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Sample records for phenylketonuria pku development

  1. What Are Common Symptoms of Phenylketonuria (PKU)?

    MedlinePlus

    ... Overview Condition Information What are common symptoms? How many people are affected? ... are common symptoms of phenylketonuria (PKU)? Skip sharing on social media links Share this: Page Content Children with untreated ...

  2. How Do Health Care Providers Diagnose Phenylketonuria (PKU)?

    MedlinePlus

    ... Information Clinical Trials Resources and Publications How do health care providers diagnose phenylketonuria (PKU)? Skip sharing on social ... disabilities. 2 How are newborns tested for PKU? Health care providers conduct a PKU screening test using a ...

  3. Muscle-directed gene therapy for phenylketonuria (PKU): Development of transgenic mice with muscle-specific phenylalanine hydroxylase expression

    SciTech Connect

    Harding, C.O.; Messing, A.; Wolff, J.A.

    1994-09-01

    Phenylketonuria (PKU) is an attractive target for gene therapy because of shortcomings in current therapy including lifelong commitment to a difficult and expensive diet, persistent mild cognitive deficits in some children despite adequate dietary therapy, and maternal PKU syndrome. Phenylalanine hydroxylase (PAH) is normally expressed only in liver, but we propose to treat PKU by introducing the gene for PAH into muscle. In order to evaluate both the safety and efficacy of this approach, we have a developed a trangenic mouse which expresses PAH in both cardiac and skeletal muscle. The transgene includes promoter and enhancer sequences from the mouse muscle creatine kinase (MCK) gene fused to the mouse liver PAH cDNA. Mice which have inherited the transgene are healthy, active, and do not exhibit any signs of muscle weakness or wasting. Ectopic PAH expression in muscle is not detrimental to the health, neurologic function, or reproduction of the mice. Pah{sup enu2} hyperphenylalaninemic mice, a model of human PAH deficiency, bred to carry the transgene have substantial PAH expression in cardiac and skeletal muscle but none in liver. Muscle PAH expression alone does not complement the hyperphenylalaninemic phenotype of Pah{sup enu2} mice. However, administration of reduced tetrahydrobiopterin to transgenic Pah{sup enu2} mice is associated with a 25% mean decrease in serum phenylalanine levels. We predict that ectopic expression of PAH in muscle along with adequate muscle supplies of reduced biopterin cofactor will decrease hyperphenylalaninemia in PKU.

  4. Phenylketonuria (PKU). ARC Q&A #101-53.

    ERIC Educational Resources Information Center

    Arc, Arlington, TX.

    This fact sheet uses a question-and-answer format to summarize what is known about phenylketonuria (PKU), an inherited metabolic disease that leads to mental retardation and other developmental disabilities if untreated in infancy. Questions and answers address the following topics: what PKU is; how PKU is inherited; the diagnosis of PKU; the…

  5. Parental strategies to help children with phenylketonuria (PKU) cope with feeling different.

    PubMed

    Zwiesele, Sheila; Bannick, Allison; Trepanier, Angela

    2015-08-01

    This study assessed feelings of differentness in children with phenylketonuria (PKU) and elicited parental coping strategies. A total of 22 parents of 7- to 12-year-old patients with PKU completed qualitative interviews, which assessed whether they think their children feel different from their peers and identified potential solution strategies. The results showed that most parents indicated their child feels different due to PKU, which is frequently triggered by situations surrounding food. PKU community involvement and educating others about PKU were perceived by parents as useful coping strategies. Talking to children about differences was frequently used but one of the least effective strategies. Extended family, clinicians, and teachers also attempted to help children cope with feeling different with varying degrees of success. We concluded that most parents perceive that their child with PKU feels different and have developed strategies to manage these feelings. However, a subset struggle with helping their child cope and may benefit from assistance from healthcare providers.

  6. A Current Look at Phenylketonuria (PKU).

    ERIC Educational Resources Information Center

    Fischer, Margaret

    Research was reviewed on the current status of phenylketonuria, an hereditary amino acid metabolic disorder that can cause severe mental retardation, physical complications, and emotional difficulties if not detected and treated early in childhood. A majority of the research cited was published in the 1960's. Topics covered were: discovery of…

  7. What Are Common Treatments for Phenylketonuria (PKU)?

    MedlinePlus

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  8. Mental health and social functioning in early treated Phenylketonuria: the PKU-COBESO study.

    PubMed

    Jahja, Rianne; Huijbregts, Stephan C J; de Sonneville, Leo M J; van der Meere, Jaap J; Bosch, Annet M; Hollak, Carla E M; Rubio-Gozalbo, M Estela; Brouwers, Martijn C G J; Hofstede, Floris C; de Vries, Maaike C; Janssen, Mirian C H; van der Ploeg, Ans T; Langendonk, Janneke G; van Spronsen, Francjan J

    2013-01-01

    This article presents a new Dutch multicenter study ("PKU-COBESO") into cognitive and behavioral sequelae of early and continuously treated Phenylketonuria (PKU) patients. Part of the study sample will consist of young adult PKU patients who have participated in a large neuropsychological study approximately 10 years ago, when they were 7-to-15-year-olds (Huijbregts et al., 2002 [1]). Their neurocognitive development will be mapped in association with their earlier and continued metabolic history, taking into account possible changes in, for instance, medication. A second part of the sample will consist of PKU patients between the ages of 7 and approximately 40 years (i.e., born in or after 1974, when neonatal screening was introduced in The Netherlands), who have not participated in the earlier neuropsychological study. Again, their cognitive functioning will be related to their metabolic history. With respect to aspects of cognition, there will be an emphasis on executive functioning. The concept of executive functioning will however be extended with further emphasis on the impact of cognitive deficits on the daily lives of PKU patients, aspects of social cognition, social functioning, and behavior/mental health (i.e., COgnition, BEhavior, SOcial functioning: COBESO). In addition to a description of the PKU-COBESO study, some preliminary results with respect to mental health and social functioning will be presented in this article. Thirty adult PKU patients (mean age 27.8, SD 6.4) and 23 PKU patients under the age of 18 years (mean age 11.0, SD 3.3) were compared to 14 (mean age 26.9 years, SD 5.9) and 7 matched controls (mean age 10.5, SD 2.6) respectively, with respect to their scores on the Adult Self-Report or Child Behavior Checklist (measuring mental health problems) and the Social Skills Checklist or Social Skills Rating System (measuring social skills). Whereas there were very few significant group differences (except for mental health problems in the

  9. Education of Students with Phenylketonuria (PKU): Information for Teachers, Administrators and Other School Personnel.

    ERIC Educational Resources Information Center

    National Inst. of Child Health and Human Development (NIH), Bethesda, MD.

    This booklet summarizes current knowledge about phenylketonuria (PKU), an inherited condition that results in severe mental retardation if untreated, and discusses the psychoeducational implications of the condition. The introduction stresses the importance of early diagnosis (during the first days of life) and the effectiveness of a diet that…

  10. Phenylketonuria

    MedlinePlus

    ... without the ability to properly break down an amino acid called phenylalanine. Causes Phenylketonuria (PKU) is inherited, which ... which is needed to break down the essential amino acid phenylalanine. Phenylalanine is found in foods that contain ...

  11. Cognitive Outcomes in Early-Treated Adults With Phenylketonuria (PKU): A Comprehensive Picture Across Domains

    PubMed Central

    2017-01-01

    Objective: Phenylketonuria (PKU) is an inherited metabolic disease which affects cognitive functions due to an inability to metabolize phenylalanine which leads to the accumulation of toxic by-products (Phe) in the brain. PKU can be effectively treated with a low phenylalanine diet, but some cognitive deficits remain. Studies have reported impairments, especially for processing speed and executive functions, but there is a lack of comprehensive assessment across cognitive domains. Moreover, it is important to establish outcomes in early treated adults with PKU (AwPKU) who have better metabolic control than groups previously reported in the literature. Method: We tested 37 AwPKU with an unprecedented number of tasks (N = 28) and measures (N = 44) and compared results with 30 controls matched for age and education. Results: We found (a) group impairments, particularly in tasks tapping speed of processing and complex executive functions; (b) high variability across participants, with a sizable number of AwPKU with completely normal performance (about 38%); (c) but also a sizable number of participants who were clearly impaired (about 24%); and (d) good performance in tasks tapping verbal learning, verbal memory and orthographic processing, indicating no generalized learning impairment. Conclusion: Our results indicate good outcomes, but also that deficits are still present with current treatment policies. PMID:28080075

  12. Pharmacologic inhibition of L-tyrosine degradation ameliorates cerebral dopamine deficiency in murine phenylketonuria (PKU).

    PubMed

    Harding, Cary O; Winn, Shelley R; Gibson, K Michael; Arning, Erland; Bottiglieri, Teodoro; Grompe, Markus

    2014-09-01

    Monoamine neurotransmitter deficiency has been implicated in the etiology of neuropsychiatric symptoms associated with chronic hyperphenylalaninemia in phenylketonuria (PKU). Two proposed explanations for neurotransmitter deficiency in PKU include first, that chronically elevated blood L-phenylalanine (Phe) inhibits the transport of L-tyrosine (Tyr) and L-tryptophan (Trp), the substrates for dopamine and serotonin synthesis respectively, into brain. In the second hypothesis, elevated Phe competitively inhibits brain tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) activities, the rate limiting steps in dopamine and serotonin synthesis. Dietary supplementation with large neutral amino acids (LNAA) including Tyr and Trp has been recommended for individuals with chronically elevated blood Phe in an attempt to restore amino acid and monoamine homeostasis in brain. As a potential alternative treatment approach, we demonstrate that pharmacologic inhibition of Tyr degradation through oral administration of nitisinone (NTBC) yielded sustained increases in blood and brain Tyr, decreased blood and brain Phe, and consequently increased dopamine synthesis in a murine model of PKU. Our results suggest that Phe-mediated inhibition of TH activity is the likely mechanism of impaired dopamine synthesis in PKU. Pharmacologic inhibition of Tyr degradation may be a promising adjunct therapy for CNS monoamine neurotransmitter deficiency in hyperphenylalaninemic individuals with PKU.

  13. Phenylketonuria (PKU)

    MedlinePlus

    ... Disorder (ASD) Intellectual and Developmental Disabilities (IDDs) Newborn Screening NICHD News and Spotlights Getting to Know the New NICHD Director Neuroscience Research Resources NIH Scientists Combine ...

  14. High dose sapropterin dihydrochloride therapy improves monoamine neurotransmitter turnover in murine phenylketonuria (PKU).

    PubMed

    Winn, Shelley R; Scherer, Tanja; Thöny, Beat; Harding, Cary O

    2016-01-01

    Central nervous system (CNS) deficiencies of the monoamine neurotransmitters, dopamine and serotonin, have been implicated in the pathophysiology of neuropsychiatric dysfunction in phenylketonuria (PKU). Increased brain phenylalanine concentration likely competitively inhibits the activities of tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH), the rate limiting steps in dopamine and serotonin synthesis respectively. Tetrahydrobiopterin (BH4) is a required cofactor for TH and TPH activity. Our hypothesis was that treatment of hyperphenylalaninemic Pah(enu2/enu2) mice, a model of human PKU, with sapropterin dihydrochloride, a synthetic form of BH4, would stimulate TH and TPH activities leading to improved dopamine and serotonin synthesis despite persistently elevated brain phenylalanine. Sapropterin (20, 40, or 100mg/kg body weight in 1% ascorbic acid) was administered daily for 4 days by oral gavage to Pah(enu2/enu2) mice followed by measurement of brain biopterin, phenylalanine, tyrosine, tryptophan and monoamine neurotransmitter content. A significant increase in brain biopterin content was detected only in mice that had received the highest sapropterin dose, 100mg/kg. Blood and brain phenylalanine concentrations were unchanged by sapropterin therapy. Sapropterin therapy also did not alter the absolute amounts of dopamine and serotonin in brain but was associated with increased homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), dopamine and serotonin metabolites respectively, in both wild type and Pah(enu2/enu2) mice. Oral sapropterin therapy likely does not directly affect central nervous system monoamine synthesis in either wild type or hyperphenylalaninemic mice but may stimulate synaptic neurotransmitter release and subsequent metabolism.

  15. Are neuropsychological impairments in children with early-treated phenylketonuria (PKU) related to white matter abnormalities or elevated phenylalanine levels?

    PubMed

    Anderson, Peter J; Wood, Stephen J; Francis, Dorothy E; Coleman, Lee; Anderson, Vicki; Boneh, Avihu

    2007-01-01

    This study aimed to enhance our understanding of neuropsychological functioning in children with early-treated phenylketonuria (PKU) and assess the relative impact of white matter abnormalities (WMA) and neurotransmitter deficiencies on cognitive functions in this population. The study consisted of 33 children with early-treated PKU and 34 healthy control children aged between 7 to 18 years. All children had a neuropsychological evaluation that included measures of general intelligence, attention, processing speed, memory and learning, executive function, and academic achievement. Children in the PKU group also had a magnetic resonance (MR) brain scan. When compared with the control group, the PKU group exhibited global cognitive impairment including lower IQ, attention problems, slow information processing, reduced learning capacity, mild executive impairments, and educational difficulties. Children in the PKU group with extensive WMA (n = 14) displayed significant impairments across all cognitive domains. Metabolic control correlated weakly to moderately with attention, executive, and memory/learning factors. Within the PKU group, regressions revealed that executive function and attention factors were independently related to severity of WM pathology and age, while the memory and learning factor was independently related to metabolic control and age. It is concluded that children with early-treated PKU exhibit a global pattern of impairment, with a particular deficit in processing speed. WM pathology extending into frontal and subcortical regions correlates with the greatest deficits and a profile of impairment consistent with diffuse WM damage. Our findings also offer some support for dopamine depletion in the prefrontal cortex, however adverse consequences as a result of norepinephrine and serotonin deficiencies should not be discounted.

  16. Phenylketonuria

    NASA Astrophysics Data System (ADS)

    Lane, J. D.; Neuhoff, V.

    1980-05-01

    Phenylketonuria is a genetic defect that leads to imbecility, if the diagnosis is not made directly after birth. Since the development of imbecility can be almost totally halted by suitable dietary treatment, phenylketonuria is of more interest to neurochemists than to clinicians. This genetic defect is not known to occur in animals. It is therefore necessary to develop suitable models for neurochemical analysis. Most successful is the simultaneous application to developing rats of α-methyl-phenylalanine (an inhibitor of phenylalanine hydroxylase), together with phenylalanine. With this treatment it is possible to induce changes in the central nervous system which are surprisingly similar to those found in patients with phenylketonuria. This model is therefore of great importance in the analyses of the disturbances of metabolism, which finally causes the severe defects in normal brain function.

  17. Phenylketonuria

    MedlinePlus

    ... Encourage children with PKU to focus on sports, music or favorite hobbies, not on just what they ... having a baby: Follow a low-phenylalanine diet. Women with PKU can prevent birth defects by sticking ...

  18. Phenylketonuria and maternal phenylketonuria.

    PubMed

    Purnell, H

    2001-07-01

    Phenylketonuria is a genetic disease affecting 1:10,000 to 14,000 live births. In NSW there is an average of nine cases diagnosed each year (Dietitians Working Party 1996). This paper discusses the management of phenylketonuria, and in particular the value of breastfeeding, complemented with a low phenylalanine infant formula, in facilitating easier maintenance of satisfactory phenylalanine blood levels. The 'diet for life' approach to managing phenylketonuria is to avoid long-term neurological deficits and, in particular, the risk that maternal PKU, which is not under strict dietary control, will have adverse effects on infants born of mothers with the disease. There have been 31 successful pregnancies to 1997 managed by the Nutrition and Dietetics Department of The Children's Hospital at Westmead, Sydney. The Maternal PKU diet is presented with the case of a client with phenylketonuria who has achieved two normal pregnancies and breastfed her second child for six months.

  19. Learning about Phenylketonuria (PKU)

    MedlinePlus

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  20. What Is Phenylketonuria (PKU)?

    MedlinePlus

    ... have it? For more information... Acknowledgments Concept 15 : DNA and proteins are key molecules of the cell nucleus. Learn the basic chemistry of DNA and proteins. Concept 27 : Mutations are changes in ...

  1. Hepatitis virus protein X-Phenylalanine Hydroxylase fusion proteins identified in PKU mice treated with AAV-WPRE vectors

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Utilizing the Pahenu2 mouse model for phenylketonuria (PKU), we developed an improved expression vector containing the Woodchuck Hepatitis Virus post-transcriptional regulatory element inserted into a rAAV-mPAH construct (rAAV-mPAH-WPRE) for treatment of PKU. Following portal vein delivery of these ...

  2. Phenylketonuria: An Inborn Error of Phenylalanine Metabolism

    PubMed Central

    Williams, Robin A; Mamotte, Cyril DS; Burnett, John R

    2008-01-01

    Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine (Phe) metabolism resulting from deficiency of phenylalanine hydroxylase (PAH). Most forms of PKU and hyperphenylalaninaemia (HPA) are caused by mutations in the PAH gene on chromosome 12q23.2. Untreated PKU is associated with an abnormal phenotype which includes growth failure, poor skin pigmentation, microcephaly, seizures, global developmental delay and severe intellectual impairment. However, since the introduction of newborn screening programs and with early dietary intervention, children born with PKU can now expect to lead relatively normal lives. A better understanding of the biochemistry, genetics and molecular basis of PKU, as well as the need for improved treatment options, has led to the development of new therapeutic strategies. PMID:18566668

  3. Is overweight an issue in phenylketonuria?

    PubMed

    Rocha, Júlio C; MacDonald, Anita; Trefz, Friedrich

    2013-01-01

    Dietary treatment may be associated with an increased risk of obesity in phenylketonuria (PKU). The earliest studies describe a tendency for overweight in PKU, but not all recent publications confirm this, although there are an increasing number of studies describing increased obesity in female patients with PKU. There is little data describing the metabolic consequences of obesity in PKU. It is difficult to interpret and compare published results due to variable patient age, differing dietary treatment approaches, poor treatment adherence, inconsistencies in metabolic control achieved, variable criteria used to classify overweight. There is also a lack of comparison with normal population data which is widely variable between countries. Generally in PKU it is unknown if obesity etiology is a result of the underlying condition, a treatment consequence, or an outcome of inadequate metabolic control. Differences in treatment strategies, target ranges for blood phenylalanine concentrations and severity of PKU can alter nutritional intakes and dietary experiences which ultimately modulate the course of overweight development. It is clear further investigation is required. Treating overweight and obesity in the general population is difficult and no studies have described the impact of obesity treatment strategies in PKU. However, the PKU management team has an important role in monitoring nutritional status and preventing overweight and obesity. It is important that PKU treatment attends to the general aspects of nutrition, feeding behavior and exercise in order to prevent the development of overweight in these individuals.

  4. Classic Phenylketonuria: Diagnosis Through Heterozygote Detection

    ERIC Educational Resources Information Center

    Griffin, Robert F.; Elsas, Louis J.

    1975-01-01

    In an attempt to improve the identification of the asymptomatic carrier of classic phenylketonuria (PKU) 59 male and female normal control Ss were differentiated from 18 males and females heterozgous for PKU. (DB)

  5. Nutritional Management of Phenylketonuria

    PubMed Central

    MacLeod, Erin L.; Ney, Denise M.

    2010-01-01

    Phenylketonuria (PKU) is caused by deficient activity of the enzyme phenylalanine hydroxylase, needed to convert the essential amino acid (AA) phenylalanine (phe) to tyrosine. In order to prevent neurological damage, lifelong adherence to a low-phe diet that is restricted in natural foods and requires ingestion of a phe-free AA formula to meet protein needs is required. The goal of nutritional management for those with PKU is to maintain plasma phe concentrations that support optimal growth, development, and mental functioning while providing a nutritionally complete diet. This paper reviews developing a lifelong dietary prescription for those with PKU, outcomes of nutritional management, compliance with the low-phe diet across the life cycle, and new options for nutritional management. An individualized dietary prescription is needed to meet nutrient requirements, and the adequacy of phe intake is monitored with assessment of blood phe levels. Elevated phe concentrations may occur due to illness, excessive or inadequate phe intake, or inadequate intake of AA formula. Although normal growth and development occurs with adherence to the low-phe diet, it is important to monitor vitamin, mineral and essential fatty acid status, especially in those who do not consume sufficient AA formula. Given the growing population of adults with PKU, further research is needed to understand the risks for developing osteoporosis and cardiovascular disease. There are promising new options to liberalize the diet and improve metabolic control such as tetrahydrobiopterin therapy or supplementation with large neutral AAs. Moreover, foods made with glycomacropeptide, an intact protein that contains minimal phe, improves the PKU diet by offering a palatable alternative to AA formula. In summary, continued efforts are needed to overcome the biggest challenge to living with PKU – lifelong adherence to the low-phe diet. PMID:22475869

  6. Requirements for a minimum standard of care for phenylketonuria: the patients’ perspective

    PubMed Central

    2013-01-01

    Phenylketonuria (PKU, ORPHA716) is an inherited disorder that affects about one in every 10,000 children born in Europe. Early and continuous application of a modified diet is largely successful in preventing the devastating brain damage associated with untreated PKU. The management of PKU is inconsistent: there are few national guidelines, and these tend to be incomplete and implemented sporadically. In this article, the first-ever pan- European patient/carer perspective on optimal PKU care, the European Society for Phenylketonuria and Allied Disorders (E.S.PKU) proposes recommendations for a minimum standard of care for PKU, to underpin the development of new pan-European guideline for the management of PKU. New standards of best practice should guarantee equal access to screening, treatment and monitoring throughout Europe. Screening protocols and interpretation of screening results should be standardised. Experienced Centres of Expertise are required, in line with current European Union policy, to guarantee a defined standard of multidisciplinary treatment and care for all medical and social aspects of PKU. Women of childbearing age require especially intensive management, due to the risk of severe risks to the foetus conferred by uncontrolled PKU. All aspects of treatment should be reimbursed to ensure uniform access across Europe to guideline-driven, evidence-based care. The E.S.PKU urges PKU healthcare professionals caring for people with PKU to take the lead in developing evidence based guidelines on PKU, while continuing to play an active role in serving as the voice of patients and their families, whose lives are affected by the condition. PMID:24341788

  7. Nutritional issues in treating phenylketonuria.

    PubMed

    Feillet, François; Agostoni, Carlo

    2010-12-01

    A phenylalanine (Phe)-restricted diet is the mainstay of phenylketonuria (PKU) treatment, and, in recent years, the nutritional management of PKU has become more complex in order to optimize patients' growth, development and diet compliance. Dietary restriction of Phe creates a diet similar to a vegan diet, and many of the nutritional concerns and questions applicable to vegans who wish to avoid animal products are also relevant to patients with PKU. Owing to their nutritional characteristics, breast milk and breastfeeding should be given greater consideration as a useful food in patients with PKU and in those with other inborn errors of metabolism. Further key issues for consideration include the quality of the available amino acid substitutes, the neurotrophic and neuroprotective effects of added long-chain polyunsaturated fatty acids (e.g. docosahexaenoic acid), micronutrient deficiencies, bone disease and antioxidant status. Long-term dietary guidance and monitoring of the nutritional status of patients with PKU should be part of a follow-up programme that continues for life.

  8. PKU (Phenylketonuria) in Your Baby

    MedlinePlus

    ... Collaboratives Launch Prematurity research centers What is team science? More than 75 years of solving problems March ... Get informed Take action Participate & Support Make a donation Giving opportunities Our corporate partners Tools & Resources Careers ...

  9. How Is PKU Monitored?

    MedlinePlus

    Skip to main content. PKU Clinic - University of Washington, Seattle Home | Contact Us | Site Map PKU Management For Health Care Providers RECIPES about pku UW PKU Clinic News & Events What is PKU? What is the diet ...

  10. Neuropsychology of Early-Treated Phenylketonuria: Specific Executive Function Deficits.

    ERIC Educational Resources Information Center

    Welsh, Marilyn C.; And Others

    1990-01-01

    Early-treated phenylketonuria (PKU) children and unaffected peers were evaluated on four executive function (EF) tasks and one nonexecutive task. The PKU children scored lower than unaffected children on EF tasks, but not on the nonexecutive task. The PKU children's composite EF score was correlated with concurrent and mean lifetime phenylalanine…

  11. The birth prevalence of PKU in populations of European, South Asian and sub-Saharan African ancestry living in South East England.

    PubMed

    Hardelid, P; Cortina-Borja, M; Munro, A; Jones, H; Cleary, M; Champion, M P; Foo, Y; Scriver, C R; Dezateux, C

    2008-01-01

    Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism (OMIM 261600). Treatment with a low-phenylalanine diet following early ascertainment by newborn screening prevents impaired cognitive development, the major disease phenotype in PKU. The overall birth prevalence of PKU in European, Chinese and Korean populations is approximately 1/10,000. Since the human PAH locus contains PKU-causing alleles and polymorphic core haplotypes that describe and corroborate an out-of-Africa range expansion in modern human populations, it is of interest to know the prevalence of PKU in different ethnic groups with diverse geographical origin. We estimated PKU prevalence in South East England, where a sizeable proportion of the population are of Sub-Saharan African or South Asian ancestry. Over the period 1994 to 2004 167 children were diagnosed with PKU. Using birth registration and census data to derive denominators, PKU birth prevalence per 10,000 live births (95% Bayesian credible intervals) was estimated to be 1.14 (0.96-1.33) among white, 0.11 (0.02-0.37) among black, and 0.29 (0.10-0.63) among Asian ethnic groups. This suggests that PKU is up to an order of magnitude less prevalent in populations with Sub-Saharan African and South Asian ancestry that have migrated to the UK.

  12. Management of Newborn Infants with Phenylketonuria.

    ERIC Educational Resources Information Center

    Health Services Administration (DHEW/PHS), Rockville, MD. Bureau of Community Health Services.

    The booklet covers the identification, diagnosis, and clinical treatment of newborns with Phenylketonuria (PKU), an inborn error of metabolism, which, if untreated, can lead to mental retardation. An initial section considers biochemical and genetic factors of PKU including a diagram of aromatic amino acid hydroxylation systems. Screening…

  13. State-of-the-art 2003 on PKU gene therapy.

    PubMed

    Ding, Zhaobing; Harding, Cary O; Thöny, Beat

    2004-01-01

    Phenylketonuria (or PKU) is a well-known and widespread genetic disease for which many countries perform newborn screening, and life-long dietary restriction is still the ultimate and effective therapy. However, the diet is complicated, unpalatable, and expensive. The long-term effects of diet discontinuation in adults, except for the serious adverse effects of maternal hyperphenylalaninemia upon the developing fetus, have not been systematically studied, but cognitive decline and neurologic abnormalities have been anecdotally reported. Thus, alternative approaches for PKU therapy, including gene therapy, must be further explored. Here we summarize past present nonviral and viral gene transfer approaches, both in vitro studies and preclinical animal trials, to delivering the PAH gene into liver or other organs as potential alternatives to life-long phenylalanine-restricted dietary therapy.

  14. Molecular genetics and diagnosis of phenylketonuria: state of the art.

    PubMed

    Blau, Nenad; Shen, Nan; Carducci, Carla

    2014-07-01

    Detection of individuals with phenylketonuria (PKU), an autosomal recessively inherited disorder in phenylalanine degradation, is straightforward and efficient due to newborn screening programs. A recent introduction of the pharmacological treatment option emerged rapid development of molecular testing. However, variants responsible for PKU do not all suppress enzyme activity to the same extent. A spectrum of over 850 variants, gives rise to a continuum of hyperphenylalaninemia from very mild, requiring no intervention, to severe classical PKU, requiring urgent intervention. Locus-specific and genotypes database are today an invaluable resource of information for more efficient classification and management of patients. The high-tech molecular methods allow patients' genotype to be obtained in a few days, especially if each laboratory develops a panel for the most frequent variants in the corresponding population.

  15. Genetic interaction between pku300 and fbn2b controls endocardial cell proliferation and valve development in zebrafish.

    PubMed

    Wang, Xu; Yu, Qingming; Wu, Qing; Bu, Ye; Chang, Nan-Nan; Yan, Shouyu; Zhou, Xiao-Hai; Zhu, Xiaojun; Xiong, Jing-Wei

    2013-03-15

    Abnormal cardiac valve morphogenesis is a common cause of human congenital heart disease. The molecular mechanisms regulating endocardial cell proliferation and differentiation into cardiac valves remain largely unknown, although great progress has been made on the endocardial contribution to the atrioventricular cushion and valve formation. We found that scotch tape(te382) (sco(te382)) encodes a novel transmembrane protein that is crucial for endocardial cell proliferation and heart valve development. The zebrafish sco(te382) mutant showed diminished endocardial cell proliferation, lack of heart valve leaflets and abnormal common cardinal and caudal veins. Positional cloning revealed a C946T nonsense mutation of a novel gene pku300 in the sco(te382) locus, which encoded a 540-amino-acid protein on cell membranes with one putative transmembrane domain and three IgG domains. A known G3935T missense mutation of fbn2b was also found ∼570 kb away from pku300 in sco(te382) mutants. The genetic mutant sco(pku300), derived from sco(te382), only had the C946T mutation of pku300 and showed reduced numbers of atrial endocardial cells and an abnormal common cardinal vein. Morpholino knockdown of fbn2b led to fewer atrial endocardial cells and an abnormal caudal vein. Knockdown of both pku300 and fbn2b phenocopied these phenotypes in sco(te382) genetic mutants. pku300 transgenic expression in endocardial and endothelial cells, but not myocardial cells, partially rescued the atrial endocardial defects in sco(te382) mutants. Mechanistically, pku300 and fbn2b were required for endocardial cell proliferation, endocardial Notch signaling and the proper formation of endocardial cell adhesion and tight junctions, all of which are crucial for cardiac valve development. We conclude that pku300 and fbn2b represent the few genes capable of regulating endocardial cell proliferation and signaling in zebrafish cardiac valve development.

  16. Adult phenylketonuria presenting with subacute severe neurologic symptoms.

    PubMed

    Seki, M; Takizawa, T; Suzuki, S; Shimizu, T; Shibata, H; Ishii, T; Hasegawa, T; Suzuki, N

    2015-08-01

    We report a 48-year-old Japanese woman with phenylketonuria (PKU) who presented with severe neurological symptoms more than 30 years after discontinuation of dietary treatment. She was diagnosed with PKU at 6-years-old and was treated with a phenylalanine restricted diet until she was 15 years old. When she was 48-years-old she started having difficulty walking. After several months, she presented with severe disturbance of consciousness and was admitted. She was diagnosed as having neurological complications associated with PKU. We observed temporal changes in her laboratory data, brain MRI and single-photon emission computed tomography (SPECT) scan findings. Brain MRI on T2-weighted, fluid-attenuated inversion recovery and diffusion-weighted images revealed high intensity lesions in her bilateral frontal lobes and 123I-IMP SPECT showed marked and diffuse hypoperfusion in the bilateral cerebrum and cerebellum. After the resumption of dietary treatment, serum phenylalanine concentrations immediately decreased to the normal range. However, her neurological symptoms took longer to improve. We also found no clear temporal association between MRI findings and clinical severity. SPECT abnormalities showed marked improvement after treatment. It is well known that PKU patients who discontinue the dietary restriction from their childhood develop minor neurological impairments. However, PKU patients with late-onset severe neurological symptoms are very rare. To our knowledge, this is the first report regarding SPECT findings of PKU patients with late-onset severe neurological deterioration.

  17. PHENYLKETONURIA, A COMPREHENSIVE BIBLIOGRAPHY, 1964.

    ERIC Educational Resources Information Center

    Children's Bureau (DHEW), Washington, DC.

    INTENDED AS AN AID TO PROFESSIONAL AND TECHNICAL PERSONS INTERESTED IN PHENYLKETONURIA (PKU), THE BIBLIOGRAPHY LISTS AND ANNOTATES 817 ITEMS. CONTENT DIVISIONS ARE (1) GENERAL--MONOGRAPHS AND ARTICLES, (2) BIOCHEMISTRY--METABOLISM, EXPERIMENTS, TESTS, AND CASES IN WHICH THE EMPHASIS IS ON BIOCHEMISTRY, (3) GENETICS--GENE STUDIES, HEREDITARY…

  18. Challenges to breastfeeding infants with phenylketonuria.

    PubMed

    Banta-Wright, Sandra A; Kodadek, Sheila M; Steiner, Robert D; Houck, Gail M

    2015-01-01

    Breastfeeding duration for infants with phenylketonuria (PKU) is less than other full-term infants. However, no study has examined the challenges encountered by mothers' breastfeeding infants with PKU. In 75 mothers of a child with PKU, three categories of breastfeeding challenges were identified: common breastfeeding issues, breastfeeding and PKU, and no challenges. The common breastfeeding issues can be identified in the literature but for these mothers, the issues are heightened due to frequent phenylalanine (Phe) monitoring. Even so, many mothers adapt breastfeeding to maintain desired Phe levels. A few mothers had no issues and were the exception, not the norm.

  19. Surface-enhanced Raman scattering (SERS) for detection of phenylketonuria for newborn screening

    NASA Astrophysics Data System (ADS)

    Javanmard, M.; Davis, R. W.

    2014-02-01

    Diagnosis of Phenylketonuria (PKU) in newborns is important because it can potentially help prevent mental retardation since it is treatable by dietary means. PKU results in phenylketonurics having phenylalanine levels as high as 2 mM whereas the normal upper limit in healthy newborns is 120 uM. To this end, we are developing a microfluidic platform integrated with a SERS substrate for detection of high levels of phenylalanine. We have successfully demonstrated SERS detection of phenylalanine using various SERS substrates fabricated using nanosphere lithography, which exhibit high levels of field enhancement. We show detection of SERS at clinically relevant levels.

  20. Mouse Models of Human Phenylketonuria

    PubMed Central

    Shedlovsky, A.; McDonald, J. D.; Symula, D.; Dove, W. F.

    1993-01-01

    Phenylketonuria (PKU) results from a deficiency in phenylalanine hydroxylase, the enzyme catalyzing the conversion of phenylalanine (PHE) to tyrosine. Although this inborn error of metabolism was among the first in humans to be understood biochemically and genetically, little is known of the mechanism(s) involved in the pathology of PKU. We have combined mouse germline mutagenesis with screens for hyperphenylalaninemia to isolate three mutants deficient in phenylalanine hydroxylase (PAH) activity and cross-reactive protein. Two of these have reduced PAH mRNA and display characteristics of untreated human PKU patients. A low PHE diet partially reverses these abnormalities. Our success in using high frequency random germline point mutagenesis to obtain appropriate disease models illustrates how such mutagenesis can complement the emergent power of targeted mutagenesis in the mouse. The mutants now can be used as models in studying both maternal PKU and somatic gene therapy. PMID:8375656

  1. Late-Treated Phenylketonuria and Partial Reversibility of Intellectual Impairment

    ERIC Educational Resources Information Center

    Grosse, Scott D.

