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reSearch Magazine Issue 2

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This biannual publication, reSearch, is dedicated to the mission of informing and inspiring readers by highlighting scientific performance at The Research Institute at Nationwide Children's Hospital.

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reSearch Magazine Issue 2

  1. 1. Overseeing Nutrition cutting-Edge, crib-Side Research Accelerates Preemies’ feeding Skills research A PublicAtion of The ReseaRch InsTITuTe aT naTIonwIde chIldRen’s hospITal
  2. 2. SP Ri ng/SuMMER 2008 research is dedicated to the mission of informing and inspiring table of contents readers by highlighting scientific performance at the Research institute at nationwide children’s hospital. this publication is produced biannually by the Marketing and Public Relations Department at nationwide children’s hospital. fe at ure s 4 Tracking a sugar Thief to shed light on the powers of Streptococcus pneumoniae, Samantha King, PhD, and her lab are focusing on how these bacteria colonize the airway and how this colonization leads to disease. Recent research into the leadeRshIp bacteria’s unique ability to modify sugars has led Dr. King’s group to The Research Institute at develop a convicting theory: this bacterium is a thief. nationwide children’s hospital John a. Barnard, Md President 8 Facilitating Feeding through a one-of-a-kind program, Sudarshan Jadcherla, MD, is working to lauren o. Bakaletz, phd Vice President, Basic Sciences Research ensure that perinatal feeding disorders are curbed at the crib side and don’t continue beyond a baby’s stay in the nicu. Kelly Kelleher, Md, Mph Vice President, Health Services Research william e. smoyer, Md 12 a new steroid-sensitive cell? Vice President, Clinical and Translational Research When Richard Ransom, PhD, began his kidney-based research he didn’t Grant Morrow III, Md intend to contradict more than 30 years worth of well-accepted theory Medical Director regarding kidney disease. Yet that is exactly what he seems to be doing. daniel R. Mann Vice President, Research Administration and Operations e xt ras Katherine s. Milem 7 noteworthy Vice President, Research Business Services news about the Research institute and its faculty. research 16 secondhand smoke signals Writer and Editor the response of a young child’s cardiovascular system to secondhand smoke. Melissa hamilton Art Director on thE covER Tanya Bender Sudarshan Jadcherla, MD, oversees Noah Braden as he successfully bottle feeds. Photographers Through unique crib-side research, Dr. Jadcherla is helping babies (especially those Brad smith born prematurely) reach one of their most important developmental milestones: dan smith feeding orally. Manager, Research communications Jan arthur contact us at ResearchMagazine@nationwidechildrens.org
  3. 3. RIO shows that high school girls TM are more likely to experience a lower extremity injury playing soccer than in eight other sports.* More than 7 million U.S. high school students are at risk for becoming a statistic…all because they play a sport. It’s these sports statistics that Dawn Comstock, PhD, principal investigator in the Center for Injury Research and Policy at The Research Institute, focuses on. Dr. Comstock leads the National High School Sport-Related Injury Surveillance Study, the only nationally representative study of U.S. high school sport-related injuries. Certified athletic trainers from 100 nationally representative U.S. high schools use an internet-based data collection tool, RIO™, to prospectively report athletic exposure and injury data for athletes participating in nine sports (boys’ football, soccer, basketball, wrestling, and baseball and girls’ soccer, volleyball, basketball, and softball). Through RIO™ and evaluation of data from national emergency department data, Dr. Comstock’s research has shed light on injury related to rule breaking in sports, injuries obtained during practice versus in competition, injury related to wrestling, rugby, soccer, football, martial arts, ice hockey, lacrosse, field hockey, skating and injury to knees, ankles, lower extremities, and concussions. By monitoring patterns of injury and identifying sport- specific risk factors, the Center for Injury Research and Policy works to influence targeted, evidence-based interventions and in turn reduce rates of high school sport-related injuries. *Fernandez WG, Yard EE, Comstock RD. Epidemiology of lower extremity injuries among U.S. high school athletes. Acad Emerg Med. 2007 Jul;14(7):641-5. research | 3
  4. 4. Samantha King, PhD Tracking T he smeared, black lines spread sporadically across a thin, paper-like membrane may not look like much to the untrained eye, but to Samantha King, PhD, they are the trail of a thief she is spending a Sugar her research career trying to catch. As principal investigator in the Center for Microbial Pathogenesis at The Research Institute, Dr. King studies Streptococcus pneumoniae, (pneumococcus), a particularly crafty bacterium responsible for pneumonia, otitis media, sinusitis, bacteremia and meningitis. Thief To cause infection, pneumococcus first takes up residence in the nasopharynx. Yet, this entrance does not always ensure disease. “Pneumococcus colonizes about 50 percent of people asymptomatically,” said Dr. King. “Most times, the body will clear the colonization, but other times it will go on to cause InvesTIgaTIng disease. We really don’t understand how this happens.” BacTerIa’s To shed light on the powers of the pneumococcus, Dr. King and her lab are focusing on how these bacteria colonize body sweeT secreT surfaces and how this colonization leads to disease. Recent sTraTegy research into the bacteria’s unique ability to modify sugars has led Dr. King’s group to develop a convicting theory: this bacterium is a thief. 4 | research
