMA biomarker study


Northwestern University Feinberg School of Medicine has been selected as a clinical site in the Network for Excellence in Neuroscience Clinical Trials (NEXT) through the National Institute of Neurological Diseases and Stroke of the National Institutes of Health.

It is anticipated that the first NEXT project to be conducted by the Northwestern team will be a biomarker study of Spinal Muscular Atrophy (SMA), a genetic disease that attacks nerve cells, or motor neurons, in the spinal cord. Motor neurons communicate with voluntary muscles such as those in the arms and legs, and as the neurons are lost, individuals with SMA lose the ability to use the muscles. Nancy Kuntz, MD; Christine DiDonato, PhD; Debra Weese-Mayer, MD; Kristin Krosschell, PT/MA; and Pallavi Patwari, MD are co-investigators on this study.  Read more.

From left: Pallavi Patwari, MD; Nancy Kuntz, MD; Kristin Krosschell, PT/MA; Christine DiDonato, PhD; Debra Weese-Mayer, MD

 

PLoSOne2011_Costa     

Ependymomas, the third most common type of brain tumor in children, are chemoresistant and radioresistant, and recur in approximately half of patients. Location, staging and age of the patient are all factors in successful treatment. The most common form of treatment is surgical resection followed by radiation therapy in older children (or chemotherapy in younger children). Recent studies have focused on characterizing molecular abnormalities and discovering biomarkers for targeted therapy. The laboratory of Marcelo Bento Soares, PhD examined expression of microRNAs (miRNAs) in ependymomas to identify molecular markers of value for clinical management. The scientists identified miRNAs that are differentially expressed in ependymomas (either up-regulated or down-regulated) compared with normal ependymal tissue. They also uncovered significant associations of miRNAs with clinical behavior. Published in the October 2011 issue of PLoS One, this is the first report of clinically relevant miRNAs in ependymomas. First author Fabricio Costa, PhD is a research scientist in the Soares laboratory and the Maeve McNicholas Memorial Foundation Scholar in Cancer Biology and Epigenomics.  

 Figure: Heat Map representations for miRNA expression in ependymomas and normal controls (Fabricio Costa, PhD).

 
Karna Murthy

A study published in the November 2011 issue of the American Journal of Obstetrics and Gynecology (AJOG) used data from the National Vital Statistics System to calculate national trends and racial differences in late-preterm induction (LPI), which is used by clinicians to induce childbirth in women before term gestation. After controlling for confounding risk factors, the data suggest that the threshold for initiating LPI may have decreased in the U.S., and that the odds of LPI were highest and rose more rapidly for black women than for other ethnic groups. The authors point out that “this study cannot define all of the factors that may account for the rise in LPI or for the origins in the racial/ethnic differences that have persisted.” They concur that risks associated with term labor versus neonatal and infant morbidity and mortality should be addressed. The publication was selected as an editors’ choice in AJOG. First author Karna Murthy, MD, MSc is assistant professor of Pediatrics and a member of the Institute for Healthcare Studies at the Feinberg School, an attending physician in Neonatology at Children’s Memorial, and a member of the Smith Child Health Research Program of the research center.

   
 NatureGenetics2011    

Kawasaki disease (KD) is a rare childhood condition that involves inflammation of the blood vessels, sometimes resulting in heart problems. It is thought that a virus or infection combined with genetic factors may cause KD. A group of international consortia on the genetics of KD conducted a genome-wide association study in patients and controls, and identified two loci that exceed the threshold for significance. One of these confirms previous findings. The second, a functional polymorphism in the IgG receptor gene FCGR2A conferring elevated disease risk, may help explain immune activation in KD pathogenesis, and the mechanism of response to intravenous immunoglobulin, the only proven therapy. Anne Rowley, MD and Stanford Shulman, MD, recognized experts in KD from Children’s Memorial, were co-authors on the publication in the November 2011 issue of Nature Genetics. Rowley is professor of Pediatrics and Microbiology-Immunology at the Feinberg School, and an attending physician in Infectious Diseases at Children’s Memorial. Shulman is the Virginia H. Rogers Professor of Pediatric Infectious Disease at the Feinberg School, and head of Infectious Diseases at Children’s Memorial. Both are members of the Clinical and Translational Research Program of the research center.

Figure from Khor CC et al; Nature Genetics 2011 Nov 13;43(12):1241-6. Regional association and linkage disequilibrium plots for regions on chromosomes 1 and 19 showing association with Kawasaki disease. Reprinted with permission of Nature Publishing Group.   