    2010-01-01

    Individuals with late-treated phenylketonuria (PKU) not detected by newborn screening but who followed dietary treatment for at least 12 months before 7 years of age have intelligence quotient (IQ) scores that range from severe impairment to the low-normal range. Among adults with late-treated PKU in California, 85% of those who were born from…

  2. Transitory Hyperphenylalaninaemia in Children with Continuously Treated Phenylketonuria.

    ERIC Educational Resources Information Center

    Griffiths, Peter; Smith, Caroline; Harvie, Ann

    1997-01-01

    Cognitive and behavioral effects of temporarily elevating levels of phenylalanine in treated phenylketonuria (PKU) were investigated in a triple-blind crossover study with 16 early and continuously treated children and adolescents with PKU. Results suggest that intellectual ability, memory, and conduct are not affected by medium-term elevated…

  3. PKU and the Schools: Information for Teachers, Administrators and Other School Personnel.

    ERIC Educational Resources Information Center

    Health Services Administration (DHEW/PHS), Rockville, MD. Bureau of Community Health Services.

    Designed to acquaint teachers, administrators and other school personnel with phenylketonuria (PKU - an inborn error of metabolism which requires dietary intervention), the booklet reviews school problems related to the condition. Introductory information concerns the nature, treatment, and screening and diagnosis of PKU. Diet management is…

  4. A GC/MS-based metabolomic approach for reliable diagnosis of phenylketonuria.

    PubMed

    Xiong, Xiyue; Sheng, Xiaoqi; Liu, Dan; Zeng, Ting; Peng, Ying; Wang, Yichao

    2015-11-01

    Although the phenylalanine/tyrosine ratio in blood has been the gold standard for diagnosis of phenylketonuria (PKU), the disadvantages of invasive sample collection and false positive error limited the application of this discriminator in the diagnosis of PKU to some extent. The aim of this study was to develop a new standard with high sensitivity and specificity in a less invasive manner for diagnosing PKU. In this study, an improved oximation-silylation method together with GC/MS was utilized to obtain the urinary metabolomic information in 47 PKU patients compared with 47 non-PKU controls. Compared with conventional oximation-silylation methods, the present approach possesses the advantages of shorter reaction time and higher reaction efficiency at a considerably lower temperature, which is beneficial to the derivatization of some thermally unstable compounds, such as phenylpyruvic acid. Ninety-seven peaks in the chromatograms were identified as endogenous metabolites by the National Institute of Standards and Technology (NIST) mass spectra library, including amino acids, organic acids, carbohydrates, amides, and fatty acids. After normalization of data using creatinine as internal standard, 19 differentially expressed compounds with p values of <0.05 were selected by independent-sample t test for the separation of the PKU group and the control group. A principal component analysis (PCA) model constructed by these differentially expressed compounds showed that the PKU group can be discriminated from the control group. Receiver-operating characteristic (ROC) analysis with area under the curve (AUC), specificity, and sensitivity of each PKU marker obtained from these differentially expressed compounds was used to evaluate the possibility of using these markers for diagnosing PKU. The largest value of AUC (0.987) with high specificity (0.936) and sensitivity (1.000) was obtained by the ROC curve of phenylacetic acid at its cutoff value (17.244 mmol/mol creatinine

  5. Fifty years of phenylketonuria newborn screening - A great success for many, but what about the rest?

    PubMed

    Groselj, Urh; Tansek, Mojca Zerjav; Battelino, Tadej

    2014-01-01

    Guthrie's landmark discovery and the subsequent implementation of the first newborn screening programs for phenylketonuria (PKU) and other inherited errors of metabolism (IEM) could be - in a 50 year retrospective - easily considered among the greatest advances in medicine. They have not just improved the quality of hundreds of thousands of lives, but also transformed our understanding and approach to PKU and IEM in general. However, according to the available albeit very scarce data, many countries and regions seem not to share the benefits of the last 50 years of development. Many of them have not yet introduced the newborn screening for PKU or face significant problems in its implementation. In addition, the issue seems to be underrated by the relevant professional forums. Action to improve the current situation should urgently be taken.

  6. Undiagnosed phenylketonuria in parents of phenylketonuric patients, is it worthwhile to be checked?

    PubMed

    Wiedemann, A; Leheup, B; Battaglia-Hsu, S-F; Jonveaux, P; Jeannesson, E; Feillet, F

    2013-01-01

    In our phenylketonuria (PKU) cohort of 120 patients, we uncovered a couple of cases of undiagnosed mild phenylketonuria (mPKU)/hyperphenylalaninemia (mHPA) in maternal parents of the PKU cohort. This finding prompted us to evaluate the risk of either mild phenylketonuria or mild hyperphenylalaninemia in the parent population whose children were diagnosed with hyperphenylalaninemia (HPA). Taking into account the phenylalanine hydroxylase (PAH) mutation carrier frequency and the PAH mild mutation rate, we estimated that the prevalence of the parental mPKU/mHPA varied widely, from 1/74 in Turkey to 1/708 in Lithuania. The benefits of the parental detection procedure described here are the prevention of further maternal PKU syndrome, the follow-up of the newly detected patients and the accuracy of the genetic counseling provided to these families. This very simple procedure should be incorporated into neonatal PKU management of the hospitals in countries where a routine systematic neonatal screening is operational.

  7. Diet Management of PKU for Infants and Preschool Children.

    ERIC Educational Resources Information Center

    Acosta, Phyllis B.; Wenz, Elizabeth

    The report focuses on the diet management of infant and preschool children with phenylketonuria (PKU), a congenital deficiency resulting in brain damage. The effective methods for rapidly lowering serum phenylalanine levels following diagnosis are discussed, a method for prescribing and calculating the phenylalanine-restricted diet is described,…

  8. Altered DNA methylation in PAH deficient phenylketonuria.

    PubMed

    Dobrowolski, Steven F; Lyons-Weiler, James; Spridik, Kayla; Biery, Amy; Breck, Jane; Vockley, Jerry; Yatsenko, Svetlana; Sultana, Tamanna

    2015-01-01

    While phenylalanine (PHE) is the toxic insult in phenylketonuria (PKU), mechanisms underlying PHE toxicity remain ill-defined. Altered DNA methylation in response to toxic exposures is well-recognized. DNA methylation patterns were assessed in blood and brain from PKU patients to determine if PHE toxicity impacts methylation. Methylome assessment, utilizing methylated DNA immunoprecipitation and paired-end sequencing, was performed in DNA obtained from brain tissue of classical PKU patients, leukocytes from poorly controlled PKU patients, leukocytes from well controlled PKU patients, and appropriate control tissues. In PKU brain tissue, expression analysis determined the impact of methylation on gene function. Differential methylation was observed in brain tissue of PKU patients and expression studies identified downstream impact on gene expression. Altered patterns of methylation were observed in leukocytes of well controlled and poorly controlled patients with more extensive methylation in patients with high PHE exposure. Differential methylation of noncoding RNA genes was extensive in patients with high PHE exposure but minimal in well controlled patients. Methylome repatterning leading to altered gene expression was present in brain tissue of PKU patients, suggesting a role in neuropathology. Aberrant methylation is observed in leukocytes of PKU patients and is influenced by PHE exposure. DNA methylation may provide a biomarker relating to historic PHE exposure.

  9. Early-Treated Phenylketonuria: Neuropsychologic Consequences.

    ERIC Educational Resources Information Center

    Brunner, Robert L.; And Others

    1983-01-01

    The neuropsychologic performance of 27 children (about 6 to 13 years old) with early-treated phenylketonuria (PKU) was evaluated and correlated with their serum phenylalanine concentrations at several ages. (Author/SEW) Journal Availability: The Journal of Pediatrics; The C. V. Mosby Company, 11830 Westline Industrial Drive, St. Louis, MO 63141.

  10. Intelligence and Phenylketonuria: Effects of Diet Termination.

    ERIC Educational Resources Information Center

    Koff, Elissa; And Others

    1979-01-01

    Trends in intellectual functioning before and after diet termination were examined in 30 children (5-11 years old) with PKU (Phenylketonuria, a metabolic disorder) treated before 6 weeks of age and on a liberal diet for a mean of 3 years since the mean age of 59 months. Journal availability: C.V. Mosby Company, 11830 Westline Industrial Drive, St.…

  11. Delayed diagnosis of phenylketonuria - a case report of two siblings.

    PubMed

    Narayanan, Deepa; Barski, Robert; Henderson, Mick J; Luvai, Ahai; Chandrajay, Deepak; Stainforth, Collette; Bradley, Jacqueline; Rogozinski, Hazel; Sharma, Reena

    2014-05-01

    Phenylketonuria (PKU), is an autosomal recessive condition affecting the amino acid metabolism. The UK National newborn screening programme was commenced in 1969 and PKU is one among the five conditions included in the screening programme. We present the case history of two siblings of a family with a delayed diagnosis of PKU. This case history highlights such an occurrence. PKU should be considered as an important differential in the diagnosis of adult patients with learning difficulties, seizures and behavioural problems. It would be prudent to instigate plasma and urine amino/organic acid analyses in adult patients with unexplained neuropsychological manifestations.

  12. National PKU News

    MedlinePlus

    ... and History Staff & Board How Much Phe Guthrie-Koch Scholarship Books Resources Support Us Contact Us Donors ... new Amino Acid Analysis Results This Year’s Guthrie-Koch PKU Scholarship Winners © 2016 National PKU News

  13. Phenylketonuria Scientific Review Conference: state of the science and future research needs.

    PubMed

    Camp, Kathryn M; Parisi, Melissa A; Acosta, Phyllis B; Berry, Gerard T; Bilder, Deborah A; Blau, Nenad; Bodamer, Olaf A; Brosco, Jeffrey P; Brown, Christine S; Burlina, Alberto B; Burton, Barbara K; Chang, Christine S; Coates, Paul M; Cunningham, Amy C; Dobrowolski, Steven F; Ferguson, John H; Franklin, Thomas D; Frazier, Dianne M; Grange, Dorothy K; Greene, Carol L; Groft, Stephen C; Harding, Cary O; Howell, R Rodney; Huntington, Kathleen L; Hyatt-Knorr, Henrietta D; Jevaji, Indira P; Levy, Harvey L; Lichter-Konecki, Uta; Lindegren, Mary Lou; Lloyd-Puryear, Michele A; Matalon, Kimberlee; MacDonald, Anita; McPheeters, Melissa L; Mitchell, John J; Mofidi, Shideh; Moseley, Kathryn D; Mueller, Christine M; Mulberg, Andrew E; Nerurkar, Lata S; Ogata, Beth N; Pariser, Anne R; Prasad, Suyash; Pridjian, Gabriella; Rasmussen, Sonja A; Reddy, Uma M; Rohr, Frances J; Singh, Rani H; Sirrs, Sandra M; Stremer, Stephanie E; Tagle, Danilo A; Thompson, Susan M; Urv, Tiina K; Utz, Jeanine R; van Spronsen, Francjan; Vockley, Jerry; Waisbren, Susan E; Weglicki, Linda S; White, Desirée A; Whitley, Chester B; Wilfond, Benjamin S; Yannicelli, Steven; Young, Justin M

    2014-06-01

    New developments in the treatment and management of phenylketonuria (PKU) as well as advances in molecular testing have emerged since the National Institutes of Health 2000 PKU Consensus Statement was released. An NIH State-of-the-Science Conference was convened in 2012 to address new findings, particularly the use of the medication sapropterin to treat some individuals with PKU, and to develop a research agenda. Prior to the 2012 conference, five working groups of experts and public members met over a 1-year period. The working groups addressed the following: long-term outcomes and management across the lifespan; PKU and pregnancy; diet control and management; pharmacologic interventions; and molecular testing, new technologies, and epidemiologic considerations. In a parallel and independent activity, an Evidence-based Practice Center supported by the Agency for Healthcare Research and Quality conducted a systematic review of adjuvant treatments for PKU; its conclusions were presented at the conference. The conference included the findings of the working groups, panel discussions from industry and international perspectives, and presentations on topics such as emerging treatments for PKU, transitioning to adult care, and the U.S. Food and Drug Administration regulatory perspective. Over 85 experts participated in the conference through information gathering and/or as presenters during the conference, and they reached several important conclusions. The most serious neurological impairments in PKU are preventable with current dietary treatment approaches. However, a variety of more subtle physical, cognitive, and behavioral consequences of even well-controlled PKU are now recognized. The best outcomes in maternal PKU occur when blood phenylalanine (Phe) concentrations are maintained between 120 and 360 μmol/L before and during pregnancy. The dietary management treatment goal for individuals with PKU is a blood Phe concentration between 120 and 360 μmol/L. The use

  14. Classroom Demonstration of a Spot Test for Pbenylpyruvic Acid and Its Relationship to Phenylketonuria

    ERIC Educational Resources Information Center

    Halkides, Christopher J.

    2004-01-01

    Classical phenylketonuria (PKU) is caused by a lack activity in the enzyme phenylalanine hydroxylase, leading to elevated concentrations of phenylalanine in the blood. A simple demonstration and three advanced demonstrations of a spot test for phenylpyruvic acid and its relationship to phenylketonuria are given.

  15. What Is the Diet for PKU?

    MedlinePlus

    Skip to main content. PKU Clinic - University of Washington, Seattle Home | Contact Us | Site Map PKU Management For Health Care Providers RECIPES about pku UW PKU Clinic News & Events What is PKU? What is the diet ...

  16. [Maternal phenylketonuria].

    PubMed

    Bókay, János; Kiss, Erika; Simon, Erika; Szőnyi, László

    2013-05-05

    Elevated maternal phenylalanine levels during pregnancy are teratogenic, and may result in embryo-foetopathy, which could lead to stillbirth, significant psychomotor handicaps and birth defects. This foetal damage is known as maternal phenylketonuria. Women of childbearing age with all forms of phenylketonuria, including mild variants such as hyperphenylalaninaemia, should receive detailed counselling regarding their risks for adverse foetal effects, optimally before contemplating pregnancy. The most assured way to prevent maternal phenylketonuria is to maintain the maternal phenylalanine levels within the optimal range already before conception and throughout the whole pregnancy. Authors review the comprehensive programme for prevention of maternal phenylketonuria at the Metabolic Center of Budapest, they survey the practical approach of the continuous maternal metabolic control and delineate the outcome of pregnancies of mothers with phenylketonuria from the introduction of newborn screening until most recently.

  17. CRISPR RNA-guided FokI nucleases repair a PAH variant in a phenylketonuria model

    PubMed Central

    Pan, Yi; Shen, Nan; Jung-Klawitter, Sabine; Betzen, Christian; Hoffmann, Georg F.; Hoheisel, Jörg D.; Blau, Nenad

    2016-01-01

    The CRISPR/Cas9 system is a recently developed genome editing technique. In this study, we used a modified CRISPR system, which employs the fusion of inactive Cas9 (dCas9) and the FokI endonuclease (FokI-dCas9) to correct the most common variant (allele frequency 21.4%) in the phenylalanine hydroxylase (PAH) gene - c.1222C>T (p.Arg408Trp) - as an approach toward curing phenylketonuria (PKU). PKU is the most common inherited diseases in amino acid metabolism. It leads to severe neurological and neuropsychological symptoms if untreated or late diagnosed. Correction of the disease-causing variants could rescue residual PAH activity and restore normal function. Co-expression of a single guide RNA plasmid, a FokI-dCas9-zsGreen1 plasmid, and the presence of a single-stranded oligodeoxynucleotide in PAH_c.1222C>T COS-7 cells – an in vitro model for PKU – corrected the PAH variant and restored PAH activity. Also in this system, the HDR enhancer RS-1 improved correction efficiency. This proof-of-concept indicates the potential of the FokI-dCas9 system for precision medicine, in particular for targeting PKU and other monogenic metabolic diseases. PMID:27786189

  18. CRISPR RNA-guided FokI nucleases repair a PAH variant in a phenylketonuria model.

    PubMed

    Pan, Yi; Shen, Nan; Jung-Klawitter, Sabine; Betzen, Christian; Hoffmann, Georg F; Hoheisel, Jörg D; Blau, Nenad

    2016-10-27

    The CRISPR/Cas9 system is a recently developed genome editing technique. In this study, we used a modified CRISPR system, which employs the fusion of inactive Cas9 (dCas9) and the FokI endonuclease (FokI-dCas9) to correct the most common variant (allele frequency 21.4%) in the phenylalanine hydroxylase (PAH) gene - c.1222C>T (p.Arg408Trp) - as an approach toward curing phenylketonuria (PKU). PKU is the most common inherited diseases in amino acid metabolism. It leads to severe neurological and neuropsychological symptoms if untreated or late diagnosed. Correction of the disease-causing variants could rescue residual PAH activity and restore normal function. Co-expression of a single guide RNA plasmid, a FokI-dCas9-zsGreen1 plasmid, and the presence of a single-stranded oligodeoxynucleotide in PAH_c.1222C>T COS-7 cells - an in vitro model for PKU - corrected the PAH variant and restored PAH activity. Also in this system, the HDR enhancer RS-1 improved correction efficiency. This proof-of-concept indicates the potential of the FokI-dCas9 system for precision medicine, in particular for targeting PKU and other monogenic metabolic diseases.

  19. The Long-Term Use of a Low-Phenylalanine Diet in Late-Treated Phenylketonuria: A Single Case Report

    ERIC Educational Resources Information Center

    Hewitt, Philippa; Cottle, Mandy; Coleman, Carol

    2006-01-01

    Background: When phenylketonuria (PKU) is not diagnosed and long-term treatment commenced within the first few weeks of life, permanent brain damage will occur. There is some evidence to show that late diagnosed or untreated people with PKU who have severe challenging behaviours may benefit from a low phenylalanine diet [Harper & Reid (1987)…

  20. Congenital and Neurological Abnormalities in Infants with Phenylketonuria

    ERIC Educational Resources Information Center

    Johnson, Charles F.; And Others

    1978-01-01

    Examined was the occurrence of congenital and neurological abnormalities in 150 children with phenylketonuria (PKU--a metabolic disorder which may result in mental retardation) age 1 year or older, who have been treated with a restricted phenylalanine diet, according to the protocol used in a nation-wide longitudinal collaborative study.…

  1. Phenylketonuria: nutritional advances and challenges

    PubMed Central

    2012-01-01

    Despite the appearance of new treatment, dietary approach remains the mainstay of PKU therapy. The nutritional management has become complex to optimize PKU patients' growth, development and diet compliance. This paper review critically new advances and challenges that have recently focused attention on potential relevant of LCPUFA supplementation, progress in protein substitutes and new protein sources, large neutral amino acids and sapropterin. Given the functional effects, DHA is conditionally essential substrates that should be supplied with PKU diet in infancy but even beyond. An European Commission Programme is going on to establish quantitative DHA requirements in this population. Improvements in the palatability, presentation, convenience and nutritional composition of protein substitutes have helped to improve long-term compliance with PKU diet, although it can be expected for further improvement in this area. Glycomacropeptide, a new protein source, may help to support dietary compliance of PKU subject but further studies are needed to evaluate this metabolic and nutritional issues. The PKU diet is difficult to maintain in adolescence and adult life. Treatment with large neutral amino acids or sapropterin in selected cases can be helpful. However, more studies are necessary to investigate the potential role, dose, and composition of large neutral amino acids in PKU treatment and to show long-term efficacy and tolerance. Ideally treatment with sapropterin would lead to acceptable blood Phe control without dietary treatment but this is uncommon and sapropterin will usually be given in combination with dietary treatment, but clinical protocol evaluating adjustment of PKU diet and sapropterin dosage are needed. In conclusion PKU diet and the new existing treatments, that need to be optimized, may be a complete and combined strategy possibly positive impacting on the psychological, social, and neurocognitive life of PKU patients. PMID:22305125

  2. Genetics Home Reference: phenylketonuria

    MedlinePlus

    ... Information & Resources MedlinePlus (4 links) Encyclopedia: Phenylketonuria Encyclopedia: Serum Phenylalanine Screening Health Topic: Newborn Screening Health Topic: Phenylketonuria Genetic and Rare Diseases Information Center (1 link) Phenylketonuria Additional NIH Resources ( ...

  3. Formulation and PEGylation optimization of the therapeutic PEGylated phenylalanine ammonia lyase for the treatment of phenylketonuria

    PubMed Central

    Bell, Sean M.; Wendt, Dan J.; Zhang, Yanhong; Long, Shinong; Tsuruda, Laurie; Zhao, Bin; Laipis, Phillip; Fitzpatrick, Paul A.

    2017-01-01

    Phenylketonuria (PKU) is a genetic metabolic disease in which the decrease or loss of phenylalanine hydroxylase (PAH) activity results in elevated, neurotoxic levels of phenylalanine (Phe). Due to many obstacles, PAH enzyme replacement therapy is not currently an option. Treatment of PKU with an alternative enzyme, phenylalanine ammonia lyase (PAL), was first proposed in the 1970s. However, issues regarding immunogenicity, enzyme production and mode of delivery needed to be overcome. Through the evaluation of PAL enzymes from multiple species, three potential PAL enzymes from yeast and cyanobacteria were chosen for evaluation of their therapeutic potential. The addition of polyethylene glycol (PEG, MW = 20,000), at a particular ratio to modify the protein surface, attenuated immunogenicity in an animal model of PKU. All three PEGylated PAL candidates showed efficacy in a mouse model of PKU (BTBR Pahenu2) upon subcutaneous injection. However, only PEGylated Anabaena variabilis (Av) PAL-treated mice demonstrated sustained low Phe levels with weekly injection and was the only PAL evaluated that maintained full enzymatic activity upon PEGylation. A PEGylated recombinant double mutant version of AvPAL (Cys503Ser/Cys565Ser), rAvPAL-PEG, was selected for drug development based on its positive pharmacodynamic profile and favorable expression titers. PEGylation was shown to be critical for rAvPAL-PEG efficacy as under PEGylated rAvPAL had a lower pharmacodynamic effect. rAvPAL and rAvPAL-PEG had poor stability at 4°C. L-Phe and trans-cinnamate were identified as activity stabilizing excipients. rAvPAL-PEG is currently in Phase 3 clinical trials to assess efficacy in PKU patients. PMID:28282402

  4. Genetics of Phenylketonuria: Then and Now.

    PubMed

    Blau, Nenad

    2016-06-01

    More than 950 phenylalanine hydroxylase (PAH) gene variants have been identified in people with phenylketonuria (PKU). These vary in their consequences for the residual level of PAH activity, from having little or no effect to abolishing PAH activity completely. Advances in genotyping technology and the availability of locus-specific and genotype databases have greatly expanded our understanding of the correlations between individual gene variant, residual PAH activity, tetrahydrobiopterin (BH4 ) responsiveness, and the clinical PKU phenotype. Most patients (∼76%) have compound heterozygous PAH gene variants and one mutated allele may markedly influence the activity of the second mutated allele, which in turn may influence either positively or negatively the activity of the biologically active heterotetrameric form of the PAH. While it is possible to predict the level of BH4 responsiveness (∼71%) and PKU severity (∼78%) from the nature of the underlying gene variants, these relationships remain complex and incompletely understood. A greater understanding of these relationships may increase the potential for individualized management of PKU in future. Inherited deficiencies in BH4 metabolism account for about 1%-2% of all hyperphenylalaninemias and are clinically more severe than PKU. Almost 90% of all patients are deficient in 6-pyruvoyl-tetrahydropterin synthase and dihydropteridine reductase.

  5. A case of maternal phenylketonuria syndrome presenting with unilateral renal agenesis.

    PubMed

    Gokmen, Tulin; Oguz, Serife Suna; Altug, Nahide; Akar, Melek; Erdeve, Omer; Dilmen, Ugur

    2011-04-01

    Maternal phenylketonuria (mPKU) during pregnancy leads to the risk of spontaneous abortion or a teratogenic syndrome depending on the level of maternal phenylalaninemia. Mental retardation, microcephaly, congenital cardiopathy and intrauterine growth retardation are frequently seen in patients who intake an unrestricted diet before conception. The clinical picture shows variation in classic PKU. Severe neurological symptoms are not seen in all untreated cases of PKU syndromes. For this reason, mPKU can be seen in undiagnosed mothers. We hereby present a case who underwent investigations due to the presence of microcephaly and congenital cardiopathy. The diagnosis of PKU syndrome of the mother was determined following assessment of the baby. Furthermore, the unilateral renal agenesis that was detected in our case is the first case reported in the literature in which mPKU accompanies renal agenesis.

  6. Costs and Outcomes over 36 Years of Patients with Phenylketonuria Who Do and Do Not Remain on a Phenylalanine-Restricted Diet

    ERIC Educational Resources Information Center

    Guest, J. F.; Bai, J. J.; Taylor, R. R.; Sladkevicius, E.; Lee, P. J.; Lachmann, R. H.

    2013-01-01

    Background: To quantify the costs and consequences of managing phenylketonuria (PKU) in the UK and to estimate the potential implications to the UK's National Health Service (NHS) of keeping patients on a phenylalanine-restricted diet for life. Methods: A computer-based model was constructed depicting the management of PKU patients over the first…

  7. Breast-feeding success among infants with phenylketonuria.

    PubMed

    Banta-Wright, Sandra A; Shelton, Kathleen C; Lowe, Nancy D; Knafl, Kathleen A; Houck, Gail M

    2012-08-01

    Breast milk is the nutrition of choice for human infants (American Academy of Pediatrics, 2005; American Association of Family Physicians, 2008; Association of Women's Health Obstetric and Neonatal Nurses, 2005; Canadian Paediatric Society, 2005; U.S. Preventive Services Task Force, 2008; World Health Organization, 2009). In comparison to standard commercial formula, human breast milk has a lower concentration of protein and a lower content of the amino acid phenylalanine (Phe). For infants with phenylketonuria (PKU), these attributes of human breast milk make it ideal as a base source of nutrition. The purpose of this study was to compare the incidence and duration of breast-feeding and corresponding Phe levels of breast-fed and formula-fed infants with PKU in the caseload of a pediatric metabolic clinic at an urban tertiary-care medical center. Charts were reviewed for infants diagnosed with PKU beginning with 2005 and ending with 1980, the year no further breast-feeding cases were identified in the PKU population. During the first year of life, most of the infants, whether breast-fed or formula-fed, had similar mean Phe levels. However, the frequency distributions revealed that more breast-fed infants with PKU had Phe levels within the normal range (120-360 μmol/L) and were less likely to have low Phe levels (<120 μmol/L) than formula-fed infants with PKU. Further research is needed to understand how mothers manage breast-feeding in the context of PKU.

  8. Parenting a child with phenylketonuria or galactosemia: implications for health-related quality of life.

    PubMed

    ten Hoedt, Amber E; Maurice-Stam, Heleen; Boelen, Carolien C A; Rubio-Gozalbo, M Estela; van Spronsen, Francjan J; Wijburg, Frits A; Bosch, Annet M; Grootenhuis, Martha A

    2011-04-01

    Parents of children with chronic disorders have an impaired health-related quality of life (HRQoL) compared to parents of healthy children. Remarkably, parents of children with a metabolic disorder reported an even lower HRQoL than parents of children with other chronic disorders. Possibly, the uncertainty about the course of the disease and the limited life expectancy in many metabolic disorders are important factors in the low parental HRQoL. Therefore, we performed a cross-sectional study in parents of children with phenylketonuria (PKU, OMIM #261600) and galactosemia (OMIM #230400), metabolic disorders not affecting life expectancy, in order to investigate their HRQoL compared to parents of healthy children and to parents of children with other metabolic disorders. A total of 185 parents of children with PKU and galactosemia aged 1-19 years completed two questionnaires. Parents of children with PKU or galactosemia reported a HRQoL comparable to parents of healthy children and a significantly better HRQoL than parents of children with other metabolic disorders. Important predictors for parental mental HRQoL were the psychosocial factors emotional support and loss of friendship. As parental mental functioning influences the health, development and adjustment of their children, it is important that treating physicians also pay attention to the wellbeing of the parents. The insight that emotional support and loss of friendship influence the HRQoL of the parents enables treating physicians to provide better support for these parents.

  9. The oxidative molecular regulation mechanism of NOX in children with phenylketonuria.

    PubMed

    He, Ying-Zhong; Gu, Xue-Fan; Lu, Li-Hua; Liang, Li-Li

    2014-11-01

    Phenylketonuria (PKU) is the most frequent inherited disorder of amino acid metabolism. In our previous work, we investigated the role of NADPH oxidase (NOX) in a Pahenu2-BTBR PKU mouse model, and an in vitro cell culture model of PKU. In the current study, we evaluated various oxidative stress parameters, namely total antioxidant capacity (T-AOC), glutathione (GSH) and maleic dialdehyde (MDA) in the plasma of 40 PKU children, for further investigating the oxidative molecular regulation mechanism of NOX in PKU. It was observed that T-AOC and GSH markedly decreased in PKU as compared with the control group (P<0.01), and seemed to correlate negatively with Phe level. However, there was no statistical difference in MDA level among the three groups. And 8-isoprostane in the blood samples of PKU2 groups was slightly higher than control group (P<0.05). Additionally, mRNA levels of subunits of NOX included p47(phox) and p67(phox) significantly increased in PKU group (P<0.01). These results reflected that NOX is the important source of reactive oxygen species and is involved in the oxidative molecular regulation mechanism in PKU, which shows a new perspective toward understanding the biological underpinnings of PKU.

  10. [Neonatal screening for congenital hypothyroidism and phenylketonuria].

    PubMed

    Velázquez, A; Loera-Luna, A; Aguirre, B E; Gamboa, S; Vargas, H; Robles, C

    1994-01-01

    A newborn screening program for congenital hypothyroidism (CH) and phenylketonuria (PKU) was conducted in 140 163 infants from the Federal District and the states of Mexico and Tlaxcala. These children were born mainly in hospitals for the non-insured population, although some were social security beneficiaries. Their filter-paper blood TSH and phenylalanine concentrations were determined 48 hours after birth. The frequency of CH was 1:1 797, with a 95 per cent confidence interval of 1:1 470 to 1:2 315, and was quite similar in the different types of hospitals. Only two PKU cases were found, for a frequency of 1:70 082, with a 95 per cent confidence interval of 0 to 1:4 762. This work demonstrates the feasibility of newborn screening programs in Mexico, identifies the problems to be solved in order to achieve a wide coverage and establishes the high frequency of CH in the Mexican population.

  11. Multiple origins for phenylketonuria in Europe

    PubMed Central

    Eisensmith, R. C.; Okano, Y.; Dasovich, M.; Wang, T.; Güttler, F.; Lou, H.; Guldberg, P.; Lichter-Konecki, U.; Konecki, D. S.; Svensson, E.; Hagenfeldt, L.; Rey, F.; Munnich, A.; Lyonnet, S.; Cockburn, F.; Connor, J. M.; Pembrey, M. E.; Smith, I.; Gitzelmann, R.; Steinmann, B.; Apold, J.; Eiken, H. G.; Giovannini, M.; Riva, E.; Longhi, R.; Romano, C.; Cerone, R.; Naughten, E. R.; Mullins, C.; Cahalane, S.; Özalp, I.; Fekete, G.; Schuler, D.; Berencsi, G. Y.; Nász, I.; Brdicka, R.; Kamaryt, J.; Pijackova, A.; Cabalska, B.; Boszkowa, K.; Schwartz, E.; Kalinin, V. N.; Jin, L.; Chakraborty, R.; Woo, S. L. C.

    1992-01-01

    Phenylketonuria (PKU), a disorder of amino acid metabolism prevalent among Caucasians and other ethnic groups, is caused primarily by a deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH). PKU is a highly heterogeneous disorder, with more than 60 molecular lesions identified in the PAH gene. The haplotype associations, relative frequencies, and distributions of five prevalent PAH mutations (R158Q, R261Q, IVS10nt546, R408W, and IVS12nt1) were established in a comprehensive European sample population and subsequently were examined to determine the potential roles of several genetic mechanisms in explaining the present distribution of the major PKU alleles. Each of these five mutations was strongly associated with only one of the more than 70 chromosomal haplotypes defined by eight RFLPs in or near the PAH gene. These findings suggest that each of these mutations arose through a single founding event that occurred within time periods ranging from several hundred to several thousand years ago. From the significant differences observed in the relative frequencies and distributions of these five alleles throughout Europe, four of these putative founding events could be localized to specific ethnic subgroups. Together, these data suggest that there were multiple, geographically and ethnically distinct origins for PKU within the European population. PMID:1361100

  12. Morphometric analysis of gray matter integrity in individuals with early-treated phenylketonuria.

    PubMed

    Christ, Shawn E; Price, Mason H; Bodner, Kimberly E; Saville, Christopher; Moffitt, Amanda J; Peck, Dawn

    2016-05-01

    The most widely-reported neurologic finding in individuals with early-treated phenylketonuria (PKU) is abnormality in the white matter of the brain. In contrast, much less is known regarding the impact of PKU on cortical gray matter (GM) structures. Presently, we applied advanced morphometric methods to the analysis of high-resolution structural MRI images from a sample of 19 individuals with early-treated PKU and an age- and gender-matched comparison group of 22 healthy individuals without PKU. Data analysis revealed decreased GM volume in parietal cortex for the PKU group compared with the non-PKU group. A similar trend was observed for occipital GM volume. There was no evidence of group-related differences in frontal or temporal GM volume. Within the PKU group, we also found a significant relationship between blood phenylalanine levels and GM volume for select posterior cortical sub-regions. Taken together with previous research on white matter and gray matter abnormalities in PKU, the present findings point to the posterior cortices as the primary site of neurostructural changes related to early-treated PKU.

  13. Intellectual Assessment of 111 Four-Year-Old Children with Phenylketonuria

    ERIC Educational Resources Information Center

    Dobson, James C.; And Others

    1977-01-01

    Available from: Arthur Retlaw and Associates, Inc., Suite 2080, 1603 Orrington Avenue, Evanston, Illinois 60201. A sample of 4-year-old children (n=111) with PKU (phenylketonuria) who were placed on dietary therapy between 3 and 92 days of age were assigned to two treatment groups based on "moderate" and "low" serum…

  14. PHENYLKETONURIA, DETECTION IN THE NEWBORN INFANT AS A ROUTINE HOSPITAL PROCEDURE.

    ERIC Educational Resources Information Center

    GUTHRIE, ROBERT; WHITNEY, STEWART

    A FIELD TRIAL OF AN INHIBITION ASSAY METHOD FOR SCREENING FOR PHENYLKETONURIA (PKU) TESTED MORE THAN 400,000 NEWBORN INFANTS PRIOR TO DISCHARGE FROM THE HOSPTIAL. IN ALL, 39 CASES WERE FOUND, A HIGHER INCIDENCE THAN HAD PREVIOUSLY BEEN EXPECTED. THE PRACTICALITY OF THE INHIBITION ASSAY METHOD WAS ALSO DEMONSTRATED. THE REPORT DETAILS THE TRIAL'S…

  15. Loss of Intellectual Function in Children with Phenylketonuria after Relaxation of Dietary Phenylalanine Restriction.