  5. 5. Colonization is Key triCKs of a sugar thief Like all bacteria, pneumococcus has developed mechanisms One of the greatest mysteries surrounding pneumococcal to evade a host’s immune system. One of its most effective colonization pertains to the bacteria’s energy source. methods is its use of capsules, protective coatings on its exterior “The pneumococcus is completely dependent on sugars for surface. But pneumococcus doesn’t stop at one capsule type for growth,” said Dr. King. “Yet, free sugars are at a very low defense; it enlists 91 capsule types, each structured differently. concentration in the human airway.” Existing preventative measures for pneumococcus infection How is it able to survive and grow without its energy source? include a vaccination strategy targeting these capsules. Dr. King hypothesizes that pneumococcus steals to survive. However, vaccine effectiveness remains questionable. Dr. King’s previous research has shown that pneumococcus “The first marketed vaccine targeted 23 of the 91 capsules, but is highly capable of modifying different sugar structures by it didn’t evoke a good immune response in people most at risk: producing enzymes that cleave sugar strains found on the immunocompromised, children under 2 years of age, and surrounding molecules. Moreover, Dr. King’s lab studies the elderly,” said Dr. King. “There is now a conjugate vaccine have shown that once pneumococcus has freed sugars from that utilizes a carrier protein and targets seven capsules. It has surrounding molecules, it steals the sugar and uses it as an been highly effective and has significantly reduced invasive energy source. disease and colonization for those capsule types.” Yet in the complicated world of infectious disease, success is not always so simple. “The problem is that although we have successfully targeted seven capsule types, we have opened the airway to other capsule types that didn’t used to cause disease as frequently,” said Dr. King. “We’re changing the pattern of disease-causing serotypes.” “Pneumococcus has to colonize the airway before it can become infectious. if we can prevent colonization, we can prevent disease.” If science continues to use this capsule-based treatment strategy, Dr. King envisions a never-ending spiral. “Even if we produce a vaccine capable of targeting 11 to 13 capsule types, history is going to repeat itself and it is impossible to create a safe and effective vaccine with 91 conjugates,” she said. Even though there are few free sugars in the human airway, there are plenty of sugar-coated molecules to steal from. In addition to the battle with so many capsule types comes the “Basically everything secreted in the human body has sugars on ever-increasing issue of antibiotic resistance. “This is a classic them,” said Dr. King. “Your airway is covered by epithelial cells organism for antibiotic resistance. Pneumococcus is naturally which are covered in sugars; immunoglobulins that protect you transformable; it can take DNA from its environment and from disease have sugars on them; mucus and the mucin layer recombine it into its own genome.” that keeps the airway from getting dry and helps clear away With the obvious need for a new treatment strategy, Dr. King’s bacteria are largely composed of sugars.” lab has chosen to move away from focusing on how the bacteria Dr. King’s research offers the first evidence of a pneumococcal cause disease and move into a more understudied field: survival strategy and provides an experimental basis for colonization. “Pneumococcus has to colonize the airway before future research. it can become infectious,” she said. “If we can prevent colonization, we can prevent disease.” In addition to a survival strategy, sugar modification also may provide pneumococcus with an additional defense mechanism. research | 5
  6. 6. M D c C options, but right now, we need to understand to what extent these bacteria can modify sugars before we can consider using it as a preventative measure or treatment strategy,” she said. A Even as they work to prove their sugar-stealing hypotheses using human samples, there will most likely be more obstacles to over- come. “We suspect that there is a lot of redundancy in the bacte- ria’s system,” said Dr. King. “Growth is an important function for bacteria in terms of being able to colonize and cause disease. The bacteria probably have multiple ways to achieve growth.” FuTuRe IMplIcaTIons “These bacteria are able to colonize for months at a time, so Understanding sugar modification could highlight the powers of they must have mechanisms to modify function of host defense pneumococcus, but at the same time could have larger implica- molecules,” she said. tions in the realm of infectious disease. “Other bacteria live in the human airway and they are going to have to overcome some Dr. King also hypothesizes that removing sugars may also allow of the same problems,” said Dr. King. “By increasing our under- the bacteria to burrow through the mucin layer, adhere to the standing of how pneumococcus colonizes, I’m sure we’re going epithelial surface where they colonize, then move toward the to increase our understanding of how other pathogens colonize.” inner ear. Pneumococcus