TAG: "Pediatrics"

Researchers receive grant to study schizophrenia in children with 22q11.2


UC Davis MIND Institute researchers will investigate this very high-risk population.

UC Davis MIND Institute

By Phyllis Brown, UC Davis

Researchers studying a genetic disorder that in childhood causes anxiety and learning differences, but in adolescence or early adulthood results in schizophrenia in nearly one third of those affected, will investigate how emotional and intellectual challenges impact the development of early psychosis symptoms in this very high-risk population, through a new five-year, $2.5 million grant from the National Institute of Mental Health.

The grant will allow the UC Davis MIND Institute’s 22q11.2 Deletion Syndrome Research Center and Clinic to assess how cognition, stress and emotions are associated with the the likelihood of developing psychosis among teens with chromosome 22q11.2 deletion syndrome, or 22q11.2DS — a genetic condition that previously has been known as Velocardiofacial Syndrome or DiGeorge Syndrome.

The symptoms of 22q11.2DS vary so widely that the condition often is misdiagnosed in childhood. Children may have a range of medical complications, including congenital heart disease, defects of the palate and mild facial anomalies. Infections are commonplace because of problems with their immune systems. Most children with 22q11.2DS have mild to moderate intellectual disability and difficulties with acquiring written and spoken language.

The center is led by Tony J. Simon, professor in the Department of Psychiatry and Behavioral Sciences, who noted that news of the grant’s selection for funding came almost 10 years to the date from when he joined the MIND Institute. “This is truly ‘the grant that the MIND Institute made’,” Simon said.

“When I arrived at the MIND Institute, my primary focus on 22q11.2DS was on the cold cognitive neuroscience aspects of the learning difficulties,” he said. “But we were so strongly influenced and shaped by the MIND’s clinical translational environment, the interaction between our researchers and clinicians, and the intense time we spend with the kids we study and their families, that our research mission and how we approach it has been literally transformed.”

“Now our approach is to combine measures of neurocognitive and emotional functioning and stress biology with established and novel clinical measures to attempt to establish, not only the predictors of risk for, but also protection against psychotic thinking symptoms. As a result we might be able to reduce the burden of psychosis symptoms on the individual and their families, and maybe even prevent the development of schizophrenia in some,” Simon said.

The research will enroll 100 youth diagnosed with 22q11.2 deletion syndrome between the ages of 12 and 18 years and 50 age- and gender-matched typically developing youth, who will receive two assessments 2-1/2 years apart over the five-year life of the project. The measures will include cognitive functioning tasks that involve either positive or negative emotional stimuli along with variants that do not contain any emotional content.

Some of the tests will be done while brain activity is measured using Event-Related Potentials (ERP) in the MIND Institute’s new ERP Lab. ERPs measure specific responses from brain cells in reaction to events, images or sounds. They are measured by placing an elasticated cap in which are embedded numerous electrodes that can detect electrical brain activity merely by resting next to the scalp.

Stress hormone levels will be sampled during testing via simple saliva tests and all participants will complete a structured interview for psychosis-proneness symptoms carried out by a highly trained clinician. Brain connectivity will be assessed using functional magnetic resonance imaging (fMRI). A third assessment will be included, at 3-1/2 years, for a subset of young people whose psychosis symptoms worsen.

Other members of the project team include Cameron Carter, professor of psychiatry and behavioral sciences and director of the Behavioral Health Center of Excellence and Imaging Research Center at UC Davis; Tara Niendam, assistant professor of psychiatry and behavioral sciences; Steven Luck, professor of psychology and director of the UC Davis Center for Mind and Brain; and Emilio Ferrer, professor of psychiatry and behavioral sciences. The team also will include consultants from Stanford University, Emory University and Tel Aviv University.

For more information visit the 22q11.2 Deletion Syndrome Research Center and Clinic on the Web at www.ucdmc.ucdavis.edu/mindinstitute/research/cabil.

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New clues to treat juvenile diabetes


Hartwell Foundation award winners include researchers from UC Davis, UC San Diego.

By Andy Fell, UC Davis

UC Davis assistant professor Mark Huising is a recipient of The Hartwell Foundation 2014 Individual Biomedical Research Award to support his early-stage research toward a cure for juvenile diabetes. Diabetes affects 10 percent of the entire United States population, including approximately a million children. Remarkably, 40 children every day receive the diagnosis of diabetes.

Huising, who works in the Department of Neurobiology, Physiology and Behavior at the UC Davis College of Biological Sciences, also holds an appointment in the Department of Physiology and Membrane Biology at the UC Davis School of Medicine. He joined UC Davis in November 2014 having previously worked at the Salk Institute in La Jolla. He is interested in how certain cells in the pancreas control the body’s response to sugar in diabetes. Achieving a balance between reduction of elevated blood sugar levels and the need to prevent potentially fatal low sugar levels is critical to maintaining health.

The Hartwell Foundation award will provide $300,000 in direct cost over three years to support Huising’s research looking at the biological signals and triggers affecting a small pool of cells in the pancreas that could be essential in regenerating control of blood sugar in this disease. The Individual Biomedical Research Award to Huising represents the ninth time a researcher from UC Davis has won such recognition from The Hartwell Foundation over the last seven years. The 12 Hartwell Foundation 2014 Individual Biomedical Research Award winners also include Shira Robbins, UC San Diego associate clinical professor of ophthalmology, for “Omega-3 Fatty Acids as a Therapy for the Prevention of Retinopathy of Prematurity.”

Islets, insulin and diabetes

Diabetes has been a prevalent health problem since ancient times. Two forms of the disease are known — Type 1, or “insulin-dependent” diabetes, and Type 2 diabetes, caused when the body fails to regulate the level of sugar properly, sending it either soaring high or dropping to very low levels.

