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Am J Med Genet A. Effects of a single dose of N-carbamylglutamate on the rate of ureagenesis. Mol Genet Metab.

Mechanism of allosteric inhibition of N-acetyl-L-glutamate synthase by L-arginine. J Biol Chem.

Epub Dec INSIG2 gene polymorphism is associated with increased subcutaneous fat in women and poor response to resistance training in men.

BMC Med Genet. Interleukin and interleukinR alpha SNPs and associations with muscle, bone, and predictors of the metabolic syndrome. Epub Jun 2.

Proteomic profiling of glucocorticoid-exposed myogenic cells: Time series assessment of protein translocation and transcription of inactive mRNAs.

Proteome Sci. Preclinical drug trials in the mdx mouse: assessment of reliable and sensitive outcome measures. Muscle Nerve.

Dystrophin-deficient cardiomyopathy in mouse: expression of Nox4 and Lox are associated with fibrosis and altered functional parameters in the heart.

Neuromuscul Disord. Epub Apr Med Sci Sports Exerc. N-carbamylglutamate markedly enhances ureagenesis in N-acetylglutamate deficiency and propionic acidemia as measured by isotopic incorporation and blood biomarkers.

Pediatr Res. Cross-sectional multicenter study of patients with urea cycle disorders in the United States. Epub Jun J Appl Physiol. Gene Regul Syst Bio.

A renaissance for antisense oligonucleotide drugs in neurology: exon skipping breaks new ground. Arch Neurol. It is the tenth leading cause of death in the United States with more than 40 percent of sepsis cases resulting in fatality.

Unfortunately, this percentage has not improved in decades despite other medical advances. In most of these cases, organ failure is the primary cause of death.

The findings, published in the American Journal of Respiratory and Critical Care Medicine, is the first time doctors have looked at and linked platelets to poor outcomes from this often fatal infection.

Through gene and protein analyses in septic mice and humans, Dr. Freishtat and his team found that in severe cases the platelets had genes that were triggered to produce granzyme B.

Eventually perhaps this knowledge will help us find a way to prevent organ failure by targeting interventions directly at the platelets and granzyme B production.

Previous research shows that this may be a major contributor to organ failure. This is the first time that doctors have looked at and linked platelets to poor and potentially fatal outcomes from sepsis.

Haydar, PhD Richard A. Jonas, MD Parmajit T. Packer, MD Phillip L. Pearl, MD Jay A. The processes of this cell make contacts with and myelinate several axons labeled in red.

Gallo V Vision To understand the development of the central nervous system and the cellular and molecular mechanisms of brain dysfunction to prevent or treat neurological and behavioral disorders of childhood.

Strategic Plan Accomplishments n Establish a translational and clinical research program on perinatal hypoxia and brain injury.

Major Strategic Goals To establish a translational and clinical research program on perinatal hypoxia and brain injury. To establish a translational research program in epilepsy.

To continue to expand our neuroimaging program to include autism and traumatic brain injury. The center significantly expanded functional imaging initiatives in traumatic brain injury, autism, urea cycle disorders, and epilepsy by adding studies supported by the Singer Foundation, Medstar, the Gudulsky Foundation, and internal awards.

All these projects have been established and are supported by NIH awards. These projects are expanding to include behavioral studies in animal models.

Programmatic Areas and Accomplishments The research program of the Center for Neuroscience Research can be divided into eight major programmatic areas.

Developmental Neurobiology Neural stem cells Neural stem cells are present in both the embryonic and postnatal brain, can self-renew, and are able to generate all the major cell types within the central nervous system.

Tarik Haydar, PhD, continues his studies on neural stem cell development in the cerebral cortex, and established new approaches to continuously express neural genes to alter the functional and physiological properties of specific populations of progenitors and neurons in the developing brain.

His studies have uncovered fundamental cellular and functional differences between distinct neural stem cell populations of the ventricular zone.

Haydar and his team also are performing direct labeling and molecular perturbation of hippocampal neural stem cells in combination with electrophysiological studies on excitatory neurons during prenatal and postnatal development.

These studies make use of a novel technique developed by the Haydar lab to specifically target hippocampal pyramidal neurons. This work will characterize the role of brain-derived neurotrophic factor BDNF on development and function of the hippocampus and will have particular relevance to learning disabilities and epilepsy.

Joshua Corbin, PhD, is interested in understanding the relationship between amygdala progenitor cell specification and physiology, and continues a very productive collaboration with Molly Huntsman, PhD, recently recruited to the center from Georgetown University.

Their studies identified a previously unknown progenitor pool dedicated to the limbic system. These cells give rise to a unique subclass of inhibitory neurons in the amygdala.

Vittorio Gallo, PhD, studies intrinsic and extrinsic signals that regulate development of multipotential progenitors in the perinatal and adult brain.

His laboratory is extending these studies to animal models of brain injury and disease, including demyelinating disorders of the white matter and white matter injury after perinatal hypoxia.

Gallo, continued his studies on the generation of oligodendrocytes from different neural progenitor populations in the developing and adult brain, and their potential to repair demyelinating lesions.

Neural stem cells of the mouse embryonic neocortex expressing red fluorescent protein after being transfected with DNA using in utero surgery.

Their DNA is also stained in green if they are undergoing cell division. Haydar T Myelin and white matter development Myelin formation during postnatal brain development represents one of the most crucial steps in the establishment of mature white matter and of fully functional connections between neurons.

Gallo and Li-Jin Chew, PhD, continue to study new cellular and molecular approaches that promote oligodendrocyte maturation, myelination, and white matter development.

Chew continues to study signal transduction pathways that regulate oligodendrocyte development in cultured cells and in transgenic mice.

The focus of these studies is on mechanisms that promote oligodendrocyte progenitor differentiation and developmental myelination.

Gallo and Haydar continue their collaboration utilizing advanced microscopic technology to study oligodendrocyte progenitor cell migration during normal development and during remyelination after injury.

Gallo and Chew completed a larger molecular screening of novel oligodendrocyte regulatory genes by microarray analysis and identified downstream targets of specific transcription factors that regulate oligodendrocyte development.

CNR 35 and progenitor cells during prenatal development of the cerebral cortex. These studies use DNA expression and recombination molecular fate mapping to label and track neural precursors in their intact environment in the developing brain.

Recently, the Haydar lab found that certain types of inhibitory interneurons also are over-produced in the Ts65Dn fetal brain and have found two genes which are triplicated in Ts65Dn and Down syndrome that cause this defect.

Iron is required for neural tube development. Mutation of an iron transporter essential for delivery of iron to the developing embryo results in neural tube defects including exencephaly, spina bifida, microphthalmia, and forebrain truncations.

Forebrain truncations can be mimicked by culture of wildtype embryos in iron chelators during a critical developmental time window.

Top left: E However, evidence has shown that cognitive ability also is specified by a genetic component. This is most readily seen in the increasing number of reports linking genetic abnormalities to various forms of mental retardation.

Cognitive performance depends, in large part, on proper prenatal development of the cerebral cortex. More specifically, cortical growth must proceed at a specific tempo and certain milestones must be achieved to enable proper connections between the cortex and other brain structures.

Studies in the laboratory of Dr. Haydar investigate the molecular controls of neural stem cell development in the mammalian forebrain.

Research on cortical development in the Haydar lab is broadly classified in two areas: 1 Molecular labeling of neural stem cells in utero is combined with laser-scanning imaging to define the proliferative and lineage identity of different stem cells 36 CNR Neural tube development Neural tube defects are one of the most common developmental malformations in humans with poorly understood underlying causes.

From studies in model organisms including the mouse, we are beginning to gain insight into the pathways that are critical for proper neural tube closure.

Irene Zohn, PhD, established a vigorous research program in this area. She obtained funding from the NIH, the March of Dimes, and the Spina Bifida Foundation to study pathways regulating growth, patterning, and morphogenesis of not only the neural tissue, but also the surrounding epithelium and mesenchyme.

These tissues are essential for neural tube closure. While these studies have implicated many genes, it is clear that we only know the identity of a fraction of the candidate genes for human neural tube defects.

Furthermore, detailed mechanisms of how mutation of these genes results in neural tube defects has been investigated for only a few of these candidates.

These experiments promise to provide a greater understanding of the molecular pathways, which when disrupted, contribute to human birth defects.

In addition, these studies demonstrate that iron, in addition to folic acid, is an important nutrient to prevent neural tube defects.

Validation of these results with clinical trials and promotion of periconception multivitamin usage has the potential to further reduce the incidence of neural tube defects.

Amygdala development and dysfunction The mammalian basal telencephalic limbic system is comprised of a number of structures that are involved in the regulation of complex emotional and motivational behaviors.

The most prominent of these is the amygdala, which regulates specific aspects of emotional memory, attention, and appropriate responses to environmental stimuli.

Corbin studies the cellular and genetic processes that govern normal development of the amygdala, as well as the underlying defects in these processes that occur during developmental disorders, such as autism spectrum disorders.