also may aid in clearing other bacteria from the airway by stealing their sugar shrouds that usually hide Dr. King’s research also may shed some light on hemolytic them from the host’s immune system. uremic syndrome (HUS), the most common cause of acute renal failure in children and a rare effect of pneumococcal infection. “Our attempt is to get the full picture of how these bacteria mod- By manipulating sugars found on the surface of red blood cells, ify sugars and then understand what effect sugar modification pneumococcus may trigger antibodies that cling to the red has on its ability to colonize and cause disease,” said Dr. King. blood cells and ultimately cause a harmful red blood cell cluster. These clusters could then cause two symptoms associated with a ThIeF noT yeT convIcTed HUS, damage to kidney cells and thrombocytopenia, a decrease Although Dr. King’s lab work has shown that pneumococ- in blood platelets. cus manipulates sugars in order to grow, these findings will ultimately need to be recreated using human samples. As they As sugar modification and colonization research grows, Dr. King learn more in the lab, Dr. King’s group will begin testing their expects to remain in the forefront. “We are building a foundation hypotheses using human epithelial cells and clinical isolates to become world experts in bacteria’s ability to modify sugar,” provided by the Section of Infectious Diseases at Nationwide said Dr. King, a foundation that could lead to sweet success. Children’s Hospital. burnaugh AM, frantz lJ, King SJ. growth of Streptococcus pneumoniae on Still, Dr. King says there is much more to learn. “In the long human glycoconjugates is dependent upon the sequential activity of bacterial term, we would like to see this information turned into vaccine exoglycosidases. J Bacteriol. 2008 Jan;190(1):221-30. Targeting ear Infections D uring early childhood, up to 83 percent of children experience at least one episode of middle ear pneumoniae, the most common bacterial agent of these infections. Meanwhile, other investigators in the center for influenzae. With assistance from commu- nity pediatricians, the center is collecting samples from both healthy children as well infection, also known as acute otitis Microbial Pathogenesis including lauren as those with chronic otitis media in an media. Dr. King continues to bring bakaletz, PhD, are targeting the second effort to understand the body’s response to science closer to an otitis media vaccine most common bacterial cause of otitis colonization as well as repeat infection. by unlocking the secrets of Streptococcus media: nontypeable Haemophilus 6 | research
  7. 7. Multiplying Muscle Treatment New Director Joins Center for Cardiovas cular and Pulmonary Research NIH Clinical and Translational Scienc Award Benefits Nationwide Children’ noteworthy | thE RESEARch inStitutE At nAtionWiDE chilDREn’S hoSPitAl Multiplying Muscle New Director Joins Center for Cardiovascular and investigators in the center for gene therapy have identified the role Pulmonary Research of a protein that increases muscle size and strength, potentially Pamela lucchesi, PhD, joins the Research institute as director of the leading to new clinical treatments to combat musculoskeletal center for cardiovascular and Pulmonary Research (previously the diseases, including Duchenne muscular dystrophy (DMD). center for cardiovascular Medicine). led by brian Kaspar, PhD, these studies focus on a protein called Dr. lucchesi has an international reputation in cardiovascular follistatin (fS). using a single injection, gene-delivery strategy research. her research interests focus on oxidant and inflammatory involving fS, investigators treated the hind leg muscles of mice. mechanisms of cardiac and vascular disease. She also currently Results showed increased muscle size and strength, quadruple that serves as a study section member for both the nih and the AhA of mice treated with proteins other than fS. the muscle enhance- and serves on the editorial board of four major cardiovascular ments were shown to be well-tolerated for more than two years. research journals. increased muscle mass and strength were also evident when this NIH Clinical and Translational Science Award strategy was tested using a model of DMD. Benefits Nationwide Children’s haidet AM, Rizo l, handy c, umapathi P, Eagle A, Shilling c, boue D, Martin Pt, in partnership with the ohio State university (oSu) and the Sahenk Z, Mendell JR, Kaspar bK. long-term enhancement of skeletal muscle mass and strength by single gene administration of myostatin inhibitors. Proc Natl Acad oSu Medical center, nationwide children’s hospital will become Sci USA. 2008 Mar 18;105(11):4318-22. part of a premier, national consortium funded by the national institutes of health (nih) aimed at transforming clinical and Is Bariatric Surgery Best During Adolescence? translational research. nationwide children’s hospital has been selected as one of only five institutions nationally to join a multi-institution clinical in october 2006 the nih launched the clinical and translational research study to understand the benefits and risks of bariatric Science Awards (ctSA) consortium in an effort to develop a new surgery in adolescents. discipline of clinical and translational research. When fully implemented in 2012, up to 60 institutions will be linked together this longitudinal study called teen-lAbS (longitudinal Assessment to energize the discipline of clinical and translational science. of bariatric Surgery) is funded by the national institutes