In juvenile diabetes, the body’s own immune system causes damage to a specialized region in the pancreas, called the islets of Langerhans, effectively rejecting the tissue. The damage is significant because the beta cells within the islets make insulin. Normally, increasing blood sugar stimulates insulin production, which causes the body’s cells to pull sugar out of circulation. The islets also house alpha cells, which make another hormone, glucagon. When blood sugar falls, alpha cells make more glucagon, which causes the liver to break out stocks of glycogen and turn it into glucose.

New insight on insulin from immature cells

At diagnosis of diabetes, the body’s immune system has already destroyed most beta cells and any ability to produce insulin. The remaining alpha cells build up and release glucagon, which causes a serious side-effect of juvenile diabetes. The majority of scientific strategies focus on means to prevent beta cell death and promote beta cell division. However, efforts to restore lost beta cells have been largely unsuccessful.

Huising has discovered that, in laboratory mice, immature beta cells may spontaneously arise from alpha cells. He proposes to identify the biochemical signals that switch alpha cells into beta cells and determine in human tissue whether such beta cells are adequately mature and functional. Huising’s approach represents a shift in the current paradigm that after birth beta cells arise exclusively through the division of existing beta cells.

If successful, Huising will harness the intrinsic potential for beta cell regeneration that exists within pancreatic islets. This approach has the benefit of blocking a serious side effect of juvenile diabetes and represents a potential path to a cure for the disease.

Biomedical research that benefits children

“The Hartwell Foundation has a strong commitment to providing financial support to stimulate discovery in early-stage, innovative biomedical research that has potential to benefit children of the United States,” said Fred Dombrose, president of The Hartwell Foundation. “Mark Huising typifies the innovative, young investigator we seek to fund. We want to make a difference.”

Top Ten Center designation

In addition to the individual award, The Hartwell Foundation designated UC Davis as one of its Top Ten Centers for Biomedical Research for the fifth consecutive year.

In selecting each research center of excellence, The Hartwell Foundation takes into account the shared values the institution has with the foundation relating to children’s health, the presence of an associated medical school and biomedical engineering program, and the quality and scope of ongoing biomedical research.

The foundation also considers the institutional commitment to support collaboration, provide encouragement, and extend technical support to the investigator, especially as related to translational approaches and technology transfer that could promote rapid clinical application of research results.

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Childhood syndrome combining lung disease, arthritis is ID’d


Discovery suggests mechanism, possible therapies for severe disorder.

By Pete Farley, UC San Francisco

Using the latest genome sequencing techniques, a research team led by scientists from UC San Francisco, Baylor College of Medicine and Texas Children’s Hospital has identified a new autoimmune syndrome characterized by a combination of severe lung disease and arthritis that currently has no therapy.

The hereditary disorder, which appears in early childhood, had never been diagnosed as a single syndrome. The new research revealed that it is caused by mutations in a single gene that disrupt how proteins are shuttled around within cells. Patients with the newly discovered syndrome have a poor prognosis, and at present can only be treated with anti-inflammatory and immunosuppressant drugs. Many have lung disease so severe that they must receive lung transplants.

Thanks to biological mechanisms revealed in the research, patients could soon have access to a wider range of therapies, according to Anthony K. Shum, M.D., UCSF assistant professor of medicine and co-senior author of the new study. “We believe that there are small molecules in development that can help correctly traffic the proteins that are misdirected in this syndrome, so that’s something we really want to go after.”

Levi B. Watkin, Ph.D., a postdoctoral fellow at Baylor; former UCSF postdoctoral fellow Birthe Jessen, Ph.D.; and Wojciech Wiszniewski, M.D., assistant professor of molecular and human genetics at Baylor, led the research, which is reported in the April online edition of Nature Genetics.

For Shum, the project was sparked when a woman was admitted to the Emergency Department at a California medical center with pulmonary hemorrhage. In the course of treating the patient, Shum learned that she had arthritis as well, and that a sibling and aunt also had both lung disease and arthritis.

Some time later, when Shum encountered the patient’s mother in the hospital’s corridor, she mentioned that a distant cousin she had never met had posted on a social media site that her own 2 1/2-year-old daughter was being treated at another hospital for pulmonary hemorrhage. Shum went to that hospital and found that, in addition to dramatic hemorrhaging in the child’s lungs, she too had arthritis.

With the help of UCSF medical students, Shum began searching for other affected family members and ultimately identified a distant relative in another state with the same syndrome. The group then sequenced DNA samples from nine family members, some with the syndrome and some who are unaffected, to search for mutations that might underlie the disorder.

“We sort of took a flyer,” Shum said. “The likelihood of finding something was low.”

UCSF scientists quickly zeroed in on a region of the genome containing a gene known as COPA, a result in which they initially had little confidence.

COPA mutations were completely unexpected,” Shum said. “The COPA protein is expressed throughout the body, and no diseases associated with this gene had ever been reported.” But an independent genetic analysis produced the same result: using this second method, Shum said, “You’ll usually see peaks spread across the genome, but we only got a single peak. It was highly significant, and COPA was right under it.”

The COPA protein is essential in intracellular transport – the process by which newly made proteins are moved to their proper locations in the cell – and the scientists found that the COPA mutations seen in the patients “cripple the protein,” said Shum, preventing it from performing this vital function.

Encouraged by the consistency and clarity of these results, Shum reached out to physicians at other institutions to see if they had seen patients with the same cluster of symptoms.

“By pure serendipity,” Shum said, he was soon contacted by co-senior author Jordan S. Orange, M.D., Ph.D., director of the Texas Children’s Hospital Center for Human Immunobiology, who had seen similar cases. Moreover, Orange’s colleague, sequencing expert James R. Lupski, M.D., Ph.D., co-senior author and Cullen Professor of Molecular and Human Genetics at Baylor, had independently fingered COPA mutations in his own genomic analyses of these cases.

Ultimately the UCSF-Baylor-Texas Children’s team identified five families in which 30 family members carried deleterious COPA mutations. Only 21 of those carriers were affected by lung and joint problems, suggesting that, although the disease is inherited, it has “incomplete penetrance” – the presence of COPA mutations does not solely determine that an individual will develop the syndrome.

