Aug 15 2014

Forced Looping Viable Strategy to Reverse Globin Switch

globinInvestigators at The Children’s Hospital of Philadelphia are exploring a new gene therapy approach that aims to reactivate the production of fetal hemoglobin as a potential intervention for patients with sickle cell disease. In the U.S., it is estimated that sickle cell disease affects 100,000 newborns, especially Hispanic-Americans and African-Americans.

The inherited disease distorts the red blood cells into a sickle shape, like the letter “C,” that blocks blood flow and damages blood vessels and many organs. A sickle cell gene mutation tells the body to make a defective type of hemoglobin, which is the oxygen transport protein in red blood cells.

Pre-empting the effects of this sickle cell gene mutation has been a focus of CHOP hematology researcher Gerd A. Blobel, MD, PhD, and the August edition of Cell reported his novel findings.  Dr. Blobel and his co-authors described how they altered the genetic architecture behind a developmentally controlled process called hemoglobin switching.

A form of hemoglobin that has anti-sickling properties is made only during the fetal period when red blood cells are produced by the liver. Shortly after birth, a transition occurs that silences the fetal globin genes as the bone marrow gradually takes over blood formation. Gene expression shifts to mostly create the adult form of hemoglobin, which in sickle cell disease will be the variant type.

Adult hemoglobin (HbA) almost completely replaces fetal hemoglobin (HbF) within six months after birth, which helps to explain why patients with sickle cell disease do not experience symptoms as newborns. It has been known for a long time that patients with sickle cell disease who have higher ratios of HbF tend to experience a milder course of the disease.

“A major driver in the field for many years has been to understand the molecular basis and the machinery that controls that switch,” Dr. Blobel said. “The goal is ultimately to overcome the silencing of the fetal globin genes and turn them back on.”

His research team’s particular strategy to manipulate gene expression not only elevates the amount of HbF but also downregulates the amount of faulty HbA, thereby reducing the sickle cell inducing properties of the mutated form of HbA.

The current study employs artificial zinc finger protein technology that Dr. Blobel and colleagues adapted for use in hemoglobin regulation and described in Cell two years ago. At the time, the zinc finger proteins were engineered in a way that they locate to specific sites on the chromosomes and foster contacts between chromosomal regulatory elements called promoters and enhancers that reside very far apart on the chromosome. This juxtaposition led to the formation of a chromosomal loop.

“Our 2012 study was the first in which such looped gene contacts were produced at a normal gene in its native location,” Dr. Blobel said. “We thought, now that we have this useful system, let’s explore whether it can be put to therapeutic use.”

In the present study, the researchers showed that they can use forced gene looping to override the stringent developmental gene expression of the globin gene cluster, which is composed of embryonic, fetal, and adult type genes responsible for the creation of hemoglobin. During development, a powerful enhancer for the expression of all these genes, called the locus control region (LCR), physically contacts the embryonic, then fetal, and later the adult genes via chromatin looping.

Dr. Blobel’s team designed zinc fingers in a way that they would promote looped contacts between the LCR and the fetal genes in adult red blood cells. This approach worked well and indeed enhanced the expression of fetal genes and reduced the level of the adult type genes. In the context of sickle cell disease, this would be a double benefit since both high fetal gene expression and low levels of the mutated toxic form of adult hemoglobin would ameliorate the disease.

“This is a novel way to manipulate gene expression via altering chromatin architecture,” Dr. Blobel said.

The researchers carried out the experiments in cultured blood cells from mice and humans. The next step is for the team to use a pre-clinical model to further test their strategy. This involves the use of genetically engineered mice bearing the human globin genes (including the sickle cell anemia gene mutation) in place of the mouse genes. These animals have manifestations of sickle cell disease similar to human patients. Blood stem cells from these mice will be modified with a viral gene transfer vector that expresses the zinc-fingered looping protein, and then used in bone marrow transplants to see if it can correct the disease in the animal model. If this is successful, the long-term goal is to start a clinical trial in humans.

The Sickle Cell Center at CHOP has a longstanding commitment to sickle cell disease research and is one of the largest programs of its kind in the U.S., providing comprehensive care to almost 1,000 patients. Dr. Blobel’s work is supported by funding from the National Institute of Diabetes Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute.

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Aug 13 2014

Investigators Explore Safety of Rotavirus Vaccine in NICU

RoatvirusClinicians in neonatal intensive care units across the country are uncertain about when to administer rotavirus vaccination to infants whose medical conditions require prolonged hospital stays, so experts at The Children’s Hospital of Philadelphia conducted a study published in Pediatrics to explore safety concerns that remain unsettled.

