Jan 30 2015

Bridging the Gap Between Womb and World

preterm babiesIn 2012 more than 10 percent of births in the United States were preterm, and nearly 1 percent of births were critically preterm (younger than 26 weeks). These numbers point to a sobering truth: every year, hundreds of thousands of babies are born before they’re ready, requiring urgent medical care immediately after (and likely during) birth.

Coming into the world too early can lead to myriad health issues. Preterm babies, particularly those born before 28 weeks, face a host of challenges, including the fight just to survive.

And preterm babies don’t just face health challenges in the hours and days following their births — many are confronted with obstacles throughout their lives. Those infants who do survive may experience temperature fluctuations, respiratory issues, gastrointestinal and cardiovascular problems, and neurological problems like abnormal blood vessel development, or damage and scarring of blood vessels in the retina.

But investigators at The Children’s Hospital of Philadelphia are on the cusp of an innovative approach to caring for these most delicate infants, one that could radically transform the way they are treated and significantly improve their outcomes.

Alan W. Flake, MD, an attending surgeon, director of the Hospital’s Center for Fetal Diagnosis and Treatment, and Professor of Surgery, Obstetrics and Gynecology, Perelman School of Medicine at the University of Pennsylvania, has been leading a groundbreaking project on the development of an extracorporeal support of the premature infant (ESPI) system.

Far more than a standard incubator or isolette, the device Dr. Flake’s team has been developing is exactly what it sounds like: an external uterus designed to help preterm infants bridge the gap between their mother’s womb and the world.

“This is an enormously promising study,” said Dr. Flake. “Our system is designed, as much as possible, to avoid the deleterious effects of preterm birth.”

Read more about this exciting program in the Research Annual Report.

Permanent link to this article: http://www.research.chop.edu/blog/bridging-gap-womb-world/

Jan 28 2015

Lessons Learned From OB Unit Closures: Planning, Communication Needed

OB unitHospital staff of obstetric (OB) units are dedicated to ensuring that an infant’s birth is a moment of wonder and joy, but after a series of hospitals in Philadelphia began closing their maternity programs, the OB units that remained open were strained by surges in patient volume, low workforce morale, and lack of care continuity, according to a new study led by researchers at The Children’s Hospital of Philadelphia.

From 1997 to 2012, 13 out of 19 hospital maternity units shut down within the city. The researchers conducted semistructured interviews with 23 obstetric department chairs, leaders of private obstetric groups, obstetricians, nurses, nurse managers, and midwives at 11 hospitals that continued their maternity units. Based on their responses, the researchers learned that better transition planning is needed to help reduce stress on the health systems’ staff and avoid fragmented care for mothers and babies.

“While the degree of obstetric unit closures was larger in Philadelphia than in any other metropolitan area, analyzing the situation may provide useful lessons for other areas as hospital consolidations, closures, and mergers have accelerated since the enactment of the Affordable Care Act,” said study leader Scott A. Lorch, MD, MSCE, a neonatologist and researcher in the Center for Outcomes Research at CHOP.

Dramatic surges in delivery volume were the greatest challenge, according to study participants. Maternity units averaged a 58 percent increase in volume, resulting in frequent overcrowding, understaffing, and lower staff morale. Moreover, the overall patient mix shifted toward poorer patients who were more likely to receive late or no prenatal care.

Prior to the closures, patients often received prenatal care at the same hospital where they gave birth. As the maternity units shut down, the patients had to choose another birthing hospital. Their prenatal health information did not always follow them to the new hospital.

“One clear message from this study is that women need help from their healthcare system in obtaining better continuity of care throughout their pregnancies,” Lorch said.

Overall, the study participants identified two main areas for improvement: better communication among hospitals before closures occurred, and the development of regional solutions to exchange health information and coordinate prenatal care with care at delivery.

“Because hospitals compete with each other for patients, local health departments may need to exercise foresight and planning, identifying hospital units at risk for closing,” Lorch said. “Easing the transition when obstetric units close should improve the experience of both patients and caregivers.”