“The fact that we discovered five unrelated families and over 20 affected individuals in just over two and half years of investigating this leads me to believe that this is by no means ultra-rare,” said Orange.

Subsequent experiments with tissue from affected patients revealed that faulty protein trafficking by mutant COPA results in a condition known as “cellular stress,” which in turn sets off an autoimmune reaction mediated by immune-system cells known at Th17 cells.

Because Th17 cells have already implicated in autoimmune diseases, particularly in rheumatoid arthritis, Shum believes that targeting these cells with drugs may provide a new therapeutic avenue for those with the syndrome.

“In our current research we’re making sure that we have a clear mechanism, so we can come up with a potential drug target,” he said.

Orange added that the new research may have ramifications that extend beyond this particular syndrome, especially for arthritis therapies.

“We are excited to learn how variants of this disease might be more broadly applicable and might be instructive to our overall understanding of arthritis,” he said.

In the meantime, Shum said, patients and their families have been gratified that the mysterious condition affecting their families is beginning to be understood.

“When I first contacted the families we located, it was a huge relief to them to know that there are other people like them and that someone is working on this disorder.”

The research was funded by the National Institutes of Health, The Jeffrey Modell Foundation, The Foundation of the American Thoracic Society, The Pulmonary Fibrosis Foundation, and The Nina Ireland Program for Lung Health at UCSF.

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A mother’s genes can influence the bacteria in her baby’s gut


Research may have applications for protecting preemies from range of intestinal diseases.

Zachary Lewis (left) and David Mills, UC Davis

By Phyllis Brown, UC Davis

Researchers at UC Davis have found that a gene, which is not active in some mothers, produces a breast milk sugar that influences the development of the community of gut bacteria in their infants. The sugars produced by these mothers, called “secretors,” are not digested by the infant, but instead nourish specific bacteria that colonize their babies’ guts soon after birth.

Mothers known as “non-secretors” have a non-functional fucosyltransferase 2 (FUT2) gene, which alters the composition of their breast milk sugars and changes how the microbial community, or microbiota, of their infants’ guts develop.

The research may have applications in a clinical setting for protecting premature infants from a range of intestinal diseases including necrotizing enterocolitis (NEC), a condition that is the second most common cause of death among premature infants in the United States.

The researchers emphasized that the finding does not suggest that breast milk from mothers without an active copy of the gene is less nourishing or healthy. Rather, it conveys the subtle and elegant choreography of one part of the human microbiome: The relationships between the mothers’ genetics, the composition of her breast milk and the development of their infants’ gut microbiota. It also reveals clues for enriching desirable bacteria in populations at risk of intestinal diseases — such as preemies.

“In no way is the nonsecretor mother’s milk less healthy, and their babies are at no greater risk,” said David Mills, Peter J. Shields Endowed Chair in Dairy Food Science at UC Davis and senior study author. “What this work does show us is that the mother’s genotype matters, and that it influences the breast milk, which clearly drives the establishment of microbes in the intestines of their babies.”

The research examining the differences in infant gut microbial populations arising from differences in human milk oligosaccharides (sugars), “Maternal Fucosyltransferase 2 Status Affects the Gut Bifidobacterial Communities of Breastfed Infants,” is published online today (April 9) in the journal Microbiome, a BioMedCentral journal.

Varieties of Bifidobacterium inhabit the gastrointestinal tracts and mouths of mammals and are one of the major genera of bacteria that make up the microbial community of the infant colon. The relationship between human genetics, breast milk and Bifidobacterium appears to have developed throughout mammalian evolution.

Development of a healthy gut microbiota can have a lifelong effect on health, and early intervention in the establishment of that microbiota could have lifelong positive effects: The early establishment of bifidobacteria has been shown to be associated with improved immune response to vaccines, development of the infants’ immature immune system, and protection against pathogens.

Bifidobacterium are known to consume the 2′-fucosylated glycans (sugars) found in the breast milk of women with the fucosyltransferase 2 mammary gene. The study found that, on average, Bifidobacterium were established earlier and more frequently in infants fed by women with an active copy of the gene, the secretors, than without one, the non-secretors.

The authors found that the intestinal tracts of infants fed by non-secretor mothers are delayed in establishing a bifidobacteria-dominated microbiota. The delay, the authors said, may be due to difficulties in the infant acquiring a species of bifidobacteria that is geared toward consuming the specific milk sugar delivered by the mother.

The research was conducted using milk samples from 44 mothers in the UC Davis Foods for Health Institute Lactation Study and fecal samples from their infants at four different time points. The researchers determined the secretor status of the mothers: 12 were non-secretor and 32 were secretor mothers. They also measured the amount and type of breast milk sugars and the amount of lactate (a beneficial molecule produced by bifidobacteria) in the infant’s feces.

The researchers determined that more infants fed by secretor mothers had high levels of bifidobacteria — 60 percent of infants versus 37.5 percent at day 6 and 80 percent versus 50 percent at day 120 –- and that infants who had more bifidobacteria had lower amounts of milk sugars left over and higher amounts of lactate in their feces.

One question that remains is whether this pattern holds true in infants living in other places.

“We are beginning to observe that infants from different parts of the world have different patterns of colonization by microbes,” said lead study author Zachary T. Lewis, a postdoctoral fellow.

“The types and levels of bacteria encountered by infants in developing countries is different from the types and levels of bacteria encountered by the babies in our UC Davis cohort, and that might account for some of the differences,” he said.

Maternal secretor status is likely only one of the many factors that influence the infant gut microbiota, Lewis said. The researchers will explore this question further in future studies.

The researchers said that understanding the mechanism behind the observed secretor/non-secretor differences may prove critical to compensating for it in situations where the infants are vulnerable, such as by providing carefully chosen pre- or probiotics. For example, prebiotics and probiotics frequently are given to premature infants  to protect them against NEC, which causes portions of the bowel to necrotize, or die.

