Nov 14 2014

Gene-regulating Protein Reaches Multiple Disease Pathways

proteinGenomic scientists at The Children’s Hospital of Philadelphia found strong evidence that the protein family, FOXA2, is a master regulator of genetically vulnerable pathways in multiple diseases.

Study leader Struan F.A. Grant, PhD, holder of the Daniel B. Burke Chair for Diabetes Research at The Children’s Hospital of Philadelphia, has long investigated the genetics of diabetes and obesity. In the current study, he focused on the Forkhead Box A transcription factor, referred to as FOXA2, which was already known to act in the liver in affecting glucose levels. Dr. Grant and colleagues started with the hypothesis that FOXA2 regulated molecular pathways that are important in endocrine biology.

As they performed their analyses, the researchers found that FOXA2 proteins acted on sites in the genome that contained genes affecting endocrine-related traits such as glycemic levels, although not type 2 diabetes. They also found strong genome occupancy patterns associated with cardiovascular traits such as lipid levels, as well as with neuropsychiatric traits and cancer.

“FOXA2 appears to function as a master regulator for over a hundred other transcription factors, so it may play an outsized role in human health and disease,” Dr. Grant said.

This computational analysis leveraged data from a team led by co-author Klaus H. Kaestner, PhD, of the Perelman School of Medicine at the University of Pennsylvania, and used two important tools of next-generation genomic analysis: chromatin immunoprecipitation and massively parallel sequencing, together abbreviated as ChIP-seq. ChIP-seq isolates the pieces of DNA that are bound by proteins such as transcription factors.

Researchers then pass those fragments through automated sequencing machines to pinpoint and inventory the regions of the genome that specific transcription factors occupy. This knowledge allows investigators to better understand how transcription factors may activate or repress genes along important biological networks, and further study of those pathways may point the way to various novel therapies.

Grant and colleagues published their study in the The Journal of Clinical Endocrinology & Metabolism.

Study funding came from the National Institutes of Health and the Ethel Brown Foerderer Fund for Excellence from CHOP.

Permanent link to this article: http://www.research.chop.edu/blog/gene-regulating-protein-reaches-multiple-disease-pathways/

Nov 12 2014

CHOP Research Leader Named to Brain Tumor Panel

brain tumorThe Children’s Hospital of Philadelphia Research Institute’s Tom Curran, PhD, FRS, was recently named to a panel of experts who will advise the Pediatric Brain Tumor Foundation (PBTF). A pediatric brain tumor expert and Deputy Scientific Director of the Research Institute,

Dr. Curran was one of seventeen volunteers appointed to the PBTF’s newly created Research Advisory Network.

Per a statement put out by the PBTF, the “Research Advisory Network will contribute insights that help shape the PBTF’s funding priorities and evaluate the impact of its research investment on the lives of children diagnosed with a brain tumor, as well as on the disease that threatens them.” Panel members come from several other children’s hospitals—including St. Jude’s, Boston Children’s, and Children’s National—as well as academic centers and industry.

“The members of the Research Advisory Network, or RAN, will provide highly informed perspectives on the biomedical research enterprise,” said the Pediatric Brain Tumor Foundation’s Dr. Joanne Salcido. According to its website, the PBTF is “the world’s largest nonprofit funder of childhood brain tumor research,” and in addition to funding studies the Foundation hosts events, offers brain tumor-related resources, and offers scholarships.

Before joining Children’s Hospital in 2006, Dr. Curran was the founding chairman of the Department of Developmental Biology at St. Jude’s Research Hospital in Memphis, Tenn. In addition to his role as deputy scientific director of CHOP Research, Dr. Curran is also a professor of Pathology and Laboratory Medicine at the Perelman School of Medicine at the University of Pennsylvania.

He is also one of the leaders of the recently established Children’s Brain Tissue Tumor Consortium (CBTTC). A multi-institutional, collaborative research organization dedicated to the collection, annotation, and analysis of children’s brain tumors, the CBTTC’s ultimate goal is to improve outcomes for children with brain tumors. The CBTTC is comprised of CHOP, the Children’s Hospital of Pittsburgh of UPMC, Seattle Children’s Hospital, and Ann & Robert H. Lurie Children’s Hospital of Chicago. The consortium’s operations center is housed at Children’s Hospital.