Lorch and colleagues published their research in the December 2014 issue of Health Affairs and spoke Dec. 8 at a forum sponsored by the journal at the National Press Club in Washington. Co-authors included Ashley Martin, MPH, and Richa Randa, MPH, both from the Center for Outcomes Research at CHOP; and Sindhu K. Srinivas, MD, MSCE, and David Grande, MD, both from Penn Medicine. The study was funded by the Agency for Healthcare Research and Quality, part of the National Institutes of Health.

Permanent link to this article: http://www.research.chop.edu/blog/lessons-learned-ob-unit-closures-planning-communication-needed/

Jan 26 2015

Jeffrey H. Silber, MD, PhD Contributes to Resident Hour, Colon Cancer Studies

Jeffrey H. Silber, MD, PhDThe Children’s Hospital of Philadelphia’s Jeffrey H. Silber, MD, PhD, contributed to two recent studies that span the research spectrum. The first, published in The Journal of the American Medical Association (JAMA), investigated changes to the number of hours medical residents can work. The second investigation, of which Dr. Silber was the lead author and which appeared in the Annals of Internal Medicine, was a study of racial disparities in colon cancer survival.

In the JAMA study, Dr. Silber and colleagues found resident duty hour reforms did not result in significantly higher 30-day readmission or mortality rates. And with the Annals of Internal Medicine investigation, the researchers showed racial disparities in colon cancer survival did not decrease over a 14-year period, from 1991 to 2005.

A pediatrician and healthcare economist, since 1997 Dr. Silber has directed CHOP’s Center for Outcomes Research. He has published extensively on the use of multivariate matching in healthcare, and has applied this approach to outcomes research in both pediatric and adult medicine and surgery, disparities research, and cancer research. Dr. Silber is a professor of Pediatrics, Anesthesiology and Critical Care at the University of Pennsylvania Perelman School of Medicine and professor of Health Care Management at The Wharton School.

With the JAMA study, the researchers sought to determine whether 2011 reforms to the number of hours residents could work had affected patient mortality and readmissions. Implemented by the Accreditation Council for Graduate Medical Education (ACGME), the reforms maintained the 2003 maximum of 80 hours a week but reduced residents’ work limit from 30 to 16 consecutive hours for first-year residents, and to 24 hours for more experienced residents.

The investigators performed an observational study of Medicare patient admissions data from July 1, 2009 to June 30, 2012, comprising some 2,790,356 patients with 6,384,273 admissions across 3104 hospitals, and examined a number of medical conditions (such as congestive heart failure and diabetes) and surgical categories. They found “no significant positive or negative associations of duty-hour reforms” with 30-day all-location mortality or 30-day all-cause readmissions.

“There has been a lot of speculation about the effect of the 2011 ACGME duty hour reforms on patient outcomes, so we looked at death and readmission rates at the national level,” said the study’s lead author, the University of Pennsylvania’s Mitesh S. Patel, MD, MBA, MS.

“Some hoped that by shortening intern shifts from 30 hours to 16 hours, less fatigued residents would lead to less medical errors and improved patient outcomes. Yet, others were concerned that shorter shifts would increase patient handoffs and leave less time for education, thereby negatively affecting patient outcomes,” said Dr. Patel. “These results show that in the first year of the reforms, neither was true.”

Presentation to Blame for Colon Cancer Survival Disparities

 The Annals of Internal Medicine study, meanwhile, examined racial disparities in colon cancer survival rates.

Dr. Silber has previously investigated racial disparities in cancer survival. In August of 2013 he published a study in JAMA that showed differences in how breast cancer patients present at diagnosis are more responsible for racial disparities in 5-year survival than treatment disparities.

In the current study, Dr. Silber and colleagues — including the Wharton School of the University of Pennsylvania’s Paul R. Rosenbaum, PhD; and Penn Medicine’s Bruce J. Giantonio, MD — examined Survey, Epidemiology, and End Results (SEER) Medicare data from 1991 to 2005 across 16 sites to determine the extent to which colon cancer disparities result from presentation at diagnosis or treatment.