of health. ultimately, this consortium will enable researchers to provide new the goal of this observational study is to identify changes in obesity- treatments more efficiently and quickly to patients. related health risks in the morbidly obese adolescent population and to compare outcomes to the more traditional adult population Since the program’s inception, only a handful of u.S. health sciences undergoing similar surgical intervention. Additional goals of this centers have been awarded ctSA grants, with the oSu/nationwide research are to determine the potential impact on psychosocial children’s collaboration being one of the few awarded this year. the impairments related to severe obesity. award totals $34.1 million and is one of the largest grants in the Medical center and the university’s history. teen-lAbS, led by Marc Michalsky, MD, at nationwide children’s, is being conducted in parallel with a study designed to examine in response to the ctSA grant, nationwide children’s, oSu similar outcomes in adult patients undergoing bariatric surgical Medical center and oSu’s seven health Sciences colleges will treatment. by comparing features of adolescent and adult bariatric partner together to create the center for clinical and translational surgery patients, research could help clarify medical and psychologi- Science (cctS). the cctS will create an environment to administer cal health outcomes of bariatric surgery. this comparison could lead the ctSA funds and provide additional administrative support and to better decision-making regarding appropriate timing of surgery funding opportunities. for young Americans whose health is increasingly threatened by extreme obesity. Learn about more research news and highlights at NationwideChildrens.org/research. research | 7
  8. 8. Facilitating Feeding cRIB-sIde sTudIes IMpRove BaBIes’ eaTInG haBITs f or some babies in the neonatal Feeding Disorders Program funded by coughing during and after feeds, intensive care unit (NICU), a grant from the National Institutes of regurgitation, failure to coordinate eating doesn’t come naturally. Health. This integrated program is the sucking and swallowing with breathing, It’s these babies that are most at only one in the world taking a multi- gastroesophageal reflux, irritability and risk for lifelong feeding issues organ perspective to understand the arching during feeds. These feeding dif- and assisted feeding methods. development of pediatric feeding ficulties can arise from a combination of disorders. Through this one-of-a-kind gastrointestinal, esophageal, behavioral, That’s why Sudarshan Jadcherla, MD, is program, Dr. Jadcherla’s specially designed neurological, structural, cardiorespiratory working to ensure that perinatal feeding research methods are helping babies and metabolic origins. disorders are curbed at the crib side and become hungry to feed. don’t continue beyond a baby’s stay in the Yet, no matter the range of symptoms NICU. As a neonatologist at Nationwide FaIluRe To Feed or causes, the desired objective is the Children’s Hospital and principal investi- Any infant that fails to eat orally is same. “For every baby diagnosed with a gator in the Center for Perinatal Research considered to have feeding difficulty. feeding disorder, the ultimate goal is full at The Research Institute, Dr. Jadcherla Symptoms of feeding difficulties include oral feeds,” said Dr. Jadcherla. is leading the Newborn and Infant apnea (difficulty breathing), spluttering, 8 | research
  9. 9. The earlier successful oral feedings begin the better. When Dr. Jadcherla and his colleagues began studying the origin of pediatric feeding disorders, they found that patients’ feeding issues started very early in life. In fact, if an infant doesn’t develop appropriate feeding skills early on, there is little hope for these skills to develop later in life. “We can help children with feeding disorders grow in other aspects, but we can’t make giant leaps with their feeding capabilities,” said Dr. Jadcherla. So when he decided to pursue his clinical and research interests, Dr. Jadcherla knew he would need to focus on perinatal pro- grams. “We can make the greatest impact during the first two months of their lives because this is when the largest trans- formation is going on in their behaviors and feeding skills,” he said. pReMaTuRe BaBIes need specIal caRe Dr. Jadcherla explains the process of his feeding studies to Noah’s mother, Kassie. As Dr. Jadcherla began trying to identify the mechanisms of feeding difficulties in chronic lung disease and neurological together and try to come up with the neonates and young infants, he found concerns. “Premature babies are even appropriate strategy.” that diagnostic methods were limited. more vulnerable because their central seeInG Is BelIevInG Several techniques had been imported and enteric nervous systems are not fully There are multiple ways to scientifically from applications in older children and formed, compared to mature infants,” investigate human diseases such as by adults, but Dr. Jadcherla questioned the said Dr. Jadcherla. “They have swallow- applying research methods to human accuracy and relevance of these methods. ing difficulties and often are receiving tissue samples or by utilizing animal intensive care.” “Healthy adults have well-regulated models. However, to study feeding neurological systems, including mature In addition to their underdeveloped difficulties in human infants, Dr. learned behaviors, and they can anatomy, premature babies are Jadcherla uses what he