“This work significantly advances our efforts to decipher how human milk amazingly orchestrates colonization of the infant gut by helpful bacteria, which then protects and guides intestinal development in the early stages of life. Understanding this incredible sequence of events will provide examples for how to repair this process where it has been disrupted, such as in premature infants or colicky babies,” Mills said.

Other study authors include Jennifer T. Smilowitz, Evan Parker, Danielle G. Lemay and Carlito Lebrilla, all of UC Davis; Sarah M. Totten of UC Davis and Stanford University: Mina Popovic of University of Moedna and Reggio Emilia, Italy; and Maxwell Van Tassel Michael J. Miller and Young-Su Jin of the University of Illinois Urbana-Champagne.

The research was supported by the University of California Discovery Grant Program, the UC Davis Research Investments in the Sciences and Engineering (RISE) Program, the California Dairy Research Foundation, the Bill and Melinda Gates Foundation, National Institutes of Health awards R01HD059127, R01HD065122, 8R01HD061923, R21AT006180, R01AT007079 and the Peter J. Shields Endowed Chair in Dairy Food Science.

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Brain imaging explains reason for language outcomes in autistic toddlers


Findings could help determine how and why treatments are effective for some, but not all.

By Scott LaFee, UC San Diego

Using functional magnetic resonance imaging (fMRI), UC San Diego School of Medicine researchers say it may be possible to predict future language development outcomes in toddlers with autistic spectrum disorder (ASD), even before they’ve been formally diagnosed with the condition.

The findings are published in today’s (April 9) online issue of the journal Neuron.

A major challenge of ASD diagnosis and treatment is that the neurological condition – which affects 1 in 68 children in the United States, mostly boys – is considerably heterogeneous. Early symptoms differ between each ASD toddler, as does progression of the condition. No uniform clinical phenotype exists, in part because the underlying causes for different subtypes of autism are diverse and not well-understood.

“There is no better example than early language development,” said senior author Eric Courchesne, Ph.D., professor of neurosciences and co-director of the Autism Center of Excellence at UC San Diego. “Some individuals are minimally verbal throughout life. They display high levels of symptom severity and may have poor clinical outcomes. Others display delayed early language development, but then progressively acquire language skills and have relatively more positive clinical outcomes.”

In other words, said Courchesne, in some children with ASD language improves substantially with age; but in some it may progress too slowly or even diminish. The neurodevelopmental bases for this variability are unknown, he said. Differences in treatment quantity do not fully account for it. But numerous studies have shown that early, accurate diagnoses of ASD can improve treatment benefits in many affected children.

“It’s important to develop more and new biological ways to identify and stratify the ASD population into clinical subtypes so that we can create better, more individualized treatments,” said co-author Karen Pierce, Ph.D., associate professor of neurosciences and co-director of the Autism Center of Excellence.

In the Neuron paper, Courchesne, first author Michael V. Lombardo, Ph.D., a senior researcher at the University of Cambridge and assistant professor at the University of Cyprus, Pierce and colleagues describe the first effort to create a process capable of detecting different brain subtypes within ASD that underlie and help explain varying development language trajectories and outcomes. “We wanted to see if patterns of brain activity in response to language can explain and predict how well language skills would develop in a toddler with ASD before that toddler actually began talking,” said Courchesne.

The researchers combined prospective fMRI measurements of neural systems’ response to speech in children at the earliest ages at which risk of ASD can be clinically detected in a general pediatric population (at approximately ages 1-2 years) with comprehensive longitudinal diagnostic and clinical assessments of language skills at 3-4 years of age.

They found that pre-diagnosis fMRI response to speech in ASD toddlers with relatively good language outcomes was highly similar to non-ASD comparison groups with robust responses to language in superior temporal cortices, a region of the brain responsible for processing sounds so that they can be understood as language.

In contrast, ASD toddlers with poor language outcomes had superior temporal cortices that showed diminished or abnormal inactivity to speech.

In sum, the study found entirely different neural substrates at initial clinical detection that precede and underlie later good versus poor language outcome in autism. These findings, said researchers, will open new avenues of progress towards identifying the causes and best treatment for these two very different types of autism.

“For the first time, our study shows a strong relationship between irregularities in speech-activation in the language-critical superior temporal cortex and actual, real-world language ability in ASD toddlers,” said Lombardo.

The scientists said fMRI imaging also showed that the brains of ASD toddlers with poor language development processed speech differently, including how neural regions governing emotion, memory and motor skills were involved.

“Our work represents one of the first attempts using fMRI to define a neurofunctional biomarker of a subtype in very young ASD toddlers,” said Pierce. “Such subtypes help us understand the differences between persons with ASD. More importantly, they can help us determine how and why treatments are effective for some, but not all, on the autism spectrum.”

Co-authors include Lisa Eyler, UCSD and Veterans Affairs San Diego Healthcare System; Cindy Carter Barnes, Clelia Ahrens-Barbeau, Stephanie Solso, and Kathleen Campbell, UCSD.

Funding for this research came, in part, from National Institute of Mental Health grants P50-MH081755, R01-MH080134 and R01-MH036840, the National Foundation for Autism Research and Jesus College, Cambridge and the British Academy.

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UCSF professor appointed to expert panel for precision medicine


Esteban Burchard will help shape President Obama’s precision medicine plan.

Esteban Burchard, UC San Francisco (Photo by Cindy Chew)

UC San Francisco’s Esteban Burchard, M.D., M.P.H., has been appointed to an expert panel advising the National Institutes of Health (NIH) on how to develop President Barack Obama’s Precision Medicine Initiative.

The $215 million initiative, announced by Obama earlier this year, aims to gather and analyze vast amounts of genetic and other patient data to develop more targeted, personalized therapies for treating diseases in the future.

The panel, composed of medicine, technology and policy leaders, will guide the NIH in its efforts to build a group of at least 1 million American volunteer research participants who will confidentially share their genetic, environmental, lifestyle and behavioral information with qualified researchers.