Rotavirus (RV) affects nearly all children at some point, often with significant diarrhea. In premature infants it can lead to severe and potentially life-threatening diarrhea and dehydration. Preterm infants are more vulnerable to the infection, in part because they miss the transfer of maternal antibody in the third trimester of pregnancy. In early infancy they are not protected against common forms of rotavirus.

RotaTeq vaccine (RV5), which was developed at CHOP, is effective at preventing rotavirus gastroenteritis, but it must be administered by 104 days of age (14 weeks, six days). Current immunization guidelines state, “preterm infants in NICUs or nurseries who are age-eligible and clinically stable may be immunized at the time of discharge.”

These recommendations put hospitals with large NICUs that often handle complicated cases of prematurity or congenital abnormalities in a time squeeze because they tend to care for babies who must stay in the hospital longer than 104 days.

“We have a population that is at extraordinary risk because they have health problems beyond prematurity and longer lengths of stay, so many would miss out on receiving the vaccine,” said Kelly C. Wade, MD, PhD, MSCE, a neonatologist at CHOP. “We would be discharging babies into the community who don’t have rotavirus protection.”

After careful consideration and discussion, a team of CHOP experts from the Divisions of Neonatology, Infectious Disease, and Pharmacology decided in 2007 to include RV5 with inpatient routine two-month vaccinations to infants receiving some enteral nutrition, also known as tube feeding, regardless of length of NICU hospitalization.

“We believe that the benefit of protecting infants against rotavirus infections outweighs the minimal risk in administering rotavirus vaccine to NICU inpatients,” said Heather M. Monk Bodenstab, PharmD, a CHOP clinical pharmacist. “We are one of very few institutions that actually do this.”

The main reason the American Academy of Pediatrics (AAP) discourages rotavirus vaccination during hospitalization is the possibility that live attenuated virus theoretically could be transmitted to neighboring unvaccinated infants also residing in the NICU. While shedding of attenuated virus has been demonstrated in immunized infants’ stools, Dr. Monk pointed out that symptomatic disease transmission is rare.

Since CHOP’s policy is not in line with the AAP recommendations, Dr. Monk Bodenstab and Dr. Wade conducted the current study in order to give some guidance and build support for the safety of inpatient RV5 vaccination as a CHOP standard of practice. The investigators performed a retrospective chart review of electronic medical records of NICU patients who CHOP routinely vaccinated with RV5 between September 2008 and 2010. They also reviewed records for any unvaccinated patients who shared the same NICU area and nurses as the vaccinated infants within 15 days of vaccination. In particular, the study team wanted to identify any unvaccinated infants who had gastrointestinal symptoms and physician orders for bowel rest, abdominal imaging, and antibiotics within 24 hours of each other, which would suggest a strong clinical suspicion of viral gastroenteritis.

“One of the most interesting findings was that there were such a small percentage of unvaccinated infants who had clinical status changes, and those could be attributed to pre-existing gastrointestinal processes or other clinical conditions,” Dr. Monk Bodenstab said. “That was reassuring for us.”

Due to the study’s design limitations, however, the results do not indicate whether or not RV5 vaccination increased the risk of virus shedding or transmission in a NICU environment. The goal of future prospective studies will be to determine how long a baby who receives the vaccine is potentially shedding the virus, if universal precautions such as diligent hand hygiene can control the spread, and if other infants are exposed, whether or not they become sick.

“None of us has any data to say for sure what would be good practice,” Dr. Wade said. “I think the policy we have at CHOP is well thought out, and it is working for us, but it is not ready for complete dissemination.  We cannot say it is what every NICU should do because you have to factor in different levels of attention to hand hygiene, nurse-to-patient ratios, and room geography.”

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Aug 11 2014

Celebrating Student Contributions to Injury Research

injury researchA recent event at the Center for Injury Research and Prevention (CIRP) celebrated the wide-ranging accomplishments of a number of students who have been working with CIRP staff and investigators. Held August 5th, the 9th Annual Student Research Day featured presentations that highlighted the scope and breadth of CIRP research, from those focused on teen driving-related topics to concussions to a study of injuries sustained by fans at Major League Baseball venues.

The students in the pediatric research training programs came to CIRP via various programs, including the CHOP Research Institute Summer Scholars Program (CRISSP) and Drexel University’s Co-op program. While many of the students hailed from Philadelphia-area schools — such as the University of Pennsylvania, Temple University, and Villanova University — students from Pennsylvania State University and the University of Kansas also presented.

The day was set up as a sort of “speed-dating” version of a symposium: Each student was given approximately five minutes to talk about his or her research, and at the end of the event a winner of the day’s best presentation was announced, chosen by CIRP investigators Helen Loeb, PhD, and Jessica H. Mirman, PhD. In all, the event featured 11 presentations.

