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TRAUMATIC BRAIN INJURY ECONOMIC COSTS
J. Mick Tilford, Ph.D., completed a cost-effectiveness analysis of technological improvement in the treatment of pediatric traumatic brain injury (TBI). The analysis was the culmination of a research project awarded to ACHRI by the Health Resources and Services Administration entitled “Economic Evaluation of Intensive Care Services for Pediatric Traumatic Brain Injury Patients.” The research project first investigated improved survival for hospitalized pediatric patients with TBI. Then, the outcomes of surviving children were measured in economic terms. Finally, the cost per quality adjusted life year gained was calculated in relation to hospital and rehabilitation costs. The economic analysis showed that on average, improving survival of children hospitalized with TBI appears to have benefits that can be justified in relation to the costs of improving survival and the costs of rehabilitation care. In other words, research that enables clinicians to improve survival of children following a traumatic brain injury appears to be a good investment. Findings from the project were published in Critical Care Medicine, Neurocritical Care, and the Journal of Trauma.

NURSING RESEARCH
Debra Jeffs, PhD, RN, was the author of a journal article entitled, “A Pilot Study of Distraction for Adolescents During Allergy Testing,” published in a special issue on pediatric pain in the Journal for Specialists in Pediatric Nursing, 12(3), July 2007. This study informs us about the individual nature of perceived pain and anxiety associated with a commonly performed procedure as well as the benefit of distraction. Because tailoring nonpharmacologic interventions, such as distraction, to the individual might increase effectiveness in reducing procedural pain, Dr. Jeffs is proposing a study of the effectiveness of choice in intervention on procedural pain perception. This work would be especially useful for repeated painful procedures, such as burn wound care that is performed in the ACH Burn Center.

Dr. Jeffs’ work with the Nursing Research Alliance of the Capital District in developing online modules on evidence-based practice for staff nurses was presented at the at the 6th Annual Evidence-Based Practice Conference in San Antonio, TX, on July 12-14, 2007. The online education modules explain the EBP process and how to move evidence into practice by providing nurses with activities to undertake with an EBP mentor. The modules are part of the learning process in the EBP Academy developed by Dr. Angela Green and the EBP committee at ACH.

INJURY PREVENTION
The All Terrain Vehicle Injury Group has completed a community ATV injury prevention campaign. The findings include that even very young children in rural areas commonly ride all terrain vehicles, but the use of safety equipment, such as a helmet, is very uncommon.

Drs. Mary E. Aitken and James C. Graham are studying unique dissemination venues for all terrain vehicle safety education messages to reach ATV users in rural communities.

Drs. Mary E. Aitken and Stephen Bowman are using a multi-faceted approach to increasing motor vehicle safety among young drivers. Components include physician advice, applying principles of graduated driver’s licenses in the family, and a multi-disciplinary coalition.

Dr. Mary E. Aitken and public health doctoral student Jennifer Shaw are using qualitative research to develop an Arkansas-specific tool kit to increase the number of children in grades K–8 who safely walk and ride bicycles to school.

Dr. Mary E. Aitken and Beverly Miller are conducting a CDC-funded project to disseminate booster seats using community-based, tailored education for rural children using community sports programs. The baseball themed program, entitled “Strike Out Child Passenger Injury,” will be implemented in rural communities in Arkansas, Indiana, Illinois, and Alabama.

With the support of Arkansas Children’s Hospital and ACHRI, CARE researchers have developed the Injury Prevention Center to better combat pediatric injury in Arkansas. The Center will form the basis for future educational, advocacy, and research programs.

CHILDHOOD OBESITY
Dr. Judy Weber found a significant decrease in percent body fat in 3rd and 4th grade children participating in a 9-month school-based obesity prevention program in the Little Rock School District. The intervention included a daily walking program, classroom exercise breaks, Personal Best Challenges (e.g., jump roping, shuttle runs, obstacle courses, etc.), changes in competitive foods (e.g., foods provided for rewards and parties in the classroom), changes in school meals (e.g., from 2% to 1% and skim milk and choices of fruits and vegetables), and the establishment of a School Wellness Committee. School staff were also encouraged to walk and participate in healthy lifestyle changes.