Burchard, whose specialty is how genetic ancestry affects drug response, said he was asked to be on the panel because of his expertise in applying precision medicine to minority children with asthma. He has recruited the largest pediatric gene-environment study of asthma in minority children in the U.S. Since 2004, more than 95 percent of all NIH funded clinical research has been performed in populations of European origin, even though it’s well known that ancestry affects both disease susceptibility and drug response.

“There are scientific advantages that can be gained by studying diverse populations,” Burchard said. “There are going to be some drugs that work really well for African Americans, and there are going to be some drugs that work really well for everybody.”

Treatments tailored to a patient’s genes

Burchard, professor of bioengineering in the UCSF School of Pharmacy has been conducting genomic research for more than a decade, completing the most comprehensive study of asthma in the United States, collecting the genetic, socioeconomic and environmental information of more than 10,000 patients.

Beyond simply finding which genes are associated with severe asthma, Burchard is studying the role a person’s genes play in determining how he or she responds to existing asthma medications.

He’s finding that genetic factors are the strongest predictor of drug response – more influential than air pollution or social factors – and some of the most severe asthma sufferers don’t respond well to common asthma drugs. Using this genetic knowledge to develop better, more targeted drugs to an individual’s specific disease profile is the promise of precision medicine.

“Forget notions of race and ethnicity. When you know specific genes involved in disease and can genetically test each individual, that’s the most effective way to identify the risk factor and the treatment,” said Burchard.

Gathering expert and public input

The working group panel will deliver a preliminary report in September to accelerate the launch of this national study of individual differences that influence health and disease outcomes. The group will gather input from patients and the scientific community through public workshops on precision medicine topics, including privacy, electronic health records, mobile health technologies, existing research cohorts, participant preferences, and inclusion of minority and underserved populations.

The plan is the outgrowth of a 2011 report from a National Academy of Sciences expert committee recommending the creation of a biomedical “knowledge network”  that would allow scientists to gather and mine vast amounts of patient data, with the goal gaining insights into the genetic and molecular basis of disease.

The committee was co-chaired by then-UCSF Chancellor Susan Desmond-Hellmann, M.D., M.P.H., and also included two other members of the UCSF faculty – Keith Yamamoto, Ph.D., vice chancellor for research, and Bernard Lo, M.D., professor of medicine emeritus and director emeritus of the Program in Medical Ethics at UCSF.

Desmond-Hellmann, now CEO of the Gates Foundation, is also serving on the president’s prestigious working group.

“I’m confident that we’ve pulled together the best of the best in this working group to put us on the right path forward,” said NIH Director Francis S. Collins, M.D., Ph.D.

“Establishing a 1 million person cohort is an audacious endeavor, but the results from studying such a large group of Americans will build the scientific evidence necessary for moving precision medicine from concept to reality.”

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UC Davis leads $4M NIH grant to study skull disorder in infants


International team includes researchers from UC Irvine, UCSF.

Simeon Boyd, UC Davis

By Phyllis Brown, UC Davis

Simeon Boyd, UC Davis professor of genetics and pediatrics, has received a nearly $4 million, five-year grant from the National Institute of Dental and Craniofacial Research to lead a team of physicians and scientists from more than 10 centers in the United States and seven international sites, including Australia, Brazil, Bulgaria, Germany, Hungary, Italy and the United Kingdom, to study craniosynostosis, the premature fusion of the bony plates of the skull in infants.

The researchers are members of the International Craniosynostosis Consortium, whose goal is to identify the genetic and environmental causes of craniosynostosis, which affects approximately 1 in 2,500 newborns worldwide, in order to find clues to prevention, better treatments and, eventually, a cure.

“Our goal is not only to identify the genetic causes of all types of craniosynostosis, but also to facilitate the early detection of the condition, by identifying biomarkers. This may allow for nonsurgical therapeutic intervention in utero in the future,” said Boyd, who is a researcher affiliated with the UC Davis MIND Institute. The conditions also have neurodevelopmental consequences: Approximately 50 percent of patients with craniosynostosis also may have learning disabilities.

During fetal development, the skull is made up of separate bony plates that allow the child’s head to grow after birth. The borders between the plates do not normally fuse completely until a child is about 2, leaving temporary soft spots at the intersections of the seams of the skull.

In craniosynostosis the bones fuse early, causing the child to have an abnormally shaped head. The disorder can lead to complications due to brain compression, such as visual problems and learning disabilities.

“This is not only a skull disease,” Boyd said. “It is a perturbation of the brain and the skull, in which the growing brain is abnormal and causes increased distension of the envelope of the brain so that signaling molecules that normally would keep the sutures open do not function properly.”

Depending upon the severity of the condition, children born with craniosynostosis frequently may require extensive neurosurgical intervention to separate the fused bones of the skull so that the child’s brain can grow.

There are a number of different types of craniosynostosis, depending on which suture is prematurely fused. For example, when the sagittal suture at the top of the head is fused the condition is called in sagittal synostosis, also known as scaphocephaly. Sagittal synostosis is the most common form of the disorder. In coronal synostosis the coronal sutures, which run from the top of the head to the ears, are fused. Several named conditions, such as Muenke syndrome, have craniosynostosis among their symptoms.

In 2012, Boyd and his consortium colleagues published a landmark study in Nature Genetics, which found that two areas of the human genome are associated with a form of the disorder, sagittal craniosynostosis. Although the condition had long been believed to be partially determined by genes – it is three times more common in boys than in girls, and identical twins are much more likely to both be affected than fraternal twins – the genes associated with the disorder had not been previously identified.

Identification of the genetic basis for the conditions is only a first step in preventive and therapeutic strategies, Boyd said.

“We want to prevent babies from being born with these disorders,” he said.