“I am honored to serve as a member of the Pediatric Brain Tumor Foundation’s Research Advisory Network,” Dr. Curran said. “I look forward to working with the Foundation, as well as my fellow Network members, to advance brain tumor research and improve the lives of children with brain tumors.”

To learn more about brain tumors and cancer care at The Children’s Hospital of Philadelphia, see the Cancer Center at CHOP. For more information about cancer research at CHOP, see the Center for Childhood Cancer Research.

Permanent link to this article: http://www.research.chop.edu/blog/chop-research-leader-named-brain-tumor-panel/

Nov 10 2014

New Autism Roadmap Website One-stop Resource for Families

autism_roadmapWith one in 68 children now thought to be affected by an autism spectrum disorder (ASD), more and more parents are struggling to understand an autism diagnosis and find the resources their children need. “Where do I begin?” families often ask.

The answer is the Autism Roadmap, a new website developed entirely as a result of philanthropy and with the expertise of nearly a dozen of the nation’s top autism experts at The Center for Autism Research (CAR) at The Children’s Hospital of Philadelphia.

Families using the Roadmap will find directories of service providers, community resources, government programs, ideas for various stages of childhood and beyond, and explanations of the latest research on ASD treatments and interventions.

“This tool has the potential to greatly improve the lives of families struggling with the maze of government, medical, and community service providers and as such, enables CAR to be a great service to the broader community,” said Robert Schultz, PhD, director of The Center for Autism Research.

Susan Wenger, who funded the website’s development along with her husband, Don, and other family members, witnessed firsthand the difficulty of finding reliable information the internet and locating autism-specific resources for their grandson. They understand how a family’s life can be turned upside down by a diagnosis of ASD.

“I wondered why, with so many kids affected by autism, wasn’t there a single clearinghouse for information,” Wenger said. “A tool like this is just so needed — it will make life so much easier for parents and grandparents to help get children diagnosed with an autism spectrum disorder the resources they need as quickly as possible.”

Families, researchers, mental and behavioral health workers, and others gave extensive input and tested the website to ensure that it was comprehensive and easy to use. Autism Roadmap provides customized information based on what families need, whether their child has been diagnosed recently or is navigating developmental milestones, from toilet training and school to adolescence and adulthood. The website will be continuously updated as new information becomes available or as resources and community information change.

“We’re extremely grateful for the Wenger’s support to help transform a longtime vision into a reality,” Dr. Schultz said.

A news report about the launch of the comprehensive, one-stop website appeared on 6abc Action News. View the broadcast here:

For more information about the CAR Autism Roadmap, visit www.carautismroadmap.org.

Permanent link to this article: http://www.research.chop.edu/blog/new-autism-roadmap-website-one-stop-resource-families/

Nov 07 2014

New Jersey’s Graduated Driver Decals Linked to Fewer Crashes

decal provisionA new study from the Center for Injury Research and Prevention provides evidence that New Jersey’s Graduated Driver Licensing (GDL) decal provision is associated with a sustained decline in crash rates among provisional teen drivers. The study, which linked New Jersey’s licensing and crash record databases to measure effects of the requirement, was published recently in the American Journal of Preventive Medicine. Crash involvement of an estimated 3,197 intermediate drivers was prevented in the first two years after the decal’s implementation.

In May 2010, New Jersey implemented Kyleigh’s Law, requiring all youth 16 to 20 years of age holding a learner’s permit or intermediate license to display a reflective decal on the front and back license plates of vehicles they are operating. On any given day there are more than 170,000 intermediate drivers on New Jersey’s roadways. The decal was intended to facilitate police enforcement of GDL restrictions and reduce teen crash rates.

While many other countries have had decals for decades, New Jersey is the first state to implement them in the U.S. And CHOP researchers are the first in any country to evaluate the long-term changes in crash rates after a decal provision went into effect.

“Decal provisions now have the support of science. The provision may encourage safer driving behaviors, both among teens and other drivers sharing the road with them,” said the study’s lead author, Allison Curry, PhD, MPH, the Center for Injury Research and Prevention’s director of Epidemiology and Biostatistics.