 

Mark Wainwright, MD, PhD participated in the Common Data Elements initiative, a NIH interagency effort to standardize naming, definitions, and data structure for clinical research variables. Comparisons of the results of studies of neurological disorders have been hampered by variability in data coding, definitions, and sample collection procedures. The CDE project objective is to enable comparison of future clinical trials results in major neurological disorders, including TBI, stroke, multiple sclerosis and epilepsy. As part of this effort, the Pediatric TBI Demographics and Clinical Assessment Working Group developed recommendations, published online in the Journal of Neurotrauma, November 2011 on the coding of clinical and demographic variables specific to pediatric TBI studies. This proposed standardization, together with the products of the other pediatric TBI working groups in imaging, biomarkers, and outcome assessment, will facilitate multi-center studies, comparison of results across studies, and high-quality meta-analyses of individual patient data.

 
Katherine Kaufer Christoffel   
Katherine Kaufer
Christoffel, MD, MPH 
 
The Center on Obesity Management and Prevention (COMP) of the Mary Ann and J. Milburn Smith Child Health Research Program fosters research related to clinical and community efforts aimed at protecting children from the childhood obesity epidemic. In August 2011, Children’s Memorial and the Williams Heart Foundation (WHF), an endowed medical research organization, formed an affiliation under which WHF supports COMP core activities and Children’s Memorial-based research conducted in collaboration with WHF. 

The research will address topics that include the etiologies of overweight and its complications, the effectiveness of approaches for reducing overweight and associated morbidity, and means for primary prevention. Led by Children’s Memorial-based Northwestern University faculty members, the work will build on the expertise and resources of COMP and the WHF in order to lay a strong foundation for successful applications for external research support, and to broaden obesity research involvement at Children’s Memorial and its university, practice, and community organization partners. Several ongoing projects were supported for acceleration over the summer and fall of 2011. These related to obesity risk tied to prenatal factors, early childhood feeding behavior and community safety attributes. The first COMP-WHF call for research project proposals has been released on the COMP website. 

The 2011 research center co-directors of the COMP-WHF effort are Katherine Kaufer Christoffel, MD, MPH and Helen J. Binns, MD, MPH, who work in close collaboration with Dr. Randall Williams and Karen Williams, BSN of the WHF. The collaborative work is guided by a Research Advisory Committee that includes active obesity researchers at Children’s Memorial and the research center.
 
 Sabrina Tsao

 

Chronic right ventricular (RV) pacing, which is used to regulate the rate of heart muscle contraction by an artificial pacemaker, is associated with harmful effects on cardiac function. In an observational multicenter study in children with isolated atrioventricular (AV) block receiving chronic ventricular pacing, the importance of the ventricular pacing site on left ventricular (LV) function was investigated. Demographics, maternal autoantibody status and echocardiographic measurements for children were retrospectively collected from patients undergoing chronic ventricular pacing for isolated AV block. In these patients, permanent ventricular pacing site is an important determinant of LV function. The results were published online in the journal Heart. Sabrina Tsao, MD, Assistant professor of Pediatrics at Northwestern University Feinberg School of Medicine and an attending physician in Cardiology was the principal investigator from Children’s Memorial Hospital.

On the recommendation of the Secretary of the U.S. Department of Health and Human Services (HHS) to implement newborn screening for critical congenital heart disease (CCHD) in order to promote early detection, a workgroup was convened to formulate strategies for safe, effective and efficient screening. The group made recommendations for a standardized approach to screening and diagnostic follow-up. It found sufficient evidence to begin screening for low blood oxygen saturation to detect CCHD in well-baby and intermediate-care nurseries. Central to the effectiveness of screening will be the development of a national technical assistance center to coordinate implementation and evaluation of newborn screening for CCHD. The recommendations were published online in Pediatrics. Praveen Kumar, MD, 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, was a member of the workgroup.

 
Joshua Goldstein

Abusive head trauma (AHT) is a common condition in children. Little is known in this condition regarding the frequency of seizures, the factors associated with their increased risk, or the association of seizures with outcome. A team from the Division of Neurology at Children’s Memorial sought to determine frequency and risks for in-hospital seizures after AHT. During the first week following hospital admission, 33 percent of patients were observed to have clinical seizures. The occurrence was associated with abnormal findings on both initial computed tomography (CT) and magnetic resonance imaging (MRI). The presenting complaint of seizures or acute mental status changes, as well as a variety of abnormal imaging findings were associated with short-term outcomes. Joshua Goldstein, MD, first author on the publication that appeared in the August 2011 issue of Neurocritical Care, is Assistant professor of Pediatrics at the Feinberg School, attending physician in Neurology at Children’s Memorial, and a member of the Neurobiology Program of the research center. 