Corbin and his lab focus on understanding the genetic and cellular pathways involved in the generation of inhibitory neurons of the amygdala from progenitor cells in the embryonic brain, and the mechanisms regulating formation of inhibitory synaptic connections of neurons generated from these progenitors.

In relation to autism spectrum disorders, one or more of these normal developmental processes are altered, which results in specific aspects of the behavioral defects characteristic of this disorder.

These studies ultimately aim to understand the link between developmental events and the assembly and function of the mature amygdala at a genetic, cellular, structural, and functional level.

From these studies, the hope is to not only elucidate the normal mechanisms of brain development, but also gain a greater understanding of the etiology of developmental disorders, such as autism spectrum disorders, in which development of the amygdala is significantly affected.

The activities of IDDRC investigators are distributed among seven areas of research, corresponding to different IDD-associated conditions: autism, brain tumors, epilepsy, neuromuscular disease, brain injury, urea cycle disorders, and white matter disorders.

In each of these areas, genetic, translational neuroscience, and behavioral science programs are integrated to provide a multidisciplinary approach to each research theme.

Each of these cores has grown based on steady institutional investment on infrastructure, personnel, state-of-the-art equipment, and software.

Embryonic progenitor cells marked in blue are observed pooling in the region of the brain that will later become the amygdala.

These cells will differentiate into a combination of inhibitory and excitatory neurons. Corbin J Brain Injury and Brain Protection Traumatic brain injury TBI is the leading cause of acquired brain damage in children, producing persistent functional disability.

The response to and recovery from TBI differs in adults and children. Brain damage from TBI is determined not only by direct mechanical injury to neural structures, but also by delayed axonal degeneration and neuronal apoptosis.

The overall goal of this research project is to determine if fundamental differences in the molecular pathways that produce neuronal death are related to brain maturity.

Gerard Gioia, PhD, and his team adapted for children four cognitive rating scales originally established to assess adults following mild TBI, and tested them in 2, children.

Lauren Krivisky, PhD, and her collaborators at National Rehabilitation Hospital are investigating the structural and functional consequences of mild TBI on brain structure CNR 37 VBM Difference maps of two patients, one with typical top and the other with atypical language dominance bottom.

Left image, left brain. Richard Jonas, MD, continues his program in researching neuroprotection during congenital heart surgery, including white matter injury prevention.

Gallo and Chew are studying signals that induce reactive gliosis after injury. They use an array of imaging and electrophysiological techniques to monitor and guide therapy.

Andrea Gropman, MD, uses magnetic resonance spectroscopic imaging MRS to examine brain based metabolic perturbations hypothesized to cause subcortical cognitive deficits in heterozygotes with the urea cycle disorder ornithine transcarbamylase deficiency OTC.

Perinatal Hypoxia and Hyperoxia Preterm birth is a major pediatric public health concern. Today, as many as 1 to 2 percent of all live births are preterm; the survival rate of these infants is 85 to 90 percent, however as many as percent of children that survive preterm birth have a high incidence of cerebral palsy, 38 CNR intellectual disability, and other cognitive handicaps.

While some prematurely-born children progressively improve, a significant percentage still suffer major cognitive deficits, as many have repeated a grade by age 8, and more than 50 percent receive special help at school.

Circulatory disturbances and oxygen deprivation are the two major causes of neurodevelopmental impairments in these children.

Hypoxia, due to lung immaturity and respiratory disturbances, is an important mechanism underlying these devastating neurological complications at this critical time in development.

The research program on perinatal hypoxia and brain injury is a collaborative effort between Dr. This model reproduces all the brain injury landmarks found in children, including cognitive behavioral abnormalities.

Animal studies are combined with clinical research on premature babies and with post-mortem human brain tissue. Green represents activation that is significantly greater in the year old group and overlaps with the group map.

The limited significant differences for both the older age groups are not visible on this display. Both of the older groups do not activate any area of yellow differently.

Axial slices are in neurological convention left is left hemisphere. Gaillard W project on the cellular effects of hyperoxia on white matter development.

Epilepsy Epilepsy affects 1 to 2 percent of all children and 8 percent will experience one seizure before adulthood. The Comprehensive Pediatric Epilepsy Program CPEP is a multidisciplinary group designed to provide clinical care and conduct clinical research into the origins, impact, and treatment of epilepsy in children.

This multidisciplinary team has active research in: 1 neuroimaging of seizure disorders; 2 mood and anxiety disorders in epilepsy populations; 3 identification and evaluation of recent onset epilepsy; 4 medication trials; and 5 development of coping and socialization skills in children with epilepsy.

Jay Salpekar, MD, is exploring mood, anxiety, and attention deficit disorders in children with epilepsy.

Sandra Cushner-Weinstein, MSW, continues her studies that examine the effect of camp on functional adaptability in children with epilepsy and expanded these models to neurofibromatosis, Tourette syndrome, and Asperger disorder.

Phillip Pearl, MD, continues his research on the GABAergic mechanisms of epileptogenicity in the inborn error of metabolism, succinic semialdehyde dehydrogenase deficiency.

This project is a collaborative effort with William H. Experimental therapeutics continues to play an important role in the epilepsy program.

Joan Conry, MD, in addition to participation in several new industry-sponsored trials, plays a leading role in the recently concluded nationwide study that evaluates the efficacy and pharmaco-genomics of ethosuximide, lamotrigine, and valproate, in childhood absence epilepsy.

Berl performs fMRI studies of working memory and language in children with epilepsy, funded through a K Award.

Gaillard leads an international and national consortium of pediatric epilepsy centers to use fMRI and other imaging modalities to evaluate children with refractory epilepsy and to investigate factors that underlie plasticity of cognitive functions.

Findings from this database are being used to inform clinical practice in the care of infants with newly diagnosed epilepsy.

The neuro-oncology program is pursuing innovative translational research in childhood low-grade gliomas, brain stem gliomas, medulloblastomas, ependymomas, and malignant glial tumors.

Results of a recent trial of bevacizumab and irinotecan for treatment of recurrent low grade gliomas will likely change how these tumors are treated.

Packer continues his research activities in neurofibromatosis type 1 NF-1 , a neurogenetic disease that has a host of manifestations including malignant and pre-malignant entities and is group chair of the Neurofibromatosis Clinical Consortium, a cooperative group of institutions funded in by the Department of Defense to perform translation studies for children and adults with neurofibromatosis.

The drug reversed learning disabilities in adult mice with neurofibromatosis type 1. Maria Acosta, MD, is the vice chair for this national study.

This study is being extended to functional imaging studies of medication response. Acosta continues collaborative work with Kathryn North, PhD, Sydney, Australia as site Primary Investigator for phenotyping of early cognitive profiles in NF-1 children and studies on their executive function.

Chandan Vaidya, PhD, continues her work using functional neuroimaging to study working memory and attention in children with ADHD, and response to treatment in relation to genetic differences in the dopamine transporter.

Adelaide Robb, MD, will extend her work in the treatment of mood disorders as a member of the NICHD collaborative effort to evaluate the use of lithium in the treatment of childhood bipolar disorder.

Robb also conducts several therapeutic trials in children with ADHD, bipolar disorder, and schizophrenia.

Vaidya, Gaillard, and Angela Bollich continue their collaborative work with Maximillian Reisenhuber, PhD Georgetown University , investigating the neurobiology of face processing in adults with autism.

These programs use functional imaging to elucidate the neurobiology of autism spectrum disorders ASD. Robb continues to investigate the effectiveness of new antipsychotics in ASD and, with Dr.

Hoffman, is investigating the genetic predispositions of adverse effects of older generation antipsychotics in at risk children.

Jun Epub Aug In press. However, only a few research centers in the world study the underlying causes and the many complications of this disorder.

Through studies of the brain at its earliest state, his laboratory breaks down the complex cellular mechanisms of brain development as it occurs in utero.

The team believes restoring a proper balance at an early stage, perhaps through the use of novel small molecules or drugs acting on Olig1 and Olig2, may promote a more normal development curve.

They located the stage of prenatal growth where the brain disorder in Down syndrome begins, and have now isolated a contributor to the onset of recognizable symptoms.

Recently, The introduction of strategies to correctly balance nerve cell production is a promising and potentially translational step toward an intervention strategy that would mitigate some, if not all, of the lifelong cognitive disabilities that go hand-in-hand with the disorder.

Blue, ubiquitin; red, p44S10; magenta, co-localization of ubiquitin and p44S Strategic Plan Accomplishments Major Strategic Goals Determine genetic variants associated with essential hypertension.

A major focus will be on those groups that suffer the most from hypertension because of genetic predisposition, exacerbated by excessive sodium consumption and stress Diagnostics.

Develop therapeutic agents that selectively target proteins whose aberrant activities lead to hypertension and treat the underlying causes of hypertension, not just its signs, symptoms, or consequences Pharmaceutical.