    ERIC Educational Resources Information Center

    Seashore, Margretta R.; And Others

    1985-01-01

    Discontinuation at ages five to six of dietary restriction in 14 children with classic phenylketonuria (PKU--a metabolic disorder which, if untreated, is associated with mental retardation) resulted in deterioration in intellectual function for some of the Ss. Deficits included visual motor integration and cognitive problem solving. (CL)

  16. Prenatal diagnosis of Chinese families with phenylketonuria.

    PubMed

    Liu, N; Kong, X D; Zhao, D H; Wu, Q H; Li, X L; Guo, H F; Cui, L X; Jiang, M; Shi, H R

    2015-11-19

    The aim of this study is to investigate the ability to prenatally diagnose phenylketonuria (PKU) by using phenylalanine hydroxylase (PAH) gene mutation analysis combined with short tandem repeat (STR) linkage analysis in 118 fetuses from 112 Chinese families. Genomic DNA was extracted from the peripheral blood from members of 112 families and the exons and exon-intron boundaries of the PAH gene were amplified by PCR. PCR products were analyzed by bi-directional Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). The three variable number of tandem repeat (VNTR) markers PAH-1, PAH-26, PAH-32 were used in the prenatal diagnosis for the PKU families. We identified a spectrum of 63 different mutations, including 61 point mutations and indels, two large exon deletion mutations, and five novel mutations. A substantial proportion of mutant alleles were accounted for by p.R243Q (15.62%), EX6-96AG (9.82%), p.V399V (7.59%), p.Y356X (6.70%), and p.R413P (5.36%). The same mutations were identified in 31 prenatally genotyped fetuses. We identified 58 fetuses that carried only one mutant allele and 29 fetuses that carried no mutations of PAH and were presumed normal. PAH gene mutation analysis combined with STR linkage analysis can provide rapid and accurate prenatal diagnosis for PKU families.

  17. Pretreatment cognitive and neural differences between sapropterin dihydrochloride responders and non-responders with phenylketonuria.

    PubMed

    Hawks, Zoë; Shimony, Joshua; Rutlin, Jerrel; Grange, Dorothy K; Christ, Shawn E; White, Desirée A

    2017-09-01

    Sapropterin dihydrochloride (BH4) reduces phenylalanine (Phe) levels and improves white matter integrity in a subset of individuals with phenylketonuria (PKU) known as "responders." Although prior research has identified biochemical and genotypic differences between BH4 responders and non-responders, cognitive and neural differences remain largely unexplored. To this end, we compared intelligence and white matter integrity prior to treatment with BH4 in 13 subsequent BH4 responders with PKU, 16 subsequent BH4 non-responders with PKU, and 12 healthy controls. Results indicated poorer intelligence and white matter integrity in non-responders compared to responders prior to treatment. In addition, poorer white matter integrity was associated with greater variability in Phe across the lifetime in non-responders but not in responders. These results underscore the importance of considering PKU as a multi-faceted, multi-dimensional disorder and point to the need for additional research to delineate characteristics that predict response to treatment with BH4.

  18. Optimal serum phenylalanine for adult patients with phenylketonuria.

    PubMed

    Okano, Yoshiyuki; Nagasaka, Hironori

    2013-12-01

    High serum phenylalanine in adult patients with phenylketonuria (PKU) causes neuropsychological and psychosocial problems that can be resolved by phenylalanine-restricted diet. Therefore, PKU patients must continue to adhere to phenylalanine-restricted diet for life, although the optimal serum phenylalanine level in later life has yet to be established. The purpose of this review was to establish the optimal serum phenylalanine level in later life of PKU patients. We evaluated oxidative stress status, nitric oxide metabolism, cholesterol-derived oxysterols, vitamin D and bone status, and magnetic resonance imaging (MRI) in adult PKU patients according to serum phenylalanine level. Oxidative stress increased markedly at serum phenylalanine of 700-800 μmol/L. Serum phenylalanine higher than 700-850 μmol/L correlated with the disturbance of nitric oxide regulatory system. Adult PKU patients had poor vitamin D status and exhibited predominance of bone resorption over bone formation. In the brain, the levels of 24S-hydroxycholesterol, a marker of brain cholesterol elimination, were low at serum phenylalanine levels exceeding 650 μmol/L. MRI studies showed high signal intensity in deep white matter on T2-weighted and FLAIR images of PKU patients with serum phenylalanine greater than 500 μmol/L, with decreased apparent diffusion coefficients. Changes in most parameters covering the entire body organs in adult PKU were almost acceptable below 700-800 μmol/L of phenylalanine level. However, the optimal serum phenylalanine level should be 500 μmol/L or less in later life for the brain to be safe.

  19. Metabolomics of Dietary Fatty Acid Restriction in Patients with Phenylketonuria

    PubMed Central

    Mütze, Ulrike; Beblo, Skadi; Kortz, Linda; Matthies, Claudia; Koletzko, Berthold; Bruegel, Mathias; Rohde, Carmen; Thiery, Joachim; Kiess, Wieland; Ceglarek, Uta

    2012-01-01

    Background Patients with phenylketonuria (PKU) have to follow a lifelong phenylalanine restricted diet. This type of diet markedly reduces the intake of saturated and unsaturated fatty acids especially long chain polyunsaturated fatty acids (LC-PUFA). Long-chain saturated fatty acids are substrates of mitochondrial fatty acid oxidation for acetyl-CoA production. LC-PUFA are discussed to affect inflammatory and haemostaseological processes in health and disease. The influence of the long term PKU diet on fatty acid metabolism with a special focus on platelet eicosanoid metabolism has been investigated in the study presented here. Methodology/Principal Findings 12 children with PKU under good metabolic control and 8 healthy controls were included. Activated fatty acids (acylcarnitines C6–C18) in dried blood and the cholesterol metabolism in serum were analyzed by liquid chromatographic tandem mass spectrometry (LC-MS/MS). Fatty acid composition of plasma glycerophospholipids was determined by gas chromatography. LC-PUFA metabolites were analyzed in supernatants by LC-MS/MS before and after platelet activation and aggregation using a standardized protocol. Patients with PKU had significantly lower free carnitine and lower activated fatty acids in dried blood compared to controls. Phytosterols as marker of cholesterol (re-) absorption were not influenced by the dietary fatty acid restriction. Fatty acid composition in glycerophospholipids was comparable to that of healthy controls. However, patients with PKU showed significantly increased concentrations of y-linolenic acid (C18:3n-6) a precursor of arachidonic acid. In the PKU patients significantly higher platelet counts were observed. After activation with collagen platelet aggregation and thromboxane B2 and thromboxane B3 release did not differ from that of healthy controls. Conclusion/Significance Long-term dietary fatty acid restriction influenced the intermediates of mitochondrial beta-oxidation. No functional

  20. An Investigation of the Neurological and Neuropsychiatric Disturbances in Adults with Undiagnosed and/or Untreated Phenylketonuria in Poland

    ERIC Educational Resources Information Center

    Mazur, Artur; Jarochowicz, Sabina; Oltarzewski, Mariusz; Sykut-Cegielska, Jolanta; Gradowska, Wanda; Januszek-Trzciakowska, Aleksandra; O'Malley, Grace; Kwolek, Andrzej

    2011-01-01

    Background: The aim of the study was to determine neurological and neuropsychiatric manifestations in a group of patients with previously undiagnosed or untreated phenylketonuria (PKU) in the south-eastern part of Poland. Methods: The study was conducted among 400 adults with severe intellectual disability who were born prior to neonatal screening…

  1. Mutation Spectrum of Six Genes in Chinese Phenylketonuria Patients Obtained through Next-Generation Sequencing

    PubMed Central

    Cen, Zhong; Yu, Li; Lin, Lin; Hao, Jing; Yang, Zhigang; Peng, Jiabao; Cui, Shujian; Huang, Jian

    2014-01-01

    Background The identification of gene variants plays an important role in the diagnosis of genetic diseases. Methodology/Principal Findings To develop a rapid method for the diagnosis of phenylketonuria (PKU) and tetrahydrobiopterin (BH4) deficiency, we designed a multiplex, PCR-based primer panel to amplify all the exons and flanking regions (50 bp average) of six PKU-associated genes (PAH, PTS, GCH1, QDPR, PCBD1 and GFRP). The Ion Torrent Personal Genome Machine (PGM) System was used to detect mutations in all the exons of these six genes. We tested 93 DNA samples from blood specimens from 35 patients and their parents (32 families) and 26 healthy adults. Using strict bioinformatic criteria, this sequencing data provided, on average, 99.14% coverage of the 39 exons at more than 70-fold mean depth of coverage. We found 23 previously documented variants in the PAH gene and six novel mutations in the PAH and PTS genes. A detailed analysis of the mutation spectrum of these patients is described in this study. Conclusions/Significance These results were confirmed by Sanger sequencing. In conclusion, benchtop next-generation sequencing technology can be used to detect mutations in monogenic diseases and can detect both point mutations and indels with high sensitivity, fidelity and throughput at a lower cost than conventional methods in clinical applications. PMID:24705691

  2. PKU and Maternal PKU: The Cure and the Problem.

    ERIC Educational Resources Information Center

    Henderson, Robert A.

    1989-01-01

    A longitudinal study is evaluating the efficacy of a phenylalanine-restricted diet in reducing disabling conditions associated with maternal hyperphenylalaninemia. Titled the Maternal PKU Collaborative Study, it is studying 162 American and Canadian women and involves diet therapy, prenatal examinations, laboratory tests, nutritional evaluation,…

  3. Recommended Guidelines for PKU Programs.

    ERIC Educational Resources Information Center

    Children's Bureau (DHEW), Washington, DC.

    A discussion of screening tests for phenylketonuria recommends and provides some data on two tests, lists five disadvantages of urine tests, and discusses three new tests. Also considered are the role of the central laboratory facility and seven suggestions for screening different types of infants at different times. Treatment or followup programs…

  4. Adherence to tetrahydrobiopterin therapy in patients with phenylketonuria.

    PubMed

    Rohr, Frances; Wessel, Ann; Brown, Matthew; Charette, Kalin; Levy, Harvey L

    2015-01-01

    Phenylketonuria (PKU) is an inborn error in phenylalanine metabolism due to deficiency of the enzyme, phenylalanine hydroxylase (PAH). Treatment includes restriction of dietary phenylalanine, and in some individuals, supplementation with the PAH cofactor, tetrahydrobiopterin (sapropterin dihydrochloride). A survey was conducted among patients with PKU who had been prescribed sapropterin to assess reasons for continuing or discontinuing the drug. The primary reason that sapropterin responders discontinued the drug was because of side effects, followed by insufficient reduction of blood phenylalanine and insurance issues. Conversely, those who remained on therapy cited increased tolerance for dietary protein as the main reason for continuation, along with lower blood phenylalanine concentrations and feeling better. This study suggests that adherence to sapropterin therapy is mainly dependent upon the increase in dietary protein allowed when on the drug.

  5. Asymmetric dimethylarginine in children with homocystinuria or phenylketonuria.

    PubMed

    Kanzelmeyer, Nele; Tsikas, Dimitrios; Chobanyan-Jürgens, Kristine; Beckmann, Bibiana; Vaske, Bernhard; Illsinger, Sabine; Das, Anibh M; Lücke, Thomas

    2012-05-01

    Plasma concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthesis from L-arginine and a cardiovascular risk factor, was found to be elevated in plasma of homocysteinemic adults. Enhanced cardiovascular risk due to homocystinuria and impaired renal function has been found in patients with phenylketonuria (PKU) on protein-restricted diet. However, it is still unknown whether ADMA synthesis is also elevated in children with homocystinuria due to cystathionine beta-synthase deficiency (classical homocystinuria), and whether ADMA may play a role in phenylketonuria in childhood. In the present study, we investigated the status of the L-arginine/NO pathway in six young patients with homocystinuria, in 52 young phenylketonuria patients on natural protein-restricted diet, and in age- and gender-matched healthy children serving as controls. ADMA in plasma and urine was determined by GC-MS/MS. The NO metabolites nitrate and nitrite in plasma and urine, and urinary dimethylamine (DMA), the dimethylarginine dimethylaminohydrolase (DDAH) metabolite of ADMA, were measured by GC-MS. Unlike urine ADMA excretion, plasma ADMA concentration in patients with homocystinuria was significantly higher than in controls (660±158 vs. 475±77 nM, P=0.035). DMA excretion rate was considerably higher in children with homocystinuria as compared to controls (62.2±24.5 vs. 6.5±2.9 μmol/mmol creatinine, P=0.068), indicating enhanced DDAH activity in this disease. In contrast and unexpectedly, phenylketonuria patients had significantly lower ADMA plasma concentrations compared to controls (512±136 vs. 585±125 nM, P=0.009). Phenylketonuria patients and controls had similar L-arginine/ADMA molar ratios in plasma. Urinary nitrite excretion was significantly higher in phenylketonuria as compared to healthy controls (1.7±1.7 vs. 0.7±1.2 μmol/mmol creatinine, P=0.003). Our study shows that the L-arginine/NO pathway is differently altered in children

  6. Food Products Made With Glycomacropeptide, a Low Phenylalanine Whey Protein, Provide a New Alternative to Amino Acid-Based Medical Foods for Nutrition Management of Phenylketonuria

    PubMed Central

    Van Calcar, Sandra C.; Ney, Denise M.

    2012-01-01

    Phenylketonuria (PKU), an inborn error in phenylalanine (phe) metabolism, requires lifelong nutrition management with a low-phe diet, which includes a phe-free amino acid-based medical formula to provide the majority of an individual’s protein needs. Compliance with this diet is often difficult for older children, adolescents and adults with PKU. The whey protein glycomacropeptide (GMP) is ideally suited for the PKU diet since it is naturally low in phe. Nutritionally complete, acceptable medical foods and beverages can be made with GMP to increase the variety of protein sources for the PKU diet. As an intact protein, GMP improves protein utilization and increases satiety compared with amino acids. Thus, GMP provides a new, more physiologic source of low-phe dietary protein for those with PKU. PMID:22818728

  7. Controlled diet in phenylketonuria and hyperphenylalaninemia may cause serum selenium deficiency in adult patients: the Czech experience.

    PubMed

    Procházková, Dagmar; Jarkovský, Jiří; Vinohradská, Hana; Konečná, Petra; Machačová, Lucie; Doležel, Zdeněk

    2013-08-01

    Phenylketonuria is an inherited disorder of metabolism of the amino acid phenylalanine caused by a deficit of the enzyme phenylalanine hydroxylase. It is treated with a low-protein diet containing a low content of phenylalanine to prevent mental affection of the patient. Because of the restricted intake of high-biologic-value protein, patients with phenylketonuria may have lower than normal serum concentrations of pre-albumin, selenium, zinc and iron. The objective of the present study was to assess the compliance of our phenylketonuric (PKU) and hyperphenylalaninemic (HPA) patients; to determine the concentration of serum pre-albumin, selenium, zinc and iron to discover the potential correlation between the amount of proteins in food and their metabolic control. We studied 174 patients of which 113 were children (age 1-18), 60 with PKU and 53 with HPA and 61 were adults (age 18-42), 51 with PKU and 10 with HPA. We did not prove a statistically significant difference in the concentration of serum pre-albumin, zinc and iron among the respective groups. We proved statistically significant difference in serum selenium concentrations of adult PKU and HPA patients (p = 0.006; Mann-Whitney U test). These results suggest that controlled low-protein diet in phenylketonuria and hyperphenylalaninemia may cause serum selenium deficiency in adult patients.

  8. Alternative therapies to address the unmet medical needs of patients with phenylketonuria.

    PubMed

    Blau, Nenad; Longo, Nicola

    2015-04-01

    Standard therapy for phenylketonuria (PKU), the most common inherited disorder in amino acid metabolism, is an onerous phenylalanine-restricted diet. Adherence to this stringent diet regimen decreases as patients get older, and this lack of adherence is directly associated with cognitive and executive dysfunction and psychiatric issues. These factors emphasize the need for alternative pharmacological therapies to help treat patients with PKU. Sapropterin dihydrochloride is a synthetic form of tetrahydrobiopterin, the cofactor of phenylalanine hydroxylase that in pharmacological doses can stabilize and increase residual enzyme activity in some patients with PKU. About one-third of all patients with PKU respond to oral sapropterin. Phenylalanine ammonia lyase (PAL) is a prokaryotic enzyme that converts phenylalanine to ammonia and trans-cinnamic acid. Phase I and II trials have shown that injectable recombinant Anabaena variabilis PAL produced in Escherichia coli conjugated with PEG can reduce phenylalanine levels in subjects with PKU. The most frequently reported adverse events were injection-site reactions, dizziness and immune reactions. Additionally, oral administration of PAL and delivery of enzyme substitution therapies by encapsulation in erythrocytes are being investigated. Novel therapies for patients with PKU appear to be options to reduce phenylalanine levels, and may reduce the deleterious effects of this disorder.

  9. Molecular characterization of phenylketonuria and tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Japan.

    PubMed

    Okano, Yoshiyuki; Kudo, Satoshi; Nishi, Yasuaki; Sakaguchi, Tomoko; Aso, Kazuyoshi

    2011-04-01

    Phenylketonuria (PKU) is a heterogeneous metabolic disorder caused by a deficiency in hepatic phenylalanine hydroxylase (PAH). On the basis of phenotype/genotype correlations, determination of phenylketonuric genotype is important for classification of the clinical phenotype and treatment of PKU, including tetrahydrobiopterin therapy. We characterized the genotypes of 203 Japanese patients with PKU and hyperphenylalaninemia using the following systems: (1) denaturing high-performance liquid chromatography with a GC-clamped primer; (2) direct sequencing; and, (3) multiplex ligation-dependent probe amplification. Of 406 mutant alleles, 390 (96%) were genotyped; 65 mutations were identified, including 22 new mutations. R413P, R241C, IVS4-1g>a, R111X and R243Q were prevalent mutations. Mutations prevalent in the Japanese cohort are also common in Korean and Northern Chinese populations, suggesting same origin. The spectrum of prevalent mutations was not significantly different among six Japanese districts, indicating that Japan comprises a relatively homogeneous ethnic group. We classified the mutations by clinical phenotypes and in vivo PAH activity and estimated the mutations with potential tetrahydrobiopterin (BH(4)) responsiveness. The frequency of BH(4) responsiveness based on the genotype was 29.1% in Japanese PKU patients. A catalog of PKU genotypes would be useful for predicting clinical phenotype, deciding on the subsequent treatment of PKU including BH(4) therapy, and genetic counseling in East Asia.

  10. Systematic Review and Meta-Analysis of Neuropsychiatric Symptoms and Executive Functioning in Adults With Phenylketonuria

    PubMed Central

    Bilder, Deborah A.; Noel, J. Kay; Baker, Erin R.; Irish, William; Chen, Yinpu; Merilainen, Markus J.; Prasad, Suyash; Winslow, Barbara J.

    2016-01-01

    ABSTRACT This systematic review and meta-analysis (MA) investigates the impact of elevated blood phenylalanine (Phe) on neuropsychiatric symptoms in adults with phenylketonuria (PKU). The meta-analysis of PKU is challenging because high-quality evidence is lacking due to the limited number of affected individuals and few placebo-controlled, double-blind studies of adults with high and low blood Phe. Neuropsychiatric symptoms associated with PKU exceed general population estimates for inattention, hyperactivity, depression, and anxiety. High Phe is associated with an increased prevalence of neuropsychiatric symptoms and executive functioning deficits whereas low Phe is associated with improved neurological performance. Findings support lifelong maintenance of low blood Phe. PMID:27805419

  11. Phenylketonuria: a 21st century perspective.

    PubMed

    van Spronsen, Francjan J

    2010-09-01

    Phenylketonuria is the most prevalent inherited defect in amino acid metabolism. Owing to mutations in the gene encoding the enzyme phenylalanine hydroxylase, the essential amino acid phenylalanine cannot be hydroxylated to tyrosine and blood and tissue concentrations of phenylalanine increase. Untreated, phenylketonuria causes severe mental retardation, epilepsy and behavioral problems. The combined effect of neonatal screening and treatment has, however, meant that phenylketonuria is now a biochemical rather than a clinical diagnosis. Treatment consists of stringent dietary restriction of natural protein intake and supplementation of amino acids other than phenylalanine by a chemically manufactured protein substitute. Although clinical outcome on a phenylalanine-restricted diet is good, neuropsychological deficits are now known to exist in dietary-treated patients with phenylketonuria, and quality of life, nutritional condition and psychosocial outcome could probably also be improved. The need for new therapeutic approaches is being met by supplementation with tetrahydrobiopterin or large neutral amino acids, whilst development of the use of phenylalanine ammonia lyase, and, in the longer term, gene therapy and chaperone treatment holds promise. This Review provides an overview of the history of phenylketonuria, the challenges of treatment today and the treatment possibilities in the near future.

  12. Phenylketonuria: a review of current and future treatments

    PubMed Central

    Al Hafid, Naz

    2015-01-01

    Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism caused by a deficiency in the hepatic enzyme phenylalanine hydroxylase (PAH). If left untreated, the main clinical feature is intellectual disability. Treatment, which includes a low Phe diet supplemented with amino acid formulas, commences soon after diagnosis within the first weeks of life. Although dietary treatment has been successful in preventing intellectual disability in early treated PKU patients, there are major issues with dietary compliance due to palatability of the diet. Other potential issues associated with dietary therapy include nutritional deficiencies especially vitamin D and B12. Suboptimal outcomes in cognitive and executive functioning have been reported in patients who adhere poorly to dietary therapy. There have been continuous attempts at improving the quality of medical foods including their palatability. Advances in dietary therapy such as the use of large neutral amino acids (LNAA) and glycomacropeptides (GMP; found within the whey fraction of bovine milk) have been explored. Gene therapy and enzyme replacement or substitution therapy have yielded more promising data in the recent years. In this review the current and possible future treatments for PKU are discussed. PMID:26835392

  13. Rapid screening of phenylketonuria using a CD microfluidic device.

    PubMed

    Chen, Bin; Zhou, Xiaomian; Li, Chunyu; Wang, Qiuping; Liu, Dayu; Lin, Bingcheng

    2011-04-08

    We herein present a compact disc (CD) microfluidic chip based hybridization assay for phenylketonuria (PKU) screening. This CD chip is composed of a polydimethylsiloxane (PDMS) top layer containing 12 DNA hybridization microchannels, and a glass bottom layer with hydrogel pad conjugated DNA oligonucleotides. Reciprocating flow was generated on the CD chip through a simple rotation-pause operation to facilitate rapid DNA hybridization. When rotated the CD chip, the sample solution was driven into the hybridization channel by centrifugal force. When stopped the CD chip, the sample plug was pulled backward through the channel by capillary force. The hybridization assay was firstly validated with control samples and was then used to analyze 30 clinical samples from pregnant women with suspected PKU fetus. The on-chip DNA hybridization was completed in 15 min with a sample consumption as low as 1.5μL, and the limit-of-detection (LOD) of DNA template was 0.7ng/μL. Among the 30 samples tested, V245V mutation was identified in 4 cases while R243Q mutation was detected in one case. Results of the hybridization assay were confirmed by DNA sequencing. This CD-chip based hybridization assay features short analysis time, simple operation and low cost, thus has the potential to serve as the tool for PKU screening.

  14. Long-term treatment of phenylketonuria with a new medical food containing large neutral amino acids

    PubMed Central

    Concolino, D; Mascaro, I; Moricca, M T; Bonapace, G; Matalon, K; Trapasso, J; Radhakrishnan, G; Ferrara, C; Matalon, R; Strisciuglio, P

    2017-01-01

    Background/Objectives: Phenylketonuria (PKU) is an autosomal recessive disease caused by deficient activity of phenylalanine hydroxylase. A low phenylalanine (Phe) diet is used to treat PKU. The diet is very restrictive, and dietary adherence tends to decrease as patients get older. Methods to improve dietary adherence and blood Phe control are continuously under investigation. Subjects/Methods: A new formula Phe-neutral amino acid (PheLNAA) has been tested in this study with the purpose of improving the compliance and lowering blood phenylalanine. The formula has been tested for nitrogen balance, and it is nutritionally complete. It is fortified with more nutritional additives that can be deficient in the PKU diet, such as B12, Biotin, DHA, Lutein and increased levels of large neutral amino acids to help lower blood Phe. The new formula has been tested on 12 patients with a loading test of 4 weeks. Results: Fifty-eight percent of patients had a significant decline in blood Phe concentration from baseline throughout the study. The PheLNAA was well tolerated with excellent compliance and without illnesses during the study. Conclusions: In conclusion, the new formula is suitable for life-long treatment of PKU, and it offers the PKU clinic a new choice for treatment. PMID:27623981

  15. Phenylketonuria and Gut Microbiota: A Controlled Study Based on Next-Generation Sequencing

    PubMed Central

    Pinheiro de Oliveira, Felipe; Mendes, Roberta Hack; Dobbler, Priscila Thiago; Mai, Volker; Pylro, Victor Salter; Waugh, Sheldon G; Vairo, Filippo; Refosco, Lilia Farret; Schwartz, Ida Vanessa Doederlein

    2016-01-01

    Phenylketonuria (PKU) is an inborn error of metabolism associated with high blood levels of phenylalanine (Phe). A Phe-restricted diet supplemented with L-amino acids is the main treatment strategy for this disease; if started early, most neurological abnormalities can be prevented. The healthy human gut contains trillions of commensal bacteria, often referred to as the gut microbiota. The composition of the gut microbiota is known to be modulated by environmental factors, including diet. In this study, we compared the gut microbiota of 8 PKU patients on Phe-restricted dietary treatment with that of 10 healthy individuals. The microbiota were characterized by 16S rRNA sequencing using the Ion Torrent™ platform. The most dominant phyla detected in both groups were Bacteroidetes and Firmicutes. PKU patients showed reduced abundance of the Clostridiaceae, Erysipelotrichaceae, and Lachnospiraceae families, Clostridiales class, Coprococcus, Dorea, Lachnospira, Odoribacter, Ruminococcus and Veillonella genera, and enrichment of Prevotella, Akkermansia, and Peptostreptococcaceae. Microbial function prediction suggested significant differences in starch/glucose and amino acid metabolism between PKU patients and controls. Together, our results suggest the presence of distinct taxonomic groups within the gut microbiome of PKU patients, which may be modulated by their plasma Phe concentration. Whether our findings represent an effect of the disease itself, or a consequence of the modified diet is unclear. PMID:27336782

  16. A comparison of phenylketonuria with attention deficit hyperactivity disorder: do markedly different aetiologies deliver common phenotypes?

    PubMed

    Stevenson, M; McNaughton, N

    2013-10-01

    Phenylketonuria (PKU) is a well-defined metabolic disorder arising from a mutation that disrupts phenylalanine metabolism and so produces a variety of neural changes indirectly. Severe cognitive impairment can be prevented by dietary treatment; however, residual symptoms may be reported. These residual symptoms appear to overlap a more prevalent childhood disorder: Attention Deficit/Hyperactivity Disorder (ADHD). However, the aetiology of ADHD is a vast contrast to PKU: it seems to arise from a complex combination of genes; and it has a substantial environmental component. We ask whether these two disorders result from two vastly different genotypes that converge on a specific core phenotype that includes similar dysfunctions of Gray's (Gray, 1982) Behavioural Inhibition System (BIS), coupled with other disorder-specific dysfunctions. If so, we believe comparison of the commonalities will allow greater understanding of the neuropsychology of both disorders. We review in detail the aetiology, treatment, neural pathology, cognitive deficits and electrophysiological abnormalities of PKU; and compare this with selected directly matching aspects of ADHD. The biochemical and neural pathologies of PKU and ADHD are quite distinct in their causes and detail; but they result in the disorder in the brain of large amino acid levels, dopamine and white matter that are very similar and could explain the overlap of symptoms within and between the PKU and ADHD spectra. The common deficits affect visual function, motor function, attention, working memory, planning, and inhibition. For each of PKU and ADHD separately, a subset of deficits has been attributed to a primary dysfunction of behavioural inhibition. In the case of ADHD (excluding the inattentive subtype) this has been proposed to involve a specific failure of the BIS; and we suggest that this is also true of PKU. This accounts for a substantial proportion of the parallels in the superficial symptoms of both disorders and

  17. Splice, insertion-deletion and nonsense mutations that perturb the phenylalanine hydroxylase transcript cause phenylketonuria in India.

    PubMed

    Bashyam, Murali D; Chaudhary, Ajay K; Kiran, Manjari; Nagarajaram, Hampapathalu A; Devi, Radha Rama; Ranganath, Prajnya; Dalal, Ashwin; Bashyam, Leena; Gupta, Neerja; Kabra, Madhulika; Muranjan, Mamta; Puri, Ratna D; Verma, Ishwar C; Nampoothiri, Sheela; Kadandale, Jayarama S

    2014-03-01

    Phenylketonuria (PKU) is an autosomal recessive metabolic disorder caused by mutational inactivation of the phenylalanine hydroxylase (PAH) gene. Missense mutations are the most common PAH mutation type detected in PKU patients worldwide. We performed PAH mutation analysis in 27 suspected Indian PKU families (including 7 from our previous study) followed by structure and function analysis of specific missense and splice/insertion-deletion/nonsense mutations, respectively. Of the 27 families, disease-causing mutations were detected in 25. A total of 20 different mutations were identified of which 7 "unique" mutations accounted for 13 of 25 mutation positive families. The unique mutations detected exclusively in Indian PKU patients included three recurrent mutations detected in three families each. The 20 mutations included only 5 missense mutations in addition to 5 splice, 4 each nonsense and insertion-deletion mutations, a silent variant in coding region and a 3'UTR mutation. One deletion and two nonsense mutations were characterized to confirm significant reduction in mutant transcript levels possibly through activation of nonsense mediated decay. All missense mutations affected conserved amino acid residues and sequence and structure analysis suggested significant perturbations in the enzyme activity of respective mutant proteins. This is probably the first report of identification of a significantly low proportion of missense PAH mutations from PKU families and together with the presence of a high proportion of splice, insertion-deletion, and nonsense mutations, points to a unique PAH mutation profile in Indian PKU patients.

  18. Growth and body composition in children with classical phenylketonuria: results in 34 patients and review of the literature.

    PubMed

    Huemer, M; Huemer, C; Möslinger, D; Huter, D; Stöckler-Ipsiroglu, S

    2007-10-01

    Treatment of phenylketonuria (PKU, OMIM 261600) means a diet restricted in natural protein and supplemented with phenylalanine (Phe)-free L-amino acid mixtures. Growth impairment has been described even in patients with a total protein intake at or above the recommended dietary allowance (RDA). In the present study, growth and body composition (fat-free mass (FFM) and fat) were recorded over 12 months in 34 treated PKU patients (mean age 8.7 years at baseline). Measurements were compared with those of healthy peers and with general population standard (Z-) scores calculated using the LMS method. In 28 PKU patients, data on birth weight and birth length were available and related to measurements at baseline of the study. Mean total protein intake in PKU patients was 124% (range 77-193%) of the RDA (DACH 2000). No significant differences in growth and body composition were present between PKU patients and healthy populations either at birth or during the study period. The significant correlation of FFM (representing muscle mass) with intake of natural protein--rather than total protein--indicates that the enhancement of tolerance to natural protein may be of value in PKU patients.

  19. Lower n-3 long-chain polyunsaturated fatty acid values in patients with phenylketonuria: a systematic review and meta-analysis.

    PubMed

    Lohner, Szimonetta; Fekete, Katalin; Decsi, Tamás

    2013-07-01

    The mainstream of phenylketonuria (PKU) management is lifelong restriction of protein intake; however, this dietary restriction may be accompanied by insufficient dietary intake of long-chain polyunsaturated fatty acids (LCPUFA). The objective of this review was to assess whether significant depletion of LCPUFA can be detected in PKU patients on low-protein diet and whether LCPUFA supplementation is an effective way to increase the availability of LCPUFA in PKU patients. The method included structured search strategy on Ovid MEDLINE, Scopus, LILACS, and the Cochrane Library CENTRAL databases, with formal inclusion/exclusion criteria, data extraction procedure, and meta-analysis. We evaluated 9 case-control studies and 6 randomized controlled trials, dated from the inception of the databases to 2012. The meta-analysis of the case-control studies showed significantly lower values of both eicosapentaenoic acid and docosahexaenoic acid (DHA) in all biomarkers investigated and that of arachidonic acid in total plasma lipids in PKU patients as compared with healthy controls. There were sufficient data to demonstrate that dietary DHA supplementation of patients with PKU significantly increases the contribution of DHA to total plasma lipids. In summary, suboptimal LCPUFA status, especially that of n-3 LCPUFA, can be detected in PKU patients. Supplementing DHA to the diet of PKU patients may improve their LCPUFA status; however, further research is needed to determine the optimal supplementation dosage and to establish beneficial functional outcomes.

  20. Behaviour and school achievement in patients with early and continuously treated phenylketonuria.

    PubMed

    Stemerdink, B A; Kalverboer, A F; van der Meere, J J; van der Molen, M W; Huisman, J; de Jong, L W; Slijper, F M; Verkerk, P H; van Spronsen, F J

    2000-09-01

    Thirty patients with early and continuously treated phenylketonuria (PKU) between 8 and 20 years of age were compared with 30 controls, matched individually for age, sex, and educational level of both parents, on behaviour rating scales for parents and teachers as well as a school achievement scale. PKU patients, as a group, demonstrated more problems in task-oriented behaviour and average academic performance than did matched controls. Interestingly, whereas male PKU patients were rated significantly lower on introversion by their teachers, female patients were rated significantly higher on introversion and lower on extraversion than matched controls. This sex difference was also reflected in the relationship between measures of dietary control and the behaviour clusters, suggesting that male and female patients respond differently to elevated Phe levels or the stress associated with PKU. The teacher rating on average academic performance of the PKU patients was associated with recent level of dietary control, which suggests that it might be improved by more strict adherence to the diet. In addition, academic performance correlated negatively with the behaviour cluster negative task orientation. Further studies are recommended to obtain a more complete evaluation of this relationship and to replicate the current findings on larger samples. Over the years a number of studies have examined behaviour and school achievement in patients with early treated phenylketonuria (PKU; McKusick 261600). In general, these studies have found that despite early treatment with a phenylalanine (Phe)-restricted diet, PKU patients demonstrate more behavioural and school problems than do healthy controls. The behaviour problems include both internalizing symptoms (e.g. solitary, unresponsive, anxious, depressed mood: Pietz et al 1997; Smith et al 1988; Weglage et al 1992) and externalizing symptoms (e.g. hyperactive, talkative, impulsive, restless: Hendrikx et al 1994; Kalverboer et al

  1. The Behavioral Consequence of Phenylketonuria in Mice Depends on the Genetic Background.

    PubMed

    Bruinenberg, Vibeke M; van der Goot, Els; van Vliet, Danique; de Groot, Martijn J; Mazzola, Priscila N; Heiner-Fokkema, M Rebecca; van Faassen, Martijn; van Spronsen, Francjan J; van der Zee, Eddy A

    2016-01-01

    To unravel the role of gene mutations in the healthy and the diseased state, countless studies have tried to link genotype with phenotype. However, over the years, it became clear that the strain of mice can influence these results. Nevertheless, identical gene mutations in different strains are often still considered equals. An example of this, is the research done in phenylketonuria (PKU), an inheritable metabolic disorder. In this field, a PKU mouse model (either on a BTBR or C57Bl/6 background) is often used to examine underlying mechanisms of the disease and/or new treatment strategies. Both strains have a point mutation in the gene coding for the enzyme phenylalanine hydroxylase which causes toxic concentrations of the amino acid phenylalanine in blood and brain, as found in PKU patients. Although the mutation is identical and therefore assumed to equally affect physiology and behavior in both strains, no studies directly compared the two genetic backgrounds to test this assumption. Therefore, this study compared the BTBR and C57Bl/6 wild-type and PKU mice on PKU-relevant amino acid- and neurotransmitter-levels and at a behavioral level. The behavioral paradigms were selected from previous literature on the PKU mouse model and address four domains, namely (1) activity levels, (2) motor performance, (3) anxiety and/or depression-like behavior, and (4) learning and memory. The results of this study showed comparable biochemical changes in phenylalanine and neurotransmitter concentrations. In contrast, clear differences in behavioral outcome between the strains in all four above-mentioned domains were found, most notably in the learning and memory domain. The outcome in this domain seem to be primarily due to factors inherent to the genetic background of the mouse and much less by differences in PKU-specific biochemical parameters in blood and brain. The difference in behavioral outcome between PKU of both strains emphasizes that the consequence of the PAH

  2. The Behavioral Consequence of Phenylketonuria in Mice Depends on the Genetic Background

    PubMed Central

    Bruinenberg, Vibeke M.; van der Goot, Els; van Vliet, Danique; de Groot, Martijn J.; Mazzola, Priscila N.; Heiner-Fokkema, M. Rebecca; van Faassen, Martijn; van Spronsen, Francjan J.; van der Zee, Eddy A.