   
Xin Liu

It has been hypothesized that vitamin D deficiency (VDD) contributes to the development of food sensitization (FS) and then food allergy. However, the epidemiological evidence is conflicting. A group from Children’s Memorial, Northwestern University, Boston, China and Australia examined whether cord blood VDD is associated with FS and whether such association can be modified by genetic variants in a prospective birth cohort. When examined alone, VDD was not associated with FS. When examined jointly with single nucleotide polymorphisms (SNPs), which cause genetic variation, a significant interaction between interleukin-4 (IL4) gene polymorphism and VDD was found: VDD increased the risk of FS among children carrying CC/CT genotypes. Similar but weaker interactions were observed for SNPs in three other genes. When all four SNPs were simultaneously considered, a strong gene-VDD interaction was evident. The data, published in the November 2011 issue of Allergy, demonstrate that VDD may increase the risk of FS among individuals with certain genotypes. Lucy Liu, MD, PhD, Assistant professor of Pediatrics at the Feinberg School and a member of the Smith Child Health Research Program of the research center was first author on the publication. 

   

Interstitial chemotherapeutic drug infusion can bypass the blood-brain barrier, and provide high regional drug concentrations without systemic exposure. However, toxicity and efficacy for drugs administered via interstitial continuous (i.c.) infusion have not been characterized. A study conducted by the Developmental Neurobiology laboratory at the research center and published online in the Journal of Neuro-Oncology indicates that vincristine (VIN) delivered via i.c. infusion is effective in reducing C6 glioblastoma tumors and prolonging survival time compared to i.v. injection. The results suggest that administering chemotherapeutic drugs via i.c. infusion may be a promising strategy for treating malignant brain tumors. 

 
Pathology lab stock photo The American College of Medical Genetics recommends that laboratories confirm abnormal or ambiguous results detected by array comparative genomic hybridization (aCGH). aCHG is a method for comparing two sets of chromosomal DNA by analyzing differences in the copy number and location of specific sequences. At present, the gold standard method for aCGH confirmation is fluorescent in situ hybridization (FISH), in which target sequences are stained with fluorescent dye for examination under fluorescence microscopy. However, FISH is not well suited for small tandem duplications or very small deletions that are detectable by oligonucleotide arrays. A group from the Departments of Pathology at Children’s Memorial and the University of Chicago developed and validated multiplex ligation-dependent probe amplification (MLPA) for aCGH confirmation. The scientists have successfully incorporated aCGH confirmation using custom-designed MLPA into normal workflow, and have used it for confirmation of all abnormal or ambiguous results. The results are published in the September 2011 issue of Diagnostic Molecular Pathology

Pallavi Patwari
Pallavi Patwari, MD presented “Pupillary dysfunction in respiratory and autonomic disorders of infancy, childhood, and adulthood (RADICA): Indication of sympathetic and parasympathetic dysfunction”, which was placed in the Best of Pediatrics Symposium at the American Thoracic Society International Conference in May. Patwari is Assistant professor of Pediatrics at the Feinberg School and attending physician in the Center for Autonomic Medicine at Children’s Memorial.
 
Tony Rankin Green Buildings

Tony Rankin, CM, facility manager for Children’s Memorial Research Center, published an article in the May 2011 issue of Today’s Facility Manager entitled “Not only money is green”. He provides facts and figures about building in a sustainable way and recycling materials, as well as highlighting examples of green projects. Noted in the article are John Van Valkenberg and Tom Morlock, engineers for the research center, who advocate for ventilation systems that cut energy and reduce wear on equipment. Rankin concludes the article by stating: “The team at [Ann & Robert H.] Lurie Children’s [Hospital of Chicago] is applying best practices in the industry as outlined by the USGBC [U.S. Green Building Council] and the Green Guide for Healthcare to create a LEED® [Leadership in Energy and Environmental Design] Certified facility that is appropriate, manageable, and meaningful.” Read the full article.
   