Danielle Cole, a Drexel Co-op student, kicked off the symposium with a discussion of her work on the Cellie Coping Kit. Originally designed to help children and their families manage the physical and emotional challenges associated with cancer treatment, the kit includes its namesake plush toy, a pack of coping cards, and a booklet for caregivers. Over the past few months, Cole helped develop cards for a version of Cellie devoted to injuries, and has been working to raise money to support the project’s development. So far, she has raised $2,500 on her own.

Later in the day, Nicholas Janigian gave a presentation on “Spectator Injuries and Medical Events at MLB Ballparks.” A Villanova University undergraduate, Janigian’s interest in his topic stems from his love of sports and the fact that there is little mention of fan injuries in the scientific literature. Overall, Janigian found that there were approximately 35 instances of fan injuries between 2010 and 2014, including a bizarre case where a fan was blinded by a hot dog shot in the stands by the Kansas City Royals’ mascot Sluggerrr.

And in what turned out to be the day’s winning presentation, Richard Hanna, a BS/MS student at Drexel University, discussed his work improving digital models of child safety restraint systems (CRS). Specifically, Hanna has been using the XBOX Kinect motion detection gaming device to build accurate 3-D models of CRS devices. “CRS designs are in a constant state of flux,” Hanna said, which can lead to confusion and misuse, but having better models can help ameliorate that.

“The Center for Injury Research and Prevention’s annual Student Research Day event offers students the chance to show off their work, and this year was no different. This year’s impressive presentations showed the impact students make during their time at CIRP. We’re so proud of everything they accomplished,” said Carol Murray, MSS, MLSP, the Center’s training manager.

To learn more about the Center for Injury Research and Prevention, and the Center’s pediatric research training programs, visit the CIRP website.

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Aug 07 2014

Biodegradable Nanoparticles May Hold Therapeutic Use

biodegradable nanoparticlesNanoparticles have been heralded as a potentially “disruptive technology” in biomedicine, and as a changing platform that could replace conventional technologies, both as drug delivery vehicles and diagnostic tools to help discover and treat disease.

First, however, researchers must demonstrate the properly timed disintegration of these extremely small structures, a process essential for their performance and their ability to be safely cleared out of a patient’s body after their job is done. A new study presents a unique method to directly measure nanoparticle degradation in real time within biological environments.

“Nanoparticles are made with very diverse designs and properties, but all of them need to be eventually eliminated from the body after they complete their task,” said cardiology researcher Michael Chorny, PhD, of The Children’s Hospital of Philadelphia (CHOP). “We offer a new method to analyze and characterize nanoparticle disassembly, as a necessary step in translating nanoparticles into clinical use.”

Dr. Chorny and colleagues described this novel methodology recently in the Proceedings of the National Academy of Sciences.

The CHOP team has long investigated biodegradable nanoparticles for medical use. With diameters ranging from a few tens to a few hundreds of nanometers, these particles are 10 to 1000 times smaller than red blood cells. One major challenge continuously monitoring the fate of nanoparticles in model biological settings and in living cells without disrupting cell functions.

“Accurately measuring nanoparticle disassembly in real time directly in media of interest, such as the interior of a living cell or other types of complex biological milieu, is challenging. Our goal here was to develop such a noninvasive method providing unbiased results,” said Dr. Chorny.

The study team used a physical phenomenon called Förster resonance energy transfer, or FRET, as a sort of molecular ruler to measure the distance between the components of their particles. Researchers labelled their formulations with fluorescent probes exhibiting the radiationless transfer of energy, i.e., FRET, when located within the same particle.

This process results in a special pattern of fluorescence, a “fingerprint” of physically intact particles, which gradually disappears as particle disassembly proceeds. This change in the nanoparticle fluorescent properties can be monitored without separating the particles from their environment, allowing for undistorted, continuous measurements of their integrity.

The rate of disassembly is highly relevant to potential applications. For instance, some nanoparticles might carry a drug intended for quick action, while others should keep the drug protected and released in a controlled fashion over time. Creating formulation properties for these tasks may require carefully adjusting the time frame of the nanoparticle disassembly. This is where this technique can become a valuable tool, greatly facilitating the optimization process.

In the current study, the scientists analyzed how nanoparticles disintegrated both in liquid and semi-liquid media, and in vascular cells simulating the fate of particles used to deliver therapy to injured blood vessels. “We found that disassembly is likely to occur more rapidly early in the vessel healing process and slow down later. This may have implications for the design of nanoparticles intended for targeted drug, gene or cell therapy of vascular disease,” said Dr. Chorny.