considers the regulate their feeding habits in a frequently on multiple medications, most important model: the human conscious manner. On the contrary, some of which repress the muscles of the infant. To properly obtain data regard- non-verbal babies are still developing digestive tract, impair swallowing skills ing babies with feeding concerns, Dr. and maturing,” he said. or airway protection skills. “All of these Jadcherla’s program utilizes diagnostic skills need to be working in order to help methods safe and effective for use in He also knew that these methods would with feeding,” he said. babies weighing as few as two pounds. be even more complicated for use in the patient population most at risk for feed- Premature babies also have other issues “Our methods have been peer reviewed, ing disorders: premature babies. A 2001 including neurological diseases and lung published and validated, but these study showed that twenty-six percent of problems all of which Dr. Jadcherla says techniques are very hard to do,” said premature babies experience swallowing play a role in successful feeding. “The gut Dr. Jadcherla. “The babies are so small dysfunction compared to 13 percent of interacts with the brain and the brain that we have to be extra careful. Since the general population of infants. interacts with the gut and both interact they are in such a fragile state, the babies with the lungs. There is cross communi- have to remain under cardiac monitor- Many neonates also experience cation. So, there is a need for integrated ing and we closely monitor their vital gastroesophageal reflux disease, mechanisms to link all of the organs signs during testing.” That’s why these research | 9
  10. 10. feeding studies are conducted at the crib He recalls a case of a heart transplant side, so the babies can receive all of their baby who had successful cardiac, usual care without disruption. respiratory and neurological outcomes post-transplant, but couldn’t eat. Her In the presence of the nurse and the health care team was considering a patient’s attending neonatologist, Dr. gastrostomy, a procedure in which a Jadcherla provides the baby with a plastic tube is inserted into the special feeding tube lined with advanced stomach through the abdomen and sensors that can capture the rhythm of used to deliver liquefied food to the muscular contractions throughout the digestive system. However, Dr. aero-digestive tract. Signals are gathered Jadcherla evaluated the baby and from the entire pathway including the found reflexes that were delayed mouth and all organs leading to the and some that were not developed duodenum, which is located just beyond properly. Her feeding strategy was the stomach. These signals are translated modified and after an eight-week into a graphic form and Dr. Jadcherla period, she was completely evaluates how these rhythms change. independent on oral feeds and went “We try to understand what is normal home without needing a gastrostomy. a recent landmark study by for a particular baby’s feeding and airway In fact, a recent landmark study by Dr. dr. Jadcherla and his team protection skills,” said Dr. Jadcherla. Jadcherla and his team at Nationwide “Once we understand where the feeding Children’s showed that these novel at nationwide children’s problems arise, at what level, what mus- diagnostic methods and multidisci- cle groups are involved, we can work to showed that these novel develop methods to modify outcomes.” plinary feeding strategies were able to transform 75 percent of babies with diagnostic methods and After this diagnostic study is complete, swallowing difficulties into oral feeders, a team of specialists including an 50 percent of whom didn’t need any multidisciplinary feeding tubes beyond discharge from the occupational therapist, nutritionist, strategies were able to neonatologist, pediatric gastroenter- hospital. Aside from the improved ologist, nurse and patient care assistant quality of life, this has major cost saving transform 75 percent of provide support for a rational, therapeutic implications as it has been estimated strategy based on Dr. Jadcherla’s findings that the health care costs for children babies with swallowing and recommendations. The team then on G-tubes is $46,875 for the first year, almost the cost of one year’s tuition at difficulties into oral feeders, works with the family to find the best method for delivering effective nutrition Harvard University. As a result of this 50 percent of whom didn’t including, when necessary, the use of study alone, $1.8 million in health care modified feeding strategies. costs related to G-tubes was avoided. need any tubes beyond Dr. Jadcherla says one of the most unique Not only is Dr. Jadcherla’s research discharge from the hospital. aspects of this program is that the studies helping to improve the health of occur in real time, in real babies. “The babies and saving them from invasive, strength of our approach is that there is costly procedures, but it is helping no guesswork. Seeing is believing.” build a foundation for understand- ing what is considered “normal” for usInG ReseaRch FoR premature babies. IMpRoved caRe There’s no guessing that Dr. As a result of advances in perinatal, Jadcherla’s research is capable of surgical and intensive care, many changing babies’ lives. immature and sick newborns are surviving more often than they would 10 | research