    2016-01-01

    To unravel the role of gene mutations in the healthy and the diseased state, countless studies have tried to link genotype with phenotype. However, over the years, it became clear that the strain of mice can influence these results. Nevertheless, identical gene mutations in different strains are often still considered equals. An example of this, is the research done in phenylketonuria (PKU), an inheritable metabolic disorder. In this field, a PKU mouse model (either on a BTBR or C57Bl/6 background) is often used to examine underlying mechanisms of the disease and/or new treatment strategies. Both strains have a point mutation in the gene coding for the enzyme phenylalanine hydroxylase which causes toxic concentrations of the amino acid phenylalanine in blood and brain, as found in PKU patients. Although the mutation is identical and therefore assumed to equally affect physiology and behavior in both strains, no studies directly compared the two genetic backgrounds to test this assumption. Therefore, this study compared the BTBR and C57Bl/6 wild-type and PKU mice on PKU-relevant amino acid- and neurotransmitter-levels and at a behavioral level. The behavioral paradigms were selected from previous literature on the PKU mouse model and address four domains, namely (1) activity levels, (2) motor performance, (3) anxiety and/or depression-like behavior, and (4) learning and memory. The results of this study showed comparable biochemical changes in phenylalanine and neurotransmitter concentrations. In contrast, clear differences in behavioral outcome between the strains in all four above-mentioned domains were found, most notably in the learning and memory domain. The outcome in this domain seem to be primarily due to factors inherent to the genetic background of the mouse and much less by differences in PKU-specific biochemical parameters in blood and brain. The difference in behavioral outcome between PKU of both strains emphasizes that the consequence of the PAH

  3. Mutation spectrum of phenylketonuria in Syrian population: genotype-phenotype correlation.

    PubMed

    Murad, Hossam; Dabboul, Amir; Moassas, Faten; Alasmar, Diana; Al-Achkar, Walid

    2013-10-10

    Characterization of the molecular basis of phenylketonuria (PKU) in Syria has been accomplished through the analysis of 78 unrelated chromosomes from 39 Syrian patients with PKU. Phenylalanine hydroxylase (PAH) gene mutations have been analyzed by using molecular detection methods based on the restriction fragment length polymorphism (RFLP), artificial constructed restriction sites (ACRS) PCR and direct DNA sequencing. 56.4% of the patients had cPKU. A mutation detection rate of 79.49% was achieved and sixteen different mutations were found: missense 56.25%, splice site 37.5%, and frameshift 6.25%. The predominant mutation in this population sample was p.R261Q G>A, p.F55>Lfs and p.R243Q G>A. No mutation in six PKU patients was observed. In 57.9% of patient genotypes, the metabolic phenotype could be predicted. The identification of the mutations in the PAH gene and the genotype-phenotype correlation should facilitate the evaluation of metabolic phenotypes, diagnosis, implementation of optimal dietary therapy, and determination of prognosis in the patients and genetic counseling for the patient's relatives.

  4. Molecular characterisation of phenylketonuria in a Chinese mainland population using next-generation sequencing.

    PubMed

    Li, Nana; Jia, Haitao; Liu, Zhen; Tao, Jing; Chen, Song; Li, Xiaohong; Deng, Ying; Jin, Xi; Song, Jiaping; Zhang, Liangtao; Liang, Yu; Wang, Wei; Zhu, Jun

    2015-10-27

    Phenylketonuria (PKU) is an inherited autosomal recessive disorder of phenylalanine metabolism, mainly caused by a deficiency of phenylalanine hydroxylase (PAH). The incidence of various PAH mutations differs among race and ethnicity. Here we report a spectrum of PAH mutations complied from 796 PKU patients from mainland China. The all 13 exons and adjacent intronic regions of the PAH gene were determined by next-generation sequencing. We identified 194 different mutations, of which 41 are not reported before. Several mutations reoccurred with high frequency including p.R243Q, p.EX6-96A > G, p.V399V, p.R241C, p.R111*, p.Y356*, p.R413P, and IVS4-1G > A. 76.33% of mutations were localized in exons 3, 6, 7, 11, 12. We further compared the frequency of each mutation between populations in northern and southern China, and found significant differences in 19 mutations. Furthermore, we identified 101 mutations that are not reported before in Chinese population, our study thus broadens the mutational spectrum of Chinese PKU patients. Additionally, 41 novel mutations will expand and improve PAH mutation database. Finally, our study offers proof that NGS is effective, reduces screening times and costs, and facilitates the provision of appropriate genetic counseling for PKU patients.

  5. Molecular characterisation of phenylketonuria in a Chinese mainland population using next-generation sequencing

    PubMed Central

    Li, Nana; Jia, Haitao; Liu, Zhen; Tao, Jing; Chen, Song; Li, Xiaohong; Deng, Ying; Jin, Xi; Song, Jiaping; Zhang, Liangtao; Liang, Yu; Wang, Wei; Zhu, Jun

    2015-01-01

    Phenylketonuria (PKU) is an inherited autosomal recessive disorder of phenylalanine metabolism, mainly caused by a deficiency of phenylalanine hydroxylase (PAH). The incidence of various PAH mutations differs among race and ethnicity. Here we report a spectrum of PAH mutations complied from 796 PKU patients from mainland China. The all 13 exons and adjacent intronic regions of the PAH gene were determined by next-generation sequencing. We identified 194 different mutations, of which 41 are not reported before. Several mutations reoccurred with high frequency including p.R243Q, p.EX6-96A > G, p.V399V, p.R241C, p.R111*, p.Y356*, p.R413P, and IVS4-1G > A. 76.33% of mutations were localized in exons 3, 6, 7, 11, 12. We further compared the frequency of each mutation between populations in northern and southern China, and found significant differences in 19 mutations. Furthermore, we identified 101 mutations that are not reported before in Chinese population, our study thus broadens the mutational spectrum of Chinese PKU patients. Additionally, 41 novel mutations will expand and improve PAH mutation database. Finally, our study offers proof that NGS is effective, reduces screening times and costs, and facilitates the provision of appropriate genetic counseling for PKU patients. PMID:26503515

  6. The Impact of Phenylalanine Levels on Cognitive Outcomes in Adults With Phenylketonuria: Effects Across Tasks and Developmental Stages

    PubMed Central

    2017-01-01

    Objective: Phenylketonuria (PKU) is due to an inability to metabolize the amino acid phenylalanine (Phe), leading to its accumulation in the brain. Phe levels can be controlled following a protein-free diet, but cognitive impairments are still present. A number of questions remain to be answered related to which type of metabolic control is important, the age when it is important, the cognitive functions which are most affected and, the best tests to use to monitor cognitive health. Method: We investigated the impact of metabolic control at different ages on cognitive performance in 37 early treated adults with PKU. Results: (a) Phe variation was as associated to performance as average Phe showing that stable dietary control is as important as strict control; (b) For some tasks, current and adult Phe were stronger predictors of performance than childhood or adolescent Phe, showing the importance of a strict diet even in adulthood; and (c) The relationship between performance and Phe levels varied depending on time and cognitive domain. For some functions (sustained attention, visuomotor coordination), Phe at the time of testing was the best predictor. While for other functions (visual attention, executive functions) there was a diminishing or stable relationship across time. Conclusion: Results show the importance of selecting the right tasks to monitor outcomes across ages, but also that the impact of bio-chemical disruptions is different for different functions, at different ages. We show how inherited metabolic diseases offer us a unique vantage point to inform our understanding of brain development and functioning. PMID:28240926

  7. Depression and anxiety among parents of phenylketonuria children

    PubMed Central

    Gunduz, Mehmet; Arslan, Nur; Unal, Ozlem; Cakar, Sevim; Kuyum, Pınar; Bulbul, Selda F.

    2015-01-01

    Objective: To investigate the existence of depression and/or anxiety with underlying risk factors among parents of children with classical phenylketonuria (PKU). Methods: This cross-sectional study was conducted in the Division of Pediatric Metabolism, Ankara Children’s Hospital, Dokuz Eylul University, Kırıkkale University, and Erzurum Local Research Hospital, Turkey, between January and July 2014. Parents of 61 patients and 36 healthy controls completed the self-report questionnaires. We used Beck Depression Inventory (BDI) to assess the parental depression and State-Trait Anxiety Inventory S-T (STAI S-T) to assess parental anxiety. Results: Depression and anxiety scores were significantly higher in the case group (BDI 12.3±9.1; STAI-S: 38.2±9.6; STAI-T: 43.2±6.9) than controls (BDI: 5.4±4.1 p=0.000; STAI-S: 31.8±7.6 p=0.001; STAI-T: 37.0±7.2 p=0.000). Mothers of the patients had higher scores than the other parental groups (BDI: p=0.000, STAI-S: p=0.001 and STAI-T: p=0.000). Logistic regression analysis showed that low educational level of the parent was the only independent factor for depression (OR 9.96, 95% CI: 1.89-52.35, p=0.007) and state anxiety (OR: 6.99, 95% CI: 1.22-40.48, p=0.030) in the case group. Conclusion: A subset of parents with PKU patients have an anxiety or depressive disorder. Supportive services dealing with the parents of chronically ill children such as PKU are needed in order to reduce the level of anxiety. PMID:26492114

  8. A randomized, placebo-controlled, double-blind study of sapropterin to treat ADHD symptoms and executive function impairment in children and adults with sapropterin-responsive phenylketonuria.

    PubMed

    Burton, B; Grant, M; Feigenbaum, A; Singh, R; Hendren, R; Siriwardena, K; Phillips, J; Sanchez-Valle, A; Waisbren, S; Gillis, J; Prasad, S; Merilainen, M; Lang, W; Zhang, C; Yu, S; Stahl, S

    2015-03-01

    Symptoms of attention deficit-hyperactivity disorder (ADHD), particularly inattention, and impairments in executive functioning have been reported in early and continuously treated children, adolescents, and adults with phenylketonuria (PKU). In addition, higher blood phenylalanine (Phe) levels have been correlated with the presence of ADHD symptoms and executive functioning impairment. The placebo-controlled PKU ASCEND study evaluated the effects of sapropterin therapy on PKU-associated symptoms of ADHD and executive and global functioning in individuals who had a therapeutic blood Phe response to sapropterin therapy. The presence of ADHD inattentive symptoms and executive functioning deficits was confirmed in this large cohort of 206 children and adults with PKU, of whom 118 responded to sapropterin therapy. In the 38 individuals with sapropterin-responsive PKU and ADHD symptoms at baseline, sapropterin therapy resulted in a significant improvement in ADHD inattentive symptoms in the first 4 weeks of treatment, and improvements were maintained throughout the 26 weeks of treatment. Sapropterin was well-tolerated with a favorable safety profile. The improvements in ADHD inattentive symptoms and aspects of executive functioning in response to sapropterin therapy noted in a large cohort of individuals with PKU indicate that these symptoms are potentially reversible when blood Phe levels are reduced.

  9. A Specific Nutrient Combination Attenuates the Reduced Expression of PSD-95 in the Proximal Dendrites of Hippocampal Cell Body Layers in a Mouse Model of Phenylketonuria.

    PubMed

    Bruinenberg, Vibeke M; van Vliet, Danique; Attali, Amos; de Wilde, Martijn C; Kuhn, Mirjam; van Spronsen, Francjan J; van der Zee, Eddy A

    2016-03-26

    The inherited metabolic disease phenylketonuria (PKU) is characterized by increased concentrations of phenylalanine in the blood and brain, and as a consequence neurotransmitter metabolism, white matter, and synapse functioning are affected. A specific nutrient combination (SNC) has been shown to improve synapse formation, morphology and function. This could become an interesting new nutritional approach for PKU. To assess whether treatment with SNC can affect synapses, we treated PKU mice with SNC or an isocaloric control diet and wild-type (WT) mice with an isocaloric control for 12 weeks, starting at postnatal day 31. Immunostaining for post-synaptic density protein 95 (PSD-95), a post-synaptic density marker, was carried out in the hippocampus, striatum and prefrontal cortex. Compared to WT mice on normal chow without SNC, PKU mice on the isocaloric control showed a significant reduction in PSD-95 expression in the hippocampus, specifically in the granular cell layer of the dentate gyrus, with a similar trend seen in the cornus ammonis 1 (CA1) and cornus ammonis 3 (CA3) pyramidal cell layer. No differences were found in the striatum or prefrontal cortex. PKU mice on a diet supplemented with SNC showed improved expression of PSD-95 in the hippocampus. This study gives the first indication that SNC supplementation has a positive effect on hippocampal synaptic deficits in PKU mice.

  10. A Specific Nutrient Combination Attenuates the Reduced Expression of PSD-95 in the Proximal Dendrites of Hippocampal Cell Body Layers in a Mouse Model of Phenylketonuria

    PubMed Central

    Bruinenberg, Vibeke M.; van Vliet, Danique; Attali, Amos; de Wilde, Martijn C.; Kuhn, Mirjam; van Spronsen, Francjan J.; van der Zee, Eddy A.

    2016-01-01

    The inherited metabolic disease phenylketonuria (PKU) is characterized by increased concentrations of phenylalanine in the blood and brain, and as a consequence neurotransmitter metabolism, white matter, and synapse functioning are affected. A specific nutrient combination (SNC) has been shown to improve synapse formation, morphology and function. This could become an interesting new nutritional approach for PKU. To assess whether treatment with SNC can affect synapses, we treated PKU mice with SNC or an isocaloric control diet and wild-type (WT) mice with an isocaloric control for 12 weeks, starting at postnatal day 31. Immunostaining for post-synaptic density protein 95 (PSD-95), a post-synaptic density marker, was carried out in the hippocampus, striatum and prefrontal cortex. Compared to WT mice on normal chow without SNC, PKU mice on the isocaloric control showed a significant reduction in PSD-95 expression in the hippocampus, specifically in the granular cell layer of the dentate gyrus, with a similar trend seen in the cornus ammonis 1 (CA1) and cornus ammonis 3 (CA3) pyramidal cell layer. No differences were found in the striatum or prefrontal cortex. PKU mice on a diet supplemented with SNC showed improved expression of PSD-95 in the hippocampus. This study gives the first indication that SNC supplementation has a positive effect on hippocampal synaptic deficits in PKU mice. PMID:27102170

  11. [Diagnostics and treatment of phenylketonuria].

    PubMed

    Bayat, Allan; Møller, Libeth Birk; Lund, Allan Meldgaard

    2015-02-16

    Primary phenylalanine hydroxylase deficiency, also known as phenylketonuria, results in accumulation of phenylalanine in the blood. Early identification and treatment prevents the majority of clinical sequelae to the disease, but psychological and neurodevelopmental problems can occur in some patients. This article reviews the symptoms, diagnosis, classification and strategies of treatment and management of phenylketonuria. Finally we review new pharmacological and non-pharmaco-logical means of treatment.

  12. [Early diagnosis of phenylketonuria. Follow up of 2 cases].

    PubMed

    Raimann, E; Cornejo, V; Perales, C G; Barros, T; Moraga, M; Colombo, M

    1992-09-01

    A screening program for the early diagnosis of phenylketonuria was initiated 24 months ago in the Servicio de Salud Metropolitano Central. Since then, 2 cases with phenylketonuria have been early diagnosed. These patients started their nutritional treatment, consisting of a phenylalanine restricted diet at 14 and 17 days of age. The children are submitted to periodic medical, anthropometric, neurologic, biochemical and psychometric analysis. With a strict control they maintain phenylalanine plasma levels between 2 and 6 mg%. Both patients have a normal psychomotor development at 4.5 and 6.5 months of age and an anthropometric development at p50 of NCHS.

  13. Energy recovery transport design for PKU FEL

    SciTech Connect

    Guimei Wang; Yu-Chiu Chao; KUI Zhao; Xiangyang Lu; Jiejia Zhuang; Chuyu Liu; Zhenchao Liu; Jiaer Chen

    2007-06-25

    A free-electron laser based on superconducting linac is under construction in Peking University(PKU). To increase FEL output power, energy recovery is chosen as one of the most potential and popular way. The design of beam transport system for energy recovery is presented, which is suitable for Peking University construction area. Especially, a chicane structure is chosen to change path length at +/-18 degree and R56 in the arc is adjusted for fully bunch compression.

  14. Reduced availability of brain amines during critical phases of postnatal development in a genetic mouse model of cognitive delay.

    PubMed

    Pascucci, Tiziana; Andolina, Diego; Ventura, Rossella; Puglisi-Allegra, Stefano; Cabib, Simona

    2008-06-27

    Serotonin (5-HT), dopamine (DA) and noradrenaline (NE) play important roles in brain postnatal maturation. Therefore, deficits in brain availability of biogenic amines during critical developmental phases might underlie neurodevelopmental disturbances associated with cognitive impairment. To test this hypothesis we evaluated brain availability of 5-HT, DA and NE, of their immediate precursors 5-hydroxytryptophan and 3,4-dihydroxy-l-phenylalanine, and of large neutral amino acids phenylalanine, tyrosine and tryptophan, in developing PahEnu2 mice, the genetic model of Phenylketonuria (PKU) a cause of severe cognitive delay. We found deficits of brain amine levels in PKU pups between day 14 and 35 of postnatal life, when pups of the healthy background showed developmental peak increases of amines and precursors. 5-HT deficits were most pronounced, were unrelated with brain availability of the amino acid precursor tryptophan, but overlapped with peak brain phenylalanine concentrations and reduced availability of 5-HT direct precursor 5-hydroxytryptophan. These results identify a critical window of brain amine availability susceptible to disturbances in a genetic mouse model of pathological neurodevelopment and suggest a mechanism of interference with brain aminergic synthesis in PKU and non-PKU hyperphenylalaninemia.

  15. Outcomes of referrals to Child Protective Services for medical neglect in patients with phenylketonuria: Experiences at a single treatment center.

    PubMed

    Bannick, Allison A; Laufman, Jason D; Edwards, Heidi L; Ventimiglia, June; Feldman, Gerald L

    2015-08-01

    Phenylketonuria (PKU) results in an accumulation of phenylalanine (phe) in the blood which can lead to multiple health consequences in affected individuals. Treatment for PKU is available; however adherence to medical management recommendations can be difficult. When recommendations are not followed and the health of a child is at risk, one intervention that may be necessary is a referral for medical neglect to the local child protective services (CPS) agency. This study summarizes the cases that were referred from our metabolic clinic at the Children's Hospital of Michigan to CPS, and the outcomes of that intervention. CPS referrals helped to improve adherence to medical management recommendations in the majority of cases, including a lower blood phe level for the child; however, at times that improvement did not occur until after a second referral and/or the child's temporary removal from the home.

  16. Variability in phenylalanine control predicts IQ and executive abilities in children with phenylketonuria.

    PubMed

    Hood, Anna; Grange, Dorothy K; Christ, Shawn E; Steiner, Robert; White, Desirée A

    2014-04-01

    A number of studies have revealed significant relationships between cognitive performance and average phenylalanine (Phe) levels in children with phenylketonuria (PKU), but only a few studies have been conducted to examine the relationships between cognitive performance and variability (fluctuations) in Phe levels. In the current study, we examined a variety of indices of Phe control to determine which index best predicted IQ and executive abilities in 47 school-age children with early- and continuously-treated PKU. Indices of Phe control were mean Phe, the index of dietary control, change in Phe with age, and several indices of variability in Phe (standard deviation, standard error of estimate, and percentage of spikes). These indices were computed over the lifetime and during 3 developmental epochs (<5, 5.0-9.9, and ≥10 years of age). Results indicated that variability in Phe was generally a stronger predictor of cognitive performance than other indices of Phe control. In addition, executive performance was better predicted by variability in Phe during older than younger developmental epochs. These results indicate that variability in Phe should be carefully controlled to maximize cognitive outcomes and that Phe control should not be liberalized as children with PKU age.

  17. Fluctuations in phenylalanine concentrations in phenylketonuria: a review of possible relationships with outcomes.

    PubMed

    Cleary, Maureen; Trefz, Friedrich; Muntau, Ania C; Feillet, François; van Spronsen, Francjan J; Burlina, Alberto; Bélanger-Quintana, Amaya; Giżewska, Maria; Gasteyger, Christoph; Bettiol, Esther; Blau, Nenad; MacDonald, Anita

    2013-12-01

    Fluctuations in blood phenylalanine concentrations may be an important determinant of intellectual outcome in patients with early and continuously treated phenylketonuria (PKU). This review evaluates the studies on phenylalanine fluctuations, factors affecting fluctuations, and if stabilizing phenylalanine concentrations affects outcomes, particularly neurocognitive outcome. Electronic literature searches of Embase and PubMed were performed for English-language publications, and the bibliographies of identified publications were also searched. In patients with PKU, phenylalanine concentrations are highest in the morning. Factors that can affect phenylalanine fluctuations include age, diet, timing and dosing of protein substitute and energy intake, dietary adherence, phenylalanine hydroxylase genotype, changes in dietary phenylalanine intake and protein metabolism, illness, and growth rate. Even distribution of phenylalanine-free protein substitute intake throughout 24h may reduce blood phenylalanine fluctuations. Patients responsive to and treated with 6R-tetrahydrobiopterin seem to have less fluctuation in their blood phenylalanine concentrations than controls. An increase in blood phenylalanine concentration may result in increased brain and cerebrospinal fluid phenylalanine concentrations within hours. Although some evidence suggests that stabilization of blood phenylalanine concentrations may have benefits in patients with PKU, more studies are needed to distinguish the effects of blood phenylalanine fluctuations from those of poor metabolic control.

  18. Child and Parent Attributions in Chronic Pediatric Conditions: Phenylketonuria (PKU) as an Exemplar

    ERIC Educational Resources Information Center

    Antshel, Kevin M.; Brewster, Scott; Waisbren, Susan E.

    2004-01-01

    Background: Attribution theory, self-regulation, self-handicapping and sick role theories all suggest that children with chronic disease may be held to different standards. This study assesses child and parent attributions in pediatric chronic health conditions and addresses how attributional style may be related to treatment adherence. Methods:…

  19. Institutionalizing China's Research University through Academic Mobility: The Case of PKU

    ERIC Educational Resources Information Center

    Xiaoguang, Shi

    2015-01-01

    Academic mobility is becoming a tread in academic life and a professional development globally, regionally and nationally. This article makes use of a case university--Peking University (PKU)--as an analytical approach to explore how and why academic mobility can happen in China's research universities. The author first presents an overview of the…

  20. Glycomacropeptide, a low-phenylalanine protein isolated from cheese whey, supports growth and attenuates metabolic stress in the murine model of phenylketonuria

    PubMed Central

    Solverson, Patrick; Murali, Sangita G.; Brinkman, Adam S.; Nelson, David W.; Clayton, Murray K.; Yen, Chi-Liang Eric

    2012-01-01

    Phenylketonuria (PKU) is caused by a mutation in the phenylalanine (phe) hydroxylase gene and requires a low-phe diet plus amino acid (AA) formula to prevent cognitive impairment. Glycomacropeptide (GMP) contains minimal phe and provides a palatable alternative to AA formula. Our objective was to compare growth, body composition, and energy balance in Pahenu2 (PKU) and wild-type mice fed low-phe GMP, low-phe AA, or high-phe casein diets from 3–23 wk of age. The 2 × 2 × 3 design included main effects of genotype, sex, and diet. Fat and lean mass were assessed by dual-energy X-ray absorptiometry, and acute energy balance was assessed by indirect calorimetry. PKU mice showed growth and lean mass similar to wild-type littermates fed the GMP or AA diets; however, they exhibited a 3–15% increase in energy expenditure, as reflected in oxygen consumption, and a 3–30% increase in food intake. The GMP diet significantly reduced energy expenditure, food intake, and plasma phe concentration in PKU mice compared with the casein diet. The high-phe casein diet or the low-phe AA diet induced metabolic stress in PKU mice, as reflected in increased energy expenditure and intake of food and water, increased renal and spleen mass, and elevated plasma cytokine concentrations consistent with systemic inflammation. The low-phe GMP diet significantly attenuated these adverse effects. Moreover, total fat mass, %body fat, and the respiratory exchange ratio (CO2 produced/O2 consumed) were significantly lower in PKU mice fed GMP compared with AA diets. In summary, GMP provides a physiological source of low-phe dietary protein that promotes growth and attenuates the metabolic stress induced by a high-phe casein or low-phe AA diet in PKU mice. PMID:22297302

  1. Glycomacropeptide, a low-phenylalanine protein isolated from cheese whey, supports growth and attenuates metabolic stress in the murine model of phenylketonuria.

    PubMed

    Solverson, Patrick; Murali, Sangita G; Brinkman, Adam S; Nelson, David W; Clayton, Murray K; Yen, Chi-Liang Eric; Ney, Denise M

    2012-04-01

    Phenylketonuria (PKU) is caused by a mutation in the phenylalanine (phe) hydroxylase gene and requires a low-phe diet plus amino acid (AA) formula to prevent cognitive impairment. Glycomacropeptide (GMP) contains minimal phe and provides a palatable alternative to AA formula. Our objective was to compare growth, body composition, and energy balance in Pah(enu2) (PKU) and wild-type mice fed low-phe GMP, low-phe AA, or high-phe casein diets from 3-23 wk of age. The 2 × 2 × 3 design included main effects of genotype, sex, and diet. Fat and lean mass were assessed by dual-energy X-ray absorptiometry, and acute energy balance was assessed by indirect calorimetry. PKU mice showed growth and lean mass similar to wild-type littermates fed the GMP or AA diets; however, they exhibited a 3-15% increase in energy expenditure, as reflected in oxygen consumption, and a 3-30% increase in food intake. The GMP diet significantly reduced energy expenditure, food intake, and plasma phe concentration in PKU mice compared with the casein diet. The high-phe casein diet or the low-phe AA diet induced metabolic stress in PKU mice, as reflected in increased energy expenditure and intake of food and water, increased renal and spleen mass, and elevated plasma cytokine concentrations consistent with systemic inflammation. The low-phe GMP diet significantly attenuated these adverse effects. Moreover, total fat mass, %body fat, and the respiratory exchange ratio (CO(2) produced/O(2) consumed) were significantly lower in PKU mice fed GMP compared with AA diets. In summary, GMP provides a physiological source of low-phe dietary protein that promotes growth and attenuates the metabolic stress induced by a high-phe casein or low-phe AA diet in PKU mice.

  2. Molecular epidemiology, genotype-phenotype correlation and BH4 responsiveness in Spanish patients with phenylketonuria.

    PubMed

    Aldámiz-Echevarría, Luis; Llarena, Marta; Bueno, María A; Dalmau, Jaime; Vitoria, Isidro; Fernández-Marmiesse, Ana; Andrade, Fernando; Blasco, Javier; Alcalde, Carlos; Gil, David; García, María C; González-Lamuño, Domingo; Ruiz, Mónica; Ruiz, María A; Peña-Quintana, Luis; González, David; Sánchez-Valverde, Felix; Desviat, Lourdes R; Pérez, Belen; Couce, María L

    2016-08-01

    Phenylketonuria (PKU), the most common inborn error of amino acid metabolism, is caused by mutations in the phenylalanine-4-hydroxylase (PAH) gene. This study aimed to assess the genotype-phenotype correlation in the PKU Spanish population and the usefulness in establishing genotype-based predictions of BH4 responsiveness in our population. It involved the molecular characterization of 411 Spanish PKU patients: mild hyperphenylalaninemia non-treated (mild HPA-NT) (34%), mild HPA (8.8%), mild-moderate (20.7%) and classic (36.5%) PKU. BH4 responsiveness was evaluated using a 6R-BH4 loading test. We assessed genotype-phenotype associations and genotype-BH4 responsiveness in our population according to literature and classification of the mutations. The mutational spectrum analysis showed 116 distinct mutations, most missense (70.7%) and located in the catalytic domain (62.9%). The most prevalent mutations were c.1066-11G>A (9.7%), p.Val388Met (6.6%) and p.Arg261Gln (6.3%). Three novel mutations (c.61-13del9, p.Ile283Val and p.Gly148Val) were reported. Although good genotype-phenotype correlation was observed, there was no exact correlation for some genotypes. Among the patients monitored for the 6R-BH4 loading test: 102 were responders (87, carried either one or two BH4-responsive alleles) and 194 non-responders (50, had two non-responsive mutations). More discrepancies were observed in non-responders. Our data reveal a great genetic heterogeneity in our population. Genotype is quite a good predictor of phenotype and BH4 responsiveness, which is relevant for patient management, treatment and follow-up.

  3. Shape analysis of corpus callosum in phenylketonuria using a new 3D correspondence algorithm

    NASA Astrophysics Data System (ADS)

    He, Qing; Christ, Shawn E.; Karsch, Kevin; Peck, Dawn; Duan, Ye

    2010-03-01

    Statistical shape analysis of brain structures has gained increasing interest from neuroimaging community because it can precisely locate shape differences between healthy and pathological structures. The most difficult and crucial problem is establishing shape correspondence among individual 3D shapes. This paper proposes a new algorithm for 3D shape correspondence. A set of landmarks are sampled on a template shape, and initial correspondence is established between the template and the target shape based on the similarity of locations and normal directions. The landmarks on the target are then refined by iterative thin plate spline. The algorithm is simple and fast, and no spherical mapping is needed. We apply our method to the statistical shape analysis of the corpus callosum (CC) in phenylketonuria (PKU), and significant local shape differences between the patients and the controls are found in the most anterior and posterior aspects of the corpus callosum.

  4. Tetrahydrobiopterin, its mode of action on phenylalanine hydroxylase, and importance of genotypes for pharmacological therapy of phenylketonuria.

    PubMed

    Heintz, Caroline; Cotton, Richard G H; Blau, Nenad

    2013-07-01

    In about 20%-30% of phenylketonuria (PKU) patients (all phenotypes of PAH deficiency), Phe levels may be controlled through phenylalanine hydroxylase cofactor tetrahydrobiopterin therapy. These patients can be diagnosed by an oral tetrahydrobiopterin challenge and are characterized by mutations coding for proteins with substantial residual PAH activity. They can be treated with a commercially available synthetic form of tetrahydrobiopterin, either as a monotherapy or as adjunct to the diet. This review article summarizes molecular and metabolic bases of PKU and the importance of the tetrahydrobiopterin loading test used for PKU patients. On the basis of in vitro residual PAH activity, more than 1,200 genotypes from patients challenged with tetrahydrobiopterin were categorized as predictive for tetrahydrobiopterin responsiveness or non-responsiveness and correlated with the loading test, phenotype, and residual in vitro PAH activity. The coexpression of two distinct PAH mutant alleles revealed possible dominance effects (positive or negative) by one of the mutations on residual activity as result of interallelic complementation. The treatment of the transfected cells with tetrahydrobiopterin showed an increase in residual PAH activity with several mutations coexpressed.

  5. The Enduring Behavioral Changes in Rats with Experimental Phenylketonuria*

    PubMed Central

    Andersen, Arnold E.; Rowe, Vernon; Guroff, Gordon

    1974-01-01

    The biochemical features of phenylketonuria have been reproduced in developing rat pups by administering to them a combination of p-chloro-DL-phenylalanine plus L-phenylalanine for the first 21 days after birth. During the treatment period, the experimental animals show delayed eye opening and decreased brain weight compared with controls given saline. Neuropathological examination of developing animals reveals deficient myelination and some inhibition of cerebellar maturation. When tested as adults, after a long recovery period, animals with phenylketonuria are hyperactive in activity wheels. Adult rats are deficient in reversing a position choice and demonstrate impaired performance in a Y-maze. Rats treated with p-chloro-DL-phenylalanine plus L-phenylalanine during the vulnerable period of rapid brain development thus have enduring behavioral changes that persist throughout life. Images PMID:4521053

  6. Challenges of Implementation of the National Phenylketonuria Screening Program in Iran: A Qualitative Study

    PubMed Central

    Heidari, Alireza; Arab, Mohammad; Etemad, Koorosh; Damari, Behzad; Kabir, Mohammad Javad

    2016-01-01

    Introduction Newborn screening (NBS) is a public health measure aimed at identification of early cases, management of afflicted infants, and making efforts to reduce the morbidity and mortality among newborns. All countries may face challenges in implementation of screening programs. The present study aimed to determine the challenges of implementation of the National Phenylketonuria (PKU) Screening Program in Iran. Methods In this qualitative study, 38 health policymakers, managers, and PKU experts in Iran were purposively selected as the respondents in 2015. The semi-structured interview was used for collecting the required data and information. After transcription of interviews, their content was analyzed using framework analysis. Results The results were categorized into five main themes and 22 subthemes. The main themes extracted from data were management challenges, diagnosis challenges, treatment challenges, care challenges, and patients’ family problems. Each category consisted of several subthemes. Conclusion Considering the challenges of implementing this program, some measures such as increased stability of managers in the health system, greater interaction of the Ministry of Health and Medical Education with the heath stakeholders, improving the level of parents’ awareness, the use of efficient information systems, support and legal backing for requiring parents who refuse newborn screening for various reasons, and appropriate insurance coverage seem necessary to be taken. PMID:27957302

  7. Adjusting diet with sapropterin in phenylketonuria: what factors should be considered?

    PubMed

    MacDonald, Anita; Ahring, Kirsten; Dokoupil, Katharina; Gokmen-Ozel, Hulya; Lammardo, Anna Maria; Motzfeldt, Kristina; Robert, Martine; Rocha, Júlio César; van Rijn, Margreet; Bélanger-Quintana, Amaya

    2011-07-01

    The usual treatment for phenylketonuria (PKU) is a phenylalanine-restricted diet. Following this diet is challenging, and long-term adherence (and hence metabolic control) is commonly poor. Patients with PKU (usually, but not exclusively, with a relatively mild form of the disorder) who are responsive to treatment with pharmacological doses of tetrahydrobiopterin (BH4) have either lower concentrations of blood phenylalanine or improved dietary phenylalanine tolerance. The availability of a registered formulation of BH4 (sapropterin dihydrochloride, Kuvan®) has raised many practical issues and new questions in the dietary management of these patients. Initially, patients and carers must understand clearly the likely benefits (and limitations) of sapropterin therapy. A minority of patients who respond to sapropterin are able to discontinue the phenylalanine-restricted diet completely, while others are able to relax the diet to some extent. Care is required when altering the phenylalanine-restricted diet, as this may have unintended nutritional consequences and must be undertaken with caution. New clinical protocols are required for managing any dietary change while maintaining control of blood phenylalanine, ensuring adequate nutrition and preventing nutritional deficiencies, overweight or obesity. An accurate initial evaluation of pre-sapropterin phenylalanine tolerance is essential, and the desired outcome from treatment with sapropterin (e.g. reduction in blood phenylalanine or relaxation in diet) must also be understood by the patient and carers from the outset. Continuing education and support will be required thereafter, with further adjustment of diet and sapropterin dosage as a young patient grows.