Determine the outcome of electrolyte disorders and the pathogenesis of pediatric renal diseases such as HIVassociated nephropathy that can adversely affect the growth and clinical outcome of affected children, elucidation of the mechanisms that affect the clinical outcome, and development of new treatments for these disorders Outcomes Research.

Jose as collaborating investigator, was renewed. Jose continues to perform collaborative studies in human essential hypertension in several ethnic groups, including African Americans, European Caucasians, Chinese, Filipinos, Ghanaians, Hispanics, and Thai.

Jose forged collaborative research with several institutions, including the National Institute of Molecular Biology and Biotechnology, the Marine Science Institute of the University of the Philippines, the National Kidney and Transplant Center, Philippines and the Philippine Genome Center, to study the genetics of essential hypertension in Filipinos.

Programmatic Areas and Accomplishments Adult-onset Hypertension Induced by Fluid and Electrolyte Disorders of Childhood Patricio Ray, MD, Robert Parrott Professor of Pediatrics, tests the hypothesis that some forms of adult-onset essential hypertension may be caused by electrolyte disorders during childhood.

He studies the chronic effects of potassium, chloride, and sodium deprivation in developing rodent kidneys. Ray hypothesizes that these electrolyte disorders induce silent and progressive renal vascular and epithelial injury, causing functional and structural tubule-interstitial disorders, salt wasting, or salt-sensitive hypertension.

Kitman Wai, MD, a clinical fellow in pediatric intensive care, works with Dr. Ray in exploring how sepsis-induced fluid-electrolyte disorders, hypotension, and vascular leakage induce acute kidney injury in criticallyill children.

Ray collaborates with Pedro A. Jose, MD, PhD, to explore the mechanisms involved in the pathogenesis of hypertension induced by chronic potassium deprivation in young animal models that mimic the renal disorders seen in children subjected to chronic hypokalemia.

Lipid rafts, which are membrane microdomains containing specific subsets of lipids and proteins, serve as signaling platforms and play important roles in signal transduction in a variety of mammalian cells.

Yu on this project. Oxidative Stress and Mitochondria Hewang Li, MD, PhD, studies the hypothesis that the increased oxidative stress caused by the absence of the D5R is due, in part, to increased production of reactive oxygen species ROS in the mitochondria.

Increased mitochondrial production of ROS is important in the pathogenesis of Dr. Jose and his research team showed that AT1R donor is ubiquitinated with fenoldopam Fen treatment.

FLIM images, histograms, and decay graphs of cells in the absence top or presence middle and bottom of an acceptor Ub fluorophore are shown.

With Fen treatment in the presence of acceptor, the donor lifetime had two peaks: the first was quenched at 1. Li H essential hypertension.

About 0. Mitochondrial dysfunctions can result in disorders in the kidney, which are associated with perturbation of water and salt excretion, and the pathogenesis of hypertension.

This project aims to understand the D5R regulation of mitochondrial ROS in the kidney, identify the signal pathways involved in this process, and examine mitochondria-ROS as a molecular, biochemical, and physiological biomarker of essential hypertension.

Inflammation in Hypertension, Obesity, and Metabolic Syndrome Ines Armando, PhD, is testing the hypothesis that dopamine, through the D2 dopamine receptor D2R , regulates immune function and oxidative stress in the kidney.

Armando tests whether the dysfunction of the D2R results in renal inflammation, oxidative stress, and hypertension could be a contributing factor in the development of metabolic syndrome.

A number of pathological conditions other than CMPR 45 classical immune diseases have as a causal factor, or are associated with, alterations in the inflammatory response.

Tissue inflammation, infiltration of inflammatory cells, and oxidative stress in the kidney play an important role in the induction and maintenance of high blood pressure levels.

Furthermore, obesity and metabolic syndrome are now considered low-grade systemic inflammatory diseases. Dopamine has regulatory functions on the immune response.

Annabelle M. Armando in this project. Villar, MD, PhD, test the hypothesis that sorting nexins are important in the recycling of internalized dopamine receptors to the plasma membrane, and that the aberration of this regulatory function leads to hypertension.

Sodium Transporters and Hypertension Xiaoyan Wang, MD, PhD, tests the hypothesis that sodium transporters, especially the sodium chloride cotransporter in the distal convoluted tubule, are important in the sodium retention associated with deletion of specific dopamine receptor subtypes.

This hypothesis is tested using molecular, biological, and biochemical methods in human GRK4 transgenic and GRK4 knockout mice.

Salt-Sensitivity Dr. Jose, Laureano D. Asico, DVM, and Crisanto Escano, DVM, study the mechanisms involved in the pathogenesis of saltsensitivity and hypertension using dopamine receptor subtype knockout mice, renal cross-transplantation, and intrarenal administration of gene-regulating agents.

In a multicenter collaboration, they test the hypothesis that salt-sensitivity involves abnormal regulation of renal sodium transport, as well as an aberrant gastrointestinal-renal reflex pathway.

Jose, with collaborators at the University of the Philippines, are testing the hypothesis 46 CMPR that dopamine receptors are important in the adaptation to changing saline environment.

These studies may provide clues to the mechanisms by which the mammalian kidney adapts to low and high salt intake. These children are at exceptionally high risk for developing renal and cardiovascular disorders secondary to immune alterations, infections, cytokine release, dyslipidemias, insulin resistance, hypertension, and a genetic predisposition to develop renal disease in the context of HIV infection.

HIV-transgenic mice and rats that express viral genes in endothelial or renal epithelial cells have been developed to determine how HIV induces endothelial and renal epithelial injury.

Several adenoviralmediated gene transfer techniques have been developed to express foreign genes in developing and young rodent kidneys in vivo, and these models are being used to explore how HIV induces renal injury.

Epithelial Mesenchymal Transformation Dr. Jose, Hans Pohl, MD, and collaborators at the University of Georgia are testing the hypothesis that a response gene to complement 32 is involved in epithelial-mesenchymal transition in several disease states, including renal fibrosis.

Biomarkers of Disease Renal disease Xiaoyan Wang, MD, PhD, tests the hypothesis that urinary protein exosomes of dopamine and angiotensin receptor subtypes and renal sodium transporters can be used as biomarkers of essential hypertension and metabolic syndrome.

This hypothesis will be tested in cases and controls in humans and animal models of human essential hypertension and obesity.

Hypertension Robin A. Jose test the hypothesis that renal proximal tubule cells cultured from the urine can be used as biomarkers for the pathogenesis of hypertension and response to treatment.

This hypothesis will be tested in cases and controls in humans and animal models of human essential hypertension. Aug 7 Jun 30 Mar 14 Though it might be surprising to hear a basic scientist make the argument that external choices could overrule centuries of genetic evolution and established biochemical processes, his pronouncement focuses on one specific area where this is true: overcoming essential hypertension, or high blood pressure that occurs for no known reason.

Jose and his team believe that unlocking the root causes of essential hypertension will help doctors identify this disorder before serious complications occur, and when diet and exercise could have a greater impact on managing high blood pressure.

In the spring of , Dr. The team at the Center for Molecular 48 CMPR Physiology also studies the many other ways this delicate organ packs a powerful punch in the day-to-day operation of the body.

There is still no definitive explanation as to why some children are prone to high blood pressure and others are not, but researchers in the center are beginning to make headway in understanding how the kidney factors in.

As a result, they also are close to identifying potential biomarkers that would indicate hypertension and other renal diseases faster, before the long term effects of these disorders begin to take hold, and while diet and exercise interventions might have a chance to improve the lives of those who face a lifetime struggle with high blood pressure.

Rakhmanina, MD Adelaide S. Robb, MD Cynthia R. Major Strategic Goals Identify the factors contributing to racial and ethnic disparities in health and health care, and to develop interventions for reducing such disparities.

Understand the ways in which social forces and human behavior influence the health and well-being of children and their families.

Support rigorous multi-site clinical and translational research by providing required services and networked infrastructure. Support the career development of junior faculty.

By design, the spectrum of research conducted by the center is wide-ranging, including investigator-initiated efforts focused on multiple aspects of pediatric disease and prevention.

Investigators in the center work together on projects that range from a focus on pregnancy outcomes to specific health conditions such as asthma, to environmental and social forces, that together result in significant health disparities.

Additionally, many of these investigations provide a training ground for junior faculty with career development awards and utilize the resources of our Clinical Research Center CRC , thereby demonstrating the significant synergies that exist across the programmatic areas in the center.

Several of the research programs in the center relevant to health disparities are described below. Psychosocial and behavioral risk factors in minority populations The research of Jill Joseph, MD, PhD, Director of the Center for Clinical and Community Research, focuses on issues relevant to the health and well-being of disadvantaged families.

This includes long-standing collaborations across the Washington, DC, region, including Head Start programs in Montgomery County, obstetric providers throughout Washington, DC, and multiple other academic institutions.