One of the most common forms of cancer, colon and rectal cancer account for approximately 10 percent of new cancer cases each year worldwide. According to the National Cancer Institute (NCI), five-year survival rates for colon and rectal cancer vary widely depending on how early it is detected. Based on data from 2004 to 2010, 89.8 percent of patients with localized cancer survived five years after being diagnosed, while only 12.9 percent of patients with distant or metastasized cancer survived five years. And during 2014 the NCI estimates 2014 there will be approximately 50,000 deaths from colon and rectal cancer.

Using SEER data, Dr. Silber and colleagues matched 7,677 black patients aged 65 and older with three groups of 7,677 white patients aged 65 and older — who were followed until 2009 — to investigate the roles of demographics, presentation, and treatment in survival. Finding a “persistent disparity,” the researchers’ data showed a 9.9 percent difference in five-year survival between black and white patients when matched for demographics. When matched for presentation the disparity was 4.9 percent, and when matched for treatment it was 4.3 percent.

“In conclusion, more of the racial disparity in colon cancer survival is explained by differences in health at diagnosis (both the state of the cancer and comorbid conditions) than by differences in subsequent treatment,” the authors write. “Our study suggests that the most effective route to reducing the racial survival disparity is to find ways to reduce the disparity in presentation, so fewer black patients present with advanced disease.”

To read more about the JAMA study, see Penn Medicine’s press release. And for more information about the Annals of Internal Medicine paper, see the journal.

Permanent link to this article: http://www.research.chop.edu/blog/chop-expert-contributes-resident-hour-colon-cancer-studies/

Jan 23 2015

Beyond the Bandages, Nurses Treat Trauma


Pediatric nurses play a key role in preventing injury-related post-traumatic stress by providing trauma-informed care.

It’s no surprise that nurses know trauma. With roughly 2.7 million nurses working in the U.S., versus about 900,000 physicians (according to the American Association of Colleges of Nursing and The Henry J. Kaiser Family Foundation, respectively), nurses are on the front line of clinical care. Nurses are very often the first clinical staff patients meet, and do everything from performing triage and physical exams to conducting research.

Indeed, a recent study from CHOP and Penn State Hershey Children’s Hospital published in the Journal of Pediatric Nursing confirms that pediatric trauma nurses are knowledgeable about practicing trauma-informed care, but points to the need for additional nurse training to help families cope after a child’s injury.

When an injury occurs, both the child and family members may experience traumatic stress reactions interfering with a full recovery. Pediatric nurses play a key role in preventing injury-related post-traumatic stress by providing trauma-informed care, which includes recognizing pre-existing trauma, addressing stress associated with the traumatic event, minimizing potentially traumatic aspects of treatment, and identifying children who need additional monitoring or referrals for more help.

Researchers surveyed nurses across five trauma centers about their knowledge, opinions, and current practices in addressing psychological recovery in their injured patients. More than 90 percent of the nurses surveyed recognize the importance of attending to psychosocial needs as part of trauma nursing care, and 75 to 80 percent report that they encourage parents to turn to family and friends for support and help parents manage a child’s pain and anxiety during procedures. However, fewer nurses surveyed reported directly assessing a child or parent’s distress or providing specific instruction in how to cope with difficult or painful experiences.

“When a child is hospitalized for an injury, nurses play a key role not only in medical care, but also in helping families cope and fully recover emotionally,” said Nancy Kassam-Adams, PhD, director of CHOP’s Center for Pediatric Traumatic Stress. “Taken together with other recent studies that found only one in five trauma centers routinely screen child and youth for traumatic stress responses, these results help to identify gaps in current practice and point to possible policy and training needs.”

The results of this survey suggest that efforts to improve trauma-informed pediatric nursing care should highlight specific skills related to helping patients and their parents manage emotional responses to difficult medical experiences.

In a blog post about the study published on the Center for Research and Injury’s blog, CHOP nurse Christie Alminde, RN, CPN notes nurses’ skills and experiences are “well suited to provide excellent trauma-informed care.”