  11. 11. have in the past; therefore the field of MoRE AnSWERS nEEDED College of Wisconsin to study this perinatal feeding disorders is full of As Dr. Jadcherla continues to identify relationship. He and his team will also unknowns. “A premature baby is not undiscovered reflexes, he will also work continue to study the long-term effects expected to eat independently, but to better understand how feeding and of their overall research. under those circumstances, what is breathing are related. “The airway While the need for answers continues normal?” asked Dr. Jadcherla. develops from the esophagus to drive Dr. Jadcherla’s work, he says during the first month of embryonic To help determine “normal” functioning, he is truly fueled by the belief that his life and from the primitive gut Dr. Jadcherla also performs his motility research could help prevent feeding develops a long bud which develops studies on healthy premature babies, problems for babies and children, a into the lungs. There is an obvious those who have had an uncomplicated cause that hits close to home. relationship between the esophagus neonatal course. So far, he has docu- and the lungs,” said Dr. Jadcherla. “I’m greatly inspired by my own mented motility ranges of the esophagus “Also, the real activity of swallowing children who were born prematurely,” and the pharynx, but there is much left happens in the pharynx and it is very said Dr. Jadcherla. “Fortunately, my to learn. close to the airway. Therefore, the children are healthy and doing very “We still have not recognized all of the relationship between the pharynx well, but they have taught me what it reflexes involved with feeding. It’s a and the airway is critical in order to means to feed them and what it means very complicated process,” he said. develop safe feeding strategies.” He to bring them into good overall growth has received grants from the National and development.” Institutes of Health and the Medical apple Juice acidity study i n a recent study, Dr. Jadcherla used a product found be one of the reasons for frequent swallowing noted in at your local grocery store to examine the mechanisms younger infants. of gastroesophageal reflux (gER), a common condition Jadcherla SR, hoffmann Rg, Shaker R. Effect of maturation of the of prematurity. magnitude of mechanosensitive and chemosensitive reflexes in the premature human esophagus. J Pediatr. 2006 Jul;149(1):77-82. babies with gER often experience acidic reflux. Dr. Jadcherla and colleagues used apple juice made for babies to mimic the effects of reflux. Apple juice is slightly acidic and full of vitamin c (ascorbic acid). this approach allowed them to study the effects acid levels have on the esophagus and airway protection mechanisms of babies, such as in episodes of gER. they found that babies at different ages used different swallowing mechanisms in order to respond to levels of acidity in the esophagus. this may be due to the chemical sensory receptors in the esophagus of younger babies not recognizing the same ph levels as those in older babies. this maturation difference could research | 11
  12. 12. A New Steroid- Sensitive Cell? Richard Ransom, PhD, shows laboratory steroids and clinical steroids. hoW utiliZing StERoiDS in thE lAb coulD Yet that is exactly what he seems to be doing. By investigating the mechanisms of the kidney’s most specialized cell type, Dr. MiniMiZE thE EffEctS of clinicAl StERoiDS Ransom is shedding new light on kidney function and steroid in chilDREn, All bY unEARthing thE PoWER sensitivity. More importantly, he is searching for new ways to of thE KiDnEY’S MoSt SPEciAliZED cEll tYPE. reverse the damaging effects of steroids, the most commonly A used treatment for kidney diseases. lthough admittedly unconventional by nature, thE MoSt coMMon chilDhooD KiDnEY Richard Ransom, PhD, principal investigator in the DiSoRDER Center for Clinical and Translational Research at Of all of the conditions negatively affecting the kidneys, The Research Institute, doesn’t consider himself to Dr. Ransom’s research focuses on the one most common in be a troublemaker. So when he began his kidney- children: nephrotic syndrome. Nephrotic syndrome is a based research he didn’t intend to contradict more than 30 years label for a group of diseases that all cause the kidney filtering worth of well-accepted theory regarding kidney disease. system to leak, and it is one of the first signs of more serious kidney-damaging diseases. 12 | research
  13. 13. anaToMy oF a podocyTe as the kidney’s most specialized cell type, podocytes are essential to blood filtra- tion. Much like a foot, a properly functioning podocyte has a large, main body and then fans out to longer, spaced-apart digits. The secondary branches of the digits intertwine with others from adjacent podocytes, spreading all across the glomerular capillary. Their specialized shape allows for plenty of surface area between the digits, allowing for rapid filtration of blood. Beneath the podocyte shown here is the membrane that surrounds the glomerular capillary. Image courtesy of Smoyer WE & Mundel P, J Mol Med 76:172-183 (1998). Children with nephrotic syndrome have faulty filters in the urine. Each glomerulus contains a looped blood vessel that their kidneys. As the body’s blood filtering system, the is covered with a layer of cells called podocytes, one of the most kidneys remove excess water, salt and waste products. specialized, complex cell types in the human body. Healthy kidneys keep disease-fighting antibodies and In properly functioning kidneys, podocytes take on a unique protein in the blood, which helps the blood soak up water shape. Much like a foot (“pod” is Greek for foot) podocytes have from