LUNG FUNCTION
The infant Pulmonary Lab continued an ongoing study to test healthy and wheezy infants from 1 month to 3 years of age. When completed, it will possibly be one of the largest studies of this age-group that would provide an almost permanent infrastructure of Normative data for infants within Arkansas, the USA and abroad.

The Lab uses state of the art along with novel including patented techniques in infant lung function testing. Similar to other large Medical Centers in the US, the lab also provides a unique service by testing patients with chronic lung disease such as cystic fibrosis in order to optimize their clinical care. Since 1996, it is the first and remains the only lab in the State that has been performing comprehensive lung function testing in infants.

ASTHMA AND ALLERGY
Dr. Tamara Perry, a Robert Wood Johnson Foundation Faculty Scholar, began a project evaluating asthma in the Delta region of Arkansas and impact of environmental factors on asthma. Dr. Perry’s preliminary findings suggest high rates of inadequately controlled asthma as evidenced by activity limitation, medication use, and increased healthcare utilization among children with asthma living in the Delta Region of Arkansas.

Dr. Perry and colleagues examined the relationship between school environmental conditions and classroom aeroallergen concentrations in the 33 Pulaski County Head Start (HS) Program sites. Their findings suggest that aeroallergens were commonly detected in Pulaski County HS center classrooms with dog and mouse allergens detected in 100% of centers. Median classroom allergen concentrations were low, and classroom characteristics were not strongly predictive of increased allergen exposure.

Dr. Amy Scurlock, in collaboration with the Lung Cell Biology Laboratory (Drs. Stacie Jones and Richard Kurten), continued work to develop a mouse model to study the association between peanut sensitization and development of airway hyperresponsiveness and asthma. The goal of this model is to help define the basic immune mechanisms that result in peanut allergy and airway sensitization.

BIRTH DEFECTS
Dr. Sarah Blossom, working with the Center for Birth Defects Research and Prevention group at ACHRI, conducted a preliminary study demonstrating cytokine alterations in plasma of women with a congenital heart defect-affected pregnancy. These data suggest that maternal immune dysfunction may play a role in the development of congenital heart defects. Dr. Blossom was awarded a CUMG grant entitled Establishing a link between maternal immune dysfunction and congenital heart defects (December 2007-December 2009) to further study immune function in women in mid trimester diagnosed with fetal congenital heart defect.

Dr. Charlotte Hobbs and colleagues have determined that the occurrence of neural tube defects in Arkansas have decreased significantly since the introduction of local, state and national public health intervention efforts. The Arkansas Center for Birth Defects Research and Prevention, which is part of ACHRI, played a leading role in the local and statewide prevention efforts.

Throughout Arkansas, the Arkansas Center for Birth Defects Research and Prevention staff have conducted over 800 home visits and determined that women who have had pregnancies affected by neural tube defects, heart defects, and limb defects have biomarkers indicating that they may be exposed to chronic oxidative stress. The researchers know that oxidative stress impairs the normal development of the fetus. The findings from their study may be used to provide more targeted and effective preconception care, which will result in more babies being born healthy.

Dr. Charlotte Hobbs and colleagues discovered that women who have had offspring with congenital heart defects have alterations in folate-related metabolism. This finding has implications for the etiology of congenital heart defects and will contribute to the knowledge base on which to build more targeted and comprehensive preconception care.
With their collaborators in the National Birth Defects Prevention Study, the Arkansas Center for Birth Defects discovered that women who have lifestyle exposures, such as smoking, obesity, and diabetes, that increase oxidative stress, are more likely to have pregnancies affected by birth defects.

