Preemies’ feeding Skills
A PublicAtion of The ReseaRch InsTITuTe aT naTIonwIde chIldRen’s hospITal
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
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
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.
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
contact us at
RIO shows that high school girls
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
*Fernandez WG, Yard EE, Comstock RD. Epidemiology of lower
extremity injuries among U.S. high school athletes. Acad Emerg Med.
research | 3
Samantha King, PhD
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
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
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
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
“Pneumococcus has to colonize the
airway before it can become infectious.
if we can prevent colonization, we can
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
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
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.
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.”
“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.
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
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?
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
Learn about more research
news and highlights at
research | 7
cRIB-sIde sTudIes IMpRove BaBIes’ eaTInG haBITs
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
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
“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
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.
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
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
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
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
A New Steroid-
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
used treatment for kidney diseases.
lthough admittedly unconventional by nature,
thE MoSt coMMon chilDhooD KiDnEY
Richard Ransom, PhD, principal investigator in the
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
12 | research
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
“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.
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
strong, very unpleasant side effects for children. consulting the
lead to weight gain, and can make children more
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.
“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
research | 15
Secondhand Smoke Signals
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
absorbed six times more nicotine than
pa I d
700 children’s Drive PERMit no. 777
columbus, ohio 43205-2696