  8. A Comparison of Risperidone and Buspirone for Treatment of Behavior Disorders in Children with Phenylketonuria

    PubMed Central

    FAYYAZI, Afshin; SALARI, Elham; KHAJEH, Ali; GAJARPOUR, Abdi

    2014-01-01

    Objective Many patients with late-diagnosed phenylketonuria (PKU) suffer from severe behavior problems. This study compares the effects of buspirone and risperidone on reducing behavior disorders in these patients. Materials & Methods In this crossover clinical trial study, patients with severe behavior disorders after medical examination were randomly divided into two groups of two 8-week crossover treatments with risperidone or buspirone. Patient behavioral disorders before and after treatment by each drug was rated by parents on the Nisonger Child Behavior Rating Form (NCBRF), and after treatment by each drug, were assessed by a physician through clinical global impression (CGI). Results Thirteen patients were able to complete the therapy period with these two medications. The most common psychiatric diagnoses were intellectual disability accompanied by pervasive developmental disorder NOS, and intellectual disability accompanied by autistic disorder. Risperidone was significantly effective in reducing the NCBRF subscales of hyperactivity disruptive/stereotypic, and conduct problems. Treatment by buspirone only significantly decreased the severity of hyperactivity, but other behavior aspects showed no significant differences. Assessment of the severity of behavior disorder after treatment by risperidone and buspirone showed significant differences in reducing hyperactivity and masochistic/stereotype. Conclusion Although buspirone is effective in controlling hyperactivity in patients with PKU, it has no preference over risperidone. Therefore, it is recommended as an alternative to risperidone. PMID:25657768

  9. Reassessment of Phenylalanine Tolerance in Adults with Phenylketonuria is Needed as Body Mass Changes

    PubMed Central

    MacLeod, Erin L.; Gleason, Sally T.; van Calcar, Sandra C.; Ney, Denise M.

    2009-01-01

    Lifelong treatment of phenylketonuria (PKU) includes a phenylalanine (phe) restricted diet that provides sufficient phe for growth and maintenance plus phe-free amino acid formula to meet requirements for protein, energy and micronutrients. Phe tolerance (mg phe/kg body weight/day) is the amount of phe those with PKU can consume and maintain acceptable blood phe levels; it requires individual assessment because of varying phenylalanine hydroxylase activity. The objective was to reassess phe tolerance in 8 adults with PKU considering phe requirements, blood phe levels, genotype and phe tolerance at 5 years of age. Subjects had not received a personalized assessment of phe tolerance in several years, and 5 subjects were overweight, body mass index (BMI) 25–28. With the guidance of a metabolic dietitian, 7 subjects increased phe tolerance (by 15–173%) without significantly increasing blood phe concentration. Increased phe tolerance was associated with both improved dietary compliance and inadequate phe intake at the onset of the protocol compared with current requirements. Improved dietary compliance reflected increased consumption of protein equivalents from amino acid formula and increased frequency of formula intake, from 2.2 to 3 times per day. Predictors of higher final phe tolerance following reassessment included being male and having a lower BMI (R2=0.588). This suggests that the rising trend of overweight and obesity may affect assessment of phe tolerance in adults. Therefore, interaction with the metabolic dietitian to reassess phe tolerance in relation to body mass is essential throughout adulthood to insure adequate intake of phe to support protein synthesis and prevent catabolism. PMID:19747868

  10. Remarkable differences: the course of life of young adults with galactosaemia and PKU.

    PubMed

    Bosch, A M; Maurice-Stam, H; Wijburg, F A; Grootenhuis, M A

    2009-12-01

    Although the need for insight in factors influencing the quality of life of patients with an inborn error of metabolism is recognized, psychological adjustment of adults with metabolic diseases has not been properly studied. Adult patients with PKU were demonstrated not to differ from healthy controls in terms of their course of life (CoL) and health-related quality of life (HRQoL). However, adults with galactosaemia had a lower HRQoL with significant lower scores on the domains of cognitive and social function. This study investigated the CoL and the social demographical outcomes in these young adults with galactosaemia, and compared them with the general population and with PKU patients. A total of 15 (88%) adult patients with classical galactosaemia participated in this study. Classical galactosaemia patients had a delayed social and psychosexual development compared to their peers from the general population and to PKU patients. Also, they were significantly less frequently married or living together and significantly less frequently employed than the general population. Our study shows a stark contrast between patients with galactosaemia and patients with PKU, although both are diagnosed in the neonatal period and need life-long dietary restrictions. The observed difference is likely due to the long-term somatic complications frequently seen in galactosaemia and thus not due to the burden of a chronic disease necessitating life-long dietary restrictions. We conclude that it is essential that parents and clinicians encourage children with galactosaemia to participate in peer-related activities in order to stimulate social performance, which may result in a more normal CoL.

  11. Wechsler subscale IQ and subtest profile in early treated phenylketonuria

    PubMed Central

    Griffiths, P; Demellweek, C; Fay, N; Robinson, P; Davidson, D

    2000-01-01

    AIM—Mildly depressed IQ is common in treated phenylketonuria. This study explored whether a particular intellectual ability profile typifies early and continuously treated phenylketonuria and whether component skills comprising the IQ relate to socioeconomic and treatment factors.
METHODS—IQ scores were collected retrospectively from variants of the "Wechsler intelligence scale for children" performed at age 8 on 57 children with early treated, classic phenylketonuria. The mental ability pattern underlying IQ was investigated by analysing subscale and subtest scores and dietary factors, such as historical phenylalanine blood concentrations.
RESULTS—The children's mean full scale IQ of 91.11 was significantly below the healthy population norm. There was a significant discrepancy between their mean verbal IQ (94.65) and mean performance IQ (89.42), suggestive of a spatial deficit, but the data did not support a biochemical or sociological explanation. Individual Wechsler subtests had no distinctive pattern. Phenylalanine control at age 2 was predictive of overall IQ. At this age, children with annual median phenylalanine < 360 µmol/litre (recommended UK upper limit) had a mean IQ 10 points higher than those above.
CONCLUSIONS—Early and continuous treatment of phenylketonuria does not necessarily lead to normalisation of overall IQ. Verbal intelligence in the primary school years appears to normalise if blood phenylalanine is maintained below 360 µmol/litre in infancy, but spatial intelligence may remain poor. However, the discrepancy in skill development is not the result of social status or treatment variables. Perhaps weak spatial intelligence is an ancillary effect of a protective rearing style occasioned by the dietary treatment regimen.
 PMID:10685922

  12. The Electro-Encephalogram in Phenylketonuria

    ERIC Educational Resources Information Center

    Todd, Peter G.; Pitt, D. B.

    1973-01-01

    Evaluated were electroencephalographic findings in 24 untreated (ages from 4 to 38 years) patients suffereing from phenylketonuria (a metabolic disorder producing severe mental retardation if not treated with proper diet during the early years). (DB)

  13. An Objective Approach to Measurement of Interpersonal Behavior in Phenylketonuria

    ERIC Educational Resources Information Center

    Friedman, C. J.; And Others

    1971-01-01

    Among the findings were that PKU Children judged to be emotionally disturbed and inadequate in communication performed more poorly than those PKU children judged nondisturbed and more adequate in communication under two of the three social stimulus interaction condictions. (Author)

  14. Probabilistic modelling to assess exposure to three artificial sweeteners of young Irish patients aged 1-3 years with PKU and CMPA.

    PubMed

    O'Sullivan, Aaron J; Pigat, Sandrine; O'Mahony, Cian; Gibney, Michael J; McKevitt, Aideen I

    2016-11-01

    The choice of suitable normal foods is limited for individuals with particular medical conditions, e.g., inborn errors of metabolism (phenylketonuria - PKU) or severe cow's milk protein allergy (CMPA). Patients may have dietary restrictions and exclusive or partial replacement of specific food groups with specially formulated products to meet particular nutrition requirements. Artificial sweeteners are used to improve the appearance and palatability of such food products to avoid food refusal and ensure dietary adherence. Young children have a higher risk of exceeding acceptable daily intakes for additives than adults due to higher food intakes kg(-1) body weight. The Budget Method and EFSA's Food Additives Intake Model (FAIM) are not equipped to assess partial dietary replacement with special formulations as they are built on data from dietary surveys of consumers without special medical requirements impacting the diet. The aim of this study was to explore dietary exposure modelling as a means of estimating the intake of artificial sweeteners by young PKU and CMPA patients aged 1-3 years. An adapted validated probabilistic model (FACET) was used to assess patients' exposure to artificial sweeteners. Food consumption data were derived from the food consumption survey data of healthy young children in Ireland from the National Preschool and Nutrition Survey (NPNS, 2010-11). Specially formulated foods for special medical purposes were included in the exposure model to replace restricted foods. Inclusion was based on recommendations for adequate protein intake and dietary adherence data. Exposure assessment results indicated that young children with PKU and CMPA have higher relative average intakes of artificial sweeteners than healthy young children. The reliability and robustness of the model in the estimation of patient additive exposures was further investigated and provides the first exposure estimates for these special populations.

  15. Phenylketonuria

    MedlinePlus

    ... foods. There are special formulas for newborns. For older children and adults, the diet includes many fruits and vegetables. It also includes some low-protein breads, pastas and cereals. Nutritional formulas provide the vitamins and minerals you can' ...

  16. Complete correction of hyperphenylalaninemia following liver-directed, recombinant AAV2/8 vector-mediated gene therapy in murine phenylketonuria.

    PubMed

    Harding, C O; Gillingham, M B; Hamman, K; Clark, H; Goebel-Daghighi, E; Bird, A; Koeberl, D D

    2006-03-01

    Novel recombinant adeno-associated virus vectors pseudotyped with serotype 8 capsid (rAAV2/8) have recently shown exciting promise as effective liver-directed gene transfer reagents. We have produced a novel liver-specific rAAV2/8 vector expressing the mouse phenylalanine hydroxylase (Pah) cDNA and have administered this vector to hyperphenylalaninemic PAH-deficient Pah(enu2) mice, a model of human phenylketonuria (PKU). Our hypothesis was that this vector would produce sufficient hepatocyte transduction frequency and PAH activity to correct blood phenylalanine levels in murine PKU. Portal vein injection of recombinant AAV2/8 vector into five adult Pah(enu2) mice yielded complete and stable (up to 17 weeks) correction of serum phenylalanine levels. Liver PAH activity was corrected to 11.5+/-2.4% of wild type liver activity and was associated with a significant increase in phenylalanine clearance following parenteral phenylalanine challenge. Although questions of long-term safety and stability of expression remain, recombinant AAV2/8-mediated, liver-directed gene therapy is a promising novel treatment approach for PKU and allied inborn errors of metabolism.

  17. Complete correction of hyperphenylalaninemia following liver-directed, recombinant AAV2/8 vector-mediated gene therapy in murine phenylketonuria

    PubMed Central

    Harding, CO; Gillingham, MB; Hamman, K; Clark, H; Goebel-Daghighi, E; Bird, A; Koeberl, DD

    2009-01-01

    Novel recombinant adeno-associated virus vectors pseudo-typed with serotype 8 capsid (rAAV2/8) have recently shown exciting promise as effective liver-directed gene transfer reagents. We have produced a novel liver-specific rAAV2/8 vector expressing the mouse phenylalanine hydroxylase (Pah) cDNA and have administered this vector to hyperphenylalaninemic PAH-deficient Pahenu2 mice, a model of human phenylketonuria (PKU). Our hypothesis was that this vector would produce sufficient hepatocyte transduction frequency and PAH activity to correct blood phenylalanine levels in murine PKU. Portal vein injection of recombinant AAV2/8 vector into five adult Pahenu2 mice yielded complete and stable (up to 17 weeks) correction of serum phenylalanine levels. Liver PAH activity was corrected to 11.5±2.4% of wild type liver activity and was associated with a significant increase in phenylalanine clearance following parenteral phenylalanine challenge. Although questions of long-term safety and stability of expression remain, recombinant AAV2/8-mediated, liver-directed gene therapy is a promising novel treatment approach for PKU and allied inborn errors of metabolism. PMID:16319949

  18. Co-existence of phenylketonuria either with maple syrup urine disease or Sandhoff disease in two patients from Iran: emphasizing the role of consanguinity.

    PubMed

    Abiri, Maryam; Talebi, Saeed; Uitto, Jouni; Youssefian, Leila; Vahidnezhad, Hassan; Shirzad, Tina; Salehpour, Shadab; Zeinali, Sirous

    2016-10-01

    Most inborn errors of metabolism (IEMs) are inherited in an autosomal recessive manner. IEMs are one of the major concerns in Iran due to its extensive consanguineous marriages. Herein, we report two patients with two co-existent IEMs: a girl affected by classic phenylketonuria (PKU) and maple syrup urine disease (MSUD) and a male patient affected with Sandhoff disease and PKU, where Sandhoff disease was suspected due to the presence of a cherry-red spot in the eyes at 6 months which is unrelated to PKU. Sequencing of candidate genes in the first patient revealed one novel and three recurrent compound heterozygous mutations of p.Ser231Pro and p.Ala300Ser in the PAH gene and p.Glu330Lys and p.Arg170Cys mutations in the BCKDHB gene. Genetic testing results in the second patient showed previously reported homozygous mutations of p.Arg261Gln in the PAH and p.Arg533Cys mutation in the HEXB gene. Genetic testing confirmed the clinical diagnosis of both diseases in both patients. To the best of our knowledge; this is the first report of the co-existence of two distinct genetic disorders in two individuals from Iran. Co-existent different IEMs in patients complicated the clinical diagnosis and management of the diseases.

  19. DNA methylation in the pathophysiology of hyperphenylalaninemia in the PAH(enu2) mouse model of phenylketonuria.

    PubMed

    Dobrowolski, S F; Lyons-Weiler, J; Spridik, K; Vockley, J; Skvorak, K; Biery, A

    2016-09-01

    Phenylalanine hydroxylase deficient phenylketonuria (PKU) is the paradigm for a treatable inborn error of metabolism where maintaining plasma phenylalanine (Phe) in the therapeutic range relates to improved clinical outcomes. While Phe is the presumed intoxicating analyte causal in neurologic damage, the mechanism(s) of Phe toxicity has remained elusive. Altered DNA methylation is a recognized response associated with exposure to numerous small molecule toxic agents. Paralleling this effect, we hypothesized that chronic Phe over-exposure in the brain would lead to aberrant DNA methylation with secondary influence upon gene regulation that would ultimately contribute to PKU neuropathology. The PAH(enu2) mouse models human PKU with intrinsic hyperphenylalaninemia, abnormal response to Phe challenge, and neurologic deficit. To examine this hypothesis, we assessed DNA methylation patterns in brain tissues using methylated DNA immunoprecipitation and paired end sequencing in adult PAH(enu2) animals maintained under either continuous dietary Phe restriction or chronic hyperphenylalaninemia. Heterozygous PAH(enu2/WT) litter mates served as controls for normal Phe exposure. Extensive repatterning of DNA methylation was observed in brain tissue of hyperphenylalaninemic animals while Phe restricted animals displayed an attenuated pattern of aberrant DNA methylation. Affected gene coding regions displayed aberrant hypermethylation and hypomethylation. Gene body methylation of noncoding RNA genes was observed and among these microRNA genes were prominent. Of particular note, observed only in hyperphenylalaninemic animals, was hypomethylation of miRNA genes within the imprinted Dlk1-Dio3 locus on chromosome 12. Aberrant methylation of microRNA genes influenced their expression which has secondary effects upon the expression of targeted protein coding genes. Differential hypermethylation of gene promoters was exclusive to hyperphenylalaninemic PAH(enu2) animals. Genes with

  20. Biochemical Evaluation of Phenylalanine Ammonia Lyase from Endemic Plant Cyathobasis fruticulosa (Bunge) Aellen. for the Dietary Treatment of Phenylketonuria

    PubMed Central

    Aydaş, Selcen Babaoğlu; Aslım, Belma

    2016-01-01

    Summary Enzyme substitution therapy with the phenylalanine ammonia lyase (PAL) is a new approach to the treatment of patients with phenylketonuria (PKU). This enzyme is responsible for the conversion of phenylalanine to trans-cinnamic acid. We assessed the PAL enzyme of the endemic plant Cyathobasis fruticulosa (Bunge) Aellen. for its possible role in the dietary treatment of PKU. The enzyme was found to have a high activity of (64.9±0.1) U/mg, with the optimum pH, temperature and buffer (Tris–HCl and l-phenylalanine) concentration levels of pH=8.8, 37 °C and 100 mM, respectively. Optimum enzyme activity was achieved at pH=4.0 and 7.5, corresponding to pH levels of gastric and intestinal juice, and NaCl concentration of 200 mM. The purification of the enzyme by 1.87-fold yielded an activity of 98.6 U/mg. PAL activities determined by HPLC analyses before and after purification were similar. Two protein bands, one at 70 and the other at 23 kDa, were determined by Western blot analysis of the enzyme. This enzyme is a potential candidate for serial production of dietary food and biotechnological products. PMID:27956861

  1. Biochemical Evaluation of Phenylalanine Ammonia Lyase from Endemic Plant Cyathobasis fruticulosa (Bunge) Aellen. for the Dietary Treatment of Phenylketonuria.

    PubMed

    Şirin, Seda; Aydaş, Selcen Babaoğlu; Aslım, Belma

    2016-09-01

    Enzyme substitution therapy with the phenylalanine ammonia lyase (PAL) is a new approach to the treatment of patients with phenylketonuria (PKU). This enzyme is responsible for the conversion of phenylalanine to trans-cinnamic acid. We assessed the PAL enzyme of the endemic plant Cyathobasis fruticulosa (Bunge) Aellen. for its possible role in the dietary treatment of PKU. The enzyme was found to have a high activity of (64.9±0.1) U/mg, with the optimum pH, temperature and buffer (Tris-HCl and l-phenylalanine) concentration levels of pH=8.8, 37 °C and 100 mM, respectively. Optimum enzyme activity was achieved at pH=4.0 and 7.5, corresponding to pH levels of gastric and intestinal juice, and NaCl concentration of 200 mM. The purification of the enzyme by 1.87-fold yielded an activity of 98.6 U/mg. PAL activities determined by HPLC analyses before and after purification were similar. Two protein bands, one at 70 and the other at 23 kDa, were determined by Western blot analysis of the enzyme. This enzyme is a potential candidate for serial production of dietary food and biotechnological products.

  2. Intense beams from gases generated by a permanent magnet ECR ion source at PKU

    SciTech Connect

    Ren, H. T.; Chen, J. E.; Peng, S. X.; Lu, P. N.; Yan, S.; Zhou, Q. F.; Zhao, J.; Yuan, Z. X.; Guo, Z. Y.

    2012-02-15

    An electron cyclotron resonance (ECR) ion source is designed for the production of high-current ion beams of various gaseous elements. At the Peking University (PKU), the primary study is focused on developing suitable permanent magnet ECR ion sources (PMECRs) for separated function radio frequency quadrupole (SFRFQ) accelerator and for Peking University Neutron Imaging Facility. Recently, other kinds of high-intensity ion beams are required for new acceleration structure demonstration, simulation of fusion reactor material irradiation, aviation bearing modification, and other applications. So we expanded the ion beam category from O{sup +}, H{sup +}, and D{sup +} to N{sup +}, Ar{sup +}, and He{sup +}. Up to now, about 120 mA of H{sup +}, 83 mA of D{sup +}, 50 mA of O{sup +}, 63 mA of N{sup +}, 70 mA of Ar{sup +}, and 65 mA of He{sup +} extracted at 50 kV through a {phi} 6 mm aperture were produced by the PMECRs at PKU. Their rms emittances are less than 0.2 {pi} mm mrad. Tungsten samples were irradiated by H{sup +} or He{sup +} beam extracted from this ion source and H/He holes and bubbles have been observed on the samples. A method to produce a high intensity H/He mixed beam to study synergistic effect is developed for nuclear material irradiation. To design a He{sup +} beam injector for coupled radio frequency quadruple and SFRFQ cavity, He{sup +} beam transmission experiments were carried out on PKU low energy beam transport test bench and the transmission was less than 50%. It indicated that some electrode modifications must be done to decrease the divergence of He{sup +} beam.

  3. Complexities of Parental Understanding of Phenylketonuria

    ERIC Educational Resources Information Center

    Sibinga, Maarten S.; Friedman, C. Jack

    1971-01-01

    Parental understanding of PKU, investigated through a questionnaire, was evaluated as to completeness and with respect to distortion. Education of parents was found to be unrelated to their understanding or tendency to distort. Effectiveness of the pediatrician's communication with parents is discussed. (Author/KW)

  4. Heat-transfer-based detection of SNPs in the PAH gene of PKU patients

    PubMed Central

    Vanden Bon, Natalie; van Grinsven, Bart; Murib, Mohammed Sharif; Yeap, Weng Siang; Haenen, Ken; De Ceuninck, Ward; Wagner, Patrick; Ameloot, Marcel; Vermeeren, Veronique; Michiels, Luc

    2014-01-01

    Conventional neonatal diagnosis of phenylketonuria is based on the presence of abnormal levels of phenylalanine in the blood. However, for carrier detection and prenatal diagnosis, direct detection of disease-correlated mutations is needed. To speed up and simplify mutation screening in genes, new technologies are developed. In this study, a heat-transfer method is evaluated as a mutation-detection technology in entire exons of the phenylalanine hydroxylase (PAH) gene. This method is based on the change in heat-transfer resistance (Rth) upon thermal denaturation of dsDNA (double-stranded DNA) on nanocrystalline diamond. First, ssDNA (single-stranded DNA) fragments that span the size range of the PAH exons were successfully immobilized on nanocrystalline diamond. Next, it was studied whether an Rth change could be observed during the thermal denaturation of these DNA fragments after hybridization to their complementary counterpart. A clear Rth shift during the denaturation of exon 5, exon 9, and exon 12 dsDNA was observed, corresponding to lengths of up to 123 bp. Finally, Rth was shown to detect prevalent single-nucleotide polymorphisms, c.473G>A (R158Q), c.932T>C (p.L311P), and c.1222C>T (R408W), correlated with phenylketonuria, displaying an effect related to the different melting temperatures of homoduplexes and heteroduplexes. PMID:24741310

  5. Mutation analysis in Turkish phenylketonuria patients.

    PubMed Central

    Ozgüç, M; Ozalp, I; Coşkun, T; Yilmaz, E; Erdem, H; Ayter, S

    1993-01-01

    Forty-four classical PKU patients have been screened for various mutations. The newly identified IVS 10 splicing mutation was found in 32% of the mutant alleles and comprises 74.5% of the mutations that could be typed: 261arg-gln (6.8%), 158arg-gly (2.3%), 252arg-trp (1.1%), 280glu-lys (-), and 272gly-stop (-) were the other mutations that were screened. Images PMID:8445616

  6. Phenylketonuria and Complex Spatial Visualization: An Analysis of Information Processing.

    ERIC Educational Resources Information Center

    Brunner, Robert L.; And Others

    1987-01-01

    The study of the ability of 16 early treated phenylketonuric (PKU) patients (ages 6-23 years) to solve complex spatial problems suggested that choice of problem-solving strategy, attention span, and accuracy of mental representation may be affected in PKU patients, despite efforts to maintain well-controlled phenylalanine concentrations in the…

  7. PKU-RBRC Workshop on Transverse Spin

    SciTech Connect

    Avakian,H.; Bunce, G.; Yuan, F.

    2008-06-30

    Understanding the structure of the nucleon is a fundamental question in subatomic physics, and it has been under intensive investigation for the last several years. Modern research focuses in particular on the spin structure of the nucleon. Experimental and theoretical investigations worldwide over the last few decades have established that, contrary to nave quark model expectations, quarks carry only about 30% of the totd spin of the proton. The origin of the remaining spin is the key question in current hadronic physics and also the major driving forces for the current and future experiments, such as RHIC and CEBAF in US, JPARC in Japan, COMPASS at CERN in Europe, FAIR at GSI in Germany. Among these studies, the transverse-spin physics develops actively and rapidly in the last few years. Recent studies reveal that transverse-spin physics is closely related to many fundamental properties of the QCD dynamics such as the factorization, the non-trivial universality of the parton distribution and fragmentation functions. It was very timely to bring together the theorists and experimentalists in this field at this workshop to review and discuss the latest developments and future perspective in hadronic spin physics. This workshop was very success iu many aspects. First of all, it attracted almost every expert working in this field. We had more than eighty participants in total, among them 27 came from the US institutes, 13 from Europe, 3 from Korea, and 2 from Japan. The rest participants came from local institutes in China. Second, we arranged plenty physics presentations, and the program covers all recent progresses made in the last few years. In total, we had 47 physics presentations, and two round table discussions. The discussion sessions were especially very useful and very much appreciated by all participants. In addition, we also scheduled plenty time for discussion in each presentation, and the living discussions impressed and benefited all participants.

  8. Study on urinary metabolic profile of phenylketonuria by micellar electrokinetic capillary chromatography with dual electrochemical detection--potential clinical application in fast diagnosis of phenylketonuria.

    PubMed

    Zhang, Dongli; Li, Wenli; Zhang, Junbo; Tang, Wanrong; Qian, Chenxu; Feng, Minghao; Chu, Qingcui; Ye, Jiannong

    2011-05-23

    The urinary metabolic marker compounds, namely phenylpyruvic acid (PPA), 2-hydroxyphenylacetic acid (oOPAA), 4-hydroxyphenylacetic acid (pOPAA), phenyllactic acid (PLA) and phenylacetic acid (PAA) of phenylketonuric individuals were detected by a novel method of micellar electrokinetic capillary chromatography with capacitively coupled contactless conductivity detection and amperometric detection (MECC-C(4)D/AD). Electrophoretic runs were performed in a 35 mmol L(-1) SDS/60 mmol L(-1) H(3)BO(3)-Na(2)B(4)O(7) running buffer (pH 8.2) at a separation voltage of 16 kV, and five marker compounds and the major coexisting compound uric acid (UA) could be well separated within 23 min. Highly linear response was obtained for five marker compounds over three orders of magnitude with detection limits ranging from 6.6×10(-6) to 6.4×10(-8) g mL(-1) (S/N=3). The proposed method has been used to detect the marker compounds simultaneously in urine samples with the advantages of obtaining more information about target analytes and avoiding redundant measurements and high assay cost. Urinary patterns in phenylketonuric babies were distinct and easily distinguished from those of healthy newborns. The proposed MECC-C(4)D/AD method could find clinical application in early noninvasive diagnosis of phenylketonuria (PKU), as significant differences could be found in the urinary content of five marker compounds among the phenylketonuric babies without or with dietotherapy and the healthy babies.

  9. Identification and Quantitation of Phenylalanine in the Brain of Patients with Phenylketonuria by Means of Localized in Vivo1H Magnetic-Resonance Spectroscopy

    NASA Astrophysics Data System (ADS)

    Kreis, R.; Pietz, J.; Penzien, J.; Herschkowitz, N.; Boesch, C.

    Localized proton MR spectroscopy was used to identify phenylalanine (PHE) and to quantitate its cerebral concentration in patients with type I phenylketonuria (PKU). Data acquisition was optimized for the detection of low-concentration metabolites, using a short TE (20 ms) double Hahn-echo localization sequence for large volumes within the head coil and for smaller volumes using a surface coil, Previously described methods to quantitate localized MR spectra were extended to cover the case of low-concentration metabolites, unevenly distributed in three brain compartments and measured in difference spectra only. PHE content was determined in difference spectra of four PKU patients with respect to normals and in one patient before and after an oral load of L-PHE, PHE concentrations of 0.3 to 0.6 mmol/kg brain tissue were obtained, resulting in a concentration gradient for PHE between blood and brain tissue of 2.4 to 3.0, No significant changes were found for the abundant metabolites in gray or white matter. Previously reported MRI changes were confirmed to be due to increased cerebro-spinal-fluid-like spaces.

  10. A limited spectrum of phenylalanine hydroxylase mutations is observed in phenylketonuria patients in western Poland and implications for treatment with 6R tetrahydrobiopterin.

    PubMed

    Dobrowolski, Steven F; Borski, K; Ellingson, C C; Koch, R; Levy, H L; Naylor, E W

    2009-06-01

    Phenylketonuria (PKU) is an autosomal recessive defect in hepatic metabolism of phenylalanine, which is secondary to mutations in the phenylalanine hydroxylase (PAH) gene. Sixty-seven ethnically Polish PKU patients, followed at the Outpatient Department of Pediatrics and Developmental Medicine in Poznan, Poland, were assessed for mutations in the PAH gene. Two mutations were identified in 61 of 67 patients and a single mutation was identified in the remaining six patients. The four most prevalent mutations (p.R408W, 68%; c.1066-11G>A, 6%; c.1315+1G>A, 5.2%; c.822-832delGCCCATGTATA, 3.7%) accounted for 83% of the mutant alleles. Fifteen additional mutations were identified of which most (13/15) were observed in an individual patient. Before knowledge of PAH genotypes, 19 patients were challenged with a 20 mg kg(-1) dose of 6R tetrahydrobiopterin (BH(4)) and serum phenylalanine concentration was monitored in hospital over 24 h. Two patients responded to the BH(4) challenge with a reduction of serum phenylalanine concentration >30% from baseline. PAH genotypes of the two responsive patients would have been predicted, as they contained mutations recognized as BH(4) responsive, whereas the 17 patients who were unresponsive would have been predicted as their mutations were either recognized as non-responsive or were highly deleterious frame-shift mutations. Overall, only 7.5% (5/ 67) of patients had PAH mutations recognized as responsive to co-factor therapy. Among the PKU patients from western Poland, PAH mutations responsive to BH(4) therapy are poorly represented; therefore, genotyping may be useful for identifying candidate patients likely to respond to BH(4) before physiological challenge.

  11. Phenylketonuria: treatment in adolescence and adult life.

    PubMed

    Brenton, D P; Tarn, A C; Cabrera-Abreu, J C; Lilburn, M

    1996-07-01

    In our clinic the decision on whether to continue with dietary treatment of phenylketonuria or not is left to each adolescent and adult patient after the advantages and disadvantages, as discussed in this paper, of continuing diet have been presented to them. As a result 61 of 132 patients have stopped diet or declined to restart and only 4 of them have phenylalanine values below 1000 mumol/l. Seventy-one patients have remained on diet or started again with phenylalanine values below 1000 mumol/l in 58 of them. This series of 132 excludes women who returned to diet to conceive.

  12. Estimating the probability of IQ impairment from blood phenylalanine for phenylketonuria patients: a hierarchical meta-analysis.

    PubMed

    Fonnesbeck, Christopher J; McPheeters, Melissa L; Krishnaswami, Shanthi; Lindegren, Mary Louise; Reimschisel, Tyler

    2013-09-01

    Though the control of blood phenylalanine (Phe) levels is essential for minimizing impairment in individuals with phenylketonuria (PKU), the empirical basis for the selection of specific blood Phe levels as targets has not been evaluated. We evaluated the current evidence that particular Phe levels are optimal for minimizing or avoiding cognitive impairment in individuals with PKU. This work uses meta-estimates of blood Phe-IQ correlation to predict the probability of low IQ for a range of Phe levels. We believe this metric is easily interpretable by clinicians, and hence useful in making recommendations for Phe intake. The median baseline association of Phe with IQ was estimated to be negative, both in the context of historical (median = -0.026, 95 % BCI = [-0.040, -0.013]) and concurrent (-0.007, [-0.014, 0.000]) measurement of Phe relative to IQ. The estimated additive fixed effect of critical period Phe measurement was also nominally negative for historical measurement (-0.010, [-0.022, 0.003]) and positive for concurrent measurement (0.007, [-0.018, 0.035]). Probabilities corresponding to historical measures of blood Phe demonstrated an increasing chance of low IQ with increasing Phe, with a stronger association seen between blood Phe measured during the critical period than later. In contrast, concurrently-measured Phe was more weakly correlated with the probability of low IQ, though the correlation is still positive, irrespective of whether Phe was measured during the critical or non-critical period. This meta-analysis illustrates the utility of a Bayesian hierarchical approach for not only combining information from a set of candidate studies, but also for combining different types of data to estimate parameters of interest.

  13. Application of natural and amplification created restriction sites for the diagnosis of PKU mutations.

    PubMed Central

    Eiken, H G; Odland, E; Boman, H; Skjelkvåle, L; Engebretsen, L F; Apold, J

    1991-01-01

    PCR amplification, either conventional, or as site directed mutagenesis using primers with mismatched 3'-ends, followed by restriction endonuclease digestion, provides rapid, non-isotope assays of known mutations in the human phenylalanine hydroxylase gene. Such assays were shown to have the potential to detect all of the 18 presently reported phenylketonuria mutations. The practical applicability of this approach was demonstrated for eight mutations in Norwegian phenylketonuria patients, among them the most common ones. Images PMID:1851292

  14. Classroom Demonstration of a Spot Test for Phenylpyruvic Acid and Its Relationship to Phenylketonuria

    NASA Astrophysics Data System (ADS)

    Halkides, Christopher J.

    2004-03-01

    A classroom demonstration of a spot test for phenylketonuria using ferric chloride is discussed. The chemistry is similar to that used in Phenistix test strips. Some background information on screening infants for phenylketonuria is also given.

  15. Duty factor variation possibility from 1% to 100% with PKU microwave driven Cs-free volume H- sources

    NASA Astrophysics Data System (ADS)

    Peng, S. X.; Zhang, T.; Ren, H. T.; Zhang, A. L.; Xu, Y.; Zhang, J. F.; Guo, Z. Y.; Chen, J. E.

    2016-02-01

    Microwave driven cesium-free volume H- sources, that have the ability to deliver tens of mA H- at 35 keV both in CW and 10% duty factor (100 Hz/1 ms), were developed at Peking University (PKU) [S. X. Peng et al., in Proceeding of IPAC 2015, WEPWA027, Richmond, Virginia, USA, 3-8 May 2015]. Recently, special efforts were paid on the investigation of duty factor variation possibility from 1% to 100% with them. Most of the experiments were carried out with a pulsed length (τ) of 1 ms and different intervals of 99 ms, 49 ms, 39 ms, 29 ms, 19 ms, 9 ms, 4 ms, 2 ms, 1 ms, 0.5 ms, and 0 ms, respectively. Other experiments were focused on CW operation and fixed duty factor of 1%. Experimental results prove that PKU H- sources can deliver tens of mA H- at duty factor from 1% to 100%. The RF power efficiency increases steadily with the increasing of duty factor from 1% to CW at a fixed pulsed length. Under a given duty factor and pulsed length, RF power efficiency keeps constant and the H- current increases with RF power linearly. Details will be presented in the paper.