Dr. Charlotte Hobbs and researchers developed a clinical algorithm based on sophisticated statistical modeling that may used to identify women who are at high risk of having infants with birth defects. Although, this algorithm is in the early stages of development, it has the potential to provide a basis for personalized preconception care.

Dr. Charlotte Hobbs was awarded a $3.9 million grant from the National Institute of Child Health and Human Development to identify lifestyle exposures and common genetic variants that increase the risk of congenital heart defects. Using cutting edge genomic technology provided by ACHRI, she will have the ability to discover new risk factors the impact of which may be modified prior to conception to optimize pregnancy outcomes.

Using data from the National Birth Defects Prevention Study, Dr. Sadia Malik and colleagues investigated the association between congenital heart defects and maternal smoking. They found that maternal smoking and tobacco exposure during pregnancy are associated with an increased risk of congenital heart defects, especially septal and right-sided obstructive defects.

Using data from the National Birth Defects Prevention Study, Dr. Sadia Malik and colleagues addressed the hypothesis that infants with congenital heart defects are more likely to be small for gestational age than infants without congenital heart defects after controlling for selected maternal and infant characteristics. They found that infants with congenital heart defects are approximately twice as likely to be small for gestational age as control subjects.

SEXUAL-RISK PREVENTION
The Parents Matter Program, a parent-based, sexual-risk prevention program for African American pre-adolescents, was evaluated in a randomized controlled trial. The program was developed by Dr. Nicholas Long and colleagues. Results provided preliminary evidence for the efficacy of the parenting program. The CDC, sponsor of the study, is in the process of a national dissemination of the parenting program. The program is also being implemented in Africa.

SEXUAL ABUSE
Jerry G. Jones, MD, and Toss Worthington, RNP, in the Center for Children at Risk reported that 25% of girls who required surgical repair of genital and anal injuries were sexually abused or assaulted. When injuries are not due to an MVA, sexual abuse or molestation should be considered in addition to straddle injuries, and appropriate consultations should be requested when indicated.

ENVIRONMENTAL TOXICANTS
Children are particularly vulnerable to exposure to environmental chemicals. It has been found that approximately 10% of children 6-10 years of age have detectable levels of trichloroethylene, a common environmental chemical, in the blood. To determine the impact of perinatal trichloroethylene exposure, Dr. Sarah Blossom exposed mice throughout development (pregnancy and early life) to low levels of trichloroethylene. The offspring exhibited altered immune function. Remarkably, the young mice also showed abnormal social behavior and increased biomarkers of oxidative stress in the brain and developing immune system. These studies could potentially pave the way for a novel mouse model of autism and will be expanded through collaboration with Dr. Jill James’ laboratory.

Dr. Blossom has also been selected to present these findings in an oral platform presentation at the annual Society of Toxicology meeting (March 2008).

Dr. Horacio Gomez-Acevedo is developing mathematical models for the alterations in the programmed cell death (apoptosis) of T cells during the exposure of mice to trichloroethylene. The modeling will produce computer simulations that can test an experimental hypothesis of treatment after trichloroethylene exposure. This approach will be expanded to incorporate more aspects of the autoimmunity induced by this contaminant.

PEDIATRIC ANESTHESIOLOGY AND PAIN MEDICINE
Dr. Saif Siddiqui and colleagues participated in a clinical trial to evaluate the safe and effective dose of medication used during patient intubation.

Dr Persis Shroff and colleagues published a review of the anesthetic management of patients with pediatric vascular lesions.

Dr. Michael Schmitz and colleagues are participating in a clinical trial to evaluate the safe and effective dose of oral hydromorphone on pediatric post-operative pain.

Dr. Luis Zabala and colleagues participated in a NIH trial to determine the safe and effective use of sodium nitroprusside in pediatric patients undergoing surgery.

Dr. Saif Siddiqui and colleagues completed a retrospective review of the safety and effectiveness of epidural anesthesia in patients who underwent surgical treatment for empyema.