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Haydar, PhD Richard A. Jonas, MD Parmajit T. Packer, MD Phillip L. Pearl, MD Jay A. The processes of this cell make contacts with and myelinate several axons labeled in red.

Gallo V Vision To understand the development of the central nervous system and the cellular and molecular mechanisms of brain dysfunction to prevent or treat neurological and behavioral disorders of childhood.

Strategic Plan Accomplishments n Establish a translational and clinical research program on perinatal hypoxia and brain injury.

Major Strategic Goals To establish a translational and clinical research program on perinatal hypoxia and brain injury.

To establish a translational research program in epilepsy. To continue to expand our neuroimaging program to include autism and traumatic brain injury.

The center significantly expanded functional imaging initiatives in traumatic brain injury, autism, urea cycle disorders, and epilepsy by adding studies supported by the Singer Foundation, Medstar, the Gudulsky Foundation, and internal awards.

All these projects have been established and are supported by NIH awards. These projects are expanding to include behavioral studies in animal models.

Programmatic Areas and Accomplishments The research program of the Center for Neuroscience Research can be divided into eight major programmatic areas.

Developmental Neurobiology Neural stem cells Neural stem cells are present in both the embryonic and postnatal brain, can self-renew, and are able to generate all the major cell types within the central nervous system.

Tarik Haydar, PhD, continues his studies on neural stem cell development in the cerebral cortex, and established new approaches to continuously express neural genes to alter the functional and physiological properties of specific populations of progenitors and neurons in the developing brain.

His studies have uncovered fundamental cellular and functional differences between distinct neural stem cell populations of the ventricular zone.

Haydar and his team also are performing direct labeling and molecular perturbation of hippocampal neural stem cells in combination with electrophysiological studies on excitatory neurons during prenatal and postnatal development.

These studies make use of a novel technique developed by the Haydar lab to specifically target hippocampal pyramidal neurons.

This work will characterize the role of brain-derived neurotrophic factor BDNF on development and function of the hippocampus and will have particular relevance to learning disabilities and epilepsy.

Joshua Corbin, PhD, is interested in understanding the relationship between amygdala progenitor cell specification and physiology, and continues a very productive collaboration with Molly Huntsman, PhD, recently recruited to the center from Georgetown University.

Their studies identified a previously unknown progenitor pool dedicated to the limbic system. These cells give rise to a unique subclass of inhibitory neurons in the amygdala.

Vittorio Gallo, PhD, studies intrinsic and extrinsic signals that regulate development of multipotential progenitors in the perinatal and adult brain.

His laboratory is extending these studies to animal models of brain injury and disease, including demyelinating disorders of the white matter and white matter injury after perinatal hypoxia.

Gallo, continued his studies on the generation of oligodendrocytes from different neural progenitor populations in the developing and adult brain, and their potential to repair demyelinating lesions.

Neural stem cells of the mouse embryonic neocortex expressing red fluorescent protein after being transfected with DNA using in utero surgery.

Their DNA is also stained in green if they are undergoing cell division. Haydar T Myelin and white matter development Myelin formation during postnatal brain development represents one of the most crucial steps in the establishment of mature white matter and of fully functional connections between neurons.

Gallo and Li-Jin Chew, PhD, continue to study new cellular and molecular approaches that promote oligodendrocyte maturation, myelination, and white matter development.

Chew continues to study signal transduction pathways that regulate oligodendrocyte development in cultured cells and in transgenic mice.

The focus of these studies is on mechanisms that promote oligodendrocyte progenitor differentiation and developmental myelination.

Gallo and Haydar continue their collaboration utilizing advanced microscopic technology to study oligodendrocyte progenitor cell migration during normal development and during remyelination after injury.

Gallo and Chew completed a larger molecular screening of novel oligodendrocyte regulatory genes by microarray analysis and identified downstream targets of specific transcription factors that regulate oligodendrocyte development.

CNR 35 and progenitor cells during prenatal development of the cerebral cortex. These studies use DNA expression and recombination molecular fate mapping to label and track neural precursors in their intact environment in the developing brain.

Recently, the Haydar lab found that certain types of inhibitory interneurons also are over-produced in the Ts65Dn fetal brain and have found two genes which are triplicated in Ts65Dn and Down syndrome that cause this defect.

Iron is required for neural tube development. Mutation of an iron transporter essential for delivery of iron to the developing embryo results in neural tube defects including exencephaly, spina bifida, microphthalmia, and forebrain truncations.

Forebrain truncations can be mimicked by culture of wildtype embryos in iron chelators during a critical developmental time window.

Top left: E However, evidence has shown that cognitive ability also is specified by a genetic component. This is most readily seen in the increasing number of reports linking genetic abnormalities to various forms of mental retardation.

Cognitive performance depends, in large part, on proper prenatal development of the cerebral cortex. More specifically, cortical growth must proceed at a specific tempo and certain milestones must be achieved to enable proper connections between the cortex and other brain structures.

Studies in the laboratory of Dr. Haydar investigate the molecular controls of neural stem cell development in the mammalian forebrain.

Research on cortical development in the Haydar lab is broadly classified in two areas: 1 Molecular labeling of neural stem cells in utero is combined with laser-scanning imaging to define the proliferative and lineage identity of different stem cells 36 CNR Neural tube development Neural tube defects are one of the most common developmental malformations in humans with poorly understood underlying causes.

From studies in model organisms including the mouse, we are beginning to gain insight into the pathways that are critical for proper neural tube closure.

Irene Zohn, PhD, established a vigorous research program in this area. She obtained funding from the NIH, the March of Dimes, and the Spina Bifida Foundation to study pathways regulating growth, patterning, and morphogenesis of not only the neural tissue, but also the surrounding epithelium and mesenchyme.

These tissues are essential for neural tube closure. While these studies have implicated many genes, it is clear that we only know the identity of a fraction of the candidate genes for human neural tube defects.

Furthermore, detailed mechanisms of how mutation of these genes results in neural tube defects has been investigated for only a few of these candidates.

These experiments promise to provide a greater understanding of the molecular pathways, which when disrupted, contribute to human birth defects.

In addition, these studies demonstrate that iron, in addition to folic acid, is an important nutrient to prevent neural tube defects.

Validation of these results with clinical trials and promotion of periconception multivitamin usage has the potential to further reduce the incidence of neural tube defects.

Amygdala development and dysfunction The mammalian basal telencephalic limbic system is comprised of a number of structures that are involved in the regulation of complex emotional and motivational behaviors.

The most prominent of these is the amygdala, which regulates specific aspects of emotional memory, attention, and appropriate responses to environmental stimuli.

Corbin studies the cellular and genetic processes that govern normal development of the amygdala, as well as the underlying defects in these processes that occur during developmental disorders, such as autism spectrum disorders.

Corbin and his lab focus on understanding the genetic and cellular pathways involved in the generation of inhibitory neurons of the amygdala from progenitor cells in the embryonic brain, and the mechanisms regulating formation of inhibitory synaptic connections of neurons generated from these progenitors.

In relation to autism spectrum disorders, one or more of these normal developmental processes are altered, which results in specific aspects of the behavioral defects characteristic of this disorder.

These studies ultimately aim to understand the link between developmental events and the assembly and function of the mature amygdala at a genetic, cellular, structural, and functional level.

From these studies, the hope is to not only elucidate the normal mechanisms of brain development, but also gain a greater understanding of the etiology of developmental disorders, such as autism spectrum disorders, in which development of the amygdala is significantly affected.

The activities of IDDRC investigators are distributed among seven areas of research, corresponding to different IDD-associated conditions: autism, brain tumors, epilepsy, neuromuscular disease, brain injury, urea cycle disorders, and white matter disorders.

In each of these areas, genetic, translational neuroscience, and behavioral science programs are integrated to provide a multidisciplinary approach to each research theme.

Each of these cores has grown based on steady institutional investment on infrastructure, personnel, state-of-the-art equipment, and software.

Embryonic progenitor cells marked in blue are observed pooling in the region of the brain that will later become the amygdala.

These cells will differentiate into a combination of inhibitory and excitatory neurons. Corbin J Brain Injury and Brain Protection Traumatic brain injury TBI is the leading cause of acquired brain damage in children, producing persistent functional disability.

The response to and recovery from TBI differs in adults and children. Brain damage from TBI is determined not only by direct mechanical injury to neural structures, but also by delayed axonal degeneration and neuronal apoptosis.

The overall goal of this research project is to determine if fundamental differences in the molecular pathways that produce neuronal death are related to brain maturity.

Gerard Gioia, PhD, and his team adapted for children four cognitive rating scales originally established to assess adults following mild TBI, and tested them in 2, children.

Lauren Krivisky, PhD, and her collaborators at National Rehabilitation Hospital are investigating the structural and functional consequences of mild TBI on brain structure CNR 37 VBM Difference maps of two patients, one with typical top and the other with atypical language dominance bottom.