Consortium researchers from the United States include:

  • Jon Bernstein, Stanford University
  •  Michael Cunningham, University of Washington
  •  John Graham, Cedars-Sinai
  •  Virginia Kimonis, UC Irvine
  •  Ophir Klein, UC San Francisco
  •  Pedro Sanchez-Lara, Children’s Hospital Los Angeles
  •  Joan Richtsmeier, Pennsylvania State University
  •  Paul Romitti, University of Iowa
  •  Joan Stoler, Boston Children’s Hospital

International collaborators include:

  •  Andrew Wilkie, Oxford University, United Kingdom
  •  Wanda Lattanzi, Universita Cattolica del Sacro Cuore, Italy
  •  Tony Roscioli, University of Sydney, Australia
  •  Emil Simeonov and Radka Kaneva, Medical University, Sofia Bulgaria
  •  Bernd Wollnik, University of Cologne, Germany
  •  Eva Olah, University of Debrecen, Hungary
  •  Maria Rita Passos-Bueno, University of Sao Paolo, Brazil

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Scientists link unexplained childhood paralysis to eneterovirus D68


UCSF-led team rules out other pathogens with comprehensive sequencing.

By Laura Kurtzman, UC San Francisco

A research team led by UC San Francisco scientists has found the genetic signature of enterovirus D68 (EV-D68) in half of the California and Colorado children diagnosed with acute flaccid myelitis – sudden, unexplained muscle weakness and paralysis – between 2012 and 2014, with most cases occurring during a nationwide outbreak of severe respiratory illness from EV-D68 last fall.

The finding strengthens the association between EV-D68 infection and acute flaccid myelitis, which developed in only a small fraction of those who got sick. The scientists could not find any other pathogen capable of causing these symptoms, even after checking the cerebrospinal fluid for every known infectious agent.

Researchers analyzed the genetic sequences of EV-D68 in children with acute flaccid myelitis and discovered that they all corresponded to a new strain of the virus, designated strain B1, which emerged about four years ago and had mutations similar to those found in poliovirus and another closely related nerve-damaging virus, EV-D70. The B1 strain was the predominant circulating strain detected during the 2014 EV-D68 respiratory outbreak, and the researchers found it both in respiratory secretions and – for the first time – in a blood sample from one child as his acute paralytic illness was worsening.

The study also included a pair of siblings, both of whom were infected with genetically identical EV-D68 virus, yet only one of whom developed acute flaccid myelitis.

“This suggests that it’s not only the virus, but also patients’ individual biology that determines what disease they may present with” said Charles Chiu, M.D., Ph.D., an associate professor of Laboratory Medicine and director of UCSF-Abbott Viral Diagnostics and Discovery Center. “Given that none of the children have fully recovered, we urgently need to continue investigating this new strain of EV-D68 and its potential to cause acute flaccid myelitis.”

Among the 25 patients with acute flaccid myelitis in the study, 16 were from California and nine were from Colorado. Eleven were part of geographic clusters of children in Los Angeles and in Aurora, Colorado, who became symptomatic at the same time, and EV-D68 was detected in seven of these patients.

Although the researchers found EV-D68 in the children’s respiratory secretions and in the blood from one case, they did not find it in cerebrospinal fluid. The researchers said this may not be surprising given that other nerve-damaging viruses, like polio, are also extremely difficult to detect in cerebrospinal fluid.

Eighty percent of the children reported having an upper respiratory illness about six days, on average, before their acute flaccid myelitis symptoms began. Slightly more reported having a fever, including all of the cases from the clusters in California and Colorado.

Samples were collected more than a week after the children began showing symptoms of an upper respiratory infection, and this likely made it much harder to find EV-D68. There may also be other reasons to explain why the virus was not found in cerebrospinal fluid in children with neurological symptoms.

“The lack of detectable virus in CSF could also mean that the neurological symptoms are coming from an aberrant immune response to recent EV-D68 infection and not because the virus is directly invading neurons,” said Chiu, senior author on the paper published today (March 30) in The Lancet Infectious Diseases.

This study was supported by grants from the National Institutes of Health, a University of California Discovery Award, an Abbott Viral Discovery Award and the Centers for Disease Control and Prevention Emerging Infections Program.

Other authors include Alexander Greninger, M.D., Ph.D., Samia Naccache, Ph.D., Guixia Yu, B.S., Sneha Somasekar, B.S., Scot Federman, B.A., and Doug Stryke, B.S., of UCSF; Kevin Messacar, M.D., and Samuel Dominguez, M.D., Ph.D., of Children’s Hospital Colorado and University of Colorado School of Medicine, Aurora; Anna Clayton, B.S., M.P.H., Christopher Anderson, B.S., Shigeo Yagi, Ph.D., Sharon Messenger, Ph.D., Debra Wadford, Ph.D., Dongxiang Xia, M.D., Ph.D., and Carol Glaser, D.V.M., M.D., of the California Department of Public Health; Keith Van Haren, M.D., of Lucile Packard Children’s Hospital at Stanford University; and Grace Aldrovandi, M.D., of Children’s Hospital Los Angeles and University of Southern California.

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For most children with HIV, low immune cell count, cells rebound after treatment


Study led by UCLA doctor finds t-cell level returns to normal with time.

Paul Krogstad, UCLA

By Enrique Rivero, UCLA

Most children with HIV who have low levels of a key immune cell eventually recover levels of this cell after they begin treatment, according to a new study conducted by researchers at UCLA and other institutions in the U.S. and Brazil.

The researchers were funded by the National Institutes of Health.

“We were pleased to find that the vast majority of children experience immune system recovery with effective therapy,” said Dr. Paul Krogstad, professor of pediatric infectious diseases and of molecular and medical pharmacology at the David Geffen School of Medicine at UCLA, and the study’s first author. “Our study also provided the most detailed information to date about the timing of this recovery in school-age children.”

Krogstad is also a member of the UCLA AIDS Institute and Center for AIDS Research.

CD4+ t cells are a major target of HIV. In about 15 percent of adult patients, the cells fail to rebound after the virus has been suppressed with medication, a scenario that is associated with life-threatening illnesses.

The new study, which was published online in the journal AIDS, was intended to determine to what extent children who were infected with HIV around the time of birth were at risk for this condition and whether this failure carried with it a major risk for serious infection.