tissues. But kidneys with damaged filters may leak a large, main body and then fan out to longer, spaced-apart dig- protein into the urine causing swelling throughout the body. its. These digits are spread all across the glomerular capillary and Therefore, children diagnosed with nephrotic syndrome have their specialized shape allows for plenty of surface area between high levels of protein in their urine, low levels of protein in the digits, allowing for rapid filtration of blood. their blood, and swelling around their eyes, legs, hands or stomach. These children also become immunosuppressed In cases of nephrotic syndrome, however, the mechanism from loss of antibodies into their urine, and become more that keeps the digits spaced apart is disrupted and the cells susceptible to sometimes fatal, secondary infections. If squish together. With this unique shape disturbed, the protein continues to leak into the urine, parts of the kidney filtering surface area changes and protein flows freely through downstream of the filter become damaged, and this often the glomerulus, out of the kidneys and lost in the urine. leads to end-stage renal disease, a condition that requires dialysis or kidney transplant. Since changes in the shape of podocytes are directly related to the symptoms of nephrotic syndrome, Dr. Ransom has AMEnDing A 30-YEAR-olD thEoRY identified this as an important structure for studying the The foundation of nephrotic syndrome theory was developed in mechanisms of the disorder. In fact, he believes that the 1974 when researcher Robert J. Shalhoub classified nephrotic reason steroid therapy has been successful is, at least in part, syndrome as a disorder of the immune system. Shalhoub because glucocortocoids work directly to repair the shape and proposed that the overactivity of white blood cells known as function of podocytes. lymphocytes creates a toxin that damages portions of the kidney making it more permeable to protein. Steroids known And Dr. Ransom’s preliminary research supports this theory. as glucocorticoids have long been used as the primary When he applied steroids to an isolated podocyte in the treatment for nephrotic syndrome. The Shalhoub hypothesis laboratory, the steroids protected the podocyte from damage maintains that this steroid therapy works because steroids are and repaired previous injury. These findings begin to question deadly to white blood cells. the Shalhoub hypothesis, which indicates that steroids act only on white blood cells. Cultured podocytes in the laboratory are Although this theory-based treatment has been generally no longer attached to a glomerulus and therefore are no longer effective for more than 30 years, Dr. Ransom’s research in contact with blood flow or an immune system. findings have revealed possible shortcomings in the Shalhoub hypothesis. According to Dr. Ransom, there is an Further research also has provided Dr. Ransom with an idea overlooked, steroid-sensitive cell important in nephrotic of how steroids protect the podocytes. Podocyte foot syndrome: the podocyte. processes contain large amounts of a protein called actin that, as it does in muscles, can form contractile filaments. PRobing thE PoDocYtE When he treated the cultured cells with steroids, the actin As part of their filtering makeup, the kidneys are comprised of filaments became more resistant to actin-disrupting drugs. millions of tiny structures called glomeruli that filter blood from Dr. Ransom believes that steroids may influence the turnover research | 13
  14. 14. “The steroid regime these kids undergo is considerable and steroid therapy has very steroids can have psychological effects, can increase swelling, affect metabolism and susceptible to diabetes and osteoporosis at an unusually young age.” rate of actin filaments which constantly reassemble them- After receiving steroids for six to eight weeks, about 80 per- selves to maintain the podocyte’s “skeleton.” These actin cent of kids with nephrotic syndrome no longer have protein filaments may also exert force on the underlying capillary in their urine. However, many will later relapse and will be and control the fluid dynamics of the glomerulus. “The prescribed stronger doses of steroids to diminish the frequency shape of the cell is probably based on its ability to maintain and intensity of future relapses. This cycle can continue for properly organized actin filaments,” said Dr. Ransom. This is years since the average age of onset for nephrotic syndrome an important finding considering changes in shape lead to is 2. Most children will never grow out of the syndrome and changes in function, particularly in podocytes, which form will continue steroid therapy throughout their entire lives, one of the most complex structures of any cell in the body. or will go on to lose kidney function and will require dialysis and a kidney transplant. bREAKing thE StERoiD cYclE What do these preliminary findings mean for treatment of Thanks to a recent grant from the National Institutes of nephrotic syndrome? Dr. Ransom hopes they can lead to new Health, Dr. Ransom will be able to pursue animal models treatments for nephrotic syndrome that have fewer negative of nephrotic syndrome to help clarify the podocyte/steroid side effects than current steroid therapies. relationship. He plans to create a mouse model that expresses a highly sensitive steroid receptor only in podocytes. “We’ll “The steroid regime these kids undergo is considerable and try to affirm our hypothesis that if we give animals lower steroid therapy has very