Left image, left brain. Richard Jonas, MD, continues his program in researching neuroprotection during congenital heart surgery, including white matter injury prevention.

Gallo and Chew are studying signals that induce reactive gliosis after injury. They use an array of imaging and electrophysiological techniques to monitor and guide therapy.

Andrea Gropman, MD, uses magnetic resonance spectroscopic imaging MRS to examine brain based metabolic perturbations hypothesized to cause subcortical cognitive deficits in heterozygotes with the urea cycle disorder ornithine transcarbamylase deficiency OTC.

Perinatal Hypoxia and Hyperoxia Preterm birth is a major pediatric public health concern. Today, as many as 1 to 2 percent of all live births are preterm; the survival rate of these infants is 85 to 90 percent, however as many as percent of children that survive preterm birth have a high incidence of cerebral palsy, 38 CNR intellectual disability, and other cognitive handicaps.

While some prematurely-born children progressively improve, a significant percentage still suffer major cognitive deficits, as many have repeated a grade by age 8, and more than 50 percent receive special help at school.

Circulatory disturbances and oxygen deprivation are the two major causes of neurodevelopmental impairments in these children.

Hypoxia, due to lung immaturity and respiratory disturbances, is an important mechanism underlying these devastating neurological complications at this critical time in development.

The research program on perinatal hypoxia and brain injury is a collaborative effort between Dr. This model reproduces all the brain injury landmarks found in children, including cognitive behavioral abnormalities.

Animal studies are combined with clinical research on premature babies and with post-mortem human brain tissue. Green represents activation that is significantly greater in the year old group and overlaps with the group map.

The limited significant differences for both the older age groups are not visible on this display. Both of the older groups do not activate any area of yellow differently.

Axial slices are in neurological convention left is left hemisphere. Gaillard W project on the cellular effects of hyperoxia on white matter development.

Epilepsy Epilepsy affects 1 to 2 percent of all children and 8 percent will experience one seizure before adulthood.

The Comprehensive Pediatric Epilepsy Program CPEP is a multidisciplinary group designed to provide clinical care and conduct clinical research into the origins, impact, and treatment of epilepsy in children.

This multidisciplinary team has active research in: 1 neuroimaging of seizure disorders; 2 mood and anxiety disorders in epilepsy populations; 3 identification and evaluation of recent onset epilepsy; 4 medication trials; and 5 development of coping and socialization skills in children with epilepsy.

Jay Salpekar, MD, is exploring mood, anxiety, and attention deficit disorders in children with epilepsy.

Sandra Cushner-Weinstein, MSW, continues her studies that examine the effect of camp on functional adaptability in children with epilepsy and expanded these models to neurofibromatosis, Tourette syndrome, and Asperger disorder.

Phillip Pearl, MD, continues his research on the GABAergic mechanisms of epileptogenicity in the inborn error of metabolism, succinic semialdehyde dehydrogenase deficiency.

This project is a collaborative effort with William H. Experimental therapeutics continues to play an important role in the epilepsy program.

Joan Conry, MD, in addition to participation in several new industry-sponsored trials, plays a leading role in the recently concluded nationwide study that evaluates the efficacy and pharmaco-genomics of ethosuximide, lamotrigine, and valproate, in childhood absence epilepsy.

Berl performs fMRI studies of working memory and language in children with epilepsy, funded through a K Award. Gaillard leads an international and national consortium of pediatric epilepsy centers to use fMRI and other imaging modalities to evaluate children with refractory epilepsy and to investigate factors that underlie plasticity of cognitive functions.

Findings from this database are being used to inform clinical practice in the care of infants with newly diagnosed epilepsy. The neuro-oncology program is pursuing innovative translational research in childhood low-grade gliomas, brain stem gliomas, medulloblastomas, ependymomas, and malignant glial tumors.

Results of a recent trial of bevacizumab and irinotecan for treatment of recurrent low grade gliomas will likely change how these tumors are treated.

Packer continues his research activities in neurofibromatosis type 1 NF-1 , a neurogenetic disease that has a host of manifestations including malignant and pre-malignant entities and is group chair of the Neurofibromatosis Clinical Consortium, a cooperative group of institutions funded in by the Department of Defense to perform translation studies for children and adults with neurofibromatosis.

The drug reversed learning disabilities in adult mice with neurofibromatosis type 1. Maria Acosta, MD, is the vice chair for this national study.

This study is being extended to functional imaging studies of medication response. Acosta continues collaborative work with Kathryn North, PhD, Sydney, Australia as site Primary Investigator for phenotyping of early cognitive profiles in NF-1 children and studies on their executive function.

Chandan Vaidya, PhD, continues her work using functional neuroimaging to study working memory and attention in children with ADHD, and response to treatment in relation to genetic differences in the dopamine transporter.

Adelaide Robb, MD, will extend her work in the treatment of mood disorders as a member of the NICHD collaborative effort to evaluate the use of lithium in the treatment of childhood bipolar disorder.

Robb also conducts several therapeutic trials in children with ADHD, bipolar disorder, and schizophrenia.

Vaidya, Gaillard, and Angela Bollich continue their collaborative work with Maximillian Reisenhuber, PhD Georgetown University , investigating the neurobiology of face processing in adults with autism.

These programs use functional imaging to elucidate the neurobiology of autism spectrum disorders ASD.

Robb continues to investigate the effectiveness of new antipsychotics in ASD and, with Dr. Hoffman, is investigating the genetic predispositions of adverse effects of older generation antipsychotics in at risk children.

Jun Epub Aug In press. However, only a few research centers in the world study the underlying causes and the many complications of this disorder.

Through studies of the brain at its earliest state, his laboratory breaks down the complex cellular mechanisms of brain development as it occurs in utero.

The team believes restoring a proper balance at an early stage, perhaps through the use of novel small molecules or drugs acting on Olig1 and Olig2, may promote a more normal development curve.

They located the stage of prenatal growth where the brain disorder in Down syndrome begins, and have now isolated a contributor to the onset of recognizable symptoms.

Recently, The introduction of strategies to correctly balance nerve cell production is a promising and potentially translational step toward an intervention strategy that would mitigate some, if not all, of the lifelong cognitive disabilities that go hand-in-hand with the disorder.

Blue, ubiquitin; red, p44S10; magenta, co-localization of ubiquitin and p44S Strategic Plan Accomplishments Major Strategic Goals Determine genetic variants associated with essential hypertension.

A major focus will be on those groups that suffer the most from hypertension because of genetic predisposition, exacerbated by excessive sodium consumption and stress Diagnostics.

Develop therapeutic agents that selectively target proteins whose aberrant activities lead to hypertension and treat the underlying causes of hypertension, not just its signs, symptoms, or consequences Pharmaceutical.

Determine the outcome of electrolyte disorders and the pathogenesis of pediatric renal diseases such as HIVassociated nephropathy that can adversely affect the growth and clinical outcome of affected children, elucidation of the mechanisms that affect the clinical outcome, and development of new treatments for these disorders Outcomes Research.

Jose as collaborating investigator, was renewed. Jose continues to perform collaborative studies in human essential hypertension in several ethnic groups, including African Americans, European Caucasians, Chinese, Filipinos, Ghanaians, Hispanics, and Thai.

Jose forged collaborative research with several institutions, including the National Institute of Molecular Biology and Biotechnology, the Marine Science Institute of the University of the Philippines, the National Kidney and Transplant Center, Philippines and the Philippine Genome Center, to study the genetics of essential hypertension in Filipinos.

Programmatic Areas and Accomplishments Adult-onset Hypertension Induced by Fluid and Electrolyte Disorders of Childhood Patricio Ray, MD, Robert Parrott Professor of Pediatrics, tests the hypothesis that some forms of adult-onset essential hypertension may be caused by electrolyte disorders during childhood.

He studies the chronic effects of potassium, chloride, and sodium deprivation in developing rodent kidneys.

Ray hypothesizes that these electrolyte disorders induce silent and progressive renal vascular and epithelial injury, causing functional and structural tubule-interstitial disorders, salt wasting, or salt-sensitive hypertension.

Kitman Wai, MD, a clinical fellow in pediatric intensive care, works with Dr. Ray in exploring how sepsis-induced fluid-electrolyte disorders, hypotension, and vascular leakage induce acute kidney injury in criticallyill children.

Ray collaborates with Pedro A. Jose, MD, PhD, to explore the mechanisms involved in the pathogenesis of hypertension induced by chronic potassium deprivation in young animal models that mimic the renal disorders seen in children subjected to chronic hypokalemia.

Lipid rafts, which are membrane microdomains containing specific subsets of lipids and proteins, serve as signaling platforms and play important roles in signal transduction in a variety of mammalian cells.

Yu on this project. Oxidative Stress and Mitochondria Hewang Li, MD, PhD, studies the hypothesis that the increased oxidative stress caused by the absence of the D5R is due, in part, to increased production of reactive oxygen species ROS in the mitochondria.