“When we incorporate an understanding of traumatic stress into our routine interactions with children and families, we can provide trauma-informed nursing care that not only reduces the impact of difficult or frightening medical events for our pediatric patients, but also helps with their emotional reactions to illness and injury,” writes Alminde.

For more information and resources about medical traumatic stress, see the Center for Pediatric Trauma Stress. And to learn more about this study, see the full press release.

Permanent link to this article: http://www.research.chop.edu/blog/beyond-bandages-nurses-treat-trauma/

Jan 21 2015

$50 Million Gift to Fund Research Transformation at CHOP

Raymond G. Perelman.

CHOP will establish the Raymond G. Perelman Campus, an eight-acre area that will serve as a hub of pediatric research and clinical innovation at CHOP.

The Children’s Hospital of Philadelphia (CHOP) today announced a $50 million gift from Raymond G. Perelman. This gift, equal to the largest ever received by CHOP, will directly support a wide range of pediatric research, tackling the toughest and most challenging pediatric illnesses and establishing CHOP as a global center for innovative pediatric study.

In recognition of this extraordinary gift for research, CHOP will establish the Raymond G. Perelman Campus, an eight-acre area that will serve as a hub of pediatric research and clinical innovation at CHOP.

“The significant research funding associated with this gift underscores the commitment of Raymond Perelman to world-class pediatric research and medicine,” said Mortimer J. Buckley, chair, Board of Trustees at The Children’s Hospital of Philadelphia. “Through his generosity, Mr. Perelman is first and foremost improving the lives of children for generations to come and we will always be grateful for his altruism,” he said.

Raymond G. PerelmanBorn in Philadelphia, Raymond G. Perelman was raised in the Feltonville and Olney sections of the city and attended the University of Pennsylvania. After serving in WWII, he began a 50-year career with American Paper Products Co., and is currently CEO of RGP Holdings. Mr. Perelman has served on many Boards of Directors, and has been active in numerous civic organizations, including the Philadelphia Museum of Art, Penn Medicine, and the Albert Einstein Health Center.

“We know first-hand the tremendous resource that CHOP represents to families in the Philadelphia region, across the country and around the world,” said Raymond G. Perelman. “This gift will help to ensure that critically important pediatric research, conducted on this campus, remains second to none; in addition to making a tangible difference in the lives of children around the globe for many years to come, it is my hope and expectation that advances in medical research funded by this gift will benefit us all,” he said.

The gift also establishes the “Raymond G. Perelman Research Fund,” that will provide direct support for:

  • Raymond G. Perelman Center for Cellular & Molecular Therapeutics, designed to re-engineer the body’s immune system to fight, and defeat, cancer, metabolic diseases and other catastrophic illnesses through the efforts of the world’s leading experts in immunotherapy and molecular therapy.
  • Perelman Scholars, two new tenure-track faculty positions at CHOP to be filled by candidates from among the world’s finest pediatric researchers.
  • Perelman Fund for Research Innovation, a permanent source of reliable funding for the CHOP Research Institute to strategically identify and support new pilot research initiatives.
  • Perelman Endowed Chair in Pediatric Ophthalmology to support a highly skilled researcher and physician-scientist seeking to break new ground and forge novel paths critical to understanding and treating ophthalmologic diseases in children.
  • Research Support for general research activities of the CHOP Research Institute.

The newly named Raymond G. Perelman Campus comprises an eight-acre portion of the CHOP site located on Civic Center Boulevard just south of the main hospital and encompasses its most state-of-the-art research and clinical centers, including the Ruth and Tristram Colket, Jr. Translational Research Building, which opened in 2009; the new Buerger Center for Advanced Pediatric Care, under construction and slated to open this summer; and a 2.6-acre landscaped plaza.

To learn more about this extraordinary gift, see the full press release.