“New” Virus for Kawasaki Disease

JInfectDis2011Rowley  
A multi-institutional group of scientists led by Anne Rowley, MD sought to test the hypothesis of a “new” virus associated with Kawasaki disease (KD). A serious pediatric illness that causes inflammation of the blood vessels and can damage the coronary arteries of the heart, KD’s cause remains unknown. Clinical and epidemiologic data support the hypothesis of a ubiquitous agent that likely causes an inconsequential respiratory infection in the vast majority of children but disseminates and results in KD in a subset of children who are genetically predisposed. Using immunofluorescence, high-throughput sequencing and transmission electron microscopy, the group determined that intracytoplasmic inclusion bodies consistent with aggregates of viral protein and RNA were detected in KD but not in control patients. The RNA did not match up with any known viral sequence. These findings are compatible with the hypothesis that the infectious agent of KD may be a “new” virus. A figure from the publication was featured on the cover of the April 1, 2011 issue of the Journal of Infectious Diseases. Rowley is Professor of Pediatrics and Microbiology-Immunology at the Feinberg School; attending physician in Infectious Diseases at Children’s Memorial; and a member of the Clinical and Translational Research Program of the research center. 

Above: Confocal immunofluorescence for intracytoplasmic inclusion bodies (ICI, green) and cytokeratin (red) in Kawasaki Disease ciliated bronchial epithelium. Nuclei are stained with DAPI (blue). Image courtesy of Anne Rowley, MD.

 

Computer Aided Medication Management Helps Treat ADHD  

Medication management of attention-deficit/hyperactivity disorder (ADHD) is often suboptimal.In the June 13, 2011 online issue of Pediatrics, John Lavigne, PhD and colleagues revealed the results of a randomized medication trial in 24 practices involving the use of a software program to assist in monitoring improvement in patients on ADHD medications when compared to usual treatment. Children in both specialized care and treatment-as-usual groups improved on ADHD rating scales, but there were no group differences in improvement rates. Brief physician training alone did not produce improvements. When recommended titration procedures were followed, however, outcomes were better for total and inattentive ADHD symptoms on the ADHD rating scales. The authors concluded that computer-assisted medication management can contribute to better treatment outcomes in primary care medication treatment of ADHD. Lewis R. First, MD, editor-in-chief of Pediatrics, commented on the findings on his blog. Lavigne is Professor of Psychiatry and Behavioral Sciences at the Feinberg School; Psychologist-in-Chief at Children’s Memorial; and a member of the Mary Ann & J. Milburn Smith Child Health Research Program of the research center. 
 

Disruption of White Blood Cell Production  

Granulopoiesis is the process of making healthy granulocytes, or white blood cells, from blood progenitor and precursor cells. When granulopoiesis is perturbed, life-threatening neutropenia, which increases vulnerability to infectious disease, or leukemia develops. The laboratory of Seth Corey, MD, MPH studies Src activation, which has been shown to be involved in leukemogenesis. The mechanism whereby receptor tyrosine kinases, cytokine receptors, and integrins activate Src is not known. In the June 2, 2011 online issue of Blood, the group demonstrated that Granulocyte Colony-Stimulating Factor (G-CSF) activates Lyn, the predominant Src kinase in myeloid cells, through Gab2-mediated recruitment of Shp2. Following G-CSF stimulation, Lyn dynamically associates with Gab2 in a spatio-temporal manner. The group proposed that Gab2 forms a complex with Lyn and following G-CSF stimulation, Gab2 recruits Shp2, which leads to Lyn activation. Corey is Professor of Pediatrics and Cell and Molecular Biology and Sharon B. Murphy, MD and Steven T. Rosen, MD Endowed Chair in Cancer Biology Research at the Feinberg School; Director of Oncology Research; Co-director of the Hematology-Oncology Fellowship Program; Attending physician, Children’s Memorial Center for Cancer and Blood Disorders; a member of the Cancer Biology and Epigenomics Program; and director of the Pediatric Drug Development Center of the research center. 
 
NP-C Disease Study 
NPCDiseaseAhlgren      

Niemann-Pick type C disease (NP-C) is a rare, fatal genetic disease in which patients are not able to metabolize cholesterol and other lipids properly within the cell. Consequently, excessive amounts of cholesterol accumulate within the liver and spleen and excessive amounts of other lipids accumulate in the brain. NP-C patients can suffer severe liver disease, breathing difficulties, developmental delay, seizures, poor muscle tone, lack of coordination, problems with feeding, and an inability to move the eyes vertically. The laboratory of Sara Ahlgren, PhD cloned the zebrafish equivalent of the NP-C gene, npc1, and analyzed its gene expression and activity. The data suggest abnormal accumulation of cholesterol in npc1-morphant cells. Developmentally, early cell fate or survival was not disrupted; however, early morphogenetic movements in the development of anatomical structures were delayed, and the actin cytoskeleton network, which is considered essential for pushing the cell forward in the surrounding environment, was abnormal. Defects were rescued with the expression of mouse NPC1 at times and locations where the target gene is not known to have a function, demonstrating functional gene conservation, and by treatments with steroids, suggesting that reduced steroidogenesis contributed to abnormal cell movements. Cell death was found in anterior tissues of npc1-morphants at later stages, consistent with findings in mammals. These results show that npc1 is required early for proper cell movements and cholesterol localization and later for cell survival. The findings were published in the July 2011 issue of the Journal of Lipid Research. First author Tyler Schwend, PhD, a former graduate student in the Ahlgren laboratory, is currently a postdoctoral fellow at Kansas State University. Second author Evyn Loucks, MS, a research associate in the Ahlgren laboratory, contributed equally to the study. Ahlgren is Assistant professor of Pediatrics at the Feinberg School and the Crown Family Research Scholar in Developmental Systems Biology.