Dr. Curry and the study team linked New Jersey’s licensing and motor vehicle crash databases from January 2006 through June 2012 to compare monthly rates of police-reported crashes for intermediate drivers in the four years before the decal’s implementation and in the two years after. The researchers showed in the first two years after the new decal requirement took effect the crash rate for young intermediate drivers declined 9.5 percent, as compared to the previous four years before decal implementation.

More dramatic effects were observed for single-vehicle crashes involving older intermediate drivers, with rates decreasing 13 percent per year for 18-year-olds and nearly 17 percent for 19-year-olds. In the previous four years before the decal was put into practice, the rate of single-vehicle crashes did not significantly decrease in either group.

A previous study on the decal’s first year of implementation found a 14 percent increase in the rate of GDL-related citations issued to intermediate drivers, but the increase seemed to be concentrated in the few months after implementation.

“There is definitely more we need to learn, in particular with respect to the specific mechanisms by which the decals reduced crashes,” noted Dr. Curry. “The end result, however, is that many fewer teens crashed.”

To learn more about the Center for Injury Research and Prevention work on teen driver safety and other topics, visit the Center’s website.

Permanent link to this article: http://www.research.chop.edu/blog/new-jerseys-graduated-driver-decals-linked-fewer-crashes/

Nov 05 2014

Collaborative International Study Finds Childhood Epilepsy Genes

childhood epilepsy

The study adds to the list of gene mutations previously reported to be associated with these severe epilepsy syndromes, called epileptic encephalopathies.

An international team of researchers recently identified gene mutations that can cause severe, difficult-to-treat forms of childhood epilepsy. Many of the mutations disrupt functioning in the synapse, the highly dynamic junction at which nerve cells communicate with one another.

“This research represents a paradigm shift in epilepsy research, giving us a new target on which to focus treatment strategies,” said pediatric neurologist Dennis Dlugos, MD, director of the Pediatric Regional Epilepsy Program at The Children’s Hospital of Philadelphia, and one of the study’s co-authors. “There is tremendous potential for new drug development and personalized treatment strategies, which is our task for the years to come.”

Epilepsies are amongst the most common disorders of the central nervous system, affecting up to 3 million patients in the United States. Up to one third of all epilepsies are resistant to treatment with antiepileptic medication and may be associated with other disabilities such as intellectual impairment and autism. In many patients with severe epilepsies, no cause for the seizures can be identified, but there is increasing evidence that genetic factors may play a causal role.

Multiple researchers from the U.S. and Europe performed the research, the largest collaborative study to date focused on the genetic roots of severe epilepsies. The scientists reported their results recently in the American Journal of Human Genetics. Two international research consortia collaborated on the study: the Epi4K/EPGP Consortium, funded by the National Institute of Neurological Disorders and Stroke (NINDS), and the European EuroEPINOMICS consortium.

The study adds to the list of gene mutations previously reported to be associated with these severe epilepsy syndromes, called epileptic encephalopathies. The researchers sequenced the exomes of 356 patients with severe childhood epilepsies, as well as their parents. The scientists looked for “de novo” mutations — those that arose in affected children, but not in their parents. In all, they identified 429 such de novo mutations.

The research teams used a method called family-based exome sequencing, which looks at the part of the human genome that carries the blueprints for proteins. When comparing the sequence information in children with epilepsy with that of their parents, the researchers were able to identify the de novo changes that arose in the genomes of the affected children. While de novo changes are increasingly recognized as the genetic cause for severe seizure disorders, not all de novo changes are necessarily disease-causing.

But the most surprising finding is related to a gene called DNM1, which was found to be mutated in five patients. When the researchers looked on a network level, they found that many of the genes that were found to be mutated in patients had a clear connection with the function of the synapse.

This research finding, says Dr. Dlugos, provides important information about the functional roles of the genes that were identified. “We knew that synaptic genes were important but not to this extent,” he added.

To read more about this study, see the full press release. To learn more about The Children’s Hospital of Philadelphia’s epilepsy resources and research, see the Pediatric Regional Epilepsy Program website.