While immediately relevant to restenosis therapy and magnetically guided delivery, the current research also has much broader potential applications, said Dr. Chorny. “Nanoparticles could be formulated with contrast agents for diagnostic imaging, or could deliver anticancer drugs to a tumor,” he said. “Our measuring tool can help researchers to develop and optimize their nanomedicine formulations for a range of medical uses.”

More information about the study is available on the Research website.

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Aug 05 2014

Climate Change Could Mean More Kidney Stones

kidney stones

The delay between high daily temperatures and kidney stone presentation was short, peaking within three days of exposure to hot days.

As daily temperatures increase, so does the number of patients seeking treatment for kidney stones. In a study that may both reflect and foretell climate change’s impact on human health, a research team found a link between hot days and kidney stones in 60,000 patients in several U.S. cities with varying climates.

“We found that as daily temperatures rise, there is a rapid increase in the probability of patients presenting over the next 20 days with kidney stones,” said Gregory E. Tasian, MD, MSc, MSCE, a pediatric urologist and epidemiologist at The Children’s Hospital of Philadelphia. Along with CHOP’S Ron Keren, MD, MPH, Dr. Tasian published the study team’s findings recently in Environmental Health Perspectives, the journal of the National Institute of Environmental Health Sciences.

Kidney stones are a painful condition that brings half a million patients a year to emergency rooms. While stones remain more common in adults, the numbers of children developing kidney stones have climbed at a dramatically high rate over the last 25 years. When patients cannot pass stones on their own, surgery may be necessary.

The investigators analyzed the records of more than 60,000 adults and children with kidney stones between 2005 and 2011 in Atlanta, Chicago, Dallas, Los Angeles and Philadelphia, in connection with weather data. Dr. Tasian and colleagues described the risk of stone presentation for the full range of temperatures in each city. The delay between high daily temperatures and kidney stone presentation was short, peaking within three days of exposure to hot days.

The study’s broader context is in patterns of global warming. The authors note that other scientists have reported that overall global temperatures between 2000 and 2009 were higher than 82 percent of temperatures over the past 11,300 years. Furthermore, increases in greenhouse gas emissions are projected to raise earth’s average temperatures by 2 to 8 ͦF (1 to 4.5 ͦC) by 2100.

“These findings point to potential public health effects associated with global climate change,” said Dr. Tasian. “However,” he cautioned, “although 11 percent of the U.S. population has had kidney stones, most people have not. It is likely that higher temperatures increase the risk of kidney stones in those people predisposed to stone formation.” Higher temperatures contribute to dehydration, which leads to a higher concentration of calcium and other minerals in the urine that promote the growth of kidney stones.

The researchers also found that very low outdoor temperatures increased the risk of kidney stones in three cities: Atlanta, Chicago and Philadelphia. The authors suggest that as frigid weather keeps people indoors more, higher indoor temperatures, changes in diet, and decreased physical activity may increase their risk of kidney stones. Moreover, the researchers argue that the number of hot days in a given year may better predict kidney stone risk than the mean annual temperature.

“Kidney stone prevalence has already been on the rise over the last 30 years, and we can expect this trend to continue, both in greater numbers and over a broader geographic area, as daily temperatures increase,” concluded Dr. Tasian. “With some experts predicting that extreme temperatures will become the norm in 30 years, children will bear the brunt of climate change.”

To read more about kidney stones and urology research, see the Hospital’s website.

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Jul 31 2014

CKiD Study Spurs New Insights Into Chronic Kidney Disease

chronic kidney diseaseIdentifying the best strategies to slow the progression to kidney failure for children with chronic kidney disease (CKD) is a constant challenge for clinicians. They must finely tune their treatment plans and judiciously anticipate when to begin dialysis or place patients on a kidney transplant waiting list.

The Chronic Kidney Disease in Children Study (CKiD) is a prospective cohort study that was initiated in 2003 to provide evidence to help inform these disease management decisions. A decade later, almost 900 children between the ages of 1 and 16 with decreased kidney function have entered the study. As a one of two clinical coordinating centers for CKiD, The Children’s Hospital of Philadelphia has contributed many research projects under the leadership of principal investigator Susan L. Furth, MD, chief of the division of nephrology.

The data collected from the CKiD has prompted new insights and approaches to improve care for children with CKD. These include a new gold standard in the measurement of kidney function, identification of acidosis and low birth rate as risk factors for poor growth, models to predict overall rates of decline of kidney function over time, and awareness that children with chronic kidney disease have a remarkable constellation of risk factors for heart disease.

“The rationale for CKiD was that chronic kidney disease and end stage renal disease in this country in adults really are a substantial burden,” Dr. Furth said. “The latest estimate is 10 million Americans have chronic kidney disease. It’s very likely that many of the origins of chronic kidney disease in adults start in children. We’ve found ways that we can intervene to extend life and promote the health of these kids.”