  16. Tryptophan Metabolism in a Patient with Phenylketonuria and Scleroderma

    PubMed Central

    Drummond, Keith N.; Michael, Alfred F.; Good, Robert A.

    1966-01-01

    Phenylketonuria and severe focal scleroderma were observed in a white male child. This is the first instance in which the association of these two rare disorders has been reported. Studies carried out on this patient provide a possible explanation for the abnormalities of indole metabolism in phenylketonuria. On an unrestricted diet, when serum phenylalanine levels were elevated, excessive urinary excretion of indolic tryptophan metabolites was seen 18-24 hours after oral tryptophan loading, and tryptophan was demonstrable in the stool. This was not observed when the serum phenylalanine was within normal limits on a low phenylalanine diet. Impaired intestinal tryptophan absorption secondary to elevated serum phenylalanine, by providing tryptophan substrate for bacterial degradation to indolic compounds which are absorbed and excreted in the urine, may partially explain the abnormalities of indole metabolism in phenylketonuria. ImagesFig. 1 PMID:5929533

  17. Risk factors for developing mineral bone disease in phenylketonuric patients.

    PubMed

    Mirás, Alicia; Bóveda, M Dolores; Leis, María R; Mera, Antonio; Aldámiz-Echevarría, Luís; Fernández-Lorenzo, José R; Fraga, José M; Couce, María L

    2013-03-01

    There is a compromised bone mass in phenylketonuria patients compared with normal population, but the mechanisms responsible are still a matter of investigation. In addition, tetrahydrobiopterin therapy is a new option for a significant proportion of these patients and the prevalence of mineral bone disease (MBD) in these patients is unknown. We conducted a cross-sectional observational study including 43 phenylketonuric patients. Bone densitometry, nutritional assessment, physical activity questionnaire, biochemical parameters, and molecular study were performed in all patients. Patients were stratified by phenotype, age and type of treatment. The MBD prevalence in phenylketonuria was 14%. Osteopenic and osteoporotic (n=6 patients) had an average daily natural protein intake significantly lower than the remaining (n=37) patients with PKU (14.33 ± 8.95 g vs 21.25 ± 20.85 g). Besides, a lower body mass index was found. There were no statistical differences in physical activity level, calcium, phosphorus and fat intake, and in phenylalanine, vitamin D, paratohormone, docosahexaenoic and eicosapentaenoic acid blood levels. Mutational spectrum was found in up to 30 different PAH genotypes and no relationship was established among genotype and development of MBD. None of the twelve phenylketonuric patients treated with tetrahydrobiopterin (27.9%), for an average of 7.1 years, developed MBD. Natural protein intake and blood levels of eicosapentaenoic acid were significantly higher while calcium intake was lower in these patients. This study shows that the decrease in natural protein intake can play an important role in MBD development in phenylketonuric patients. Therapy with tetrahydrobiopterin allows a more relaxed protein diet, which is associated with better bone mass.

  18. Molecular analysis of contiguous exons of the phenylalanine hydroxylase gene: identification of a new PKU mutation.

    PubMed Central

    Dianzani, I; Camaschella, C; Saglio, G; Ferrero, G B; Ramus, S; Ponzone, A; Cotton, R G

    1993-01-01

    A modified application of the chemical cleavage of mismatch (CCM) method has been used to screen three contiguous exons (exons 9, 10, and 11) of the phenylalanine hydroxylase gene in 17 Italian PKU patients. A new nonsense heterozygous C-->G transversion within exon 11 (S359X) was identified in a single patient. Only one of the four mutations previously reported in this DNA region in Caucasians was found. This lesion, IVS X-546, was detected in five of the 34 PKU alleles examined. Our results underline the versatility of the CCM method for scanning a gene for multiple mutations. Images PMID:8097261

  19. Molecular analysis of contiguous exons of the phenylalanine hydroxylase gene: identification of a new PKU mutation.

    PubMed

    Dianzani, I; Camaschella, C; Saglio, G; Ferrero, G B; Ramus, S; Ponzone, A; Cotton, R G

    1993-03-01

    A modified application of the chemical cleavage of mismatch (CCM) method has been used to screen three contiguous exons (exons 9, 10, and 11) of the phenylalanine hydroxylase gene in 17 Italian PKU patients. A new nonsense heterozygous C-->G transversion within exon 11 (S359X) was identified in a single patient. Only one of the four mutations previously reported in this DNA region in Caucasians was found. This lesion, IVS X-546, was detected in five of the 34 PKU alleles examined. Our results underline the versatility of the CCM method for scanning a gene for multiple mutations.

  20. Collaborative Study of Children Treated for Phenylketonuria: Study Design

    ERIC Educational Resources Information Center

    Williamson, Malcolm; And Others

    1977-01-01

    Available from: Arthur Retlaw and Associates, Inc., Suite 2080, 1603 Orrington Avenue, Evanston, Illinois 60201. Described is a study in which a large sample of children (n=444) with phenylketonuria (an inborn metabolic error usually related to impaired cognitive ability) were treated under controlled conditions from near birth to 6 years of age.…

  1. Speech and Language Skills in Children with Early Treated Phenylketonuria.

    ERIC Educational Resources Information Center

    Ozanne, Anne E.; And Others

    1990-01-01

    The study of 29 children, age 7 months to 16 years, with early treated phenylketonuria found no significant differences on speech and/or language measures when compared with controls matched for age, sex, and socioeconomic level. Examination of individual scores, however, did reveal linguistic impairment in a small number of subjects. (Author/JDD)

  2. PHENYLKETONURIA, AN INHERITED METABOLIC DISORDER ASSOCIATED WITH MENTAL RETARDATION.

    ERIC Educational Resources Information Center

    CENTERWALL, WILLARD R.; CENTERWALL, SIEGRIED A.

    ADDRESSED TO PUBLIC HEALTH WORKERS AND PHYSICIANS IN GENERAL PRACTICE, THE PAMPHLET INTRODUCES METHODS OF DETECTING AND MANAGING PHENYLKETONURIA, AN INHERITED METABOLIC DISORDER ASSOCIATED WITH MENTAL RETARDATION. INFORMATION, UPDATED FROM THE 1961 EDITION, IS INCLUDED ON THE INCIDENCE AND GENETICS, BIOCHEMISTRY, AND CLINICAL COURSE OF THE…

  3. Results of loading doses of aspartame by two phenylketonuric (PKU) children compared with two normal children.

    PubMed

    Koch, R; Schaeffler, G; Shaw, N F

    1976-11-01

    Separate tolerance tests with aspartame at 34 mg/kg-day and phenylalanine at 19 mg/kg-day were compared. The results reveal that slight serum elevation of phenylalanine and tyrosine occurred in the two PKU and the normal healthy adolescents. It would appear that the phenylalanine in the sweetener aspartame is small enough to be of little clinical significance.

  4. Prefrontal Cortex Cognitive Deficits in Children Treated Early and Continuously for PKU.

    ERIC Educational Resources Information Center

    Diamond, Adele; Prevor, Meredith B.; Druin, Donald P.; Callender, Glenda

    1997-01-01

    Hypothesized that elevated ratio of phenylalanine to tyrosine in blood of children with phenylketonuria uniquely affects cognitive functions dependent on prefrontal cortex because of the special sensitivity of prefrontally projecting dopamine neurons to small decreases in tyrosine. Found that children whose phenylalanine levels were three to five…

  5. Newborn Screening for Genetic-Metabolic Diseases: Progress, Principles and Recommendations.

    ERIC Educational Resources Information Center

    Holtzman, Neil A.

    This monograph, designed for persons involved in the organization and regulation of screening of newborns infants for Phenylketonuria (PKU) and other genetic-metabolic diseases reviews new developments in the field, makes recommendations, and provides information about specific conditions other than PKU that are detectable by screening. Discussed…

  6. OMEGA-3 LONG-CHAIN POLYUNSATURATED FATTY ACIDS IN OLDER CHILDREN

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Phenylketonuria (PKU), the most prevalent inborn error of metabolism, is usually secondary to low hepatic activity of phenylalanine hydroxylase, the enzyme that catalyzes conversion of phenylalanine to tyrosine. Growth and development of infants and children with PKU who are managed by mandatory n...

  7. Preservation of high phenylalanine ammonia lyase activities in roots of Japanese Striped corn: a potential oral therapeutic to treat phenylketonuria.

    PubMed

    López-Villalobos, Arturo; Lücker, Joost; López-Quiróz, Ana Angela; Yeung, Edward C; Palma, Kristoffer; Kermode, Allison R

    2014-06-01

    Phenylketonuria (PKU) is an inherited metabolic disorder caused by deficient phenylalanine hydroxylase (PAH) activity, the enzyme responsible for the disposal of excess amounts of the essential amino acid phenylalanine (Phe). Phenylalanine ammonia-lyase (PAL, EC 4.3.1.5) has potential to serve as an enzyme substitution therapy for this human genetic disease. Using 7-day-old Japanese Striped corn seedlings (Japonica Striped maize, Zea mays L. cv. japonica) that contain high activities of PAL, we investigated a number of methods to preserve the roots as an intact food and for long-term storage. The cryoprotectant effects of maple syrup and other edible sugars (mono- and oligosaccharides) were evaluated. Following thawing, the preserved roots were then examined to determine whether the rigid plant cell walls could protect the PAL enzyme from proteolysis during simulated (in vitro) digestion comprised of gastric and intestinal phases. While several treatments led to retention of PAL activity during freezing, upon thawing and in vitro digestion, root tissues that had been previously frozen in the presence of maple syrup exhibited the highest residual PAL activities (∼50% of the initial enzyme activity), in marked contrast to all of the treatments using other edible sugars. The structural integrity of the root cells, and the stability of the functional PAL tetramer were also preserved with the maple syrup protocol. These results have significance for the formulation of oral enzyme/protein therapeutics. When plant tissues are adequately preserved, the rigid cell walls constitute a protective barrier even under harsh (e.g. gastrointestinal-like) conditions.

  8. Doxycycline hinders phenylalanine fibril assemblies revealing a potential novel therapeutic approach in phenylketonuria.

    PubMed

    De Luigi, Ada; Mariani, Alessandro; De Paola, Massimiliano; Re Depaolini, Andrea; Colombo, Laura; Russo, Luca; Rondelli, Valeria; Brocca, Paola; Adler-Abramovich, Lihi; Gazit, Ehud; Del Favero, Elena; Cantù, Laura; Salmona, Mario

    2015-10-29

    A new paradigm for the aetiopathology of phenylketonuria suggests the presence of amyloid-like assemblies in the brains of transgenic mouse models and patients with phenylketonuria, possibly shedding light on the selective cognitive deficit associated with this disease. Paralleling the amyloidogenic route that identifies different stages of peptide aggregation, corresponding to different levels of toxicity, we experimentally address for the first time, the physico-chemical properties of phenylalanine aggregates via Small Angle, Wide Angle X-ray Scattering and Atomic Force Microscopy. Results are consistent with the presence of well-structured, aligned fibres generated by milliMolar concentrations of phenylalanine. Moreover, the amyloid-modulating doxycycline agent affects the local structure of phenylalanine aggregates, preventing the formation of well-ordered crystalline structures. Phenylalanine assemblies prove toxic in vitro to immortalized cell lines and primary neuronal cells. Furthermore, these assemblies also cause dendritic sprouting alterations and synaptic protein impairment in neurons. Doxycycline counteracts these toxic effects, suggesting an approach for the development of future innovative non-dietary preventive therapies.

  9. Doxycycline hinders phenylalanine fibril assemblies revealing a potential novel therapeutic approach in phenylketonuria

    PubMed Central

    De Luigi, Ada; Mariani, Alessandro; De Paola, Massimiliano; Re Depaolini, Andrea; Colombo, Laura; Russo, Luca; Rondelli, Valeria; Brocca, Paola; Adler-Abramovich, Lihi; Gazit, Ehud; Del Favero, Elena; Cantù, Laura; Salmona, Mario

    2015-01-01

    A new paradigm for the aetiopathology of phenylketonuria suggests the presence of amyloid-like assemblies in the brains of transgenic mouse models and patients with phenylketonuria, possibly shedding light on the selective cognitive deficit associated with this disease. Paralleling the amyloidogenic route that identifies different stages of peptide aggregation, corresponding to different levels of toxicity, we experimentally address for the first time, the physico-chemical properties of phenylalanine aggregates via Small Angle, Wide Angle X-ray Scattering and Atomic Force Microscopy. Results are consistent with the presence of well-structured, aligned fibres generated by milliMolar concentrations of phenylalanine. Moreover, the amyloid-modulating doxycycline agent affects the local structure of phenylalanine aggregates, preventing the formation of well-ordered crystalline structures. Phenylalanine assemblies prove toxic in vitro to immortalized cell lines and primary neuronal cells. Furthermore, these assemblies also cause dendritic sprouting alterations and synaptic protein impairment in neurons. Doxycycline counteracts these toxic effects, suggesting an approach for the development of future innovative non-dietary preventive therapies. PMID:26510963

  10. Improvements of PKU PMECRIS for continuous hundred hours CW proton beam operation

    SciTech Connect

    Peng, S. X. Ren, H. T.; Zhang, T.; Zhang, J. F.; Xu, Y.; Guo, Z. Y.; Zhang, A. L.; Chen, J. E.

    2016-02-15

    In order to improve the source stability, a long term continuous wave (CW) proton beam experiment has been carried out with Peking University compact permanent magnet 2.45 GHz ECR ion source (PKU PMECRIS). Before such an experiment a lot of improvements and modifications were completed on the source body, the Faraday cup and the PKU ion source test bench. At the beginning of 2015, a continuous operation of PKU PMECRIS for 306 h with more than 50 mA CW beam was carried out after success of many short term tests. No plasma generator failure or high voltage breakdown was observed during that running period and the proton source reliability is near 100%. Total beam availability, which is defined as 35-keV beam-on time divided by elapsed time, was higher than 99% [S. X. Peng et al., Chin. Phys. B 24(7), 075203 (2015)]. A re-inspection was performed after another additional 100 h operation (counting time) and no obvious sign of component failure was observed. Counting the previous source testing time together, this PMECRs longevity is now demonstrated to be greater than 460 h. This paper is mainly concentrated on the improvements for this long term experiment.

  11. Duty factor variation possibility from 1% to 100% with PKU microwave driven Cs-free volume H{sup −} sources

    SciTech Connect

    Peng, S. X. Zhang, T.; Ren, H. T.; Xu, Y.; Zhang, J. F.; Guo, Z. Y.; Zhang, A. L.; Chen, J. E.

    2016-02-15

    Microwave driven cesium-free volume H{sup −} sources, that have the ability to deliver tens of mA H{sup −} at 35 keV both in CW and 10% duty factor (100 Hz/1 ms), were developed at Peking University (PKU) [S. X. Peng et al., in Proceeding of IPAC 2015, WEPWA027, Richmond, Virginia, USA, 3–8 May 2015]. Recently, special efforts were paid on the investigation of duty factor variation possibility from 1% to 100% with them. Most of the experiments were carried out with a pulsed length (τ) of 1 ms and different intervals of 99 ms, 49 ms, 39 ms, 29 ms, 19 ms, 9 ms, 4 ms, 2 ms, 1 ms, 0.5 ms, and 0 ms, respectively. Other experiments were focused on CW operation and fixed duty factor of 1%. Experimental results prove that PKU H{sup −} sources can deliver tens of mA H{sup −} at duty factor from 1% to 100%. The RF power efficiency increases steadily with the increasing of duty factor from 1% to CW at a fixed pulsed length. Under a given duty factor and pulsed length, RF power efficiency keeps constant and the H{sup −} current increases with RF power linearly. Details will be presented in the paper.

  12. Intellectual and Developmental Status in Children With Hyperphenylalaninemia and PKU Who Were Screened in a National Program

    PubMed Central

    Aghasi, Parisa; Setoodeh, Arya; Sayarifard, Azadeh; Rashidiyan, Maryam; Sayarifard, Fatemeh; Rabbani, Ali; Mahmoudi-Gharaei, Javad

    2015-01-01

    Background: Hyperphenylalaninemia (HPA) and Phenylkeonuria (PKU) are metabolic errors caused by deficiency of phenylalanine hydroxylase enzyme, which results in increased level of phenylalanine. This increase is toxic to the growing brain. Objectives: The purpose of this study was to compare the intellectual and developmental status in HPA and PKU children with normal population in national screening program. Patients and Methods: In a historical cohort study, 41 PKU patients who had the inclusion criteria and 41 healthy children were evaluated. Wechsler preschool and primary scale of intelligence-3rd edition (WPPI-3) was used in order to assess the intellectual status of children 4 years and older and Ages and stages questionnaire (ASQ) was used to assess the developmental status of children 5 years and younger. Results: In intellectual test comparison, the two groups showed significant difference in Wechsler’s performance intelligence score and some performance subscales (P-value < 0.01). In comparison of developmental status, no significant difference was observed between the two groups (P-value > 0.05). Conclusions: Even with early diagnosis and treatment of PKU patients, these children show some deficiencies intellectually compared to normal children. This study emphasizes on necessity for screening intellectual and developmental status of PKU patients so that effective medical or educational measures can taken in case of deficiencies. PMID:26635939

  13. Challenges and pitfalls in the management of phenylketonuria.

    PubMed

    Feillet, François; van Spronsen, Francjan J; MacDonald, Anita; Trefz, Friedrich K; Demirkol, Mübeccel; Giovannini, Marcello; Bélanger-Quintana, Amaya; Blau, Nenad

    2010-08-01

    Despite recent advances in the management of phenylketonuria and hyperphenylalaninemia, important questions on the management of this disorder remain unanswered. Consensus exists on the need for neonatal screening and early treatment, yet disagreement persists over threshold levels of blood phenylalanine for starting treatment, target blood phenylalanine levels, and the management of older patient groups. The mainstay of treatment is a phenylalanine-restricted diet, but its application varies between and within countries. Beyond diet treatment, there is a lack of consensus on the use of newer treatments such as tetrahydrobiopterin. Although neonatal screening and early treatment has meant that most well-treated children grow up with near-normal IQ scores, the effect of relaxing metabolic control on cognitive and executive function later in life is still not fully understood. Although it is clear from the available literature that the active control of blood phenylalanine levels is of vital importance, there are other treatment-related factors that affect outcome. A uniform and firmly evidence-based approach to the management of phenylketonuria is required.

  14. Brain dysfunction in phenylketonuria: is phenylalanine toxicity the only possible cause?

    PubMed

    van Spronsen, F J; Hoeksma, Marieke; Reijngoud, Dirk-Jan

    2009-02-01

    In phenylketonuria, mental retardation is prevented by a diet that severely restricts natural protein and is supplemented with a phenylalanine-free amino acid mixture. The result is an almost normal outcome, although some neuropsychological disturbances remain. The pathology underlying cognitive dysfunction in phenylketonuria is unknown, although it is clear that the high plasma concentrations of phenylalanine influence the blood-brain barrier transport of large neutral amino acids. The high plasma phenylalanine concentrations increase phenylalanine entry into brain and restrict the entry of other large neutral amino acids. In the literature, emphasis has been on high brain phenylalanine as the pathological substrate that causes mental retardation. Phenylalanine was found to interfere with different cerebral enzyme systems. However, apart from the neurotoxicity of phenylalanine, a deficiency of the other large neutral amino acids in brain may also be an important factor affecting cognitive function in phenylketonuria. Cerebral protein synthesis was found to be disturbed in a mouse model of phenylketonuria and could be caused by shortage of large neutral amino acids instead of high levels of phenylalanine. Therefore, in this review we emphasize the possibility of a different idea about the pathogenesis of mental dysfunction in phenylketonuria patients and the aim of treatment strategies. The aim of treatment in phenylketonuria might be to normalize cerebral concentrations of all large neutral amino acids rather than prevent high cerebral phenylalanine concentrations alone. In-depth studies are necessary to investigate the role of large neutral amino acid deficiencies in brain.

  15. A late-diagnosed phenylketonuria case presenting with autism spectrum disorder in early childhood.

    PubMed

    Mazlum, Betül; Anlar, Banu; Kalkanoğlu-Sivri, H Serap; Karlı-Oğuz, Kader; Özusta, Şeniz; Ünal, Fatih

    2016-01-01

    Phenylketonuria is one of the most prevalent autosomal recessive hereditary disorders in Turkey. If untreated, it results in severe brain damage and can also be associated with autism in certain patients. We present a three-year old boy who exhibited the symptoms of autism and was subsequently diagnosed with phenylketonuria. This case illustrates that because the majority of autism cases are idiopathic, an occasional patient with a metabolic disorder might be overlooked especially in the era of newborn screening. We also discuss the possible pathogenetic processes leading to autistic symptoms in phenylketonuria, and wish to draw attention to the possibility of cases missed in the screening program because of less than 100% coverage or insufficient food intake before blood sampling. Clinicians should keep in mind the possibility of treatable disorders in children with autism even when such disorders appear unlikely.

  16. Late-diagnosed phenylketonuria in an eight-year-old boy with dyslexia and attention-deficit hyperactivity disorder.

    PubMed

    Yıldız, Yılmaz; Dursun, Ali; Tokatlı, Ayşegül; Coşkun, Turgay; Sivri, Hatice Serap

    2016-01-01

    Phenylketonuria, previously a common cause of severe intellectual disability, is a metabolic disorder now promptly diagnosed and effectively treated thanks to newborn screening programs. Here, we report a male patient presenting with dyslexia and attention-deficit hyperactivity disorder, who was diagnosed with mild phenylketonuria at eight years of age. Earlier recognition and treatment before the establishment of irreversible brain damage would have resulted in better neurobehavioural outcomes. Classical phenylketonuria and milder phenotypes of phenylalanine hydroxylase deficiency need to be considered in the differential diagnosis of all cognitive and behavioural problems of unknown cause.

  17. Intelligence Patterns among Children with High-Functioning Autism, Phenylketonuria, and Childhood Head Injury.

    ERIC Educational Resources Information Center

    Dennis, Maureen; Lockyer, Linda; Lazenby, Anne L.; Donnelly, Ruth E.; Wilkinson, Margaret; Schoonheyt, Wanda

    1999-01-01

    A study compared the Comprehension: Block Design IQ subtest pattern of 8 children with autism and 24 children with developmental and acquired frontal lobe disorders. Found that children with autism showed low social comprehension related to visual spatial ability, a profile which was shared by children with poorly controlled Phenylketonuria. (CR)

  18. Parental Problem-Solving Skills, Stress, and Dietary Compliance in Phenylketonuria.

    ERIC Educational Resources Information Center

    Fehrenbach, Annette M. B.; Peterson, Lizette

    1989-01-01

    Parents of 30 children with phenylketonuria, classified as being in good or poor dietary control, engaged in verbal and written problem-solving situations under conditions of both high and low time-pressure induced stress. Overall, compliant parents gave higher quality verbal and written problem-solving solutions than noncompliant parents.…

  19. In vitro residual activity of phenylalanine hydroxylase variants and correlation with metabolic phenotypes in PKU.

    PubMed

    Trunzo, Roberta; Santacroce, Rosa; Shen, Nan; Jung-Klawitter, Sabine; Leccese, Angelica; De Girolamo, Giuseppe; Margaglione, Maurizio; Blau, Nenad

    2016-12-05

    Hyperphenylalaninemias (HPAs) are genetic diseases predominantly caused by a wide range of variants in the phenylalanine hydroxylase (PAH) gene. In vitro expression analysis of PAH variants offers the opportunity to elucidate the molecular mechanisms involved in HPAs and to clarify whether a disease-associated variant is genuinely pathogenic, while investigating the severity of a metabolic phenotype, and determining how a variant exerts its deleterious effects on the PAH enzyme. To study the effects of gene variants on PAH activity, we investigated eight variants: c.611A>G (p.Y204C), c.635T>C (p.L212P), c.746T>C (p.L249P), c.745C>T (p.L249F), c.809G>A (p.R270K), c.782G>C (p.R261P), c.587C>A (p.S196Y) and c.1139C>T (p.T380M), associated with different phenotypic groups. Transient expression of mutant full-length cDNAs in COS-7 cells yielded PAH proteins with PAH activity levels between 7% and 51% compared to the wild-type enzyme. With one exception (p.Y204C, which had no significant impact on PAH function), lower PAH activity was associated with a more severe phenotype (e.g. p.L249P with 7% PAH activity, 100% of classic PKU and no BH4 responsiveness), while higher activity correlated with milder phenotypes (e.g. p.T380M with 28% PAH activity, 97% of mild HPA and 83% of BH4 responsiveness). The results of the in vitro residual PAH activity have major implications, both for our understanding of genotype-phenotype correlations, and thereby existing inconsistencies, but also for the elucidation of the molecular basis of tetrahydrobiopterin (BH4) responsiveness.

  20. The use of parenteral nutrition for the management of PKU patient undergoing chemotherapy for lymphoma: a case report.

    PubMed

    Salvarinova-Zivkovic, R; Hartnett, C; Sinclair, G; Dix, D; Horvath, G; Lillquist, Y; Stockler-Ipsiroglu, S

    2012-04-01

    The metabolic control of phenylalanine levels is a challenge during illness. We present the metabolic management of a 6 year old boy with classical PKU who was diagnosed with stage III intraabdominal Burkit's lymphoma and underwent surgical resection and chemotherapy. The metabolic control during chemotherapy was achieved by the use of parenteral custom made amino acid solution and pro-active adjustment of intake. From the 94 obtained plasma phenylalanine (Phe) levels, 18.4% were above our clinic's recommended upper limit (360 μmol/L, 6 mg/dL) while 52.7% of Phe levels were below the recommended lower limit (120 μmol/L, 2 mg/dL). Phe levels above recommended range were associated with low caloric/protein intake, while levels below recommended range reflected the difficulty in achieving the full prescribed Phe intake. We recommend early institution of custom made amino acid solution with maximum amino acid content and caloric intake to provide optimal phenylalanine control. Administration of phenylalanine via regular intravenous amino acid solution may assist in avoiding low Phe levels when prescribed intake is compromised due to vomiting and other disease related illnesses. Use of custom made, phenylalanine free amino acid solution proved beneficial in the management of blood phenylalanine levels in a PKU patient during chemotherapy for Burkitt lymphoma.

  1. Neonatal Screening Tests.

    ERIC Educational Resources Information Center

    Vigue, Charles L.

    1986-01-01

    Describes several laboratory experiments that are adaptations of clinical tests for certain genetic diseases in babies. Information and procedures are provided for tests for phenylketonuria (PKU), galactosemia, tyrosinemia, cystinuria, and mucopolysaccharidosis. Discusses the effects of each disease on the infants' development. (TW)

  2. Linking genotypes database with locus-specific database and genotype-phenotype correlation in phenylketonuria.

    PubMed

    Wettstein, Sarah; Underhaug, Jarl; Perez, Belen; Marsden, Brian D; Yue, Wyatt W; Martinez, Aurora; Blau, Nenad

    2015-03-01

    The wide range of metabolic phenotypes in phenylketonuria is due to a large number of variants causing variable impairment in phenylalanine hydroxylase function. A total of 834 phenylalanine hydroxylase gene variants from the locus-specific database PAHvdb and genotypes of 4181 phenylketonuria patients from the BIOPKU database were characterized using FoldX, SIFT Blink, Polyphen-2 and SNPs3D algorithms. Obtained data was correlated with residual enzyme activity, patients' phenotype and tetrahydrobiopterin responsiveness. A descriptive analysis of both databases was compiled and an interactive viewer in PAHvdb database was implemented for structure visualization of missense variants. We found a quantitative relationship between phenylalanine hydroxylase protein stability and enzyme activity (r(s) = 0.479), between protein stability and allelic phenotype (r(s) = -0.458), as well as between enzyme activity and allelic phenotype (r(s) = 0.799). Enzyme stability algorithms (FoldX and SNPs3D), allelic phenotype and enzyme activity were most powerful to predict patients' phenotype and tetrahydrobiopterin response. Phenotype prediction was most accurate in deleterious genotypes (≈ 100%), followed by homozygous (92.9%), hemizygous (94.8%), and compound heterozygous genotypes (77.9%), while tetrahydrobiopterin response was correctly predicted in 71.0% of all cases. To our knowledge this is the largest study using algorithms for the prediction of patients' phenotype and tetrahydrobiopterin responsiveness in phenylketonuria patients, using data from the locus-specific and genotypes database.

  3. Serum phenylalanine screening

    MedlinePlus

    ... test to look for signs of the disease phenylketonuria (PKU). The test detects abnormally high levels of ... MO: Elsevier Saunders; 2013:chap P. Read More Phenylketonuria Review Date 4/21/2015 Updated by: Neil ...

  4. CW/Pulsed H- ion beam generation with PKU Cs-free 2.45 GHz microwave driven ion source

    NASA Astrophysics Data System (ADS)

    Peng, S. X.; Ren, H. T.; Xu, Y.; Zhang, T.; Zhang, A. L.; Zhang, J. F.; Zhao, J.; Guo, Z. Y.; Chen, J. E.

    2015-04-01

    Circular accelerators used for positron emission tomography (PET, i.e. accelerator used for make radio isotopes) need several mA of CW H- ion beam for their routine operation. Other facilities, like Space Radio-Environment Simulate Assembly (SPRESA), require less than 10 mA pulsed mode H- beam. Caesium free negative hydrogen ion source is a good choice for those facilities because of its compact structure, easy operation and low cost. Up to now, there is no H- source able to produce very intense H- beams with important variation of the duty factor[1]. Recently, a new version of 2.45 GHz microwave H- ion source was designed at PKU, based on lessons learnt from the previous one. This non cesiated source is very compact thanks to its permanent magnet configuration. Special attention was paid on the design of the discharge chamber structure, electron dumping and extraction system. Source test to produce H- ion beams in pulsed and CW mode was carried out on PKU ion source test bench. In CW mode, a 10.8 mA/30keV H- beam with rms emittance about 0.16 π.mm.mrad has been obtained with only 500 W rf power. The power efficiency reaches 21 mA/kW. In pulsed mode with duty factor of 10% (100Hz/1ms), this compact source can easily deliver 20 mA H- ion beam at 35 keV with rms emittance about 0.2 π.mm.mrad when RF power is set at 2.2 kW (peak power). Several hour successive running operation in both modes and totaling more than 200 hours proves its high quality. The outside dimension of this new H- source body is ϕ116 mm × 124 mm, and the entire H- source infrastructure, including rf matching section, plasma chamber and extraction system, is ϕ310 × 180 mm. The high voltage region is limited with in a ϕ310 mm × 230 mm diagram. Details are given in this paper.

  5. [Effects of Different Pretreatment Methods on the Phenylketonuria Screening Model by FTIR/ATR Spectroscopy].

    PubMed

    Wang, Wei-wei; Wei, Wei-wei; Song, Xiang-gang; Cheng, Ya-ting; Chen, Chao; Wang, Shu-mei; Liang, Sheng-wang

    2015-05-01

    To establish a phenylketonuria screening model by FTIR/ATR spectroscopy, and to compare the effects of different pretreatment methods, such as baseline correction, smoothing, derivation, Fourier deconvolution, on the model quality. A consensus partial least squares regression method (cPLS) was used to build the quantitative model of phenylalanine in dried blood spots. The effects of different pretreatment methods on the model performance were investigated, using the correlation coefficient (r), root mean square error of prediction (RMSEP), mean relative error (MRE) and predictive accuracy (Acc). The nine-point smoothing coupled with the first differential was found to perform the best. Compared with the model by the original spectra, its r, RMSEP, MRE and Acc were improved from 0. 822 7, 115. 8, 0. 395 and 94. 6 to 0. 889 9, 102. 2, 0. 286 and 100, respectively. With the advantages of fast speed, easy process, no reagents consumption and environmental protection, the present method is expected to become a simple and green technology for rapidly screening the neonatal phenylketonuria in a large population.

  6. Phenylketonuria, congenital hypothyroidism and haemoglobinopathies: public health issues for a Brazilian newborn screening program.

    PubMed

    Botler, Judy; Camacho, Luiz Antonio Bastos; Cruz, Marly Marques da

    2012-09-01

    In this study, the frequency of detected congenital hypothyroidism, phenylketonuria and haemoglobinopathies in the State of Rio de Janeiro's (Brazil) Newborn Screening Program (NBSP) was analyzed between the years of 2005 and 2007. There were two Newborn Screening Reference Centers (named NSRC A and B) with programmatic differences. In 2007, overall detection coverage reached 80.7%. The increase in the incidence of congenital hypothyroidism (1:1,030 in 2007) was attributed to the reduction of neonatal TSH value limits over time. The incidence discrepancy of phenylketonuria between NSRC A (1:28,427) and B (1:16,522) might be partially explained by the small number of cases. The incidence of sickle cell disease and its traits were uniformly high (1:1,288 and 1:21, respectively). This was coherent with the ethnic composition of the population. The differences in laboratory methods and critical values, in addition to other programmatic issues, may explain the variances in the results and limited analysis of the role of biological and environmental determinants in the occurrence of these diseases.

  7. Transcultural pediatrics: compliance and outcome of phenylketonuria patients from families with an immigration background.

    PubMed

    Ipsiroglu, Osman S; Herle, Marion; Spoula, Elisabeth; Möslinger, Dorothea; Wimmer, Banu; Burgard, Peter; Bode, Harald; Stöckler-Ipsiroglu, Sylvia

    2005-08-01

    Living in a foreign country with a different lifestyle and a different orientation is a many-faceted challenge for immigrants. A considerable percentage (30-50%) of patients with metabolic disease come from immigrant families from Turkey and the Middle East. Phenylketonuria is one example of metabolic disease in which severe mental retardation can be entirely prevented by early detection via newborn screening and consistent dietary treatment. We report 7 phenylketonuria patients from 3 Turkish families who had considerable difficulty in coping with the diagnosis and adherence to the diet. Blood phenylalanine levels beyond recommended limits and IQ values below average, clearly demonstrate the risks arising from language as well as psychological and cultural communication barriers, despite standardized follow-up care structures and the observance of continuity by medical caregivers. To propose a basis for systematic improvement in the care of patients from immigrant families we suggest that a) the services of professional interpreters be used in case of language barriers; b) social workers with appropriate sociocultural and language competence should accompany the family in a professional manner; c) it would be meaningful to introduce treatment contracts that clearly establish the limits of the client's rights and duties as well as those of the care-givers. From the viewpoint of legislation, providing medical information is duty of the hospital and the use of translator is mandatory with patients from foreign countries and with foreign languages.