Permanent link to this article: http://www.research.chop.edu/blog/collaborative-international-study-finds-childhood-epilepsy-genes/

Nov 03 2014

Next Generation of Innovators Get Early Start on Science Careers

science careersHigh school students from Philadelphia are getting out from behind their desks to explore basic science careers in The Children’s Hospital of Philadelphia Research Institute’s state-of-the-art laboratories and work beside topnotch faculty.

It is crucial that more students are inspired and energized to become the next generation of innovators because the pipeline of young investigators in the United States has slowed to a trickle. Only 16 percent of American high school seniors are interested in a science, technology, engineering, and mathematics (STEM) career; yet job openings in STEM are expected to be among the fastest growing occupational clusters through 2020.

That is why the Research Institute’s senior leadership, Office of Responsible Research Training, Office of Research Safety, and faculty members are thrilled to have partnerships with two local schools that give bright students the opportunity to take the beaker caps off their ambitions.

“It can be an exciting and formative experience,” said Jodi Leckrone, MEd, assistant director of the Office of Responsible Research Training. “They can ask people, ‘How did you get to be a lab tech? How did you get to be a post-doc?’ And then they can start to formulate their own plan to pursue those kinds of goals.”

With beaming smiles and contagious enthusiasm, two sets of high school juniors began their work-study programs in September. Six students are from Science Leadership Academy, a partnership between the School District of Philadelphia and The Franklin Institute that provides a college-preparatory curriculum focused on science, technology, mathematics, and entrepreneurship. SLA students come to CHOP weekly for two to four hours. Each student is paired with a faculty member, and this year the hosts include Ian Krantz, MD; Motomi Enomoto-Iwamoto, DDS, PhD; Francis McGowan, MD; Eric Marsh, MD, PhD; Beverly Emanuel, PhD; and Sharon Diskin, PhD.

The other students are from Cristo Rey Philadelphia High School, an independent, Catholic college-preparatory school open to all faiths and dedicated to students from families with limited economic means. This is the first year that the Research Institute has partnered with Cristo Rey, and Robert Fabiszewski, director of the school’s work-study program, is grateful for the placements that will prepare students to realize their full potential.

“I believe this program fuels students’ passion for science and their drive toward accomplishing their dreams,” Fabiszewski said. “The sky is the limit. It’s very exciting!”

Fabiszewski selected four young women with an aptitude in science and medicine to job-share a full-time position in the neurosurgery laboratory of Adam Resnick, PhD, and Phillip (Jay) Storm, MD. Each student works in the lab one day a week and logs her work in a notebook so that the next day her classmate can pick up where she left off.  They work closely and contribute scientifically to projects focused on targeting pediatric brain tumors, in partnership with staff, technicians, graduate students, and post-docs.

“For us, the power for scientific research to be transformative extends far beyond the discovery process,” Dr. Resnick said. “Having these four students join our laboratory for an entire school year provides a unique opportunity for lasting synergy between education and research.”

Before they get to work, the students participate in an orientation and learn the basics about laboratory safety. In their first few weeks, they observe lab skills and set individual goals. By December, they will be immersed in an actual research assignment under the supervision of their faculty mentor, in accordance with the Research Institute’s Minors in Research Laboratories policy.

“Students see what a real-life lab environment is like and what the different job roles are, how they come up with project ideas, how their project idea fits within a larger question on improving health,” Leckrone said.

At the end of their work-study experience, SLA students from the 2013-2014 school year gave a short slide presentation about what they learned to their principals, advisers, faculty mentors, lab mates, and the research training staff. For example, students who completed the program described their work on cardiac stem cells, cellular and molecular mechanisms of cartilage tumors, and brain development in Cornelia de Lange Syndrome.

SLA student Amy Chen had a phenomenal experience working with Dr. McGowan last year, even though she was challenged to step out of her comfort zone.

“Every day, there was always a word that I didn’t understand,” Amy said. “I’d have to research the word in order to understand the next step of the project.”

The most amazing part, she recalled, was getting a chance to see thin slices of heart tissue from animals and humans. Spending time in the laboratory helped Amy decide that she wants to study biology and attend medical school to become a pediatric cardiology surgeon.

“I know that I will be one step ahead of my peers because of this program at CHOP,” Amy said. “One of the most important things that I achieved is building a relationship with my mentor.”