The primary goals of CKiD are to determine participants’ risk factors for decline in renal function, track their behavior and abilities to learn and think, monitor their growth, and evaluate possible connections to future cardiovascular disease. Several CHOP investigators recently have published studies related to CKiD and also presented their findings at the Pediatric Academic Societies Annual Meeting (PAS) held in May.

chronic kidney diseaseIn a study presented at PAS by Michelle Denburg, MD, MSCE, an attending nephrology physician at CHOP, researchers used CKiD data to show for the first time that children with CKD have increased risk of fracture, especially among teenage boys. Children with CKD have problems with absorbing calcium from the foods that they eat, and often as their kidney function worsens, their calcium gets low. In order to compensate, their bodies secrete a hormone that takes calcium out of their bones, which weakens them.

The study results showed that the incidence of fracture in a CKiD cohort of 556 children was two-fold higher than general population rates. Fractures of the arm and elbow were most common. These findings support the need for future CKiD research that will focus on bone frailty as an important therapeutic target in the pediatric CKD population.

Erum A. Hartung, MD, also an attending nephrology physician at CHOP, and colleagues published a study in the May issue of Pediatric Nephrology that concentrated on the neurocognition of a particular group of children with autosomal recessive polycystic kidney disease (ARPKD) who are born with abnormal kidneys. A previous CKiD study demonstrated that children with CKD have normal IQs, but they have challenges in the areas of attention and their ability to make and carry out plans. Parents of children with ARPKD had expressed concerns that their children could face increased risks for behavior and learning difficulties because they have early onset CKD and more severe high blood pressure — both of which are known risk factors for neurocognitive deficits.

The study’s results were reassuring to parents because they showed that the cognitive function of children with ARPKD was comparable to children in the CKiD cohort with mild-to-moderate kidney disease from other causes. The investigators concluded that, “Further studies are needed to determine if these findings are applicable to children with more severe manifestations of ARPKD.” Dr. Hartung also shared this study’s results at the PAS.

Dr. Furth encourages other investigators and collaborators to access the “wealth of data” in the CKiD’s national database to conduct research projects that potentially could lead to better outcomes for children with CKD. In the meantime, the CKiD’s second wave has begun, which involves a cohort of about 280 children.

“We’re looking more at vascular health and added tests of vascular stiffness to this study as we move forward,” Dr. Furth said. “Increased stiffness of the blood vessels, as measured by pulse wave velocity, has been associated with increased risk of adverse cardiovascular events in adults. We’re trying to see if this happens even earlier in children.”

Dr. Furth also is excited about a new partnership called the 4C Study with investigators in Europe. The aim is to gather a total sample size of about 1,500 children, including CKiD study participants and another cohort from a recently concluded interventional study in children with CKD called the ESCAPE trial, in order to conduct a genome-wide search for genetic risk markers of CKD progression.

“We’re finding out if there are new genetic associations with structural abnormalities of the kidney and also if there’s genetic variability that contributes to things like accelerated kidney function decline or anemia,” Dr. Furth said.

The National Institute of Diabetes and Digestive and Kidney Diseases, in collaboration with the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute, recently renewed funding for the CKiD. It is a cooperative agreement between the two clinical coordinating centers — CHOP and Children’s Mercy Hospital in Kansas City — a central biochemistry laboratory at the University of Rochester in New York, and a data coordinating center at Johns Hopkins School of Public Health in Baltimore.

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Jul 30 2014

Unique Collaboration Leads to “Dream Teams” to Advance Pediatric Research

dream teamTwo dedicated “dream teams” of investigators will shape innovative solutions to address unmet pediatric medical needs, as part of a research partnership with The Children’s Hospital of Philadelphia, Drexel University, and The Hebrew University of Jerusalem.

The joint projects each will receive $250,000 over two years in institutional funding, as administrators seek external investors interested in advancing exciting pediatric translational research with commercial viability. The dream teams rose to the top of 20 proposals submitted as a result of a research symposium in January that gave researchers from all three institutions the opportunity to connect and share ideas.

“We are thrilled by the potential for discovery that this portfolio of projects holds, and much of this important work should appeal to future donors,” said The Children’s Hospital of Philadelphia CEO Steven M. Altschuler, MD.

Funding these initial grants internally demonstrates the institutions’ commitment to be a hub of collaboration and exemplifies the inventive, diverse, and entrepreneurial spirit that formed their research consortium initiative. Dr. Altschuler, Drexel President John A. Fry, and The Hebrew University of Jerusalem President Menahem Ben-Sasson signed the research agreement in November as part of a trade mission that Philadelphia Mayor Michael A. Nutter took to Israel.