Permanent link to this article: http://www.research.chop.edu/blog/50-million-gift-fund-research-transformation-chop/

Jan 20 2015

Office Visits May Be Too Short to Detect Autism Risk

autismIdentifying autism spectrum disorder (ASD) risk early is imperative, because the earlier autism is detected the earlier clinicians will be able to intervene. In general, the younger the patient, the more effective ASD interventions are. However, according to a new study published in Pediatrics, short observations — such as an office visit — may be insufficient when it comes to assessing autism risk.

Led by the Center for Autism Research’s Judith S. Miller PhD, MS, the researchers studied a group of children aged 15 to 33 months with autism, speech delays, and typical development. The researchers asked licensed psychologists with autism expertise — who were unaware of the study participants’ status — to analyze two 10-minute video samples of the participants’ autism evaluations. The experts measured five behaviors, including responding, initiating, vocalizing, play, and response to name.

The article’s first author was Terisa Gabrielsen, PhD, NCSP, of Brigham Young University (BYU). Before moving to BYU, Dr. Gabrielsen completed training at CHOP, where she and Dr. Miller conducted research that informed the current study. That work, also published in Pediatrics, examined the feasibility of a formal autism screening process.

In the current study, the researchers found the experts missed referrals for 39 percent of the children in the autism group. Detecting autism risk based on the brief observations alone was challenging because the children who had autism showed more typical behavior (89 percent of the time) than atypical behavior (11 percent) during that short window.

“It’s not often the pediatrician’s fault that referrals are missed,” Dr. Gabrielsen said. “Even autism experts missed a high percentage of referrals within that short timeframe. Decisions for referral need to be based on more information, including autism screening and information from parents.”

In March of 2014, the Centers for Disease Control and Prevention announced that one in 68 children in the U.S. has an ASD — a 29 percent increase over the 2012 rate. The seemingly growing prevalence of ASD demonstrates the need for accurate autism referral decisions. This decision-making process should include parent observations, developmental testing, a detailed history, and autism screening tools in addition to clinical judgment, the research team concluded.

“Certainly, some young children with autism are clearly impaired and easy to recognize,” noted Dr. Miller in a press release put out by BYU. “However, this study looked at the entire range of children who present to the pediatrician’s office, and we found that many children’s impairments are not immediately obvious. For these children, formalized screening instruments and more time with a specialist may be critical.”

For more information about autism and autism research, see the Center for Autism Research. A description of diagnostic tests and other information on how parents can spot the developmental delays associated with ASD is available in the diagnosis section of Autism Roadmap. The Roadmap provides 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.

Permanent link to this article: http://www.research.chop.edu/blog/office-visits-may-short-detect-autism-risk/

Jan 16 2015

Translational Research Project Explores Enzymes’ Cancer Role

enzymeWith support from the National Cancer Institute, The Children’s Hospital of Philadelphia Matthew D. Weitzman, PhD, is studying the relation of a family of proteins to cancer. The proteins in question, the ponderously named APOBEC3 (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3) family of deaminases, play a key role in defending against viruses, but are also being investigated as a possible cause of cellular DNA damage that can lead to cancer.

Dr. Weitzman has been working closely with Abby Green, MD, currently an instructor in Pediatric Oncology. In July of 2014 Dr. Green received a grant of her own to study APOBECs — a two-year Young Investigator Award from Alex’s Lemonade Stand Foundation (ALSF).

Drs. Weitzman and Green’s work seeks to understand better how these enzymes disrupt the genome and cause mutations, and how APOBECs (pronounced AE-POE-BECK) are regulated. Their broad goal is to discover and develop new treatment methods based on a deeper understanding of the relationship between these enzymes and cancer cells. For her part, Dr. Green’s ALSF grant funds an investigation into whether the DNA mutations caused by APOBECs make cancer cells more receptive to drugs.

The work builds on recent investigations into the enzymes’ relation to cancer by Dr. Weitzman and others. In 2011 he published a paper in EMBO Reports with colleagues from the Salk Institute showing that some APOBECs could cause genomic instability. His five-year R01 grant from the National Cancer Institute seeks to build on the EMBO Reports work.