Colleen Ambron, MBA, training coordinator for the Offices of Postdoctoral Affairs & Research Safety, facilitates the SLA students’ work-study program. She encourages dedicated students like Amy to take advantage of the professional network at CHOP and establish connections with research leaders who can point them in the right direction for higher education. Perhaps former work-study students will continue working in the labs once they are in college, or maybe they will come back in between going to medical school and then onto their fellowships.

“I love working with the students,” Ambron said. “They’re really excited when they first come here, and they think, ‘Wow, this is CHOP.’ It’s an eye-opening experience for them. They are a great group of kids, and we get so many ‘thank you’s’ for giving them this opportunity.”

As interest in the high school work-study program continues to grow, Ambron and Leckrone welcome faculty who are willing to host students to contact them: ambronc@email.chop.edu and leckrone@email.chop.edu.

Permanent link to this article: http://www.research.chop.edu/blog/next-generation-innovators-get-early-start-chop/

Oct 31 2014

New Grant to Explore Eradicating HIV from Hiding Places in the Brain

HIVExploring new methods to eradicate HIV that lingers in brain cells despite conventional antiviral treatment is the focus of a new study by investigators at Children’s Hospital and Temple University. They are the joint recipients of a $4.3 million, four-year NeuroAIDS grant from the National Institute of Mental Health.

The grant funds three research projects, each targeting different biological pathways crucial to the persistence of the human immunodeficiency virus that causes AIDS. Investigators from CHOP’s section of immunology and Temple’s department of neuroscience are collaborating on these cell and animal studies to explore methods to enhance the immune system’s ability to attack HIV infection.

“This program represents a fresh look into a longstanding problem in HIV treatment—reservoirs of HIV within immune cells,” said Steven D. Douglas, M.D., chief of the section of immunology at CHOP and a professor of pediatrics at the University of Pennsylvania. “While current antiretroviral treatments can reduce the virus to undetectable levels, HIV persists latently inside cells. If drug treatment is interrupted, the virus comes surging back.”

Dr. Douglas and Jay Rappaport, Ph.D., professor of neuroscience and neurovirology at Temple University School of Medicine, are co-principal investigators of the new grant.

“All three projects seek to bypass vulnerabilities in the body’s immune system that are exploited by HIV,” said Dr. Rappaport. “By using biological tools to reinforce immune function, we aim to enable the immune system to eliminate HIV infection.”

During the first two years of the grant, the project teams will concentrate on basic biology to determine which pre-clinical approaches show the most promise for advancing into studies using animal models in the third and fourth years. The goal of the animal studies is to demonstrate proof-of-concept for strategies that could set the stage for subsequent human trials of innovative HIV treatments.

Project 1, led by Dr. Rappaport, focuses on the metabolism of ATP, the chemical that serves as energy currency in cells. Because HIV infection stimulates enzymes that degrade ATP and weaken immune responses, the research team will explore drug candidates that inhibit those enzymes.

Project 2, led by Tracy Fischer-Smith, Ph.D., assistant professor of neuroscience and neurovirology at Temple, concentrates on signaling proteins that drive immune polarization, in which cells called macrophages shift from protective roles to immune-suppressive activities. The team’s goal is to counteract those proteins’ signals and restore infection-fighting functions to immune cells.

Project 3, led by Dr. Douglas, investigates substance P, a neuropeptide with a key role in promoting inflammation during HIV infection. By manipulating NK-1R, a cell receptor that binds to substance P, the research team aims to disrupt HIV’s entry into cell reservoirs and to block the viral replication that accounts for HIV’s devastating effects.

“HIV infection disrupts immune cells by swinging a biological pendulum off balance into immune-suppressive activities that drive the disease,” said Fischer-Smith. “All three projects aim to modulate the immune system, inhibiting processes that are dangerously up-regulated, and restoring a healthy balance.”

This work is in collaboration with the Penn Mental Health AIDS Research Center at Penn Medicine and CHOP, and Temple’s Comprehensive NeuroAIDS Center—two NIH-supported centers concentrating on mental health and HIV.