“These inaugural awards are just the beginning of what the ongoing collaboration between The Children’s Hospital of Philadelphia, Hebrew University and Drexel can accomplish,” said Drexel President John A. Fry. “Together we can create new and unique opportunities that will address unmet needs in pediatrics through innovative commercial pediatric therapeutics and diagnostics.”

One dream team will be based at Drexel with Amy Throckmorton, PhD, as the principal investigator of the “Giving Kids a Chance” project that will investigate a new intravascular blood pump for pediatric patients with congenital heart disease (CHD).

The treatment of single ventricle (SV) anomalies is a formidable and costly challenge for clinical teams caring for patients with CHD, which is the most common major birth defect affecting nearly 1 percent of all newborns. Palliative repair of a SV is generally performed in a series of open-heart procedures over several years. The end result is a man-made physiology in which a SV drives blood flow through the entire circulatory system without the presence of a “right-sided” pulmonary ventricle to pump blood to the lungs. A heart transplant is a treatment option in difficult cases, if the child can survive the waiting period.

As interest is growing about the use of mechanical assistance as a bridge-to-transplant or treatment strategy, the dream team aims to develop a uniquely designed, new therapeutic device for patients with dysfunctional SV physiology. Their goal is to advance the state-of-the-art in blood pump technology, reversing the deleterious characteristics of current approaches and helping to prevent premature congestive heart failure.

dream team

“These inaugural awards are just the beginning of an ongoing collaboration between The Children’s Hospital of Philadelphia, Hebrew University and Drexel can accomplish,” said Drexel President John A. Fry.

The interdisciplinary team will combine its broad expertise in engineering, pediatric cardiology, congenital heart and cardiothoracic surgery, medical device development, and manufacturing for artificial organs. Members from Drexel will include Dr. Throckmorton, J. Yasha Kresh, PhD, and Randy Stevens, MD. They will be joined by four investigators from CHOP: David J. Goldberg, MD; Matthew Gillespie, MD; Kevin K. Whitehead, MD, PhD; and Joseph Rossano, MD. Amnon Hoffman of The Hebrew University of Jerusalem and Amiram Nir of Hadassah Medical Center will round out the team.

They will work with four industry partners: Rotor Bearing Solutions International of Charlottesville, Va.; Cardiac Assist Inc. of Pittsburgh, Pa.; Applied Rapid Technologies of Fredericksburg, Va.; and Laserage Technology Corp. of Waukegan, Ill.

A second dream team will be based at CHOP with Robert J. Levy, MD, as the principal investigator of a research project “Pediatric Transcatheter Valve Replacements: Preventing Device Failure due to Structural Degeneration.”

These investigations also will focus on CHD with a concentration on Tetralogy of Fallot (TOF). These “blue babies” have insufficient oxygen and need cardiac surgery early in life. Postoperatively patients with TOF are left with chronic malfunction of their pulmonary valve.

Ongoing research at CHOP has demonstrated that transcatheter pulmonary valve (TPV) therapy — the current best option — is susceptible to oxidative damage and structural failure. This interdisciplinary team seeks to gain a better understanding of the inflammatory and oxidative events responsible and to inhibit the early inflammatory response to TPV. They will attempt to modify the TPV material with an antioxidant as a way to prevent oxidative damage to the TPV leaflets.

Dr. Levy will collaborate with Matthew Gillespie, MD from CHOP and Joseph H. Gorman, MD and Robert C. Gorman, MD, from Penn, along with Kenneth Barbee, PhD, and Kara Spiller, PhD, from Drexel, and Gershon Golomb from The Hebrew University of Jerusalem.

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Jul 28 2014

CIRP Engineering Expert Accepts New Leadership Role


Most recently, Dr. Arbogast has extended her work to include the study of concussions, not only from motor vehicle crashes, but also from sports

The Center for Injury Research and Prevention (CIRP) proudly announced the promotion of Kristy Arbogast, PhD, to co-scientific director. She was previously and continues to serve as the Center’s director of engineering.

Dr. Arbogast has been with CIRP since its establishment in 1996 to advance the safety and health of children, adolescents, and young adults through comprehensive research that encompasses before-the-injury prevention to after-the-injury healing. She joined Flaura K. Winston, MD, PhD, and Dennis R. Durbin, MD, MSCE, as a co-investigator on the seminal Partners for Child Passenger Safety (PCPS) project, a 10-year-long national study that led to significant policy and safety design advances for child motor vehicle occupants.

“This is a natural transition for CIRP,” said Dr. Winston, scientific director and founder of CIRP. “As Kristy’s career has matured and flourished, so has CIRP. She has helped to grow our Center’s international reputation as a thought leader in child injury prevention and pediatric biomechanics.”