Above: Sterol localization defects in npc1-morphants. Left: Confocal projections from zebrafish embryos (region indicated with box) injected with either control or anti-npc1 morpholino. Right: In controls, filipin staining is diffuse throughout the field of cells. In npc1-morphants, staining appears punctate and disrupted in many cells (arrows). Image courtesy of Sara Ahlgren, PhD.

 

Why Some Kids Are Harmed by Mother’s Alcohol, But Others Aren’t
March 23, 2011

Exposure to alcohol in the womb doesn’t affect all fetuses equally. Why does one woman who drinks alcohol during pregnancy give birth to a child with physical, behavioral or learning problems — known as fetal alcohol spectrum disorder — while another woman who also drinks has a child without these problems? One answer is a gene variation passed on by the mother to her son, according to new Northwestern Medicine research. This gene variation contributes to a fetus’ vulnerability to even moderate alcohol exposure by upsetting the balance of thyroid hormones in the brain. The Northwestern Medicine study with rats is the first to identify a direct genetic mechanism of behavioral deficits caused by fetal alcohol exposure. The study was published online in the March 2011 issue of FASEB Journal. “The findings open up the possibility of using dietary supplements that have the potential to reverse or fix the dosage of the thyroid hormones in the brain to correct the problems caused by the alcohol exposure,” said Eva E. Redei, senior author of the study and the David Lawrence Stein Professor of Psychiatry and Behavioral Sciences at the Feinberg School. “In the not-too-distant future we could identify a woman’s vulnerability to alcohol if she is pregnant and target this enzyme imbalance with drugs, a supplement or another method that will increase the production of this enzyme in the hippocampus, which is where it’s needed,” Redei said. Laura Herzing, PhD, Assistant professor of Pediatrics at the Feinberg School and a member of the Human Molecular Genetics Program, is a co-author on the study. Read the full article.

--by Marla Paul

 

New Resource for Brain Tumor Data

The identification of molecular signatures predictive of clinical behavior and outcome in brain tumors has been the focus of many studies in recent years. Despite the wealth of data available in the public domain, the underlying molecular mechanisms leading to tumor initiation and progression remain largely unknown. Unfortunately, most of these data are scattered in multiple databases and supplementary materials of publications, making their retrieval, evaluation, comparison and visualization an arduous task. The laboratory of Marcelo Bento Soares, PhD has developed and implemented an open access database (BTECH), a community resource for the deposition of a wide range of molecular data derived from brain tumor studies. This comprehensive database integrates multiple datasets; a genome browser has also been developed that allows for the simultaneous visualization of the datasets and the annotated features. In addition, links are provided to the original references for users to have a more accurate understanding of each dataset. This integrated platform will facilitate uncovering interactions among genetic and epigenetic factors associated with brain tumor development. The information is published in the March 2011 issue of Neuroinformatics. First author Min Wang, PhD is Research assistant professor at the Feinberg School.

 

 Jacqueline Pongracic
Jacqueline Pongracic, MD

Reducing Asthma Severity

Research has underscored the effects of exposure and sensitization to allergens on the severity of asthma in inner-city children. It has also revealed the limitations of environmental remediation and guidelines-based therapy in achieving greater disease control. The Inner-City Anti-IgE Therapy for Asthma (ICATA) Study enrolled inner-city children, adolescents, and young adults with persistent asthma in a trial at multiple centers to assess the effectiveness of omalizumab, when added to guidelines-based therapy. The trial was conducted for 60 weeks, and the primary outcome was symptoms of asthma. Among participants, omalizumab as compared with placebo reduced the number of days with asthma symptoms by 24.5 percent. Similarly, omalizumab significantly reduced the proportion of participants who had one or more exacerbations. Improvements occurred despite reductions in the use of inhaled glucocorticoids and long-acting beta-agonists. When added to a regimen of guidelines-based therapy, omalizumab further improved asthma control, nearly eliminated seasonal peaks in exacerbations, and reduced the need for other medications to control asthma. The results were published in the March 2011 issue of the New England Journal of Medicine. Jacqueline Pongracic, MD was the Children’s Memorial study director. Pongracic is Professor of Pediatrics and Medicine at the Feinberg School, head of the Division of Allergy and Immunology at Children’s Memorial, and a member of the Mary Ann and J. Milburn Smith Child Health Research Program of the research center. 