Increased mitochondrial production of ROS is important in the pathogenesis of Dr. Jose and his research team showed that AT1R donor is ubiquitinated with fenoldopam Fen treatment.

FLIM images, histograms, and decay graphs of cells in the absence top or presence middle and bottom of an acceptor Ub fluorophore are shown.

With Fen treatment in the presence of acceptor, the donor lifetime had two peaks: the first was quenched at 1.

Li H essential hypertension. About 0. Mitochondrial dysfunctions can result in disorders in the kidney, which are associated with perturbation of water and salt excretion, and the pathogenesis of hypertension.

This project aims to understand the D5R regulation of mitochondrial ROS in the kidney, identify the signal pathways involved in this process, and examine mitochondria-ROS as a molecular, biochemical, and physiological biomarker of essential hypertension.

Inflammation in Hypertension, Obesity, and Metabolic Syndrome Ines Armando, PhD, is testing the hypothesis that dopamine, through the D2 dopamine receptor D2R , regulates immune function and oxidative stress in the kidney.

Armando tests whether the dysfunction of the D2R results in renal inflammation, oxidative stress, and hypertension could be a contributing factor in the development of metabolic syndrome.

A number of pathological conditions other than CMPR 45 classical immune diseases have as a causal factor, or are associated with, alterations in the inflammatory response.

Tissue inflammation, infiltration of inflammatory cells, and oxidative stress in the kidney play an important role in the induction and maintenance of high blood pressure levels.

Furthermore, obesity and metabolic syndrome are now considered low-grade systemic inflammatory diseases.

Dopamine has regulatory functions on the immune response. Annabelle M. Armando in this project. Villar, MD, PhD, test the hypothesis that sorting nexins are important in the recycling of internalized dopamine receptors to the plasma membrane, and that the aberration of this regulatory function leads to hypertension.

Sodium Transporters and Hypertension Xiaoyan Wang, MD, PhD, tests the hypothesis that sodium transporters, especially the sodium chloride cotransporter in the distal convoluted tubule, are important in the sodium retention associated with deletion of specific dopamine receptor subtypes.

This hypothesis is tested using molecular, biological, and biochemical methods in human GRK4 transgenic and GRK4 knockout mice.

Salt-Sensitivity Dr. Jose, Laureano D. Asico, DVM, and Crisanto Escano, DVM, study the mechanisms involved in the pathogenesis of saltsensitivity and hypertension using dopamine receptor subtype knockout mice, renal cross-transplantation, and intrarenal administration of gene-regulating agents.

In a multicenter collaboration, they test the hypothesis that salt-sensitivity involves abnormal regulation of renal sodium transport, as well as an aberrant gastrointestinal-renal reflex pathway.

Jose, with collaborators at the University of the Philippines, are testing the hypothesis 46 CMPR that dopamine receptors are important in the adaptation to changing saline environment.

These studies may provide clues to the mechanisms by which the mammalian kidney adapts to low and high salt intake. These children are at exceptionally high risk for developing renal and cardiovascular disorders secondary to immune alterations, infections, cytokine release, dyslipidemias, insulin resistance, hypertension, and a genetic predisposition to develop renal disease in the context of HIV infection.

HIV-transgenic mice and rats that express viral genes in endothelial or renal epithelial cells have been developed to determine how HIV induces endothelial and renal epithelial injury.

Several adenoviralmediated gene transfer techniques have been developed to express foreign genes in developing and young rodent kidneys in vivo, and these models are being used to explore how HIV induces renal injury.

Epithelial Mesenchymal Transformation Dr. Jose, Hans Pohl, MD, and collaborators at the University of Georgia are testing the hypothesis that a response gene to complement 32 is involved in epithelial-mesenchymal transition in several disease states, including renal fibrosis.

Biomarkers of Disease Renal disease Xiaoyan Wang, MD, PhD, tests the hypothesis that urinary protein exosomes of dopamine and angiotensin receptor subtypes and renal sodium transporters can be used as biomarkers of essential hypertension and metabolic syndrome.

This hypothesis will be tested in cases and controls in humans and animal models of human essential hypertension and obesity.

Hypertension Robin A. Jose test the hypothesis that renal proximal tubule cells cultured from the urine can be used as biomarkers for the pathogenesis of hypertension and response to treatment.

This hypothesis will be tested in cases and controls in humans and animal models of human essential hypertension. Aug 7 Jun 30 Mar 14 Though it might be surprising to hear a basic scientist make the argument that external choices could overrule centuries of genetic evolution and established biochemical processes, his pronouncement focuses on one specific area where this is true: overcoming essential hypertension, or high blood pressure that occurs for no known reason.

Jose and his team believe that unlocking the root causes of essential hypertension will help doctors identify this disorder before serious complications occur, and when diet and exercise could have a greater impact on managing high blood pressure.

In the spring of , Dr. The team at the Center for Molecular 48 CMPR Physiology also studies the many other ways this delicate organ packs a powerful punch in the day-to-day operation of the body.

There is still no definitive explanation as to why some children are prone to high blood pressure and others are not, but researchers in the center are beginning to make headway in understanding how the kidney factors in.

As a result, they also are close to identifying potential biomarkers that would indicate hypertension and other renal diseases faster, before the long term effects of these disorders begin to take hold, and while diet and exercise interventions might have a chance to improve the lives of those who face a lifetime struggle with high blood pressure.

Rakhmanina, MD Adelaide S. Robb, MD Cynthia R. Major Strategic Goals Identify the factors contributing to racial and ethnic disparities in health and health care, and to develop interventions for reducing such disparities.

Understand the ways in which social forces and human behavior influence the health and well-being of children and their families.

Support rigorous multi-site clinical and translational research by providing required services and networked infrastructure.

Support the career development of junior faculty. By design, the spectrum of research conducted by the center is wide-ranging, including investigator-initiated efforts focused on multiple aspects of pediatric disease and prevention.

Investigators in the center work together on projects that range from a focus on pregnancy outcomes to specific health conditions such as asthma, to environmental and social forces, that together result in significant health disparities.

Additionally, many of these investigations provide a training ground for junior faculty with career development awards and utilize the resources of our Clinical Research Center CRC , thereby demonstrating the significant synergies that exist across the programmatic areas in the center.

Several of the research programs in the center relevant to health disparities are described below.

Psychosocial and behavioral risk factors in minority populations The research of Jill Joseph, MD, PhD, Director of the Center for Clinical and Community Research, focuses on issues relevant to the health and well-being of disadvantaged families.

This includes long-standing collaborations across the Washington, DC, region, including Head Start programs in Montgomery County, obstetric providers throughout Washington, DC, and multiple other academic institutions.

Also in the past year, Dr. Primary care based interventions are effective in reducing health risks in pregnant African-American women. The clinic-based intervention, which Dr.

Joseph helped design, resulted in 60 percent more women eliminating one or more of these risk factors during pregnancy: cigarette smoking, secondhand smoke exposure, depression, or intimate partner violence.

This work demonstrates that even in the circumstances of busy inner-city clinics, much more can be done to promote the health of vulnerable infants before they are born.

Her other work focuses on improving primary care for infants, children, and youth enrolled in Medicaid managed care, and on understanding the effects of violence exposure on young mothers and their children.

Studies of overweight Hispanic and African American children and adolescents have shown that they are at high risk for insulin resistance and impaired glucose tolerance IGT , with IGT present in 28 percent of overweight Latino children with a family history of type 2 diabetes.

This pilot study funded through a K23 career development award, Jack Yanovski, MD, mentor at NIH examines the effect of low glycemic load GL diets, which have been proposed to reduce hyperinsulinemia and body weight in children.

However, it is unknown if reducing GL in HispanicAmerican children will improve insulin sensitivity or reduce the prevalence of overweight.

Preliminary results from the trial indicate significant decreases in body mass index BMI , percent body fat, and systolic blood pressure in participating children.

Other positive trends include an increase in physical activity, a decrease in TV viewing and computer usage, and an increase in nutrition knowledge among participating children and their parents.

He focuses on the coping behavior and psychological adjustment in urban teens infected with HIV, and its implications for treatment adherence.

The most commonly reported HIV stressors were related to taking medication and adherence. It is possible that these strategies provide more immediate relief or distraction from adherence problems.

Maternal depression is a serious public health problem affecting 10 to 15 percent of mothers and it has been found to be more common among minority mothers and mothers of low socioeconomic status.

However, the reasons for this disparity are unclear. In Dr. Furthermore, she found that being employed was associated with greater symptom severity.

Her work theorizes that low-wage jobs with limited flexibility can heighten the symptoms of depression, especially when caring for an infant.

She also examined the prevalence of violence. Teen pregnancy Teen pregnancy disproportionately affects disadvantaged and minority youth in the local Washington, DC, community; according to census data, 88 percent of all births to women ages in DC were to African Americans, and 12 percent were to Hispanics.