Dr. Arbogast has dedicated her career to safety research, focusing on the development of new auto and restraint safety designs and biofidelic child anthropomorphic dummies. Her work was recently recognized by the receipt of an honorary doctorate from Chalmers University, Sweden.

As CIRP’s co-scientific director, Dr. Arbogast will join Dr. Winston and Ayana Bradshaw, MPH, CIRP’s administrative director, in leading a group of behavioral scientists, clinicians, epidemiologists, biostatisticians, engineers, public health practitioners, and communications professionals that focus on injury prevention, violence prevention, physical and emotional recovery following injury, digital health, and pediatric biomechanics.

“I have benefitted from the interdisciplinary structure of CIRP,” Dr. Arbogast said. “Working with colleagues from diverse academic backgrounds and research interests has expanded my own understanding of child injury prevention. We are all dedicated to translating our research into action to reduce preventable child injuries and deaths.”

Most recently, Dr. Arbogast has extended her work to include the study of concussions, not only from motor vehicle crashes, but also from sports. She served on the Institute of Medicine Committee on Sports Concussions in Youth and is also a member of the National Council on Youth Sports Safety. Since 2011, Dr. Arbogast has co-led a multi-disciplinary project at CHOP called Minds Matter: Improving Pediatric Concussion Management that streamlined and standardized concussion diagnosis, treatment, and follow-up care across the CHOP network.

Dr. Arbogast continues to serve as the co-director of the National Science Foundation-sponsored Center for Child Injury Prevention Studies (CChIPS) at CHOP, University of Pennsylvania and The Ohio State University. She is also research associate professor of pediatrics at the University of Pennsylvania.

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Jul 23 2014

Platelet Granule Formation Gives Insight Into Rare Disease

plateletIf you take a normal platelet and examine it under an electron microscope, you will see a bunch of black dots. The specks may not seem like much at first, but cell biologists at The Children’s Hospital of Philadelphia Research Institute speculate that these dense granules hold the key to unlocking the mechanisms behind a rare disease called Hermansky-Pudlak syndrome (HPS) and other forms of bleeding disease.

HPS is estimated to affect one in 500,000 to one in 1,000,000 individuals worldwide. In certain places, like Puerto Rico, it is much more prevalent — about one in 1,800 individuals. People with the disease have a tendency to bruise and difficulties with blood clotting, which can be deadly under certain circumstances such a pregnancy, major surgery, or dental surgery.

“Those dense granules don’t get made in a set of patients, and the consequence of that is the patients bleed too much, and they’re not able to make blood clots efficiently,” said Michael S. Marks, PhD, who received a grant in May from the National Heart, Lung, and Blood Institute to better understand how platelet dense granules form and why their creation is disrupted in HPS.

Dense granules are lysosome-related organelles (LROs) within platelets that act as a storage compartment for small molecules such as calcium, adenosine diphosphate, and serotonin. These molecules are released when platelets begin to accumulate at sites of blood vessel damage.

“We know that there are important things stored in those granules, but we have no idea how they get there,” Dr. Marks said. “This is the first time anybody’s taken an approach to try and understand how dense granules are put together and how those molecules get stored in them.”

HPS can be difficult to diagnose because it affects multiple organs, and the symptoms can be variable and nonspecific. Mutations in the genes associated with HPS prevent the formation of LROs or impair their performance in platelets, pigment cells, and lung cells. Subsequently, in addition to excessive bleeding, a main feature of the disease is oculocutaneous albinism, which causes abnormally light coloring of the skin, hair, and eyes. By the time people with HPS reach their 30s, a lung defect called pulmonary fibrosis appears that rapidly worsens, and the lung scarring often is fatal.

“Getting a good diagnosis early would be really important,” Dr. Marks said. “That would be the most immediate impact of this grant.”

The study aims to achieve a better understanding of two dense granule integral platelet membrane proteins that Dr. Marks’ team at CHOP and a collaborating group in Colorado recently identified — SLC35D3 and VMAT2 — which may act as vehicles to import dense granule contents. The investigators suspect that this delivery is impaired in HPS, and the dense granules do not form completely. Necessary machinery could be missing at a crucial time when a dense granule’s membrane coalesces from other membranes in megakaryocytes, which are platelets’ precursor cells that reside in bone marrow. It appears that this occurs during a late stage of differentiation of platelets from megakaryocytes.

In order to test this hypothesis, scientists in Dr. Marks’ lab will collaborate with another group of experts in megakaryocyte and platelet formation from the lab of Mortimer Poncz, MD, division chief of hematology at CHOP. They will take megakaryocytes from mice and then modify them by adding fluorescent proteins that hopefully will allow the investigators to visualize dense granule formation using live cell imaging. The next step will be to put the megakaryocytes back into the mice where they will produce platelets, and then take the platelets out to analyze them.