“The grant is asking basically can we show that these enzymes actually cause those [mutational] signatures and fulfill what is predicted retrospectively,” Dr. Weitzman said. “The next questions address what regulates activity, what makes sure it doesn’t happen normally, what are the modifications, what are the interactive proteins, where’s it expressed and localized in the cell, and other fundamental questions about these potentially harmful enzymes.”

Potentially Paradoxical Proteins

 Though APOBECs have been the focus of increased attention in recent years, they remain poorly understood. How, some have wondered, could enzymes that perform an immune function also induce cancer-causing mutations? A review of these enzymes offered a possible answer: age. In their Intrinsic Immunity, Current Topics in Microbiology, the University of Minnesota’s Reuben S. Harris, PhD, and Eric W. Refsland, PhD, address the question of how, and why, enzymes whose primary role is to fight viruses could be a cause of human cancer.

“An attractive explanation for this apparent conundrum may be that [APOBECs’] innate function is important early in life and for the health of the species, for instance, in germ cells or early development, whereas the toll of cancer is not imposed in most instances until after the reproductive years,” they note. “In any event, much more work is now justified on APOBEC3B and its role in breast and, potentially, other human cancers.”

Hence the importance of studies like Drs. Weitzman and Green’s. Dr. Weitzman pointed out that while cancer genome sequencing studies have revealed a great deal of information about how cancer arises, and discovered genes associated with certain cancers, they don’t necessarily provide the mechanism by which things happen.

“We want to bridge that gap,” said Dr. Green.

And though their study is mechanistic, greater knowledge of APOBECs’ role in causing cancer, and how this family of enzymes is regulated, could lead to diagnostic and therapeutic approaches in the future. “If we find that these APOBECs are involved in pediatric cancers, there may be a diagnostic role, or a therapeutic opportunity. We have lots of translational ideas, but we just have to get this first work done,” Dr. Green added.

Indeed, it is CHOP’s unique ability to pair laboratory researchers with clinicians like Dr. Green that allows investigators to think more translationally, Dr. Weitzman noted. He said that his work has really benefitted from the input and expertise of Dr. Green, who is the first clinician to work in his lab.

“CHOP has this ability to pair basic researchers with clinicians, and both sides stimulate each other to think together about translational ideas,” Dr. Weitzman said.

Permanent link to this article: http://www.research.chop.edu/blog/translational-research-project-explores-enzymes-cancer-role/

Jan 14 2015

Researchers Receive Grant to Study TMJ Biology, Long-term Maintenance

TMJOf all the joints in the body, perhaps the most unique, complex, and understudied is the temporomandibular joint (TMJ). The TMJ, which is located close to the ears, is a bilateral movable articulation, connecting the lower jaw (mandible) to the bone at the side of the skull (temporal bone). Its structure include a distinctive feature called an articular disc that acts as a shock absorber and reduces friction so that the bony parts of the joint can glide smoothly, allowing us to chew, talk, yawn, and open our mouths wide to say “Ahhh.”

Researchers at The Children’s Hospital of Philadelphia, Eiki Koyama, DDS, PhD, a faculty member in the Division of Orthopedics, and Hyun-Duck Nah, DMD, PhD, an orthodontist in the Division of Plastic and Reconstructive Surgery who works with patients who have craniofacial deformities, recently received a grant from the National Institute of Dental & Craniofacial Research to study the development of the TMJ, the mechanisms that maintain it, and how these processes may be altered in disease. They aim to use this knowledge to inform future therapeutic strategies in pediatric and adult medicine.

The TMJ begins to form within the first few months after conception, experiences active growth during childhood and adolescence, and then undergoes adaptive remodeling throughout life. The exact prevalence of TMJ disorders in the general pediatric population is uncertain, but guidelines from the American Academy of Pediatric Dentistry cite that upwards of 25 percent of children ages 5 to 17 have some symptoms of TMJ disease, and 1 percent to 2 percent are in need of treatment.