  8. Selective activity of phenylacetate against malignant gliomas: resemblance to fetal brain damage in phenylketonuria.

    PubMed

    Samid, D; Ram, Z; Hudgins, W R; Shack, S; Liu, L; Walbridge, S; Oldfield, E H; Myers, C E

    1994-02-15

    Phenylacetate, a deaminated metabolite of phenylalanine, has been implicated in damage to immature brain in phenylketonuria. Because primary brain tumors are highly reminiscent of the immature central nervous system, these neoplasms should be equally vulnerable. We show here that sodium phenylacetate can induce cytostasis and reversal of malignant properties of cultured human glioblastoma cells, when used at pharmacological concentrations that are well tolerated by children and adults. Treated tumor cells exhibited biochemical alterations similar to those observed in phenylketonuria-like conditions, including selective decline in de novo cholesterol synthesis from mevalonate. Because gliomas, but not mature normal brain cells, are highly dependent on mevalonate for production of sterols and isoprenoids vital for cell growth, sodium phenylacetate would be expected to affect tumor growth in vivo while sparing normal tissues. Systemic treatment of rats bearing intracranial gliomas resulted in significant tumor suppression with no apparent toxicity to the host. The data indicate that phenylacetate, acting through inhibition of protein prenylation and other mechanisms, may offer a safe and effective novel approach to treatment of malignant gliomas and perhaps other neoplasms as well.

  9. Neuropsychological Deficits in Early Treated Phenylketonuric Children.

    ERIC Educational Resources Information Center

    Pennington, Bruce F.; And Others

    1985-01-01

    Six early treated children with phenylketonuria (PKU) were compared at 9 to 14 years of age on a neuropsychological measure with three groups of children with documented neurological disorders. PKU Ss had overall level of neuropsychological impairment similar to that of brain-damaged groups. PKU Ss did not show consistent pattern of…

  10. White matter integrity and executive abilities following treatment with tetrahydrobiopterin (BH4) in individuals with phenylketonuria.

    PubMed

    White, Desirée A; Antenor-Dorsey, Jo Ann V; Grange, Dorothy K; Hershey, Tamara; Rutlin, Jerrel; Shimony, Joshua S; McKinstry, Robert C; Christ, Shawn E

    2013-11-01

    Tetrahydrobiopterin (BH(4)) lowers blood phenylalanine (Phe) in individuals with PKU who are responders, but its effects on the brain and cognition have not been explored thoroughly. We examined blood Phe, microstructural white matter integrity, and executive abilities in 12 BH(4) responders before (i.e., baseline) and after (i.e., follow-up) six months of treatment with BH(4). Compared with baseline, Phe in these responders decreased by 51% during a 4 week screening period after initiation of treatment and remained lowered by 37% over the 6 month follow-up period. Significant improvements in white matter integrity, evaluated by mean diffusivity from diffusion tensor imaging, were also found following six months of treatment. Improvements in executive abilities were not identified, although six months may have been a period too brief for changes in cognition to follow changes in the brain. To our knowledge, our study is the first to explore relationships among Phe, white matter integrity, executive abilities, and BH(4) treatment within a single study.

  11. Phenylketonuria: protein content and amino acids profile of dishes for phenylketonuric patients. The relevance of phenylalanine.

    PubMed

    Pimentel, Filipa B; Alves, Rita C; Costa, Anabela S G; Torres, Duarte; Almeida, Manuela F; Oliveira, M Beatriz P P

    2014-04-15

    Phenylketonuria is an inborn error of metabolism, involving, in most cases, a deficient activity of phenylalanine hydroxylase. Neonatal diagnosis and a prompt special diet (low phenylalanine and natural-protein restricted diets) are essential to the treatment. The lack of data concerning phenylalanine contents of processed foodstuffs is an additional limitation for an already very restrictive diet. Our goals were to quantify protein (Kjeldahl method) and amino acid (18) content (HPLC/fluorescence) in 16 dishes specifically conceived for phenylketonuric patients, and compare the most relevant results with those of several international food composition databases. As might be expected, all the meals contained low protein levels (0.67-3.15 g/100 g) with the highest ones occurring in boiled rice and potatoes. These foods also contained the highest amounts of phenylalanine (158.51 and 62.65 mg/100 g, respectively). In contrast to the other amino acids, it was possible to predict phenylalanine content based on protein alone. Slight deviations were observed when comparing results with the different food composition databases.

  12. Prolonged exposure to high and variable phenylalanine levels over the lifetime predicts brain white matter integrity in children with phenylketonuria.

    PubMed

    Hood, Anna; Antenor-Dorsey, Jo Ann V; Rutlin, Jerrel; Hershey, Tamara; Shimony, Joshua S; McKinstry, Robert C; Grange, Dorothy K; Christ, Shawn E; Steiner, Robert; White, Desiree A

    2015-01-01

    In this study, we retrospectively examined the microstructural white matter integrity of children with early- and continuously-treated PKU (N=36) in relation to multiple indices of phenylalanine (Phe) control over the lifetime. White matter integrity was assessed using mean diffusivity (MD) from diffusion tensor imaging (DTI). Eight lifetime indices of Phe control were computed to reflect average Phe (mean, index of dietary control), variability in Phe (standard deviation, standard error of estimate, % spikes), change in Phe with age (slope), and prolonged exposure to Phe (mean exposure, standard deviation exposure). Of these indices, mean Phe, mean exposure, and standard deviation exposure were the most powerful predictors of widespread microstructural white matter integrity compromise. Findings from the two previously unexamined exposure indices reflected the accumulative effects of elevations and variability in Phe. Given that prolonged exposure to elevated and variable Phe was particularly detrimental to white matter integrity, Phe should be carefully monitored and controlled throughout childhood, without liberalization of Phe control as children with PKU age.

  13. A novel common large genomic deletion and two new missense mutations identified in the Romanian phenylketonuria population.

    PubMed

    Gemperle-Britschgi, Corinne; Iorgulescu, Daniela; Mager, Monica Alina; Anton-Paduraru, Dana; Vulturar, Romana; Thöny, Beat

    2016-01-15

    The mutation spectrum for the phenylalanine hydroxylase (PAH) gene was investigated in a cohort of 84 hyperphenylalaninemia (HPA) patients from Romania identified through newborn screening or neurometabolic investigations. Differential diagnosis identified 81 patients with classic PAH deficiency while 3 had tetrahydropterin-cofactor deficiency and/or remained uncertain due to insufficient specimen. PAH-genetic analysis included a combination of Sanger sequencing of exons and exon–intron boundaries, MLPA and NGS with genomic DNA, and cDNA analysis from immortalized lymphoblasts. A diagnostic efficiency of 99.4% was achieved, as for one allele (out of a total of 162 alleles) no mutation could be identified. The most prevalent mutation was p.Arg408Trp which was found in ~ 38% of all PKU alleles. Three novel mutations were identified, including the two missense mutations p.Gln226Lys and p.Tyr268Cys that were both disease causing by prediction algorithms, and the large genomic deletion EX6del7831 (c.509 + 4140_706 + 510del7831) that resulted in skipping of exon 6 based on PAH-cDNA analysis in immortalized lymphocytes. The genomic deletion was present in a heterozygous state in 12 patients, i.e. in ~ 8% of all the analyzed PKU alleles, and might have originated from a Romanian founder.

  14. CW/Pulsed H{sup −} ion beam generation with PKU Cs-free 2.45 GHz microwave driven ion source

    SciTech Connect

    Peng, S. X. Ren, H. T.; Xu, Y.; Zhang, T.; Zhang, J. F.; Zhao, J.; Guo, Z. Y.; Zhang, A. L.; Chen, J. E.

    2015-04-08

    Circular accelerators used for positron emission tomography (PET, i.e. accelerator used for make radio isotopes) need several mA of CW H- ion beam for their routine operation. Other facilities, like Space Radio-Environment Simulate Assembly (SPRESA), require less than 10 mA pulsed mode H{sup −} beam. Caesium free negative hydrogen ion source is a good choice for those facilities because of its compact structure, easy operation and low cost. Up to now, there is no H{sup −} source able to produce very intense H{sup −} beams with important variation of the duty factor{sup [1]}. Recently, a new version of 2.45 GHz microwave H{sup −} ion source was designed at PKU, based on lessons learnt from the previous one. This non cesiated source is very compact thanks to its permanent magnet configuration. Special attention was paid on the design of the discharge chamber structure, electron dumping and extraction system. Source test to produce H{sup −} ion beams in pulsed and CW mode was carried out on PKU ion source test bench. In CW mode, a 10.8 mA/30keV H{sup −} beam with rms emittance about 0.16 π·mm·mrad has been obtained with only 500 W rf power. The power efficiency reaches 21 mA/kW. In pulsed mode with duty factor of 10% (100Hz/1ms), this compact source can easily deliver 20 mA H{sup −} ion beam at 35 keV with rms emittance about 0.2 π·mm·mrad when RF power is set at 2.2 kW (peak power). Several hour successive running operation in both modes and totaling more than 200 hours proves its high quality. The outside dimension of this new H{sup −} source body is ϕ116 mm × 124 mm, and the entire H{sup −} source infrastructure, including rf matching section, plasma chamber and extraction system, is ϕ310 × 180 mm. The high voltage region is limited with in a ϕ310 mm × 230 mm diagram. Details are given in this paper.

  15. Long-term treatment with tetrahydrobiopterin in phenylketonuria: treatment strategies and prediction of long-term responders.

    PubMed

    Hennermann, Julia B; Roloff, Sylvia; Gebauer, Christine; Vetter, Barbara; von Arnim-Baas, Annabel; Mönch, Eberhard

    2012-11-01

    Tetrahydrobiopterin (BH4) responsive phenylketonuria has been described more than 10 years ago. However, criteria for the identification of long-term BH4 responsive patients are not yet established. 116 patients with phenylketonuria, aged 4-18 years, were screened for potential long-term BH4 responsiveness by at least two of the following criteria: positive neonatal BH4 loading test, putative BH4 responsive genotype, and/or milder phenotype. Patients had to be on permanent dietary treatment. 23 patients fulfilled these criteria and were tested for long-term BH4 responsiveness: 18/23 were long-term BH4 responsive, 5/23 were not. On long-term BH4 treatment over a period of 48 ± 27 months in a dose of 14.9 ± 3.3mg/kg/day phenylalanine tolerance was increased from 452 ± 201 mg/day to 1593 ± 647 mg/day, corresponding to a mean increase of 1141 ± 528 mg/day. Dietary phenylalanine intake was increased stepwise according to a clear defined protocol. In 8/18 patients, diet was completely liberalized; 10/18 patients still received phenylalanine-free amino acid formula with 0.63 ± 0.23 g/kg/day. The most predictive value for long-term BH4 responsiveness was the combination of pretreatment phenylalanine of < 1200 μmol/L, pretreatment phenylalanine/tyrosine ratio of <15, phenylalanine/tyrosine ratio of <15 on treatment, phenylalanine tolerance of >20mg/kg/day at age 3 years, positive neonatal BH4 loading, and at least one putative BH4 responsive mutation (p = 0.00024). Our data show that long-term BH4 responsiveness may be predicted already during neonatal period by determining maximum pretreatment phenylalanine and phenylalanine/tyrosine concentrations, neonatal BH4 loading and PAH genotype. A clear defined protocol is necessary to install long-term BH4 treatment.

  16. Health-related quality of life in children and adolescents with phenylketonuria: unimpaired HRQoL in patients but feared school failure in parents.

    PubMed

    Thimm, Eva; Schmidt, Lisa Elena; Heldt, Katrin; Spiekerkoetter, Ute

    2013-09-01

    Aim of the study was the evaluation of health-related quality of life (HRQoL) and the detection of deviant behavior in early-treated children and adolescents with PKU in comparison with healthy peers. Special focus was laid on the impact of compliance with treatment as defined by the national recommendations on HRQoL. Our investigation in 50 children and adolescents and their parents for the first time demonstrates that despite an overall normal HRQoL in our PKU patient collective, parents are concerned about performance in school especially when phenylalanine concentrations in their children are mainly above the therapeutic range. Adherence to target phenylalanine concentrations ameliorated markedly in patients above 10 years in comparison to younger patients due to relaxed treatment recommendations. Interestingly, this alleged improvement in metabolic control has an impact on the parent assessed but not on the patient assessed appraisal of HRQoL. However, a positive correlation between poor metabolic control and conduct problems was identified by patients' self-assessment. In conclusion, lacking adherence to the strict treatment recommendations in infancy results in significant concern about school success and success in life in parents of PKU patients. With relaxation of dietary phenylalanine restriction at 10 years of age, these concerns diminish.

  17. Birth Defects: What They Are and How They Happen

    MedlinePlus

    ... Neonatal abstinence syndrome (NAS) Neural tube defects Neurofibromatosis Organic acid metabolism disorders PKU (Phenylketonuria) in your baby ... Treatment of fatty acid oxidation disorders Treatment of organic acid metabolism disorders In This Topic Achondroplasia Amino ...

  18. Contact with Phenylketonurics and Their Families Beyond Pediatric Age: Conclusion from a Survey and Conference

    ERIC Educational Resources Information Center

    Fisch, Robert O.; And Others

    1977-01-01

    Twenty parents of children 12 years and older with PKU (phenylketonuria, a metabolic disorder which if untreated can result in mental retardation) were surveyed to determine their level of knowledge and their needs. (CL)

  19. Heart Murmurs and Your Child (For Parents)

    MedlinePlus

    ... heard before. Heart murmurs are rated on a scale from 1 to 6 based on how loud ... PKU (phenylketonuria, a genetic error of the body's metabolism). Common Heart Defects Several kinds of heart problems ...

  20. Amino Acid Metabolism Disorders

    MedlinePlus

    ... breaks the food parts down into sugars and acids, your body's fuel. Your body can use this ... process. One group of these disorders is amino acid metabolism disorders. They include phenylketonuria (PKU) and maple ...

  1. Evaluation of trace element and mineral status and related to levels of amino acid in children with phenylketonuria.

    PubMed

    Gok, Fazilet; Ekin, Suat; Dogan, Murat

    2016-07-01

    The aim of the present study was to examine trace elements (Zn, Cu, Mn, Se, Fe, Co, Cr, Ni, Cd, Pb), minerals (Ca, Mg, K), amino acids status in children with phenylketonuria and also whether they were correlated with each other in phenylketonuric patients. It has been found out that the HPA group was significantly lower than the control group with regards to Zn, Se, K, Ca, Mg and Zn/Cr levels (p<0.001, p<0.01, p<0.001, p<0.01, p<0.01 and p<0.001 respectively). In the patients with HPA, significantly strong positive correlations were observed between magnesium and calcium (r=0.791; p=0.001), also, indicates negative significant correlation between the concentrations of magnesium and phenylalanine (r=-0.591; p=0.026). The results of this study showed that, in the HPA group, phenylalanine-Mg relationship found, the presence of disease will in the evaluation of phenylalanine and other amino acids, together with the value of magnesium is required to consider.

  2. PKU Self-Management Timeline

    MedlinePlus

    ... difference between your child ‘having’ a specific self-management skill and ‘performing the skill independently’ at all times. It is important that parents Age of Child Tasks for Children ...

  3. Diseases of Phenylalanine Metabolism

    PubMed Central

    Parker, Charles E.

    1979-01-01

    Continuing investigation of the system that hydroxylates phenylalanine to tyrosine has led to new insights into diseases associated with the malfunction of this system. Good evidence has confirmed that phenylketonuria (PKU) is not caused by a simple lack of phenylalanine hydroxylase. Dihydropteridine reductase deficiency as well as defects in biopterin metabolism may also cause the clinical features of phenylketonuria. Furthermore, these diseases do not respond to the standard treatment for phenylketonuria. PMID:388868

  4. Behavioral and neurochemical characterization of new mouse model of hyperphenylalaninemia.

    PubMed

    Pascucci, Tiziana; Giacovazzo, Giacomo; Andolina, Diego; Accoto, Alessandra; Fiori, Elena; Ventura, Rossella; Orsini, Cristina; Conversi, David; Carducci, Claudia; Leuzzi, Vincenzo; Puglisi-Allegra, Stefano

    2013-01-01

    Hyperphenylalaninemia (HPA) refers to all clinical conditions characterized by increased amounts of phenylalanine (PHE) in blood and other tissues. According to their blood PHE concentrations under a free diet, hyperphenylalaninemic patients are commonly classified into phenotypic subtypes: classical phenylketonuria (PKU) (PHE > 1200 µM/L), mild PKU (PHE 600-1200 µM/L) and persistent HPA (PHE 120-600 µM/L) (normal blood PHE < 120 µM/L). The current treatment for hyperphenylalaninemic patients is aimed to keep blood PHE levels within the safe range of 120-360 µM/L through a PHE-restricted diet, difficult to achieve. If untreated, classical PKU presents variable neurological and mental impairment. However, even mildly elevated blood PHE levels, due to a bad compliance to dietary treatment, produce cognitive deficits involving the prefrontal cortical areas, extremely sensible to PHE-induced disturbances. The development of animal models of different degrees of HPA is a useful tool for identifying the metabolic mechanisms underlying cognitive deficits induced by PHE. In this paper we analyzed the behavioral and biochemical phenotypes of different forms of HPA (control, mild-HPA, mild-PKU and classic-PKU), developed on the base of plasma PHE concentrations. Our results demonstrated that mice with different forms of HPA present different phenotypes, characterized by increasing severity of behavioral symptoms and brain aminergic deficits moving from mild HPA to classical PKU forms. In addition, our data identify preFrontal cortex and amygdala as the most affected brain areas and confirm the highest susceptibility of brain serotonin metabolism to mildly elevated blood PHE.

  5. [Embryofetopathy of the newborn infant of a phenylketonuric mother. A diagnosis not to be missed].

    PubMed

    Farriaux, J P; Dhondt, J L; Largillière, C; Lacombe, A; Valat, S; Puech, F

    1993-01-01

    Children with phenylketonuria (PKU) detected in the neonatal period and who have received the appropriate diet develop normally whatever their sex. However, female PKU patients who, before becoming pregnant, do not take the precaution to follow a diet bringing phenylalanine to "normal levels" (2 to 5 mg in 100 ml of blood) give birth to children presenting with severe embryofoetal damage (e.g. intrauterine growth retardation, microcephaly, mental retardation, various malformations) directly due to their hyperphenylalaninaemia (20 mg or more in 100 ml of blood under a free diet). It is important to know these facts, since the benefits of systematic neonatal PKU detection may be cancelled by this late complication. The therapeutic approach in such cases is a follows: 1. Young women with known PKU must be informed of this risk and how it can be avoided by a preconception therapeutic diet. This means that they must permanently reside in the same geographical area, receive an adequate information at the end of puberty, use and effective contraception method and program their pregnancies preceded by a return to low phenylalanine diet. 2. Doctors must remember that because PKU detection has not become systematic until 1978, PKU girls of child-bearing are remain undetected, that they are not always mentally debilitated and can normally five birth to children with embryofoetal damage. In case of e.g. unexplained intrauterine growth retardation or microcephaly, it is necessary to perform a Guthrie test on the woman, since a prenatal diagnosis may lead to therapeutic abortion, and a postnatal diagnosis to a genetic counselling which will avoid recurrences.(ABSTRACT TRUNCATED AT 250 WORDS)

  6. Inborn errors in metabolism and 4-boronophenylalanine-fructose-based boron neutron capture therapy.

    PubMed

    Laakso, Juha; Ruokonen, Inkeri; Lapatto, Risto; Kallio, Merja

    2003-11-01

    Infusions of boronophenylalanine-fructose complex (BPA-F), at doses up to 900 mg/kg of BPA and 860 mg/kg of fructose, have been used to deliver boron to cancer tissue for boron neutron capture therapy (BNCT). In patients with phenylketonuria (PKU), phenylalanine accumulates, which is harmful in the long run. PKU has been an exclusion criterion for BPA-F-mediated BNCT. Fructose is harmful to individuals with hereditary fructose intolerance (HFI) in amounts currently used in BNCT. The harmful effects are mediated through induction of hypoglycemia and acidosis, which may lead to irreversible organ damage or even death. Consequently, HFI should be added as an exclusion criterion for BNCT if fructose-containing solutions are used in boron carriers. Non-HFI subjects may also develop symptoms, such as gastrointestinal pain, if the fructose infusion rate is high. We therefore recommend monitoring of glucose levels and correcting possible hypoglycemia promptly. Except for some populations with extremely low PKU prevalence, HFI and PKU prevalences are similar, approximately 1 or 2 per 20,000.

  7. Dictyostelium discoideum Ax2 as an Assay System for Screening of Pharmacological Chaperones for Phenylketonuria Mutations.

    PubMed

    Kim, Yu-Min; Yang, Yun Gyeong; Kim, Hye-Lim; Park, Young Shik

    2015-06-01

    In this study, we developed an assay system for missense mutations in human phenylalanine hydroxylases (hPAHs). To demonstrate the reliability of the system, eight mutant proteins (F39L, K42I, L48S, I65T, R252Q, L255V, S349L, and R408W) were expressed in a mutant strain (pah(-)) of Dictyostelium discoideum Ax2 disrupted in the indigenous gene encoding PAH. The transformed pah- cells grown in FM minimal medium were measured for growth rate and PAH activity to reveal a positive correlation between them. The protein level of hPAH was also determined by western blotting to show the impact of each mutation on protein stability and catalytic activity. The result was highly compatible with the previous ones obtained from other expression systems, suggesting that Dictyostelium is a dependable alternative to other expression systems. Furthermore, we found that both the protein level and activity of S349L and R408W, which were impaired severely in protein stability, were rescued in HL5 nutrient medium. Although the responsible component(s) remains unidentified, this unexpected finding showed an important advantage of our expression system for studying unstable proteins. As an economic and stable cell-based expression system, our development will contribute to mass-screening of pharmacological chaperones for missense PAH mutations as well as to the in-depth characterization of individual mutations.

  8. Phenylketonuria Genetic Screening Simulation

    ERIC Educational Resources Information Center

    Erickson, Patti

    2012-01-01

    After agreeing to host over 200 students on a daylong genetics field trip, the author needed an easy-to-prepare genetics experiment to accompany the DNA-necklace and gel-electrophoresis activities already planned. One of the student's mothers is a pediatric physician at the local hospital, and she suggested exploring genetic-disease screening…

  9. Showing Value in Newborn Screening: Challenges in Quantifying the Effectiveness and Cost-Effectiveness of Early Detection of Phenylketonuria and Cystic Fibrosis

    PubMed Central

    Grosse, Scott D.

    2015-01-01

    Decision makers sometimes request information on the cost savings, cost-effectiveness, or cost-benefit of public health programs. In practice, quantifying the health and economic benefits of population-level screening programs such as newborn screening (NBS) is challenging. It requires that one specify the frequencies of health outcomes and events, such as hospitalizations, for a cohort of children with a given condition under two different scenarios—with or without NBS. Such analyses also assume that everything else, including treatments, is the same between groups. Lack of comparable data for representative screened and unscreened cohorts that are exposed to the same treatments following diagnosis can result in either under- or over-statement of differences. Accordingly, the benefits of early detection may be understated or overstated. This paper illustrates these common problems through a review of past economic evaluations of screening for two historically significant conditions, phenylketonuria and cystic fibrosis. In both examples qualitative judgments about the value of prompt identification and early treatment to an affected child were more influential than specific numerical estimates of lives or costs saved. PMID:26702401

  10. ADHD, autism and neuroradiological complications among phenylketonuric children in Upper Egypt.

    PubMed

    Saad, Khaled; Elserogy, Yasser; Abdel Rahman, Ahmed A; Al-Atram, Abdulrahman Abdullah; Mohamad, Ismail L; ElMelegy, Tarek T H; Bjørklund, Geir; El-Houfy, Amira A

    2015-12-01

    The aim of this study is to evaluate the neuropsychological status in a cohort of children with early and continuously treated phenylketonuria in Assiut, Upper Egypt. The study was implemented in seventy-eight phenylketonuria (PKU) children. Only 34 patients met the inclusion criteria. Investigated patients were evaluated according to detailed history, neurological examination, Childhood Autism Rating Scale, full scale Intelligence Quotient, attention deficit hyperactivity disorder, electroencephalography and magnetic resonance imaging (MRI). This study concluded that the prognosis for early diagnosed children with PKU treated from the first weeks of life is generally good. However, they are at increased risk for neurological complications and behavioral problems. So, neonatal screening for PKU is highly recommended in Egypt, for early detection and management. In addition, neuropsychological and MRI assessments in PKU children should be done.

  11. Using simple molecular orbital calculations to predict disease: fast DFT methods applied to enzymes implicated in PKU, Parkinson's disease and Obsessive Compulsive Disorder

    NASA Astrophysics Data System (ADS)

    Hofto, Laura; Hofto, Meghan; Cross, Jessica; Cafiero, Mauricio

    2007-09-01

    Many diseases can be traced to point mutations in the DNA coding for specific enzymes. These point mutations result in the change of one amino acid residue in the enzyme. We have developed a model using simple molecular orbital calculations which can be used to quantitatively determine the change in interaction between the enzyme's active site and necessary ligands upon mutation. We have applied this model to three hydroxylase proteins: phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase, and we have obtained excellent correlation between our results and observed disease symptoms. Furthermore, we are able to use this agreement as a baseline to screen other mutations which may also cause onset of disease symptoms. Our focus is on systems where the binding is due largely to dispersion, which is much more difficult to model inexpensively than pure electrostatic interactions. Our calculations are run in parallel on a sixteen processor cluster of 64-bit Athlon processors.

  12. Current Status of Newborn Screening: Decision-Making about the Conditions to Include in Screening Programs

    ERIC Educational Resources Information Center

    Watson, Michael S.

    2006-01-01

    Newborn screening is considered a highly successful public health program that has resulted in the reduction of mortality, mental retardation, and other serious disabilities in thousands of children since the introduction of screening for phenylketonuria (PKU) in the 1960s. Programs are based in state public health departments such that each state…

  13. SOME FACTS AND FIGURES ABOUT CHILDREN AND YOUTH.

    ERIC Educational Resources Information Center

    Children's Bureau (DHEW), Washington, DC.

    IN QUESTION AND ANSWER FORM, THE PAMPHLET PRESENTS STATISTICAL DATA ON CHILDREN AND YOUTH PRIMARILY IN THE UNITED STATES. INFORMATION CONCERNS POPULATION, RESIDENCE, MOBILITY, POVERTY, WORKING MOTHERS, MARRIAGES, DIVORCES, BIRTHS, LIFE EXPECTANCY, MORTALITY, ILLNESS, HANDICAPS, HOSPITALIZATION, ADOPTIONS, PHENYLKETONURIA (PKU) LAWS, CHILD ABUSE…

  14. Monkey Retardate Learning Analysis

    ERIC Educational Resources Information Center

    Chamove, A. S.; Molinaro, T. J.

    1978-01-01

    Seven rhesus monkeys reared on diets high in phenylalanine to induce phenylketonuria (PKU--a metabolic disorder associated with mental retardation if untreated) were compared with normal, pair-fed, and younger controls; frontal brain-lesioned monkeys; and those raised on high-tryptophan diets in three object discrimination tasks. (Author)

  15. Computational study of missense mutations in phenylalanine hydroxylase.

    PubMed

    Réblová, Kamila; Kulhánek, Petr; Fajkusová, Lenka

    2015-04-01

    Hyperphenylalaninemia (HPA) is one of the most common metabolic disorders. HPA, which is transmitted by an autosomal recessive mode of inheritance, is caused by mutations of the phenylalanine hydroxylase gene. Most mutations are missense and lead to reduced protein stability and/or impaired catalytic function. The impact of such mutations varies, ranging from classical phenylketonuria (PKU), mild PKU, to non-PKU HPA phenotypes. Despite the fact that HPA is a monogenic disease, clinical data show that one PKU genotype can be associated with more in vivo phenotypes, which indicates the role of other (still unknown) factors. To better understand the phenotype-genotype relationships, we analyzed computationally the impact of missense mutations in homozygotes stored in the BIOPKU database. A total of 34 selected homozygous genotypes was divided into two main groups according to their phenotypes: (A) genotypes leading to non-PKU HPA or combined phenotype non-PKU HPA/mild PKU and (B) genotypes leading to classical PKU, mild PKU or combined phenotype mild PKU/classical PKU. Combining in silico analysis and molecular dynamics simulations (in total 3 μs) we described the structural impact of the mutations, which allowed us to separate 32 out of 34 mutations between groups A and B. Testing the simulation conditions revealed that the outcome of mutant simulations can be modulated by the ionic strength. We also employed programs SNPs3D, Polyphen-2, and SIFT but based on the predictions performed we were not able to discriminate mutations with mild and severe PKU phenotypes.

  16. Essentials of PKU for Young Adults with PKU and Their Significant Others

    MedlinePlus

    ... 1) Phenylalanine is only one of the many amino acids which are joined together to form proteins. Normally, ... eats foods containing protein, their body uses the amino acids from that protein for growth and repair of ...

  17. Determination of Phenylalanine and Tyrosine by High Performance Liquid Chromatography-Tandem Mass Spectrometry.

    PubMed

    Peat, Judy; Garg, Uttam

    2016-01-01

    Hyperphenylalaninemia/phenylketonuria (PKU) is one of the most common inborn errors of amino acid metabolism affecting about 1:15,000 infants in the United States. PKU is an autosomal recessive disorder that if untreated results in mental retardation. The most common cause of PKU is deficiency of the enzyme phenylalanine hydroxylase that converts phenylalanine to tyrosine. Tyrosine deficiency results in impaired synthesis of catecholamines and thyroxine. Less commonly, it can result from defects in the synthesis or regeneration of tetrahydrobiopterin (BH4), an essential cofactor for the enzyme phenylalanine hydroxylase. Increased phenylalanine and decreased tyrosine in blood are used in the diagnosis and follow-up of patients with PKU. LC/MS/MS method is described for the quantification of phenylalanine and tyrosine.

  18. Screening Out Controversy: Human Genetics, Emerging Techniques of Diagnosis, and the Origins of the Social Issues Committee of the American Society of Human Genetics, 1964-1973.

    PubMed

    Mitchell, M X

    2016-02-18

    In the years following World War II, and increasingly during the 1960s and 1970s, professional scientific societies developed internal sub-committees to address the social implications of their scientific expertise (Moore, Disrupting Science: Social Movements, American Scientists, and the Politics of the Military, 1945-1975. Princeton: Princeton University Press, 2008). This article explores the early years of one such committee, the American Society of Human Genetics' "Social Issues Committee," founded in 1967. Although the committee's name might suggest it was founded to increase the ASHG's public and policy engagement, exploration of the committee's early years reveals a more complicated reality. Affronted by legislators' recent unwillingness to seek the expert advice of human geneticists before adopting widespread neonatal screening programs for phenylketonuria (PKU), and feeling pressed to establish their relevance in an increasingly resource-scarce funding environment, committee members sought to increase the discipline's expert authority. Painfully aware of controversy over abortion rights and haunted by the taint of the discipline's eugenic past, however, the committee proceeded with great caution. Seeking to harness interest in and assert professional control over emerging techniques of genetic diagnosis, the committee strove to protect the society's image by relegating ethical and policy questions about their use to the individual consciences of member scientists. It was not until 1973, after the committee's modest success in organizing support for a retrospective public health study of PKU screening and following the legalization of abortion on demand, that the committee decided to take a more publicly engaged stance.

  19. Cultural aspects in the management of inborn errors of metabolism.

    PubMed

    Stockler, Sylvia; Moeslinger, Dorothea; Herle, Marion; Wimmer, Banu; Ipsiroglu, Osman S

    2012-11-01

    European Health Care Systems have not yet accommodated both previous and current migration waves. Children from immigrant families, especially children with chronic conditions, are particularly affected from the shortcomings in medical care. One condition, phenylketonuria (PKU), is an inborn error of metabolism (IEM) which results in intellectual disability unless treated with a lifelong phenylalanine (Phe) restricted diet. In our PKU clinic, patients from families who previously had emmigrated from the geographic area of Turkey to Austria, exhibited worse blood Phe control and cognitive development than comparable patients from native Austrian families. Using structured and semi-structured interviews, questionnaires, and illness narratives, we identified language, psychosocial, economic, educational and cultural barriers as factors influencing adherence to treatment. Our findings led us to conclude that access to interpreter services, exploration of the socio-cultural background and of family ecology, as well as bi-directional communication and medical decision making according to the "best interest of the child" principle, may improve outcomes in patients requiring complex treatment and care.

  20. Genotype-phenotype correlations analysis of mutations in the phenylalanine hydroxylase (PAH) gene.

    PubMed

    Bercovich, Dani; Elimelech, Arava; Zlotogora, Joel; Korem, Sigal; Yardeni, Tal; Gal, Nurit; Goldstein, Nurit; Vilensky, Bela; Segev, Roni; Avraham, Smadar; Loewenthal, Ron; Schwartz, Gerard; Anikster, Yair

    2008-01-01

    The aims of our research were to define the genotype-phenotype correlations of mutations in the phenylalanine hydroxylase (PAH) gene that cause phenylketonuria (PKU) among the Israeli population. The mutation spectrum of the PAH gene in PKU patients in Israel is described, along with a discussion on genotype-phenotype correlations. By using polymerase chain reaction/denaturing high-performance liquid chromatography (PCR/dHPLC) and DNA sequencing, we screened all exons of the PAH gene in 180 unrelated patients with four different PKU phenotypes [classic PKU, moderate PKU, mild PKU, and mild hyperphenylalaninemia (MHP)]. In 63.2% of patient genotypes, the metabolic phenotype could be predicted, though evidence is also found for both phenotypic inconsistencies among subjects with more than one type of mutation in the PAH gene. Data analysis revealed that about 25% of patients could participate in the future in (6R)-L: -erythro-5, 6, 7, 8-tetrahydrobiopterin (BH4) treatment trials according to their mutation genotypes. This study enables us to construct a national database in Israel that will serve as a valuable tool for genetic counseling and a prognostic evaluation of future cases of PKU.

  1. Cartoons vs. realistic illustration: picture preferences of adolescent patients.

    PubMed

    Dirr, K L; Katz, A A

    1989-01-01

    Illustrations are an important element in patient education materials because they engage the interest of the audience. However, little research has been conducted to determine the style of illustration that most effectively engages a patient population. This study tested the picture preferences of 39 adolescents with phenylketonuria (PKU). A survey instrument asked them to choose between cartoons and realistic illustrations. A significant number preferred realistic illustrations to cartoons.

  2. Phenylalanine hydroxylase misfolding and pharmacological chaperones.

    PubMed

    Underhaug, Jarl; Aubi, Oscar; Martinez, Aurora

    2012-01-01

    Phenylketonuria (PKU) is a loss-of-function inborn error of metabolism. As many other inherited diseases the main pathologic mechanism in PKU is an enhanced tendency of the mutant phenylalanine hydroxylase (PAH) to misfold and undergo ubiquitin-dependent degradation. Recent alternative approaches with therapeutic potential for PKU aim at correcting the PAH misfolding, and in this respect pharmacological chaperones are the focus of increasing interest. These compounds, which often resemble the natural ligands and show mild competitive inhibition, can rescue the misfolded proteins by stimulating their renaturation in vivo. For PKU, a few studies have proven the stabilization of PKU-mutants in vitro, in cells, and in mice by pharmacological chaperones, which have been found either by using the tetrahydrobiopterin (BH(4)) cofactor as query structure for shape-focused virtual screening or by high-throughput screening of small compound libraries. Both approaches have revealed a number of compounds, most of which bind at the iron-binding site, competitively with respect to BH(4). Furthermore, PAH shares a number of ligands, such as BH(4), amino acid substrates and inhibitors, with the other aromatic amino acid hydroxylases: the neuronal/neuroendocrine enzymes tyrosine hydroxylase (TH) and the tryptophan hydroxylases (TPHs). Recent results indicate that the PAH-targeted pharmacological chaperones should also be tested on TH and the TPHs, and eventually be derivatized to avoid unwanted interactions with these other enzymes. After derivatization and validation in animal models, the PAH-chaperoning compounds represent novel possibilities in the treatment of PKU.