Permanent link to this article: http://www.research.chop.edu/blog/new-grant-explore-eradicating-hiv-hiding-places-brain/

Oct 29 2014

Mitochondria Study Offers Insights into Diseases’ Underlying Causes

mitochondriaRecent work by a mitochondrial medicine pioneer from The Children’s Hospital of Philadelphia details how subtle changes in mitochondrial function may cause a broad range of common metabolic and degenerative diseases. Mitochondria are tiny energy-producing structures within our cells that contain their own DNA. The research offers “key insights into understanding the underlying cause of metabolic and neurodegenerative disorders such as diabetes, Alzheimer, Parkinson and Huntington disease, as well as human aging,” said CHOP Research’s Douglas C. Wallace, PhD.

The new research, published in the Proceedings of the National Academy of Sciences (PNAS), shows that small changes in the ratio of mutant to normal mitochondrial DNA within the thousands of mitochondrial DNAs inside each cell can cause abrupt changes in the expression of numerous genes within the nuclear DNA. Furthermore, the different proportions of mutant mitochondrial DNA that result in altered nuclear gene expression correspond to the same proportions of mutations in mitochondrial DNA that are associated with diabetes and autism; brain, heart, and muscle disease; or lethal infantile disease.

“By showing that subtle changes in the cellular proportion of the same mitochondrial DNA mutation can result in a wide range of different clinical manifestations, these findings challenge the traditional model that a single mutation causes a single disease,” said Dr. Wallace, director of the Center for Mitochondrial and Epigenomic Medicine and professor of Pathology and Laboratory Medicine at the Perelman School of Medicine at the University of Pennsylvania.

Existing in hundreds or thousands of copies outside the nucleus of every cell, mitochondria have their own DNA, distinct from the well-known DNA inside the cell nucleus. Although mitochondrial DNA (mtDNA) holds far fewer genes than nuclear DNA, mtDNA exchanges signals with nuclear DNA and participates in complicated networks of biochemical reactions essential to life.

The PNAS study builds on Dr. Wallace’s more than 40 years of investigating the mysteries of mitochondria. And it reinforces the argument he has presented over the course of his career: that mitochondria play a central, largely under-recognized role in all common human diseases. He has long argued that a traditional biomedical approach focusing on anatomy and individual organs does not provide the insights generated from a systems biology, bioenergetics-focused approach.

Examining Mitochondrial Mutations’ Effects

For the PNAS paper, Dr. Wallace and his team investigated the impacts of steadily increasing levels of a pathogenic mutation in one particular base of mitochondrial DNA. Researchers already knew that if 10 to 30 percent of a person’s mitochondrial DNA has this mutation, a person has diabetes, and sometimes autism. Individuals with an mtDNA mutation level of 50 to 90 percent have other multisystem diseases, particularly MELAS syndrome, a severe condition that involves brain and muscle impairments. Above the 90 percent level, patients die in infancy.

The investigators analyzed cultured human cells with different levels of this pathogenic mtDNA mutation to determine the effects on the gene expression of the cell. The researchers measured variations in cellular structure and function, nuclear gene expression, and production of different proteins.

Dr. Wallace argues that the medical significance of this research extends beyond the province of the relatively rare disorders typically classified as mitochondrial diseases. The gene expression profile—the pattern of gene activity seen at the level at which mtDNA mutations trigger brain disorders—parallels the profiles found in Alzheimer, Parkinson, and Huntington diseases. “The findings in this study provide strong support for the concept that common metabolic diseases such as diabetes and obesity, heart, and muscle diseases, and neurodegenerative diseases have underpinnings in energy deficiencies from malfunctioning mitochondria,” he said.

Significantly, Dr. Wallace added that the research also pertains to aging. Because mitochondrial mutations accumulate as people age, mitochondrial energy production declines, with deleterious effects on the heart, the brain and on interrelated biological systems that sustain health and life.

Future investigations will examine how different diseases are associated with the sorts of abrupt phase changes his group found in the current cellular study, Dr. Wallace noted. Some of the findings noted in the current research might become useful biomarkers in disease studies and drug development.

To read more about this landmark study, see the October issue of Bench to Bedside.