   

Ashish Chogle
Ashish Chogle, MD, MPH

Gut Homeostasis Agent

Milk fat globule-EGF factor 8 (MFG-E8) has been shown to play an important role in maintaining the integrity of the intestinal lining (mucosa) and accelerate its healing in septic mice. The laboratory of Xiao-Di Tan, MD analyzed the expression of MFG-E8 in the gut of wild type mice with and without dextran sulfate sodium (DSS)-induced colitis, characterized the pathological changes in intestinal mucosa of MFG-E8-positive and –negative mice with colitis, and examined the therapeutic role of MFG-E8 in inflammatory bowel disease (IBD) using the animal model. The data documented that there was an increase in colonic and rectal MFG-E8 expression in positive mice during the development of colitis; levels in both tissues decreased to below baseline during the recovery phase. Changes in MFG-E8 gene expression correlated to the levels of inflammatory response and injury in the mucosa in positive mice. Negative mice developed more severe injury than did positive mice during exposure to DSS with delayed healing of intestinal epithelium during the recovery phase. Administration of MFG-E8 during the recovery phase ameliorated colitis and promoted mucosal repair in both mice groups, indicating that lack of MFG-E8 causes increased susceptibility to colitis and delayed mucosal healing. These data suggest that MGF-E8 is an essential protective factor for gut homeostasis, and exogenous administration of MFG-E8 may represent a novel therapeutic target in IBD. The results were published online in the February issue of Molecular Medicine. First author Ashish Chogle, MD, MPH completed his research rotation in the Tan laboratory and is an attending physician in Gastroenterology, Hepatology and Nutrition at Children’s Memorial. 

   

Gene Therapy for Parkinson’s Disease

Alpha-synuclein (SNCA), a protein that is abundantly expressed in the brain, has been implicated in Parkinson’s disease (PD). Over-expression of human SNCA (hSNCA) leads to death of neurons that produce dopamine, known as dopaminergic (DA) neurons, in human, rodent and fly brain. This has led scientists to hypothesize that hSNCA gene silencing may reduce levels of toxic forms of SNCA and ameliorate degeneration of DA neurons in PD. To begin to develop a gene therapy for PD based on hSNCA gene silencing, the laboratory of Martha C. Bohn, PhD designed two gene silencing vectors, which were tested for efficiency and specificity of silencing, as well as toxicity in vitro. The same hSNCA silencing sequence (shRNA) was used in both vectors, but in one vector, the shRNA was embedded in a microRNA backbone and driven by a pol II promoter, and in the other the shRNA was not embedded and was driven by a pol III promoter. Both vectors silenced hSNCA to the same extent in cells transfected with hSNCA. In DA cells, neither vector decreased expression of rat SNCA. However, the embedded vector was significantly less toxic to cells. These data suggest that this embedded silencing vector may be ideal for chronic in vivo SNCA gene silencing in DA neurons. The study was published in the April 2011 issue of Brain Research. Bohn is Medical Research Institute Council Professor of Pediatrics and Professor of Molecular Pharmacology and Biological Chemistry at the Feinberg School, and director of the Neurobiology Program of the research center. 

 

Experimental Biology logoXiao-Di Tan, MD chaired a featured topic entitled “New insights on roles of extracellular mediatorsin intestinal epithelial restitution” at the 2011 Experimental Biology meeting in April. Experimental Biology is an annual meeting comprising nearly 13,000 scientists and exhibitors representing six sponsoring societies and 16 guest societies.

 
Heng-Fu Bu, PhD, research scientist in the Tan laboratory presented his work entitled “Milk fatglobule-EGF factor 8 is required for recovery of pancreas from cerulein-induced pancreatitis” at a research forum at Digestive Disease Week 2011 in May. Xiao Wang, MD, PhD, postdoctoral associate in the Tan laboratory presented her work entitled “Alcohol exposure impairs macrophage function on phagocytosis of apoptotic cells: role of milk fat globule-EGF factor 8” at a poster session at Digestive Disease Week 2011.
 