Dr. Anna Maria Onisei is in the process of conducting a review of ACH’s experience with robot-assisted laparoscopy.
Dr. Hatem Al-Takrouri and colleagues conducted a three-year retrospective review of the use of Aprotinin to reduce blood loss during spinal surgery.

Dr. Michael Schmitz and colleagues are studying clotting factors in pediatric cardiovascular surgery patients and the effect that certain medications have on a patient’s ability to form blood clots.

Dr. Michael Schmitz and D’Ann Pierce collaborated on a survey of parental use of the Internet as a resource for healthcare information.

TREATMENT OF MALNUTRITION
Dr. George Fuchs and colleagues continued research aimed finding effective ways to treat severe malnutrition and to reach the many severely malnourished children for whom treatment is not accessible. In a study conceptualized by Dr. Fuchs, the researchers demonstrated that children with severe, complicated malnutrition can be effectively and safely managed on a daily care basis. The study was conducted in an urban health clinic in Dhaka, Bangladesh. The findings were published in the Journal of Tropical Pediatric, 53:171-8, 2007.

CHLAMYDIA
Researchers in the Chlamydia Research Group at ACHRI have developed a new mouse model to investigate the initiation of the inflammatory response in the female genital tract following infection with Chlamydia. The inflammatory response is the major cause of pathology in this infection, but there is little known about the mechanism by which the bacteria initiate this response. This is the first model in which these mechanisms can actually be investigated in the animal within the first 24 hours after infection. The team is already describing events that occur within 3 hours of infection.

Using a guinea pig model of Chlamydia infection in the male, the research team has been able to characterize the immune response in the male genital tract. These are the first data describing in detail the local immune response in the male genital tract, as no other animal model exists that permits this level of detailed examination. They have evidence in the animal model that immunity to reinfection is stronger in the male than in the female and are using this information to gain insights into why this is the case.

In a study of immunoregulatory networks in Chlamydia genital tract infection, Dr. Amy Scurlock and her colleagues are examining the expanding diversity of CD4 T-effector lineages following Chalmydia genital tract infection. Their work thus far suggests that the newly described T-helper 17 response may play a role in the development of oviduct pathology following infection, particularly in the absence of the Th1 cytokine Interferon-gamma, which has previously been implicated as the primary player in both clearance of infection and development of pathology. This work is currently supported by the Marion B. Lyon New Investigator Award, and Dr. Scurlock has resubmitted her application for a NIH K08 Mentored Clinical Scientist Award in March 2008.

In a collaborative project on the immunopathogenesis of Chlamydia Trachomatis genital tract infection with Jennifer Woods, MD, of the ACH Adolescent Center, Dr. Scurlock and colleagues are examining the factors that predispose adolescent women who present for treatment at this center toward adverse outcomes following chlamydial infection. In addition, they are examining the novel hypothesis that chlamydial persistence in the gastrointestinal tract may predispose toward recurrent infections, thus increasing the risk of Fallopian tube scarring, ectopic pregnancy, and infertility. This project has resulted in an NIH subcontract with Dr. Patrik Bavoil on a study titled “Polymorphic Membrane Proteins of Chlamydia Trachomatis” in which they are examining the human antibody responses toward these proteins.