Permanent link to this article: http://www.research.chop.edu/blog/mitochondria-study-offers-insights-diseases-underlying-causes/

Oct 27 2014

Current Imaging Practices for Kidney Stones Deviate From Guidelines

kidney stonesKidney specialists across the country agree that the incidence of kidney stones is rising among children, but clinicians are unsettled on which imaging technology to choose first when diagnosing the condition, despite current guidelines that recommend ultrasound as the initial imaging study.

The Division of Urology at The Children’s Hospital of Philadelphia used to treat just a handful of children with kidney stones a year; now the multidisciplinary team at the Pediatric Kidney Stone Center evaluates and manages children with kidney stones on a daily basis.

A kidney stone develops when some substances that are normally found in the urine become highly concentrated and form solid crystals. Stones usually begin causing symptoms when they block the outflow of the urine to the bladder.

“Kidney stones truly have become a disease of childhood,” said Gregory E. Tasian, MD, MSc, MSCE, a pediatric urologist and epidemiologist at The Children’s Hospital of Philadelphia, who was the lead author of a study appearing in the November 2014 issue of Pediatrics that looked at the prevalence of the first imaging study that children obtain when they are evaluated for kidney stones.

The American Urological Association and The European Society of Paediatric Radiology recommend that a ultrasound be used as the initial imaging study to help clinicians to find a stone and look for any signs of blockage. The guidelines reserve computed tomography (CT), which delivers ionizing radiation and is associated with an increased risk of cancer in children, for cases when the ultrasound is nondiagnostic and the clinicians’ suspicion of kidney stones remains high.

“Stones can recur, so over a lifetime, a patient can be exposed to a lot of radiation both in the evaluation and then the treatment of stones,” Dr. Tasian said. “We want to limit the use of radiation when we can. By using ultrasound as the initial screening tool, we are able to identify the majority of clinically important stones and spare the child radiation.”

The Urologic Diseases in America Project, sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, supported the study led by Dr. Tasian to see how closely U.S. hospitals and clinics follow the current guidelines. The cross-sectional study focused on 9,229 children with urinary stones located in the kidney, also known as nephrolithiasis, who underwent imaging from 2003 to 2011. The study team obtained data from MarketScan, a robust database of commercial insurance claims.

The study’s results showed that clinicians deviated frequently from the recommended guidelines. Overall utilization of CT was high: An average of 63 percent of children underwent CT as the first imaging study during a kidney stone episode. Only 24 percent of children with suspected nephrolithiasis underwent ultrasound as the initial study.

“The findings also suggest that there is substantial regional variability in the use of CT,” Dr. Tasian said. “Yet even in states with the lowest initial use of CT, the prevalence was about 40 percent, and it reached almost 80 percent in some of the higher utilizing states.”

The study’s authors suggest that because the availability of CT has increased over the last 20 years and it is recognized as a reliable diagnostic tool to evaluate adults with kidney stones, clinicians are engrained in the practice patterns or resources specific to their local medical communities. They may not be aware that current best practices recently reported in the New England Journal of Medicine demonstrate that ultrasound can be used as effectively as CT to diagnose kidney stones in adults — at a lower cost and without radiation exposure.

Dr. Tasian and colleagues encouraged future studies to determine the barriers to awareness and implementation of recommended imaging practices that aim to decrease the use of ionizing radiation. Researchers also could test the effectiveness of interventions that attempt to change clinical practice and reinforce the use of ultrasound as the initial screening tool, such as clinical pathways and clinical decision support systems.

Addressing these factors promptly is imperative, if the trend that shows the incidence of kidney stones increasing among children by 10 percent annually continues. While the reasons behind this shift in epidemiology are not well known, some clinicians suspect that the rise in obesity rates, less active lifestyles, diets high in salt, and not drinking enough water may be causing more children to have kidney stones.

A recent study by Dr. Tasian also proposes that climate change may play a role, as warmer days may contribute to dehydration, which leads to a higher concentration of calcium and other minerals in the urine that promote the growth of kidney stones.

Jose E. Pulido, MD, of the Division of Urological Surgery at the University of Pennsylvania’s Perelman School of Medicine; Ron Keren, MD, MPH, of CHOP’s Center for Pediatric Clinical Effectiveness; and Urologic Diseases in America Project collaborators from the RAND Corporation and the University of California, Los Angeles also contributed to the CT imaging for kidney stones study.