The failure of CD4+ t cells to rebound occurs only infrequently in young children with HIV, said Rohan Hazra, a study author and the chief of the maternal and pediatric infectious disease branch at the NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development, which provided much of the funding for the study.

“The comparatively few children whose CD4+ cells failed to rebound did not appear to be at any greater risk for serious infection than children with higher CD4+ counts,” he said.

Hazra added that the findings do not appear to change treatment recommendations for children with HIV: antiretroviral treatment to suppress the virus and periodic follow-up examinations to detect the first signs of any serious infections.

To conduct their analysis, researchers reviewed data from three research networks caring for more than 3,700 children in the U.S., Central and South America, and the Caribbean who were infected with HIV before or during birth. The researchers followed the CD4+ cell counts of 933 children who were at least 5 years old when they started anti-HIV treatment. Healthy CD4+ cell counts range from 500 to 1,200 cells per blood sample. Fewer than 500 cells per sample is considered low, and 200 or fewer per sample is considered very low. After one year of anti-HIV treatment, 86 percent of children in the study achieved CD4+ counts of 500 or more. After two years of anti-HIV treatment, 92 percent surpassed this threshold.

The researchers also reviewed the children’s records for signs of serious illness during the course of their treatment. Known as CDC Category C events, these illnesses are a sign of the seriously weakened immune system in people with AIDS. A total of nine children experienced such events. The occurrence of these events did not differ statistically between those having CD4+ cell counts below 500 at the time of the event (four children) and those with counts above 500 (five children).

The study authors noted that compared to adults with low CD4+ counts at the beginning of treatment, CD4+ counts in children increase to 500 or more with time after treatment has begun. Yet, despite such increases, some children had Category C conditions or other significant illnesses during the first three years of HIV treatment. The researchers wrote that additional studies are needed to understand this higher risk of illness.

Additional funding was provided by several NIH institutes: the National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, the Office of AIDS Research, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Deafness and Other Communication Disorders, the National Heart Lung and Blood Institute, the National Institute of Dental and Craniofacial Research, and the National Institute on Alcohol Abuse and Alcoholism.

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Film camp offers hope for pediatric cancer patients


UC Riverside senior, cancer survivor seeking support at April 2 screening to expand program.

Cassie Nguyen, a senior public policy major and brain cancer survivor, will introduce her Spotlight On Hope Film Camp to the community on April 2.

By Bettye Miller, UC Riverside

Brain cancer. Not the diagnosis Cassie Nguyen was expecting as a sophomore at Riverside’s Martin Luther King High School. Neither was the debilitating surgery that saved her life.

Today, Nguyen is an honor student and School of Public Policy ambassador at the University of California, Riverside, where she will graduate in June. She is a 10-year cancer survivor, American Cancer Society advocate, and the creator of Spotlight On Hope Film Camp, a free filmmaking program for pediatric cancer patients that until now has been held only in Los Angeles.

Nguyen hopes to bring the film camp to UC Riverside and the Inland Empire, and is screening short films written and produced by pediatric cancer patients in the program on Thursday, April 2, from 3:30 to 6:30 p.m. in Highlander Union Building 367. The event is free and open to the public. Parking is free in Lot 1; pick up parking permits at the Kiosk on West Campus Drive at the University Avenue entrance to the campus. Reservations are requested as seating is limited and may be made online. The screening is co-sponsored by University Honors and the Women’s Resource Center.

The Riverside resident said she hopes the screening will generate support to expand the program to the Inland Empire. She hopes eventually to establish a nonprofit foundation and offer film camps across the country.

Approximately 13,500 children are diagnosed with cancer each year in the U.S., and about 25 percent of them die, Nguyen said. Although Spotlight On Hope Film Camp does not reduce the death rate, it does provide a therapeutic outlet for pediatric cancer patients, she explained.

“I know how boring the hospital scene is,” Nguyen said, recalling the surgery to remove the tumor from her brain, a year of radiation and chemotherapy, and physical therapy to learn to write with her left hand and regain mobility to address ongoing balance and difficult vision issues. “I wanted to do something to help kids take their minds off what was happening to them and give them something to look forward to.”

Nguyen suggested the film camp for young cancer patients while working as an intern for Think Ten Media Group, a production company based in Castaic that aims to use the power of media to create change and spread awareness of key issues.

She raised $700 to cover production costs of the first camp, held in September 2013, by selling plastic cancer bracelets to UCR faculty and students, family and friends in her junior year. She dedicated the first film camp to a younger cousin who died of sarcoma cancer at age 14.

Think Ten Media Group co-founders and filmmakers Ramon Hamilton and Jennifer Fischer helped Nguyen develop the Spotlight On Hope Film Camp for pediatric cancer patients at Children’s Hospital Los Angeles as part of their company’s arts education program. The UCLA School of Theater, Film and Television hosts the camp in Los Angeles.

When the film camp proved to be successful, Nguyen applied for and won a $10,000 scholarship from the Donald A. Strauss Public Service Scholarship Foundation in 2014, which funded 10 more film camps at UCLA. The foundation awards $10,000 scholarships to as many as 15 California college juniors annually to support public-service projects that the students carry out during their senior year.

Spotlight On Hope Film Camp allows patients to explore the art of green screen and special effects film-making while working in groups to create a short, green screen and special effects film. The participants, who range in age from 8 to 22, also learn about story/character development, camera technique, video and FX editing during three days of weekend classes.

“Being a pediatric patient myself, I understand how valuable a creative therapeutic outlet can be in the midst of your long, dreadful and difficult journey battling cancer,” Nguyen explained. “Spotlight On Hope Film Camp can help children live in a fantasy world that allows them to get away from all their troubles and create lasting memories.”

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Infant leaves UCLA’s Mattel hospital for home with a transplanted heart


Drayvn is the hospital’s second youngest heart transplant recipient.