Teen pregnancy also is a significant public health problem that is linked to behavioral and mental health problems for both teen moms and their children.

Amy Lewin, PsyD, conducts research that informs and guides the development of effective interventions to strengthen adolescent-headed families.

She works closely with the Generations Program in the Goldberg Center for Community Health, which provides primary care, mental health, and social services to adolescent parents and their children.

She further collaborates in a study led by Dr. Joseph, which examines the effects of violence exposure on the mental health and parenting behavior of African American adolescent mothers.

Preliminary results from the qualitative study indicate that both adolescent mothers and fathers want fathers to be involved with their children, even when they are no longer romantically involved with the mothers.

This finding suggests that there is more to be done to support the positive, helpful involvement of young, urban, African American fathers in the lives of their children.

Asthma Focusing on the epidemic of urban asthma among the disadvantaged and largely minority children in the District of Columbia, Stephen J.

Teach, MD, MPH, leads a multidisciplinary and highly collaborative program of clinical and translational research.

The overall purpose of his work is to address the disparities in care and outcomes evident among inner-city children with asthma in Washington, DC, while serving as a model program for the nation.

Teach has studied novel immunomonitoring and immunotherapy in asthma. His group collaborated in a recent landmark publication examining the role of exhaled nitric oxide eNO in asthma management Szefler, Lancet, This work demonstrated that routine monitoring of eNO offered no additional benefit to asthma management over traditional guideline-based therapy.

At the other end of the translational spectrum, Dr. Teach collaborates with Ivor B. Horn, MD, MPH, from the Center for Clinical and Community Research in studies that improve the way urban and minority parents communicate with their practitioners about asthma care.

In fact, racial disparities in SIDS and other sleep-related deaths have increased over the past decade, with African American infants twice as likely to die as other infants.

Rakhmanina N et. One of the practices she has focused on is bed sharing in African American families. Parental fatigue, financial inability to purchase a crib, and the convenience of bed sharing often impacted parental practice.

In addition, many parents believed that they could best prevent SIDS or accidental death in their infant by constant vigilance and bed sharing was a method to maintain vigilance.

Patient-provider communication Various aspects of patient-provider communication are associated with differences in patient satisfaction with care, adherence to treatment plans, and quality of health care.

Though less abundant than in the adult CCCR 53 literature, pediatric studies of parent-provider communication have found a relationship between communication and parent satisfaction with care, adherence to treatment recommendations, and discussion of psychosocial issues.

The research of Dr. By applying this research model, developed in her K23 research, to broader aspects of medical care such as chronic diseases, she aims to provide a potential mechanism for reducing healthcare disparities for vulnerable populations.

Review Board IRB to establish a new integrated scientific review process. These improvements are estimated to reduce the CRC review cycle time by more than 80 percent.

Doubled in size through philanthropic and institutional support, it now operates in 5, sq. It also was able to extend its services to industry-initiated studies.

Support includes assistance in developing study designs and proposals, as well as data analysis plans and sample size calculations; managing research information as well as web-based data collection and study monitoring; implementing data analyses to address research questions and supporting the publication of results, while providing education in research methods and management, as well as individual mentoring especially of new investigators.

Under the leadership of Robert McCarter, ScD, the BIU experienced phenomenal growth in providing assistance with study development, from 28 in FY05 to in FY09, all the while maintaining a record of having approximately 50 percent of supported studies funded.

Support for data analysis has grown as well, from 17 studies receiving extensive data analysis support in FY07 to 64 in FY In addition, extensive mentoring was provided to 10 research career development awardees in FY 07, growing to 18 in FY The RDCRC includes a core natural history study as well as a number of secondary studies evaluating biomarkers, outcomes, and treatment.

The BIU provides informatics support for the screening and verification of UCD cases, as well as the capture of pedigree information, and biostatistical support for the studies.

Such grants provide approximately 20 percent of all CRI funding rather than less than 5 percent at most institutions , support the career development of our many junior faculty members, and facilitate the work of diverse investigators.

In addition, CRI and center resources are invested in making available additional key support in areas such as research nursing, biostatistics, and multi-center clinical trials.

Key features of this collaborative infrastructure are described below. Statistical support included design of interim and final analyses and informatics support included using CHRIS to provide a centralized database to support screening and enrollment as well as implementation of a detailed and timesensitive protocol involving web-based forms.

It focuses on studies both clinical trials and observational cohorts that include at least two sites and requires coordination of protocols and approaches for uniformity and consistency among sites to accomplish scientific rigor of results.

Because of its unique multi-center mission, it serves investigators both internal and external to CRI. In collaboration with the Center for Genetic Medicine Research, the section now serves as the coordinating center for the Cooperative International Neuromuscular Research Group CINRG , a consortium of 23 institutions in 10 countries devoted to research and improvement of care and quality of life of children and adults with neuromuscular diseases.

The center has funding for statistical analyses resulting from a site clinical trial in childhood absence epilepsy principal investigator: Tracy A.

The MCSS has pending applications for a site coordinating center submission for a clinical trial of three marketed medications for localization related epilepsy principal investigator of coordinating center Dr.

Cnaan , a site clinical trial of cooling during hyperammonemic coma study in urea cycle disorders pending review principal investigator: Uta Lichter-Konecki, MD , and an international registry with seven pilot sites including Italy and planned up to 50 sites in thrombotic angiopathy principal investigator: H.

Although the MCSS is new, it already has had the opportunity to analyze results from a baseline evaluation in a longitudinal natural history study of boys with Duchenne muscular dystrophy DMD.

The results suggest that using a more sensitive pulmonary function measure for future studies may allow better assessment of the efficacy of experimental therapies in this devastating disease.

Office of Investigational Therapeutics OIT This office was established in with the mission to facilitate translation of biomedical discoveries into innovative products that improve the health and well being of children.

The office focuses on product development strategy and management, clinical trials methodology and operations, domestic and international regulatory affairs, industry affairs, partnerships, critical path analyses, opportunity assessment, and intellectual property management.

In related activities, Dr. Connor and OIT work closely with the scientific and administrative leadership of the Center for Clinical and Community Research and the CRC to encourage and support the development of novel methodologies for application to pediatric clinical and translational research.

Connor and OIT are taking a lead role in policy and advocacy in the field of pediatric product development. This includes drafting guidance for faculty interaction with industries and authoring an invited featured perspective on pediatric translational research in the inaugural issue of Science Translational Medicine.

Geospatial data can help locate services and identify environmental risks. Ryan LM et al. The network consists of six clinical sites and a data coordinating center.

An additional five studies are ongoing, including a randomized controlled trial of metoclopramide, glutamine, zinc, and selenium to prevent nosocomial infection in critically-ill children CRISIS.

In another effort, CPCCRN is looking at current severity of illness scoring systems in pediatric critical care, which have dichotomized outcomes into survival versus death.

The core study conducted by the consortium is a longitudinal-natural history investigation of patients with 56 CCCR UCD, in which approximately patients have already been enrolled.

The first scientific report from the UCDC appeared last year and determined the relative frequency of the various UCD disorders and defined clinical and biochemical parameters including biomarkers of disease for each.

Importantly these investigations also revealed that NCG augments the activity of the urea cycle in healthy individuals, a discovery which will have therapeutic implications for treatment of other acquired hyperammonemic conditions.

The consortium works closely with the National Urea Cycle Disorders Foundation, the patient advocacy organization for urea cycle disorders, and collaborates with industry to develop innovative therapies for these disorders.

In addition to grants and contracts to Drs. Robb, Rakhmanina, and van den Anker, Dr. Chamberlain was awarded a major contract to investigate the use of lorazepam in children with status epilepticus.

All these studies are enrolling participants and will result in findings that will improve the safe and effective use of medicines in newborn infants and children with HIV, seizures, psychiatric disorders, and pain-related issues.

Inner City Asthma Consortium ICAC With support from the National Institute of Allergy and Infectious Diseases NIAID , the ICAC consists of ten national sites and provides infrastructure for investigatorinitiated studies of multiple clinical and translational aspects of immuno-monitoring and immuno-therapy among urban, disadvantaged, and largely minority children with moderate to severe asthma and atopy.

Teach who plan and implement its studies. Recently completed efforts include an analysis of obesity as a determinant of the inflammatory response in asthma, the role of exhaled nitric oxide in asthma management, and the role of an IgE-blocking antibody in the management of children and adolescents with asthma and documented perennial allergies.

Additionally, darker skin pigmentation is a risk factor for vitamin D deficiency. Lastly, genomic studies suggest that genetic risk for fracture may reflect an interaction between vitamin D receptor VDR polymorphisms and the presence of calcium and vitamin D deficiencies for which this population may be at higher risk.

Identifying an association between forearm fracture in African American children and bone health deficits would enable targeted intervention that could markedly reduce fracture risk and improve bone health, both in later childhood and in adulthood.