Permanent link to this article: http://www.research.chop.edu/blog/current-imaging-practices-kidney-stones-deviate-guidelines/

Oct 24 2014

Penn Medicine Awards of Excellence Honor Faculty

excellenceThe 2014 Penn Medicine Awards of Excellence recognize faculty from The Perelman School of Medicine who exemplify the highest values of innovation, commitment to service, leadership, dedication to patient care, and scholarship and teaching. Four recipients’ distinguished work encompasses their scientific endeavors at The Children’s Hospital of Philadelphia:

“I am extremely proud of this year’s distinguished recipients of the Penn Medicine Awards of Excellence,” said J. Larry Jameson, MD, PhD, executive vice president of the University of Pennsylvania Health System and dean of The Perelman School of Medicine at the University of Pennsylvania. “The contributions of these clinicians and scientists exemplify the outstanding quality of patient care, mentoring, research, and teaching of our world-class faculty. They epitomize the preeminence and impact we all strive to achieve in our shared mission to improve human health, eradicate disease, and provide compassionate care.”

The awardees shared their reactions to this outstanding accomplishment and described some of the projects that demonstrate their drive, dedication, and professionalism. Congratulations to all of the winners!

Dr. Blobel is a hematology researcher in the Department of Pediatrics at The Children’s Hospital of Philadelphia and a professor of pediatrics at The Perelman School of Medicine: “The award recognizes the highly productive people in our group who have carried out all the work and made the lab into what it is today.

“In recent years what we consider to be our breakthroughs are related to two major areas of investigation. One involves the study of higher order chromatin architecture and the development of reagents to alter it with an eye on therapeutic uses. In particular, we have developed an approach that might be suitable as a strategy to treat sickle cell anemia.

“The other involves studies into epigenetic ‘memory’ as it pertains to cell division. During mitosis our chromatin undergoes massive changes in the way it is organized, and virtually all genes are silenced, and it is believed that specific mechanisms are in place that ensure that the correct gene expression patterns are restored upon exit from mitosis. We think that such mechanisms help cells to maintain their identity and differentiation state. Our lab has gained insights into this question and in the process developed tools that are useful to investigators pursuing similar questions.”

Read our latest blog about Dr. Blobel’s work.

Dr. Miller is a psychologist and director of research for the Division of Adolescent Medicine at The Children’s Hospital of Philadelphia, as well as an assistant professor of pediatrics: “I am so gratified to work at CHOP and Penn, with such a rich array of collaborators doing interesting and innovative work. My research on child and adolescent decision making has depended on the support of multiple clinical programs and principal investigators at CHOP, as well as an effective and talented research staff.  The overall goal of my work is to identify the ways in which children and adolescents can be involved in decision making about their own health, to enhance their sense of control and facilitate effective decision making as they mature.”

Read our latest blog about Dr. Miller’s work:

Dr. Liu is a pediatric neuro-ophthalmologist and faculty member of the Ophthalmology Division at The Children’s Hospital of Philadelphia, and a professor of neurology and ophthalmology at Penn: “I have to admit that I was humbled by the Lindback Award. Looking at some of the comments about my teaching, I didn’t realize that I had had such a positive influence as a teacher. To follow in the footsteps of other highly acclaimed, great teachers is really quite an honor — one that I never really expected.”

Dr. Marsh is an assistant professor of neurology and pediatrics at The Children’s Hospital of Philadelphia:  “I am thrilled to have been awarded the Leonard Berwick teaching award. I work hard to infuse my clinical teaching with the basic science fundamentals that are important for all students and residents to remember during their clinical training.  In my role as a physician scientist, I study the basic physiological mechanisms underlying a disease, infantile spasms, that I diagnosis and treat in children. Hence, in my day-to-day work, I attempt to merge the science and clinical realms and instill this approach to the students I teach.  I find my work, going from basic mechanisms to the patient, very fulfilling and one of the most rewarding parts of my job.”

Permanent link to this article: http://www.research.chop.edu/blog/world-class-faculty-honored-achievements/

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