PEDIATRIC CLINICAL PHARMACOLOGY AND TOXICOLOGY
In 2007, the Pediatric Pharmacology Research Unit (PPRU) at Arkansas Children’s Hospital completed its 14th year as a NIH site for pediatric pharmacology studies. The ACH PPRU is one of 13 centers throughout the United States that serves as a locus for the conduct of clinical research studies in children with the goal of optimizing drug therapy and safety for infants, children and adolescents. The PPRU currently has 12 active studies across a range of disease areas. Recent studies have focused on the pharmacology of anti-infectives, anti-convulsants, antihistamines, anti-hypertensives, and immunosuppressant drugs. The ACH PPRU collaborates with a wide number of investigators across the ACH campus in the performance of these drug studies. Other studies ongoing within the PPRU include examination of novel methods for the measurement of blood pressure in children and novel endpoints for measuring drug toxicity in children. Dr. Laura James is the Principal Investigator for the PPRU and Dr. Thomas G. Wells serves as co-investigator. Acetaminophen toxicity is the leading cause of acute liver failure in adults in the United States today. The Food and Drug Administration estimates that between 400 and 500 deaths occur annually in the United States secondary to acetaminophen overdose. Acetaminophen overdose is a major cause of drug overdose in adolescents, and over 100,000 telephone calls are made to poison control centers annually for acetaminophen overdose. In 2007, Dr. Laura James reported new data regarding the detection of biomarkers of acetaminophen toxicity in adults, children, and adolescents with acetaminophen overdose. Using a highly sensitive assay for the detection of acetaminophen protein adducts, her laboratory found that these biomarkers may be detected in human sera up to 10 days after a life-threatening overdose of acetaminophen. The current method for diagnosis of acetaminophen overdose relies upon measurement of high levels of acetaminophen in peripheral blood. High levels of acetaminophen are typically only present for 24 hours after an overdose. Measurement of the acetaminophen protein adduct biomarker offers a considerable advantage over the current method used for the diagnosis of acetaminophen overdose.

Drs. Dean Roberts and Laura James received an ABI award in 2007 for the development of proteomic approaches for the identification of specific protein adducts in acetaminophen overdose patients. These investigators, along with Dr. Jack Hinson, and investigators from UAMS and NCTR, also applied for an R01 in the fall of 2007 for a multicenter study to identify specific protein adducts in acetaminophen overdose patients.

Dr. James was also awarded an R01 grant (grant based at UAMS) to examine mechanisms of liver repair following acetaminophen overdose in the mouse. This grant will focus on the development of novel therapies for the treatment of acetaminophen overdose.

SURGERY
Dr. Sam Smith, Interim Chairman of the Department of Surgery at UAMS and Chief of Pediatric Surgery at ACH, and colleagues recent accomplishments include 1) development of preterm and term experimental diets for prevention of neonatal infections and necrotizing enterocolitis; 2) researching the association between Lewis gene blood group secretor status and necrotizing enterocolitis in neonatal intensive care unit infants at ACH; 3) the use of ultrasound by surgeons as a diagnostic tool in empyema; 4) prospectively studying children hospitalized following ATV injury; 5) study-based development of a working algorithm for the management of pediatric traumatic injuries involving pancreas, heart, kidney and penetrating torso injuries; 6) study-based definition and management of Atypical malrotation; 7) multi-institutional comparison and evaluation of laparoscopic and open pyloromyotomy; 8) examination of the emergence of MRSA infections in community-acquired soft tissue infection in pediatric patients; and 9) advancement in the teaching and utilization of the DaVinci Surgical System in robot assisted laparoscopic surgery.

NUTRITION
Research in Dr. Rosalia CM Simmen’s laboratory has shown that consumption of soy-rich foods can change lipid metabolism in fat cells of the developing mammary gland of young prepubertal rats, to favor decreased lipid synthesis. Given that 1) dietary intake of soy-rich foods is correlated with decreased breast cancer risk in adulthood, 2) soy may be anti-obesegenic, and 3) obesity is a risk factor for breast cancer, her laboratory’s findings suggest how diet can alter mammary gland development in young females to decrease adult risk for breast cancer. This study was reported at the Annual Meeting of the Endocrine Society held in Toronto in June 2007.

Dr. Rosalia CM Simmen and her group have found that two bioactive components of soy foods, namely the soy isoflavone genistein and the soy peptide lunasin can affect the way in which a tumor-cancer causing protein functions in normal mammary epithelial cells. Her studies demonstrated that in the presence of these factors, the protein called β-catenin is prevented from moving to the nucleus of cells and instead is tied up in the cell membrane in complex with the protein E-cadherin, resulting in decreased proliferation of mammary epithelial cells. Breast cancer is caused by uncontrolled mammary epithelial cell growth. This study will be presented at the Experimental Biology Annual Meeting in San Diego in April 2008 and is being carried out in collaboration with researchers from UC-Berkeley.