Pediatric TMJ disorders can be congenital or acquired, such as craniofacial abnormalities, juvenile rheumatoid arthritis, and injuries or infection that damage the joint. Symptoms and signs of TMJ disorders vary depending on etiology and severity, but commonly include difficulty opening the mouth, locking of the joint, difficulty with mastication and nutrition, and facial and jaw muscle pain. Furthermore, defective TMJ function often results in under-development of the mandible and abnormal facial growth.

In previous research, Dr. Koyama’s group demonstrated that mice with deletion of a specific gene, Indian hedgehog (Ihh), failed to form a normal TMJ. The joint lacked integral components including its distinctive articular disc, joint cavities, and the specialized cell layers that produce lubricin. Lubricin is a lubricant that protects the TMJ from frictional loads and thus is essential for long-term maintenance of joint integrity.

In the current study, the Koyama and Nah team now plan to further define the roles of Ihh and additionally to delineate the role of two genetic pathways, TGF-β1 and PTHrP, that they suggest Ihh uses to orchestrate TMJ formation, function, and lubricin production. They predict that deterioration of joint lubrication with age or by other insults may underlie disc adhesion and degenerative TMJ disorders, which are prevalent in the adult population.

While this research is still at the basic science stage, Dr. Nah, who is also a research associate professor of surgery at the Perelman School of Medicine at the University of Pennsylvania, said that the ultimate goals of the study include translation of findings to recreate a functional TMJ for those patients with missing or defective TMJs.

Permanent link to this article: http://www.research.chop.edu/blog/researchers-receive-grant-study-tmj-biology-long-term-maintenance/

Jan 12 2015

Researchers Lay Groundwork for Novel Therapy for Huntington’s Disease

Huntington’s Disease

The mutant HTT protein (mHTT) damages a brain region called the striatum, resulting in involuntary movements and severe cognitive and emotional disturbances.

New findings by researchers in the Center for Cellular and Molecular Therapeutics (CCMT) at The Children’s Hospital of Philadelphia suggest that an intricate pathway crucial to the development of Huntington’s disease (HD) rests on a “biological teeter-totter” that when carefully balanced could help to control this devastating neurodegenerative disorder.

HD affects about 30,000 Americans and is an incurable, inherited disease entailing progressive loss of brain cells and motor function, usually beginning in midlife. A defective gene produces repeated copies of a protein called huntingtin, or HTT. The mutant HTT protein (mHTT) damages a brain region called the striatum, resulting in involuntary movements and severe cognitive and emotional disturbances. A key signaling protein called mTORC1 that regulates cell growth and metabolism plays a major role in HD.

In their experiments, study leader Beverly L. Davidson, PhD, director of the CCMT, and co-investigators adjusted levels of mTORC1 in mice bred to model features of HD. They injected bioengineered viruses as a gene therapy tool to carry DNA that directed the production of regulatory proteins called Rheb and Rhes that act along the mTORC1 pathway. After the researchers restored mTORC1 activity to more normal levels, brain areas that had begun to atrophy recovered volume and permitted better motor function.

“It was particularly exciting to see plasticity in the neurons impaired by mHTT,” said Dr. Davidson, who also is on the faculty of the Perelman School of Medicine at the University of Pennsylvania. “This shows that brain cells are capable of responding even after disease onset and hints at the potential for reversing Huntington’s disease.”

She added that restoring proper balance to these delicate biological processes may offer even broader benefits in treating other neurological diseases, such as amyotrophic lateral sclerosis (ALS), fragile X mental retardation, and autism. Fragile X mental retardation and autism both feature overactive mTORC1 activity, while mTORC1 is reduced in ALS and HD.

“This pathway is poised on a biological teeter-totter, and our work highlights that it’s essential to control its activity to find the appropriate balance for each disease,” Dr. Davidson said.