Arizona Grantsmanship and Clinical Research Skills Development Workshop

Researchers from Children’s Memorial, the Feinberg School and the Van Andel Institute partnered with Phoenix Children’s Hospital and the Arizona Hospital and Healthcare Association to present “Grantsmanship and clinical research skills development” sponsored by the Arizona Biomedical Research Commission. This two-day workshop was attended by medical residents, physicians, nurses, IT professionals and hospital pharmacists seeking to develop clinical research projects and basic scientists seeking involvement with clinical research.
Led by Holly Falk-Krzesinski, PhD, director of Research Team Support & Development at Northwestern University Clinical and Translational Sciences Institute, the grantsmanship seminar covered the topics of grant resources, funding agencies and opportunities, proposal planning and components, new NIH research strategy and specific aims sections of the proposal, proposal submission and the grant review process.
The clinical and translational research symposium, moderated by Mary J.C. Hendrix, PhD, addressed how to perform successful clinical and translational research; the resources and tools necessary for personalized medicine including XenoBase; the performance of evidence-based medicine for critical care; and the challenges involved in initiating and conducting clinical and translational research. The panel of experts included Michael Kelleher, MD, Associate professor of Pediatrics at the Feinberg School and chief medical officer, Children’s Memorial; Mark S. Wainwright, MD, PhD, Associate professor of Pediatrics — Divisions of Neurology and Critical Care, program director, Pediatric Neurocritical Care at the Feinberg School, and director of the Center for Interdisciplinary Research in Pediatric Critical Illness and Injury of the research center; and Craig P. Webb, PhD, Professor, Center for Cancer Genomics and Computational Biology and director, Program for Translational Medicine at the Van Andel Institute.

 
MolCellBiol2011 figure    

Pax3, a transcription factor and multifunctional regulatory protein, is expressed early in embryogenesis. In the nervous system, Pax3 is involved in neural tube closure, neural crest development, and peripheral neuron differentiation. In a study published in the February 2011 issue of Molecular Biology of the Cell, Shunsuke Ichi, MD and colleagues examined a mechanism for Pax3 regulation of Hes1 and Neurog2 activity, and thereby stem cell maintenance and neurogenesis. The group found that Pax3 acetylation, one of the key modifications that control gene transcription during embryonic development, results in decreased Hes1 and increased Neurog2 activity, thereby promoting sensory neuron differentiation. The study was conducted by the Developmental Neurobiology laboratory at Children's Memorial Research Center and the Division of Neurosurgery at Children’s Memorial Hospital.

 

DNA methylation is well known to have a profound effect on gene expression, with abnormal DNA methylation commonly observed in cancer and many other diseases. Traditionally, DNA methylation data analysis is based on the determination of the average methylation level (the percentage of methylated CpG). This conventional methodology is unable to dissect DNA methylation patterns, the combination of methylation statuses of contiguous CpG dinucleotides in a DNA strand. In order to better decode epigenetic data, Hehuang Xie, PhD and colleagues defined “methylation entropy” and exploited it to assess the variability of DNA methylation patterns that might be observed for a given genomic locus in a cell population. Applying this novel approach, they made three important discoveries: (1) within a cell population, methylation entropy varies among genomic loci; (2) among cell populations, the methylation entropies of most genomic loci remain the same; and (3) some tumors exhibit higher methylation entropies than normal tissues. The authors anticipate that the concept of methylation entropy and the analytical methods described will add a new dimension to methylation data analysis. The study, a collaboration among the Cancer Biology and Epigenomics Program and Stem Cell Core Facility at the research center, and the Falk Brain Tumor Center and Department of Pathology and Laboratory Medicine at Children’s Memorial, was published online in Nucleic Acids Research.

 

2010

 

Ben Katz Cynthia Mears  
 Ben Katz, MD  Cynthia Mears, DO  
A collaborative study between the University of Illinois at Chicago and Children’s Memorial sought to compare adolescents who do and do not recover from acute infectious mononucleosis in terms of fatigue severity and activity levels before, during and in the two years following infection. For both groups, physical activity levels declined and sleep increased as a result of having mononucleosis. Compared with their matched controls, adolescents with chronic fatigue syndrome reported significantly higher levels of fatigue at all points and spent much more time sleeping during the day six and twelve months following infection. The two groups did not differ significantly in terms of physical activity levels before, during or after infection. There was a consistent trend for decreased physical activity in the chronic fatigue syndrome group. The authors concluded that adolescents with chronic fatigue syndrome appear to be pushing themselves in an attempt to maintain similar activity levels as their peers, but pay for it in terms of fatigue severity and an increased need for sleep, particularly during the day. The study was published in the September 2010 issue of Archives of Pediatrics and Adolescent Medicine, and was the subject of an editorial in the issue. Ben Katz, MD and Cynthia Mears, DO, Associate professor of Pediatrics at the Feinberg School; director of Uplift School-Based Health Center and an attending in General Academic Pediatrics at Children’s Memorial; and a member of the Mary Ann & J. Milburn Smith Child Health Research Program of the research center, participated in the study.