strong, very unpleasant side effects doses of steroids, they will be protected only if they have this for children,” said Dr. Ransom. Steroids can have psycho- mutant, highly sensitive steroid receptor in the podocyte,” logical effects, can said Dr. Ransom. increase swelling, affect metabo- Dr. Ransom also plans to join an upcoming study in which a lism and lead to group of clinicians using steroids to treat nephrotic syndrome weight gain, and will all modify their treatment strategies at the same time can make children in the same way. “Surprisingly, at least to a scientist, steroid more susceptible therapy can differ between clinicians in regard to dosage to diabetes and and scheduling regimen,” said Dr. Ransom. This study will osteoporosis at an provide a mechanism to accurately compare data of patients unusually young receiving steroid treatment, and will provide important age. Families and samples for research. patients can some- SticKing With ShAlhoub times find these While Dr. Ransom continues to try to improve treatment by side effects to be investigating podocytes, other elements of his research continue overwhelming. “I’ve talked to parents who feel that the on the pathway set forth by Shalhoub’s white blood cell theory. effects of the steroids on their kids are worse than the effects Some nephrotic syndrome patients do not respond to steroids at of the disease,” said Dr. Ransom. all and their kidneys continue to leak protein despite treatment. 14 | research
  15. 15. strong, very unpleasant side effects for children. consulting the lead to weight gain, and can make children more consortium A s a research scientist in a laboratory trying to understand the mechanisms of a human disorder, Dr. Ransom believes that steroids aren’t effective for these patients because they may have “faulty” white blood cells that produce too much of a protein Dr. Ransom says it is important that called p-glycoprotein. P-glycoprotein acts as a pump and discharges toxins and he gain insight from physicians who drugs from cells. It also can pump steroids out of cells as well, decreasing their diagnose and treat patients with effectiveness. nephrotic syndrome. that’s why he is a member of the Midwest Pediatric Through a multi-center clinical trial, Dr. Ransom and colleagues are collecting nephrology consortium. co-founded blood samples from patients before they receive steroids and after they by faculty at nationwide children’s conclude their first course of steroid treatment. They will then evaluate hospital, this consortium includes 27 the role of p-glycoprotein in steroid effectiveness. Do these children have pediatric nephrology programs differing amounts of p-glycoprotein in their white blood cells? Do their white throughout the Midwest. Membership blood cells produce an overabundance of p-glycoprotein when therapy starts consists of clinicians and research in order to pump out the substance? scientists who share their ideas, current findings and clinical samples with the Dr. Ransom says that one of the reasons the work with p-glycoprotein is intention of igniting multi-center clinical exciting is that if children do have elevated levels of this protein, there are and translational research into childhood commercially-available, FDA-approved drugs that are known to be inhibitors. kidney diseases. “If we can give a child a low-toxicity drug that inhibits p-glycoprotein which allows us to give them a tenth as much steroid, that would be a major step “since my focus is trying forward,” he said. to understand the basis This research could also provide a step forward in regard to understanding for a real phenomenon, the role of podocytes in other diseases. “The health of the podocyte is clearly critical in diseases that lead to kidney damage such as diabetes and HIV,” said why therapy works, what Dr. Ransom. the disease is doing, I Still, Dr. Ransom keeps his current focus in perspective. “The primary goal of this feel fortunate in being research is to minimize the effects of steroids in the lives of children,” he said. associated with the consortium,” said dr. Dr. Ransom’s recently published works: Ransom Rf. Podocyte proteomics. Contrib Nephrol. 2004;141:189-211. Ransom. “It puts me in Ransom Rf, vega-Warner v, Smoyer WE, Klein J. Differential proteomic analysis of proteins induced by contact with clinicians glucocorticoids in cultured murine podocytes. Kidney Int. 2005 Apr;67(4):1275-85. across the country who Ransom Rf, lam ng, hallett MA, Atkinson SJ, Smoyer WE. glucocorticoids protect and enhance recovery of cultured murine podocytes via actin filament stabilization. Kidney Int. 2005 Dec;68(6):2473-83. recognize the importance of research for advancing clinical treatment.” research | 15
  16. 16. Secondhand Smoke Signals J udith Groner, MD, and collaborators in the adolescents ages 9 to 14 from the same level Center for Cardiovascular and Pulmonary of parental smoking. Toddlers in the homes of Research have conducted the first study to smokers not only had higher levels of nicotine, examine the response of a young child’s but also had higher levels of markers for cardiovascular system to secondhand smoke. cardiovascular disease. According to the study, children ages 2 to 5 Presented at the American heart Association’s 48th Annual conference on cardiovascular Disease Epidemiology and Prevention. absorbed six times more nicotine than 2013 nonPRofit oRg. u.S. PoStAgE pa I d coluMbuS, oh 700 children’s Drive PERMit no. 777 columbus, ohio 43205-2696

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