Dr. Marks also will compare the same mutations in human cells by using megakaryocytes created from stem cells of patients with HPS. Deborah L. French, PhD, a specialist in making induced pluripotent stem cells, will assist with this part of the project. Dr. French is director of the Human Stem-Cell Vector Core within the Center for Cellular and Molecular Therapeutics at CHOP.

The investigators will determine if SLC35D3 and VMAT2 live on dense granule membranes and whether or not they are expressed on platelet membranes in both the human and mouse HPS models. What they discover could guide new diagnostic approaches.

“If we’re right, then we could make antibodies to those proteins,” Dr. Marks said. “Then it should be a very simple test to look for exposure of that protein when you activate platelets.”

Such a diagnostic test would be helpful for identifying HPS as well as other forms of bleeding disease due to mutations in genes that encode proteins on these dense granules. As researchers learn more about the proteins’ structure and the jobs that they perform, this knowledge could be applied to designing drug therapies that either enhance the proteins’ activity, as would be the case in HPS, or decrease the proteins’ activity, which could potentially modulate diseases that cause too much blood clotting.

“Ultimately, maybe, we’ll be able to come up with some kind of treatment,” Dr. Marks said. “That will depend on whether we’re right with some of our guesses about the proteins that are on dense granules and whether we can characterize them further and identify steps that would be downstream from them.”

Dr. Marks also is looking forward to working on a future study with Susan Guttentag, MD, that recently received grant funding. That investigation will focus on the formation of another LRO, the lamellar body, in lung epithelial cells. Dr. Guttentag and colleagues have shown that HPS models interfere with this process which underlies the lung fibrosis in HPS.

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Jul 21 2014

Putting a Dollar Amount to Autism Pays Off

autismAutism spectrum disorders (ASDs) have an enormous price tag, and experts at The Children’s Hospital of Philadelphia are hoping that all those dollar signs add up to increased attention on new research and more coordinated ways to support patients with autism throughout adulthood.

One in 68 children in the United States has ASD, making it the fastest-growing disability. It is a complex neurological and developmental condition characterized by marked deficiencies in social interaction and communication and various behavioral issues. While individual presentations may vary, the signs of ASD usually appear during the first three years of life.

David S. Mandell, ScD, associate director of the Center for Autism Research at CHOP, and co-investigators in London updated estimates of the economic effects of ASDs on individuals and their families in the U.S. and U.K. They published their results online recently in JAMA Pediatrics. The lifetime cost of supporting a patient with an ASD and intellectual disability was $2.2 million in the U.S., and the lifetime cost for a patient with an ASD without an intellectual disability was $1.4 million in the U.S.

“They are staggering numbers in many ways,” said Dr. Mandell, who is also an associate professor of psychiatry and pediatrics at the University of Pennsylvania’s Perelman School of Medicine, where he directs the Center for Mental Health Policy and Services Research. “What is most intriguing about the study is what is driving those costs.”

For families, when their child with autism is young, special education costs were the largest cost component. Lost parental wages — especially for mothers who often must leave the workplace in order to care for their children — was another hefty economic hit. Productivity loss was estimated to be $18,720 annually for U.S. caregivers of children with ASD.

A key finding, Dr. Mandell pointed out, is that most of the expenses associated with autism accrue in adulthood. Society tends to think of autism as a pediatric concern, but it is a lifelong disorder. Residential care represents a substantial portion of those annual costs in the U.S.: $36,000 for adults with an ASD who have an intellectual disability, and about half that amount for adults with an ASD without an intellectual disability.

While some adults with autism have significant impairments and require expensive 24-hour residential care in a stable, supervised environment, many others who have participated in early interventions continue to develop their skills when given social coaching and job training so that they can work and live in less restrictive housing arrangements.

“I hope that advocates will use this information to support the importance of paying for intensive, evidence-based care for children with autism that has the goal of increasing their potential for full participation in their communities, which also may come with cost-savings,” Dr. Mandell said.

Part of the challenge to conducting this study, Dr. Mandell said, is that no gigantic spreadsheet listing all of these costs in one place exists. In addition to performing an extensive literature review conducted in 2013 concentrating on U.S. and U.K studies, Dr. Mandell and his co-authors relied on a number of sources to estimate cost-related data. For future studies, he encourages multiple systems to collaborate and perform longitudinal, population-based data collection so that researchers have easier access to metrics that can be used to assess the efficiency and effectiveness of autism care on a more regular basis.

Autism Speaks, the world’s leading autism science and advocacy organization, supported this study.

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