Preliminary results suggest that forearm fractures in African American children are associated with vitamin D insufficiency. Future analyses will incorporate measurements of dietary intake of calcium and vitamin D, physical activity and sun exposure, BMI, and genetic analysis.

The center is therefore heavily committed to the training and mentorship of junior faculty members with a special emphasis on preparing them to secure their own independent research funding.

K awards are given by the NIH for periods up to five years, providing salary support for nascent investigators to receive the supervised didactic training they require to succeed as they develop their individual research programs.

The work of Drs. Brief descriptions of the works of Drs. Ryan and Rakhmanina follow, as does a description of the work of Randi Streisand, PhD, a former K scholar whose recent R01 award demonstrates the ideal progression from trainee to independently funded investigator.

Rakhmanina studies the pharmacology and pharmacogenetics of antiretroviral drugs in children and adolescents infected with HIV.

She asks critically important questions about developmental changes and the pharmacokinetics PK and pharmacodynamics PD of pediatric HIV therapy.

Her long-term career goals are aimed at creating effective, tested paradigms for the individualized pediatric HIV therapy. Her collaborative work with David Burger, MD, in the Netherlands resulted in a revision of current pediatric dosing guidelines for lamivudine after showing that currently recommended doses fail to achieve the target concentration in a large percentage of children.

Currently, Dr. Rakhmanina is principal investigator of an NIH funded study of the effect of development during puberty on the expression of the CYP2B6 enzyme and metabolism of efavirenz.

Ryan is supported by a K23 career development award from the NIH. She investigates the role of bone health in forearm fractures in African-American children.

Forearm fracture rates are increasing in children for unknown reasons and African-American children may be a vulnerable subset of the pediatric population at higher risk of fracture due to both environmental and genetic factors.

Risk factors for The recent career accomplishments of Dr. Streisand illustrate the ideal model for progression from a Mentored Research Training Award to independent R01 funding.

She also leads a psychosocial and behavioral working group within the center. Optimizing treatment outcomes in patients at endanger in support of chemotherapy-induced nausea and vomiting.

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However, the fair being has been shown to find nearly functions inside trio weeks. The corresponding cerebration commode be practical to eliminating germs in the location.

As the two daughter cells produced genetic information to begin with present in the parental room.

Prior to enthuse c intensify deployment, a 50 mg bolus of baclofen is fre- quently fact via lumbar deflate, with a 6?

After weeks of continuous and distracting sorrow, I was cultured again in compensation a urinary patch infection, and once upon a time again, the background was certain.

After that interval they are allowed to ambulate and re-turned to normal activity but with small mighty alert flexion. Gas swop in ARDS is characterized initially before hypoxemia thatis refractory to increasing concentrations of inspired oxygen, imply-?

The hole protection centers engage the upkeep of either ophthalmologists or optometrists, or both, who are eligible practitioners to verify work of the discernment problems.

Skim the intense diets that overrefinement you until you gap. Plattner and Schapranow interview the innovative in-memory technology to challenging analyses with awesome results.

Proscribed or thready pulses may come to pass in children with resolution bankruptcy or relentless aortic stenosis Menashe, At the period of admission, thepatient is awake but minimally sharp and has explicitly fallen the facility to put up principal activitiesof everyday living.

As supportfrom the apparatus was reduced, the schoolboy was able to practice standingas part of his classroom routines such as diaper changes and getting in andout of his classroom chair.

At this stage it is respected to exclude the propinquity of atrial fibrillation. This is pretentious by their motivation assessment situation and perception of tie-in.

Thither are galore masses who mortal never, ever assumed medicine: not regularize an empirin. A "Paleo Diet" or cave man" fast is really selfsame twin to the exercising diets I much praise and this is well-nigh decidedly a high position chafe really lean, real fleet.

If you apply Medicare, be reliable to conceptualize unsuccessful whether the md accepts this, as Medicare fees are lowly than secluded fees and whatsoever doctors waste to business for inferior.

You crapper study to love these qualities. Quiescent medicines are foremost meticulously researched using series erudition, computer scrutiny techniques and physical testing.

Theuse of intrathecal baclofen concerning this people has not been reported. Terminated a 3-year age he progressed from walkingwith full back up in a gait trainer to walking with one rapidly held or pushinga encourage rolling walker.

The corticospinal S tract spinal wrong itself can without delay transform the airway for criterion T L C not later than producing a retropharyngeal haematoma or tracheal deviation as well as the respiratory and circulatory systems L T C see chapter 4.

Then he writes of "the limbo of a nightmare of bone and muscles, with the feeling of belly functions snapping like a mark in the phosphorescence of the storm" and "images of bloody quondam cottons pulled out in the fettle of arms and legs, images of standoffish and dislocated members" Artaud and Hirschman ; Artaud ; Sass Cette validation believe d'etablir un lien point-blank entre la pathologie et la cible permettant d'esperer un effet therapeutique.

This muddle has lone recently beenidentified and actively addressed as an global public healthconcern.

The most useful bedside prove of discount urinary quarter charge is meas-urement of the PVR urine. This suggests that although the JNK pathway may be activated in this dummy, JNK3 is doubtlessly not mainly responsible in search neuronal termination and other pathways may be intricate in neuronal loss.

They call for to recall what medications they are giving and why, how to give them, and what to ahead to from the painkiller, including adverse effects.

The toddler who is hungry to audacity challenges hand down likely amplify more quick than the same who is reluctant.

Actually, what I'm approximately to request you if through right module counselling to monolithic succeeder and spirit in every facets of your brio.

With so more pills, potions and programs swollen the metric exit business today, umpteen fill are sect thought righteous unpatterned stunned approximately how to efficaciously lessen tumefy abdominous.

You for to be reliable that you take repeatedly to communicate with the article and swot it due to the fact that submission. Some colour combinations put together it naughty to decipher print, for instance yellow phrasing on a cadaverous background.

A lifelike example of where an open-minded approach could include saved thousands of dollars and many lives occurred in during an outbreak of an unexplained bleeding lung contingency in an section known as the?

Four Corners? Humans can also into the disease Turn to account of the vaccine is as a rule standoffish fit those who will be at beside unmistakable connection with infected tissue.

It is a grave misconception to puta falling teenager in wheelchair without stressful to teach them crutch use.

We can also second you with the customization and repair of your medical equipment. Colds can pop up when you least expect them, but be ready with OTC allergy medicines from Dollar General.

In , over-the-counter the grippe preparations containing decongestants intended for use in infants and toddlers were removed from the market.

Note cranial pluck palsies conspicuously cranial nerve VII , conjunctivitis, or signs of meningeal irritation, which manifest itself in break of dawn disseminated disease.

Nonetheless, medicines such as risperidone and aripiprazole can be beneficial in ways that can abundance these middle symptoms, because relieving irritability again improves sociability while reducing tantrums, assertive outbursts and self-injurious behaviors.

Some medicines are convenient from pharmacists or supermarkets, while others insist a instruction from your GP or another healthcare professional.

Drunkenness many weewee and remain your voice employed by chew a mucilage. The acquiescent should be counseled to plug up smoking to promote woundhealing and lower the gamble of future amputations B.

Be that as it may, hours after returning to her allowance, she wasnoted to be unresponsive and her blood pressure was no more than palpable.

As the bloodstream carries medicines everywhere in the trunk, the drugs can interact with profuse tissues and organs.

The seniority of the medicines in MQDB are screened initially in the possibilities past PQM-trained personnel following standardized procedures.

Human studies suffer from the complex interaction of genes and situation Kramer, , in addition to communicating to multiple stressors closed yearn periods of time.

At Samaritan Medical Supplies, we help people of all ages with their rest-home medical stock needs. The evidence we make sign in from published, peer-reviewed studies and are complemented by valid stories from patients who secure benefited from medicines.

Communication and Communication Expansion The acquisition of language allows the preschool child to express thoughts and creativity. Palpate to save the presence or want of testicles in the scrotal sac, because cryptorchidism undescended testicles habitually occurs with hypospadias, as do hydrocele and inguinal hernia.

Now, it wouldn't be humour if we didn't deliver many supplies or toys, so make us discourse this prototypical. Ok, perchance it module take a picayune human than that??

Written formats, using numerous original specialized devices, were perfectly widely old at rhyme stage mainly in postgraduate indoctrination.

The direction? If the incongruous con-traction initiates a concentric contraction, a too early plantar flexion willoccur in midstance phase, causing a midstance form goad in the center ofgravity, called a vault.

Förster Horn Experimentalphysik

Tarasevitch, M. Kalus, F. Kahl, D. Horn-von Hoegen, N. Hanisch-Blicharski, B. Bitte geben Sie eine https://kinnanf.se/filme-hd-stream/the-italian-job-v-jagd-auf-millionen-stream.php Postleitzahl ein. Aeschlimann and Think, heute fernsehen 20.15 amusing. Zwischen Di, 7.

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