Drayvn Johnson got a heart transplant when he was 23 days after he was born with a heart defect and only one coronary artery. Now 5 weeks old, he left Mattel Children's Hospital UCLA for home today with his mother, Nicole Eggleston. (Photo by Reed Hutchinson, UCLA)

By Amy Albin, UCLA

Staff at Mattel Children’s Hospital UCLA witnessed a happy ending today (March 11) instead of what could have easily been a tragic one  when they bid farewell to 5-week-old Drayvn Johnson, who went home with his mother, Nicole Eggleston, and two older brothers after becoming the hospital’s second youngest heart transplant recipient. He was only 23 days old when he received his new heart, which was the size of a strawberry.

“All of our heart transplant patients are special, but I think this one was special because we knew there was a risk we might not find a donor in time,” said Dr. Juan Alejos, professor of pediatric cardiology and director of the Pediatric Heart Transplant Program at Mattel Children’s Hospital UCLA

Dravyn was born with a condition called pulmonary atresia in which the pulmonary valve does not form properly. It was discovered during Eggleston’s pregnancy in a sonogram performed at 22 weeks. Doctors had thought initially that his heart could be repaired with a series of corrective surgeries performed over the first few years of Dravyn’s life.

However, when he was born in early February at an Orange County hospital, doctors found that he had only one coronary artery instead of two and determined that surgery would be too risky for the baby.

At 5 days old, Drayvn was airlifted to Mattel where doctors confirmed that the only hope for his survival was an urgent heart transplant. Miraculously, within two days after Drayvn’s name went on a list for a transplant, a donor was found. And Drayvn got his new heart. The hospital’s youngest heart recipient was a 16-day-old infant who received a transplanted heart in 1994.

The UCLA Pediatric Heart and Heart-Lung Transplant Program is one of the major referral centers for the western United States. The team has performed more than 300 pediatric heart transplants since 1984 when it did its first such surgery. The program is a coordinated effort among pediatric cardiologists, cardiothoracic surgeons, dentists, nurse practitioners, transplant coordinators, nutritional specialists, social workers and child developmental specialists. For more information, visit http://transplants.ucla.edu/heart.

The family has set up a website to help raise funds for Drayvn’s care.

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$13M gift launches new maternal and child health center


UC Berkeley’s School of Public Health to launch Wallace Maternal and Child Health Center.

By Jose Rodriguez, UC Berkeley

Dr. Helen Wallace, a world-renowned professor, mentor and advocate known for her passion for improving the lives of women and children, has left a bequest valued at more than $13 million to UC Berkeley’s School of Public Health. The funds will launch the Wallace Maternal and Child Health Center, the campus announced today (March 2).

The new center will engage in innovative, evidence-based research aimed at creating healthier generations of women, mothers, children and families in the United States. It will focus on educating and training public health leaders primarily, but not exclusively, from states west of the Mississippi River through interdisciplinary scholarships and fellowships. The funds also will create a new endowed chair.

By fostering partnerships at every level of research, from discovery science to implementation and dissemination of evidence, the Wallace Center will complement the school’s existing maternal and child health (MCH) program — one of the pre-eminent MCH leadership training programs in the nation — and the Bixby Center for Population, Health and Sustainability.

Wallace, who died in 2013 at the age of 99, mentored generations of students as a professor and chair of the school’s MCH program from 1962 to 1980. She laid important groundwork in the field by fostering collaboration across disciplines at a time when it was rare to do so, and she implemented these practices within the school, in research partnerships and in her writing. She was particularly interested in infant health, maternal mortality, health systems that improved health outcomes, and expanded delivery of health care to mothers and children.

“We are extremely excited and gratified to move our work forward with greater focus and commitment in the arena of maternal and child health, which was the vision of Dr. Helen Wallace,” said Dr. Stefano Bertozzi, dean of the School of Public Health. “The School of Public Health has been taking a leadership role on these issues at the global level for some time now through the Bixby Center for Population, Health, and Sustainability. The new Wallace Maternal and Child Health Center will deepen our work and allow us to focus on attracting and supporting students from the western United States.”

The Wallace Center will embody the values of the School of Public Health: equity, excellence, diversity, innovation, impact and collaboration. By supporting and engaging faculty and students and attracting new talent, the center will play an important role in workforce development while sustaining UC Berkeley’s reputation as a game-changer at the forefront of public health.

Wallace is remembered for visionary efforts that brought together scholars from separate disciplines, such as public health and social welfare, to advance common research goals, and for attracting the school’s first maternal and child health training grant from the federal government.

“She was well-known for mentoring her students and ensuring that what they learned on campus was put to use to benefit society,” said Sylvia Guendelman, professor and chair of the maternal and child health program at UC Berkeley. “She inspired her students to be leaders, to make a positive difference in the world.”

Among the leaders Wallace trained was Dr. Peter van Dyck, who served as associate administrator of the U.S. Health Resources and Services Administration’s Maternal and Child Health Bureau from 1999 to 2011.

“Helen Wallace assured me and others at Berkeley that in maternal and child health, we could touch individual children as well as influence public health by implementing good policy,” said van Dyck. “She was correct. She was a great mentor.”

Guendelman, who will lead the planning effort, said that the center will allow new generations of students to see Wallace’s “vision, spirit and effort endure over time.”

Wallace received her bachelor’s degree from Wellesley College in 1933, her master’s in public health cum laude from the Harvard School of Public Health in 1943 and her medical degree from the Columbia University College of Physicians and Surgeons in 1937.

She was the author of 336 journal articles and 16 textbooks — most recently, ”Health and Welfare for Families in the 21st Century,” the second edition of which was published in 2003. Besides serving as the national health chair of the National Congress of Parents and Teachers, Wallace was secretary of the maternal and child health section and a member of the committee on child health of the American Public Health Association.

She was, in addition, assistant editor of the Journal of the American Women’s Medical Association, as well as a diplomate of both the American Board of Pediatrics and the American Board of Preventive Medicine. She consulted with the World Health Organization in many countries including Uganda, the Philippines, India, Turkey, Iran, Thailand, Burma, Sri Lanka and Nepal, and trained numerous physicians in Africa and Asia.

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