In the future, the research team will focus on increasing their understanding of how they can carefully manipulate the dysregulated pathway to treat HD, with the goal of finding a potential drug therapy. Much work remains, as researchers must identify drug candidates that appropriately activate the mTORC1 pathway. Although gene therapy vectors were used for this research, Dr. Davidson envisions developing a small molecule that can appropriately modulate this pathway. Such a treatment might be combined with a gene therapy approach, also being pursued by her team and other groups, delivered directly to the brain to curtail mHTT expression.

The study team published its results online Dec. 31 in the journal Neuron. They performed a substantial part of this research in Dr. Davidson’s laboratory at the University of Iowa, before she and many of her colleagues moved to CHOP in 2014. John H. Lee, the paper’s first author, remains at the University of Iowa, where he is completing his MD/PhD training. For more information about their research, a press release is available.

The National Institutes of Health and the Roy J. Carver Trust supported this study.

Permanent link to this article: http://www.research.chop.edu/blog/researchers-lay-groundwork-novel-therapy-huntingtons-disease/

Jan 09 2015

Research Improves Training, Assessment of Teen Driving Skills

teen drivingA recent article in the Wall Street Journal on “one of the most dreaded rites of child-rearing — teaching a teenager to drive” — notes recent research on teen driving and training can help teens learn to be better drivers and so avoid accidents. The article touches on studies by Center for Injury Research and Prevention (CIRP) staff: one that examined a web-based intervention, and a more recent investigation of teen driving error frequency.

Though many parents do a good job of teaching the basics of driving — “steering, parking, and controlling the car” — the Wall Street Journal article notes that parents “are not so good, however, at teaching the skills young drivers need to actually avoid accidents, according to new research. Now, there are new techniques and even guides that have grown out of new scientific research into the parent-child dynamic in the car.”

Two studies cited by the Wall Street Journal article were led by CIRP experts. In August, JAMA Pediatrics published a study authored by Jessica Mirman, PhD, that examined the effectiveness of the web-based Teen Driving Plan (TDP) tool in improving teen driving performance as measured by the Teen On-road Driving Assessment (tODA).

Along with the Center for Injury Research and Prevention’s Allison E. Curry, PhD, MPH, and Flaura K. Winston, MD, PhD, among others, Dr. Mirman measured the TDP’s effectiveness in increasing the quantity of practice and teens’ driving performance in 217 teen-parent dyads. The dyads were randomized to receive either the TDP or standard Pennsylvania driver manuals.

She found that the “dyads reported more practice in 5 of the 6 environments and at night and in bad weather compared with control dyads.” In addition, fewer teenagers who used the TDP had their tODA’s terminated for safety reasons than did the control group, who received PA manuals. The study’s “evidence suggest that the TDP improves supervised practice and the driving performance of prelicensed teenaged drivers,” the study author’s notes.

Indeed, as the Wall Street Journal article notes, one parent who participated in Dr. Mirman’s study says the TDP helped improved her driving lessons. “Having a game plan to work with, and to be accountable for, was better,” said Monica Pica.

The second study, led by Dennis Durbin, MD, MSCE, director of CHOP Research’s Office of Clinical and Translational Research, follows Dr. Mirman’s work by investigating driving errors made by teens during their learner’s permit period. This study, published in Accident Analysis & Prevention, used the tODA at 12 and 24 weeks of study to examine driving errors in teen and adult drivers.

Dr. Durbin and colleagues found that 55 percent of novice teen drivers committed “critical errors” at the 12-week tODA and 54 percent committed errors on the 24-week tODA. Only one experienced adult driver committed a critical error at 12 weeks and one at 24 weeks.

“In comparison to a group of experienced adult drivers, a substantially higher proportion of learner teens committed safety-relevant critical driving errors at both time points of assessment,” the authors note. The finding, they write, “suggest further research is needed to better understand how teens might effectively learn skills necessary for safe independent driving while they are still under supervised conditions.”

To read more, see the Wall Street Journal article, “Better Ways to Teach Teens to Drive.” And to learn more about the research being conducted at the Center for Injury Research and Prevention, see the CIRP website.

Permanent link to this article: http://www.research.chop.edu/blog/research-improves-training-assessment-teen-driving-skills/

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