CANCER
Dr. Rosalia CM Simmen and her group published findings that endometrial carcinoma resulting from increased activity of the estrogen receptor may be caused by loss or decreased expression of a nuclear protein called Krüppel-like factor 9 (KLF9). In follow-up studies, they found decreased expression of the KLF9 gene in more advanced human endometrial tumors (Stages 2-4) compared to normal human endometrial tissues or Stage 1 endometrial tumors. This study will be expanded using rat models of endometrial carcinogenesis that are being developed with recent funding from the ACHRI/ABI program.

Dr. Rosalia CM Simmen and her group have found that the uterus exhibits increased sensitivity to the pregnancy hormone progesterone in the presence of the nuclear protein Krüppel-like factor 9 (KLF9). They found that KLF9 forms a complex with the receptor for progesterone in uterine cells and that this interaction results in increased expression of genes involved in the preparation of the uterus for embryo attachment. The findings of this study, funded by the National Institutes of Health, have important implications in increasing pregnancy success. Moreover, these findings may also provide new strategies for the treatment of several pathological states of the uterus including uterine endometrial carcinoma, endometriosis, and leioyomyoma, since these diseases are partly caused by abnormal insensitivity to progesterone.

Dr. Reza Hakkak’s laboratory focus is on developing an animal model that investigates the relationship between obesity and risk of breast cancer development. Dr. Hakkak published his findings that obesity can increase the risk of breast cancer development. He developed a model and used ovariectomized Zucker rats (as an experimental model that mimics obese postmenopausal women) to study DMBA-induced mammary tumors. Dr. Hakkak’s results suggest that adipose tissue-derived estrogen in obese animals may be sufficient to promote DMBA-induced tumors in this model. These results suggest that obesity in postmenopausal women may increase breast cancer risk due to increased breast tissue exposure to adipose tissue-derived estrogen. Dr. Hakkak is currently investigating the mechanisms for this mammary tumor promotion and the possibility of dietary intervention.

ANTIHYPERTENSIVE DRUGS
Dr. Wells continued his work ensuring that antihypertensive drugs are studied and labeled for use in children by the FDA. He and his colleagues have been participating in several antihypertensive trials this year and published preliminary data on the pharmacokinetics, dosing, and safety of valsartan in children. The FDA accepted the proposed changes in the label, and now valsartan will have pediatric dosing information in the Physicians’ Desk Reference and in common pediatric drug references. The researchers also published data from the lisinopril study that Dr. Wells helped Merck design several years ago. Lisinopril is now also labeled for use in children. They are in the process of studying several additional drugs (confidentiality issues prevent disclosing which ones). They have also continued to investigate better methods for studying antihypertensive drugs in children and have been working with one pharmaceutical company to develop a pediatric formulation for an antihypertensive (the first one to be marketed in children in the past 30 years).

EMERGENCY MEDICINE
Dr. James Graham and colleagues studied the preparedness of ambulances across the United States for the care of children in mass casualty or disaster situations and found important deficiencies. These findings were published in Pediatrics in 2007. This group is now examining emergency department preparedness for care of children in disaster situations.

A group is studying the triage or initial assessment of children in emergency departments. Persons coming to emergency departments commonly are initially assessed or triaged and categorized according to severity of illness. Because of the challenges in assessing infants and children, this initial assessment can be difficult in pediatric patients. The aim of this research would be to perform better initial assessments of children in the emergency department.

Dr. Graham and colleagues are examining the increasingly common and serious problems of emergency department overcrowding. The researchers completed two studies examining the underlying causes of emergency department overcrowding finding that there is a strong relationship between the number of very sick children in the ER and overcrowding. The number of nonurgent patients was not strongly related to measures of overcrowding.