 

CD8-positive T-cells often display strong human immunodeficiency virus (HIV) suppression in asymptomatic adults with HIV infection that diminishes as the disease progresses. Suppression of HIV replication by these cells (CD8 suppression) contributes to survival in adults and children younger than one year. Soluble CD8 suppression can also be seen in some older children with AIDS. The factor responsible, CD8-derived antiviral factor (CAF), acts at the level of HIV RNA transcription. Differential gene expression techniques have been used to define the gene(s) mediating this phenomenon in adults. Recently, CAF has been linked to exosomes secreted by CD8+ T-cells. Exosomes are vesicles secreted from multivesicular bodies into the extracellular environment when the bodies fuse with the plasma membrane. To compare the gene expression profiles from pediatric patients with each other, with those reported in two previous studies in adults and in those reportedly related to exosomes, a group led by Ben Katz used differential gene expression to study three older children with HIV infection, one of whom demonstrated soluble CD-8 suppression and two who did not. Eighteen differentially expressed genes were also seen in one adult study, and 38 such genes in a second adult study. In addition, two exosome components and some RNAs related to exosomal proteins were also differentially expressed. In children with HIV infection, the group found significant differentially expressed genes that correlated to those previously reported in studies in adults. The data lend support to the recent identification of CAF with exosomes secreted by CD8-positive T-cells. The study was published in the January 2011 issue of the Journal of Medical Virology. Katz is Professor of Pediatrics at the Feinberg School; Director of the International Travel Immunizations Program, Associate director of the International Adoptee Program and attending physician in Infectious Diseases at Children’s Memorial; and a member of the Clinical and Translational Research Program of the research center.

 

Katz and colleagues presented a paper entitled “Cytokine expression profiles characteristic of immune imbalances in persistent post-infectious fatigue” at Cytokines 2010: Cytokines in Infectious Diseases, Autoimmune Disorders and Cancer, the joint meeting of the International Cytokine Society and the International Society for Interferon and Cytokine Research, October 2010.

Katz and colleagues also presented an abstract entitled “Orthostatic tolerance testing in a prospective cohort of adolescents with chronic fatigue syndrome and recovered controls following infectious mononucleosis” at the American Autonomic Society meeting in November 2010.

 
Kelly Michelson, MD, MPH and colleagues began data collection in January for a pilot and exploratory project entitled “Evaluating family conferences in the Pediatric Intensive Care Unit”. The funding is from the National Palliative Care Research Center. The purpose of this project is to assess the feasibility of studying family conferences in the pediatric intensive care unit (PICU) and plan for a multi-center observational study of PICU family conferences. Michelson is Assistant professor of Pediatrics at the Feinberg School, attending physician in Critical Care at Children’s Memorial and a member of the Mary Ann & J. Milburn Smith Child Health Research Program of the research center.

Joel Frader 
Joel Frader, MD 

Michelson and Joel Frader, MD are co-authors of the chapter “Do not resuscitate decisions in pediatric patients” in Clinical Ethics in Anesthesiology: A Case-Based Textbook, Cambridge University Press, 2011, Gail A. Van Norman, Stanley H. Rosenbaum and Stephen Jackson, editors. Frader is Professor of Pediatrics and Medical Humanities and Bioethics at the Feinberg School; A Todd Davis Professor of General Academic Pediatrics; head of General Academic Pediatrics; Associate director of the Bridges Program — Pediatric Palliative and End of Life Care at Children’s Memorial; and a member of the Smith Child Health Research Program.

 Heart image

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.

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 
C. Shekhar
Mayanil, PhD

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.
 
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, 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 the Feinberg School; attending physician in Rheumatology at Children’s Memorial; and director of the Chicago City-wide FOCIS Center of Excellence in Clinical Immunology of the research center.
   

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.

 
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. 
 
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.

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.
 
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, 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.

 

2009

 
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.

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; Assistant professor of Pediatrics at the Feinberg School; and a member of the Neurobiology Program of the research center.

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.

   

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.
 
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.

Early-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, and the Mary Ann & J. Milburn Smith Child Health Research Program of the research center.

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, 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.

 

 

2008

 

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.  

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.

 Return to News Page