  3. Urinary biomarkers of oxidative stress and plasmatic inflammatory profile in phenylketonuric treated patients.

    PubMed

    Deon, Marion; Sitta, Angela; Faverzani, Jessica L; Guerreiro, Gillian B; Donida, Bruna; Marchetti, Desirèe P; Mescka, Caroline P; Ribas, Graziela S; Coitinho, Adriana S; Wajner, Moacir; Vargas, Carmen R

    2015-12-01

    Oxidative stress has been proposed as an important pathophysiologic feature of various inborn errors of metabolism, including phenylketonuria (PKU). Considering that there are few studies relating oxidative stress and inflammation directly in PKU disease, the aim of this study was to evaluate and correlate oxidative damage to biomolecules, antioxidant defenses, pro-inflammatory cytokines, phenylalanine (Phe) and its metabolites (phenyllactic acid--PLA and phenylacetic acid--PAA) levels in urine and plasma from patients with PKU under dietary treatment. We observed a marked increase of isoprostanes, which is a lipid peroxidation biomarker, in urine from these treated patients. Next, we demonstrated that protein oxidative damage, measured by di-tyrosine formation, was significantly increased in urine from PKU treated patients and that decreased urinary antioxidant capacity was also observed. Our findings concerning to the inflammatory cytokines interleukin-6 and interleukin-1β, both significantly increased in these patients, provide evidence that the pro-inflammatory state occurs. Besides, interleukin-1β was positively correlated with isoprostanes. We observed a negative correlation between interleukin-6 and interleukin-10, an anti-inflammatory cytokine. Di-tyrosine was positively correlated with Phe, which indicates oxidative damage to proteins, as well as with PAA. These findings may suggest that the protein damage may be induced by Phe and its metabolite PAA in PKU. Our results indicate that pro-oxidant and pro-inflammatory states occur and are, in part, correlated and protein oxidation seems to be induced by Phe and PPA in PKU patients.

  4. [The development of molecular human genetics and its significance for perspectives of modern medicine].

    PubMed

    Coutelle, C; Speer, A; Grade, K; Rosenthal, A; Hunger, H D

    1989-01-01

    The introduction of molecular human genetics has become a paradigma for the application of genetic engineering in medicine. The main principles of this technology are the isolation of molecular probes, their application in hybridization reactions, specific gene-amplification by the polymerase chain reaction, and DNA sequencing reactions. These methods are used for the analysis of monogenic diseases by linkage studies and the elucidation of the molecular defect causing these conditions, respectively. They are also the basis for genomic diagnosis of monogenic diseases, introduced into the health care system of the GDR by a national project on Duchenne/Becker muscular dystrophy, Cystic Fibrosis and Phenylketonuria. The rapid development of basic research on the molecular analysis of the human genome and genomic diagnosis indicates, that human molecular genetics is becoming a decisive basic discipline of modern medicine.

  5. Development

    ERIC Educational Resources Information Center

    Childress, Dana C.; Raver, Sharon A.; Michalek, Anne M. P.; Wilson, Corinne L.

    2013-01-01

    All eligible infants and toddlers who receive early intervention services under Part C of Individuals with Disabilities Education Act are entitled to service coordination. To examine the effectiveness of one state's service coordination training and its impact on knowledge and skill development, a pretest--posttest design with follow-up survey was…

  6. Spectrofluorimetric determination of phenylalanine based on fluorescence enhancement of europium ion immobilized with sol-gel method

    NASA Astrophysics Data System (ADS)

    Zhang, Kun; Yan, Hong-Tao; Zhou, Tie

    2011-12-01

    The analysis of phenylalanine (Phe) in serum is widely performed for the screening of newborn phenylketonuria (PKU). In this work, a novel spectrofluorimetric method for the determination of Phe was developed based on the fluorescence enhancement of Ruhemann's purple, the reaction product between Phe and ninhydrin, upon coordination with Eu 3+. A filter paper disc containing immobilized reactants (ninhydrin and Eu 3+) was fabricated by sol-gel method. The experimental parameters affecting the determination of Phe, such as the concentrations of immobilized reagents, the pH value, the reaction time and temperature were optimized. Under optimum conditions, the fluorescence intensity of Phe-ninhydrin-Eu 3+ system was linearly proportional to the concentration of Phe in the range from 5 × 10 -5 to 2 × 10 -3 mol L -1, and the limit of detection was found to be 5.2 × 10 -6 mol L -1. The relative standard deviation was 2.6% for ten replicate measurements of 1.5 × 10 -4 mol L -1 of Phe. The method has merits of sensitivity, simplicity and low cost, and has been applied to the determination of Phe in artificial serum.

  7. Unresponsiveness to tetrahydrobiopterin of phenylalanine hydroxylase deficiency.

    PubMed

    Ponzone, Alberto; Porta, Francesco; Mussa, Alessandro; Alluto, Alessandra; Ferraris, Silvio; Spada, Marco

    2010-05-01

    Conflicting results have been reported concerning the efficacy of tetrahydrobiopterin (BH4), the cofactor of phenylalanine hydroxylase, for reducing phenylalanine (Phe) concentration in phenylketonuria (PKU). We aimed to test quantitatively the effects of BH4 in PKU patients. Seven fully characterized patients were selected among a population of 130 PKU subjects as harboring PKU mutations predicted as BH4 responsive and previously considered responsive to a cofactor challenge. They received a simple Phe (100 mg/kg) and 2 combined Phe (100 mg/kg) and BH4 (20 mg/kg) oral loading tests. Cofactor was administered either before or after the amino acid. The concentrations of Phe, tyrosine (Tyr), and biopterin were measured over 24 hours after loading. The comparative analysis of the loading tests showed that in all patients plasma Phe concentrations peaked within 3 hours, and fell within 24 hours by about 50% in benign, 20% in mild, and 15% in severe phenylalanine hydroxylase deficiency regardless of BH4 administration. A consistent or moderate increase of plasma Tyr, again independent of the cofactor challenge, was observed only in the less severe forms of PAH deficiency. Mean blood biopterin concentration increased 6 times after simple Phe and 34 to 39 times after combined loading tests. The administration of BH4 does not alter Phe and Tyr metabolism in PKU patients. The clearance of plasma Phe after oral loading and, as well as Tyr production, is not related to cofactor challenge but to patient's phenotype. The assessment of BH4 responsiveness by the methods so far used is not reliable, and the occurrence of BH4-responsive forms of PKU still has to be definitely proven.

  8. DNA damage induced by phenylalanine and its analogue p-chlorophenylalanine in blood and brain of rats subjected to a model of hyperphenylalaninemia.

    PubMed

    Simon, Kellen R; Dos Santos, Rosane M; Scaini, Giselli; Leffa, Daniela D; Damiani, Adriani P; Furlanetto, Camila B; Machado, Jéssica L; Cararo, José H; Macan, Tamires P; Streck, Emilio L; Ferreira, Gustavo C; Andrade, Vanessa M; Schuck, Patrícia F

    2013-10-01

    Phenylketonuria (PKU) is a disease caused by a deficiency of phenylalanine hydroxylase (PAH), resulting in an accumulation of phenylalanine (Phe) in the brain tissue, cerebrospinal fluid, and other tissues of PKU patients. Considering that high levels of Phe are associated with neurological dysfunction and that the mechanisms underlying the neurotoxicity in PKU remain poorly understood, the main objective of this study was to investigate the in vivo and in vitro effects of Phe on DNA damage, as determined by the alkaline comet assay. The results showed that, compared to control group, the levels of DNA migration were significantly greater after acute administration of Phe, p-chlorophenylalanine (p-Cl-Phe, an inhibitor of PAH), or a combination thereof in cerebral cortex and blood, indicating DNA damage. These treatments also provoked increase of carbonyl content. Additionally, when Phe or p-Cl-Phe was present in the incubation medium, we observed an increase in the frequency and index of DNA damage in the cerebral cortex and blood, without affecting lactate dehydrogenase (LDH) release. Our in vitro and in vivo findings indicate that DNA damage occurs in the cerebral cortex and blood of rats receiving Phe, suggesting that this mechanism could be, at least in part, responsible for the neurological dysfunction in PKU patients.

  9. New PAH gene promoter KLF1 and 3'-region C/EBPalpha motifs influence transcription in vitro.

    PubMed

    Klaassen, Kristel; Stankovic, Biljana; Kotur, Nikola; Djordjevic, Maja; Zukic, Branka; Nikcevic, Gordana; Ugrin, Milena; Spasovski, Vesna; Srzentic, Sanja; Pavlovic, Sonja; Stojiljkovic, Maja

    2017-02-01

    Phenylketonuria (PKU) is a metabolic disease caused by mutations in the phenylalanine hydroxylase (PAH) gene. Although the PAH genotype remains the main determinant of PKU phenotype severity, genotype-phenotype inconsistencies have been reported. In this study, we focused on unanalysed sequences in non-coding PAH gene regions to assess their possible influence on the PKU phenotype. We transiently transfected HepG2 cells with various chloramphenicol acetyl transferase (CAT) reporter constructs which included PAH gene non-coding regions. Selected non-coding regions were indicated by in silico prediction to contain transcription factor binding sites. Furthermore, electrophoretic mobility shift assay (EMSA) and supershift assays were performed to identify which transcriptional factors were engaged in the interaction. We found novel KLF1 motif in the PAH promoter, which decreases CAT activity by 50 % in comparison to basal transcription in vitro. The cytosine at the c.-170 promoter position creates an additional binding site for the protein complex involving KLF1 transcription factor. Moreover, we assessed for the first time the role of a multivariant variable number tandem repeat (VNTR) region located in the 3'-region of the PAH gene. We found that the VNTR3, VNTR7 and VNTR8 constructs had approximately 60 % of CAT activity. The regulation is mediated by the C/EBPalpha transcription factor, present in protein complex binding to VNTR3. Our study highlighted two novel promoter KLF1 and 3'-region C/EBPalpha motifs in the PAH gene which decrease transcription in vitro and, thus, could be considered as PAH expression modifiers. New transcription motifs in non-coding regions will contribute to better understanding of the PKU phenotype complexity and may become important for the optimisation of PKU treatment.

  10. Evidence that L-carnitine and selenium supplementation reduces oxidative stress in phenylketonuric patients.

    PubMed

    Sitta, A; Vanzin, C S; Biancini, G B; Manfredini, V; de Oliveira, A B; Wayhs, C A Y; Ribas, G O S; Giugliani, L; Schwartz, I V D; Bohrer, D; Garcia, S C; Wajner, M; Vargas, C R

    2011-04-01

    It is well established that the involvement of reactive species in the pathophysiology of several neurological diseases, including phenylketonuria (PKU), a metabolic genetic disorder biochemically characterized by elevated levels of phenylalanine (Phe). In previous studies, we verified that PKU patients (treated with a protein-restricted diet supplemented with a special formula not containing L-carnitine and selenium) presented high lipid and protein oxidative damage as well as a reduction of antioxidants when compared to the healthy individuals. Our goal in the present study was to evaluate the effect of Phe-restricted diet supplemented with L-carnitine and selenium, two well-known antioxidant compounds, on oxidative damage in PKU patients. We investigated various oxidative stress parameters in blood of 18 treated PKU patients before and after 6 months of supplementation with a special formula containing L-carnitine and selenium. It was verified that treatment with L-carnitine and selenium was capable of reverting the lipid peroxidation, measured by thiobarbituric acid-reactive species, and the protein oxidative damage, measured by sulfhydryl oxidation, to the levels of controls. Additionally, the reduced activity of glutathione peroxidase was normalized by the antioxidant supplementation. It was also verified a significant inverse correlation between lipid peroxidation and L-carnitine blood levels as well as a significant positive correlation between glutathione peroxidase activity and blood selenium concentration. In conclusion, our results suggest that supplementation of L-carnitine and selenium is important for PKU patients since it could help to correct the oxidative stress process which possibly contributes, at least in part, to the neurological symptoms found in phenylketonuric patients.

  11. Post-Translational Incorporation of L-Phenylalanine into the C-Terminus of α-Tubulin as a Possible Cause of Neuronal Dysfunction

    PubMed Central

    Ditamo, Yanina; Dentesano, Yanela M.; Purro, Silvia A.; Arce, Carlos A.; Bisig, C. Gastón

    2016-01-01

    α-Tubulin C-terminus undergoes post-translational, cyclic tyrosination/detyrosination, and L-Phenylalanine (Phe) can be incorporated in place of tyrosine. Using cultured mouse brain-derived cells and an antibody specific to Phe-tubulin, we showed that: (i) Phe incorporation into tubulin is reversible; (ii) such incorporation is not due to de novo synthesis; (iii) the proportion of modified tubulin is significant; (iv) Phe incorporation reduces cell proliferation without affecting cell viability; (v) the rate of neurite retraction declines as level of C-terminal Phe incorporation increases; (vi) this inhibitory effect of Phe on neurite retraction is blocked by the co-presence of tyrosine; (vii) microtubule dynamics is reduced when Phe-tubulin level in cells is high as a result of exogenous Phe addition and returns to normal values when Phe is removed; moreover, microtubule dynamics is also reduced when Phe-tubulin is expressed (plasmid transfection). It is known that Phe levels are greatly elevated in blood of phenylketonuria (PKU) patients. The molecular mechanism underlying the brain dysfunction characteristic of PKU is unknown. Beyond the differences between human and mouse cells, it is conceivable the possibility that Phe incorporation into tubulin is the first event (or among the initial events) in the molecular pathways leading to brain dysfunctions that characterize PKU. PMID:27905536

  12. Phenylalanine hydroxylase: function, structure, and regulation.

    PubMed

    Flydal, Marte I; Martinez, Aurora

    2013-04-01

    Mammalian phenylalanine hydroxylase (PAH) catalyzes the rate-limiting step in the phenylalanine catabolism, consuming about 75% of the phenylalanine input from the diet and protein catabolism under physiological conditions. In humans, mutations in the PAH gene lead to phenylketonuria (PKU), and most mutations are mainly associated with PAH misfolding and instability. The established treatment for PKU is a phenylalanine-restricted diet and, recently, supplementation with preparations of the natural tetrahydrobiopterin cofactor also shows effectiveness for some patients. Since 1997 there has been a significant increase in the understanding of the structure, catalytic mechanism, and regulation of PAH by its substrate and cofactor, in addition to improved correlations between genotype and phenotype in PKU. Importantly, there has also been an increased number of studies on the structure and function of PAH from bacteria and lower eukaryote organisms, revealing an additional anabolic role of the enzyme in the synthesis of melanin-like pigments. In this review, we discuss these recent studies, which contribute to define the evolutionary adaptation of the PAH structure and function leading to sophisticated regulation for effective catabolic processing of phenylalanine in mammalian organisms.

  13. In vivo enzyme activity in inborn errors of metabolism

    SciTech Connect

    Thompson, G.N.; Walter, J.H.; Leonard, J.V.; Halliday, D. )

    1990-08-01

    Low-dose continuous infusions of (2H5)phenylalanine, (1-13C)propionate, and (1-13C)leucine were used to quantitate phenylalanine hydroxylation in phenylketonuria (PKU, four subjects), propionate oxidation in methylmalonic acidaemia (MMA, four subjects), and propionic acidaemia (PA, four subjects) and leucine oxidation in maple syrup urine disease (MSUD, four subjects). In vivo enzyme activity in PKU, MMA, and PA subjects was similar to or in excess of that in adult controls (range of phenylalanine hydroxylation in PKU, 3.7 to 6.5 mumol/kg/h, control 3.2 to 7.9, n = 7; propionate oxidation in MMA, 15.2 to 64.8 mumol/kg/h, and in PA, 11.1 to 36.0, control 5.1 to 19.0, n = 5). By contrast, in vivo leucine oxidation was undetectable in three of the four MSUD subjects (less than 0.5 mumol/kg/h) and negligible in the remaining subject (2 mumol/kg/h, control 10.4 to 15.7, n = 6). These results suggest that significant substrate removal can be achieved in some inborn metabolic errors either through stimulation of residual enzyme activity in defective enzyme systems or by activation of alternate metabolic pathways. Both possibilities almost certainly depend on gross elevation of substrate concentrations. By contrast, only minimal in vivo oxidation of leucine appears possible in MSUD.

  14. Simple and rapid analytical method for detection of amino acids in blood using blood spot on filter paper, fast-GC/MS and isotope dilution technique.

    PubMed

    Kawana, Shuichi; Nakagawa, Katsuhiro; Hasegawa, Yuki; Yamaguchi, Seiji

    2010-11-15

    A simple and rapid method for quantitative analysis of amino acids, including valine (Val), leucine (Leu), isoleucine (Ile), methionine (Met) and phenylalanine (Phe), in whole blood has been developed using GC/MS. In this method, whole blood was collected using a filter paper technique, and a 1/8 in. blood spot punch was used for sample preparation. Amino acids were extracted from the sample, and the extracts were purified using cation-exchange resins. The isotope dilution method using ²H₈-Val, ²H₃-Leu, ²H₃-Met and ²H₅-Phe as internal standards was applied. Following propyl chloroformate derivatization, the derivatives were analyzed using fast-GC/MS. The extraction recoveries using these techniques ranged from 69.8% to 87.9%, and analysis time for each sample was approximately 26 min. Calibration curves at concentrations from 0.0 to 1666.7 μmol/l for Val, Leu, Ile and Phe and from 0.0 to 333.3 μmol/l for Met showed good linearity with regression coefficients=1. The method detection limits for Val, Leu, Ile, Met and Phe were 24.2, 16.7, 8.7, 1.5 and 12.9 μmol/l, respectively. This method was applied to blood spot samples obtained from patients with phenylketonuria (PKU), maple syrup urine disease (MSUD), hypermethionine and neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), and the analysis results showed that the concentrations of amino acids that characterize these diseases were increased. These results indicate that this method provides a simple and rapid procedure for precise determination of amino acids in whole blood.

  15. Glycomacropeptide is a prebiotic that reduces Desulfovibrio bacteria, increases cecal short-chain fatty acids, and is anti-inflammatory in mice

    PubMed Central

    Sawin, Emily A.; De Wolfe, Travis J.; Aktas, Busra; Stroup, Bridget M.; Murali, Sangita G.; Steele, James L.

    2015-01-01

    Glycomacropeptide (GMP) is a 64-amino acid (AA) glycophosphopeptide with application to the nutritional management of phenylketonuria (PKU), obesity, and inflammatory bowel disease (IBD). GMP is a putative prebiotic based on extensive glycosylation with sialic acid, galactose, and galactosamine. Our objective was to determine the prebiotic properties of GMP by characterizing cecal and fecal microbiota populations, short-chain fatty acids (SCFA), and immune responses. Weanling PKU (Pahenu2) and wild-type (WT) C57Bl/6 mice were fed isoenergetic AA, GMP, or casein diets for 8 wk. The cecal content and feces were collected for microbial DNA extraction to perform 16S microbiota analysis by Ion Torrent PGM sequencing. SCFA were determined by gas chromatography, plasma cytokines via a Bio-Plex Pro assay, and splenocyte T cell populations by flow cytometry. Changes in cecal and fecal microbiota are primarily diet dependent. The GMP diet resulted in a reduction from 30–35 to 7% in Proteobacteria, genera Desulfovibrio, in both WT and PKU mice with genotype-dependent changes in Bacteroidetes or Firmicutes. Cecal concentrations of the SCFA acetate, propionate, and butyrate were increased with GMP. The percentage of stimulated spleen cells producing interferon-γ (IFN-γ) was significantly reduced in mice fed GMP compared with casein. In summary, plasma concentrations of IFN-γ, TNF-α, IL-1β, and IL-2 were reduced in mice fed GMP. GMP is a prebiotic based on reduction in Desulfovibrio, increased SCFA, and lower indexes of inflammation compared with casein and AA diets in mice. Functional foods made with GMP may be beneficial in the management of PKU, obesity, and IBD. PMID:26251473

  16. Complete spectrum of PAH mutations in Tataria: presence of Slavic, Turkic and Scandinavian mutations.

    PubMed

    Kuzmin, A I; Eisensmith, R C; Goltsov, A A; Sergeeva, N A; Schwartz, E I; Woo, S L

    1995-01-01

    Phenylketonuria (PKU) is an autosomal recessive disorder associated with a deficiency of hepatic phenylalanine hydroxylase (PAH). Although the molecular lesions present in the PAH genes of PKU patients have previously been determined in several Slavic populations, little is known regarding the molecular basis of PKU in the non-Slavic populations of the former Soviet Union. Guthrie card samples from twenty-one classical PKU patients residing in the Tatarian Republic were examined by a combination of denaturing gradient gel electrophoresis and direct sequence analysis. Twelve patients were of Tatarian ancestry, five were of Russian ancestry, and four were of mixed Tatarian and Russian ancestry. Two of the Tatarian patients were related, sharing one mutant allele. The single major allele identified in this study was R408W/RFLP haplotype 2/VNTR 3, which was present on 11/14 or 78.6% of all mutant chromosomes of Slavic origin, but on only 10/27 or 37.0% of mutant chromosomes of Tatarian origin. This result suggests that this allele was introduced into central Asian populations during the eastward expansion of Slavs across the Eurasian landmass. A significant influence of Turkic peoples on Tatars can be inferred from the presence of R261Q. IVS10nt546g --> a, L48S, IVS2nt5g --> c and P281L, all of which are relatively common among Turks or have been observed in Mediterranean populations. Together, these alleles are present on 11/27 or 40.7% of all mutant chromosomes in ethnic Tatars. Surprisingly, the common Scandinavian mutation IVS12ntlg --> a was also present in Tataria, as was the delta agE221D222fs mutation found previously only in Denmark. Thus, some direct or indirect gene flow from Scandinavian into Tataria seems evident. Finally, the complete absence of PAH mutations previously observed in Oriental populations suggests that there was little gene flow into Tataria from Eastern Asia.

  17. Medical Problems in Obstetrics: Inherited Metabolic Disease.

    PubMed

    Murphy, Elaine

    2015-07-01

    An increasing number of women with rare inherited disorders of metabolism are becoming pregnant. Although, in general, outcomes for women and their children are good, there are a number of issues that need to be considered. Currently, limited specific guidance on the management of these conditions in pregnancy is available. Prepregnancy counselling with information on inheritance, options for reproduction, teratogenicity risk, potential impact on maternal health and long-term health of children should be offered. With appropriate specialist management, the teratogenic risk of conditions such as maternal phenylketonuria (PKU) can be eliminated, and the risk of metabolic decompensation in disorders of energy metabolism or intoxication significantly reduced. Multidisciplinary management, and close liaison between obstetricians and other specialists, is required for those women in whom there is cardiac, renal, respiratory, joint or other organ involvement.

  18. How Darwinian reductionism refutes genetic determinism.

    PubMed

    Rosoff, Philip M; Rosenberg, Alex

    2006-03-01

    Genetic determinism labels the morally problematical claim that some socially significant traits, traits we care about, such as sexual orientation, gender roles, violence, alcoholism, mental illness, intelligence, are largely the results of the operation of genes and not much alterable by environment, learning or other human intervention. Genetic determinism does not require that genes literally fix these socially significant traits, but rather that they constrain them within narrow channels beyond human intervention. In this essay we analyze genetic determinism in light of what is now known about the inborn error of metabolism phenylketonuria (PKU), which has for so long been the poster child 'simple' argument in favor of some form of genetic determinism. We demonstrate that this case proves the exact opposite of what it has been proposed to support and provides a strong refutation of genetic determinism in all its guises.

  19. Adult human liver mesenchymal progenitor cells express phenylalanine hydroxylase.

    PubMed

    Baruteau, Julien; Nyabi, Omar; Najimi, Mustapha; Fauvart, Maarten; Sokal, Etienne

    2014-09-01

    Phenylketonuria (PKU) is one of the most prevalent inherited metabolic diseases and is accountable for a severe encephalopathy by progressive intoxication of the brain by phenylalanine. This results from an ineffective L-phenylalanine hydroxylase enzyme (PAH) due to a mutated phenylalanine hydroxylase (PAH) gene. Neonatal screening programs allow an early dietetic treatment with restrictive phenylalanine intake. This diet prevents most of the neuropsychological disabilities but remains challenging for lifelong compliance. Adult-derived human liver progenitor cells (ADHLPC) are a pool of precursors that can differentiate into hepatocytes. We aim to study PAH expression and PAH activity in a differenciated ADHLPC. ADHLPC were isolated from human hepatocyte primary culture of two different donors and differenciated under specific culture conditions. We demonstrated the high expression of PAH and a large increase of PAH activity in differenciated LPC. The age of the donor, the cellular viability after liver digestion and cryopreservation affects PAH activity. ADHLPC might therefore be considered as a suitable source for cell therapy in PKU.

  20. Adolescent development

    MedlinePlus

    Development - adolescent; Growth and development - adolescent ... During adolescence, children develop the ability to: Understand abstract ideas. These include grasping higher math concepts, and developing moral ...

  1. Brain Development

    MedlinePlus

    ... developed the f… Series Healthy Minds: Nurturing Your Child's Development Each of these age-based handouts are based ... report from the National Academy of Sciences on child and brain development. Podcast Nurturing Brain Development From Birth to Three ...

  2. Web-Based Newborn Screening System for Metabolic Diseases: Machine Learning Versus Clinicians

    PubMed Central

    Chen, Wei-Hsin; Hsu, Kai-Ping; Chen, Han-Ping; Su, Xing-Yu; Tseng, Yi-Ju; Chien, Yin-Hsiu; Hwu, Wuh-Liang; Lai, Feipei

    2013-01-01

    Background A hospital information system (HIS) that integrates screening data and interpretation of the data is routinely requested by hospitals and parents. However, the accuracy of disease classification may be low because of the disease characteristics and the analytes used for classification. Objective The objective of this study is to describe a system that enhanced the neonatal screening system of the Newborn Screening Center at the National Taiwan University Hospital. The system was designed and deployed according to a service-oriented architecture (SOA) framework under the Web services .NET environment. The system consists of sample collection, testing, diagnosis, evaluation, treatment, and follow-up services among collaborating hospitals. To improve the accuracy of newborn screening, machine learning and optimal feature selection mechanisms were investigated for screening newborns for inborn errors of metabolism. Methods The framework of the Newborn Screening Hospital Information System (NSHIS) used the embedded Health Level Seven (HL7) standards for data exchanges among heterogeneous platforms integrated by Web services in the C# language. In this study, machine learning classification was used to predict phenylketonuria (PKU), hypermethioninemia, and 3-methylcrotonyl-CoA-carboxylase (3-MCC) deficiency. The classification methods used 347,312 newborn dried blood samples collected at the Center between 2006 and 2011. Of these, 220 newborns had values over the diagnostic cutoffs (positive cases) and 1557 had values that were over the screening cutoffs but did not meet the diagnostic cutoffs (suspected cases). The original 35 analytes and the manifested features were ranked based on F score, then combinations of the top 20 ranked features were selected as input features to support vector machine (SVM) classifiers to obtain optimal feature sets. These feature sets were tested using 5-fold cross-validation and optimal models were generated. The datasets

  3. An Economic Evaluation of Neonatal Screening for Inborn Errors of Metabolism Using Tandem Mass Spectrometry in Thailand

    PubMed Central

    Thiboonboon, Kittiphong; Leelahavarong, Pattara; Wattanasirichaigoon, Duangrurdee; Vatanavicharn, Nithiwat; Wasant, Pornswan; Shotelersuk, Vorasuk; Pangkanon, Suthipong; Kuptanon, Chulaluck; Chaisomchit, Sumonta; Teerawattananon, Yot

    2015-01-01

    Background Inborn errors of metabolism (IEM) are a rare group of genetic diseases which can lead to several serious long-term complications in newborns. In order to address these issues as early as possible, a process called tandem mass spectrometry (MS/MS) can be used as it allows for rapid and simultaneous detection of the diseases. This analysis was performed to determine whether newborn screening by MS/MS is cost-effective in Thailand. Method A cost-utility analysis comprising a decision-tree and Markov model was used to estimate the cost in Thai baht (THB) and health outcomes in life-years (LYs) and quality-adjusted life year (QALYs) presented as an incremental cost-effectiveness ratio (ICER). The results were also adjusted to international dollars (I$) using purchasing power parities (PPP) (1 I$ = 17.79 THB for the year 2013). The comparisons were between 1) an expanded neonatal screening programme using MS/MS screening for six prioritised diseases: phenylketonuria (PKU); isovaleric acidemia (IVA); methylmalonic acidemia (MMA); propionic acidemia (PA); maple syrup urine disease (MSUD); and multiple carboxylase deficiency (MCD); and 2) the current practice that is existing PKU screening. A comparison of the outcome and cost of treatment before and after clinical presentations were also analysed to illustrate the potential benefit of early treatment for affected children. A budget impact analysis was conducted to illustrate the cost of implementing the programme for 10 years. Results The ICER of neonatal screening using MS/MS amounted to 1,043,331 THB per QALY gained (58,647 I$ per QALY gained). The potential benefits of early detection compared with late detection yielded significant results for PKU, IVA, MSUD, and MCD patients. The budget impact analysis indicated that the implementation cost of the programme was expected at approximately 2,700 million THB (152 million I$) over 10 years. Conclusion At the current ceiling threshold, neonatal screening using MS

  4. Screening Children with Autism for Fragile-X Syndrome and Phenylketonuria. Brief Report.

    ERIC Educational Resources Information Center

    Pueschel, Siegfried M.; And Others

    1985-01-01

    Family histories, comprehensive physical examinations, and chromosome analyses of 35 males with autism were performed. Results indicated that the fragile X syndrome may be present in less than 16 percent of persons whose family history or physical features suggest the condition's possible presence. Screening 42 autistic children for…

  5. A resolution designating December 3, 2012, as "National Phenylketonuria Awareness Day".

    THOMAS, 112th Congress

    Sen. Isakson, Johnny [R-GA

    2012-09-19

    09/19/2012 Submitted in the Senate, considered, and agreed to without amendment and with a preamble by Unanimous Consent. (consideration: CR S6469-6472; text as passed Senate: CR S6470; text of measure as introduced: CR S6465) (All Actions) Tracker: This bill has the status Passed SenateHere are the steps for Status of Legislation:

  6. A resolution designating December 3, 2014, as "National Phenylketonuria Awareness Day".

    THOMAS, 113th Congress

    Sen. Isakson, Johnny [R-GA

    2014-11-20

    12/03/2014 Resolution agreed to in Senate without amendment and with a preamble by Unanimous Consent. (All Actions) Tracker: This bill has the status Passed SenateHere are the steps for Status of Legislation:

  7. An Efficient Trio-Based Mini-Haplotyping Method for Genetic Diagnosis of Phenylketonuria

    PubMed Central

    Talebi, Saeed; Entezam, Mona; Mohajer, Neda; Kazemi-sefat, Golnaz-Ensieh; Razipour, Masoumeh; Ahmadloo, Somayeh; Setoodeh, Aria; Keramatipour, Mohammad

    2016-01-01

    Objective The phenylalanine hydroxylase (PAH) locus has high linkage disequilibrium. Haplotypes related to this locus may thus be considered sufficiently informative for genetic diagnosis and carrier screening using multi-allelic markers. In this study, we present an efficient method for haplotype analysis of PAH locus using multiplexing dyes. In addition, we explain how to resolve the dye shift challenge in multiplex short tandem repeat (STR) genotyping. Materials and Methods One hundred family trios were included in this descriptive study. The forward primer of a tetra-nucleotide STR and the reverse primer of a variable number tandem repeat (VNTR) were labeled with three different non-overlapping dyes 5-carboxyfluorescein (FAM), 6-carboxy-N,N,N’,N’-tetramethylrhodamine (HEX) and 6-carboxy-N,N,N’,N’-tetramethylrhodamine (TAMRA). The polymerase chain reaction (PCR) products from each family trio were multiplexed for capillary electrophoresis and results were analyzed using Peak Scanner software. Results Multiplexing trio products decreased the cost significantly. The TAMRA labeled products had a significant predictable shift (migrated at a slower electrophoretic rate) relative to the HEX and FAM labeled products. Through our methodology we achieve, the less inter-dye shift than intra-dye shift variance. Correcting the dye shift in the labeled products, according to the reference allele size, significantly decreased the inter-dye variability (P<0.001). Conclusion Multiplexing trio products helps to detect and resolve the dye shift accurately in each family, which otherwise would result in diagnostic error. The dye system of FAM, HEX and TAMRA is more feasible and cheaper than other dye systems. PMID:27540528

  8. A resolution designating December 3, 2013, as "National Phenylketonuria Awareness Day".

    THOMAS, 113th Congress

    Sen. Isakson, Johnny [R-GA

    2013-11-21

    11/21/2013 Referred to the Committee on the Judiciary. (text of measure as introduced: CR S8465) (All Actions) Tracker: This bill has the status IntroducedHere are the steps for Status of Legislation:

  9. Toddler development

    MedlinePlus

    Toddlers are children ages 1 to 3. CHILD DEVELOPMENT THEORIES Cognitive (thought) development skills typical for toddlers include: Early use of instruments or tools Following visual (then later, invisible) displacement (moving from ...

  10. Preschooler development

    MedlinePlus

    ... little differently. If you are concerned about your child's development, talk to your child's health care provider. PHYSICAL ... A.M. Editorial team. Related MedlinePlus Health Topics Child Development Browse the Encyclopedia A.D.A.M., Inc. ...

  11. Sustainable Development.

    ERIC Educational Resources Information Center

    Auerbach, Raymond

    1994-01-01

    Discusses South African national development priorities, sustainable development, and the future of agriculture and presents three scenarios of possible national action: production for sale and export, household food security, and conservation of natural resources. (MKR)

  12. Technology Development.

    ERIC Educational Resources Information Center

    Gomory, Ralph E.

    1983-01-01

    The evolutionary character and complexity of technological development is discussed, focusing on the steam engine and computer as examples. Additional topics include characteristics of science/technology, cultural factors in technological development, technology transfer, and problems in technological organization. (JN)

  13. [Evaluation of the usefulness for neonatal mass screening in light of 35 years personal experience].

    PubMed

    Bozkowa, K; Cabalska, B; Radomyska, B; Ołtarzewski, M; Lenartowska, I

    1999-01-01

    The results and the significance of neonatal mass-screening programmes for inborn errors of metabolism, conducted by the National Research Institute of Mother and Child (NRIMC), are discussed. As the first in Poland, in 1964, mass-screening for phenylketonuria (PKU) was introduced. The BIA-Guthrie test was used. Other Guthrie tests (GBIA) were applied in homocystinuria, tyrosinemia, histidinemia and leucinosis (Maple Syrup Urine Disease-MSUD). In the middle of the 60. the Beutler and Baluda test was introduced for galactosaemia, as well as the Efron urine test in infant screening for different inborn errors of metabolism. In the middle of the 70., neonatal mass-screening for cystic fibrosis (CF, mucoviscidosis) was started. Meconium tests and the sweat test with ion selective chloride electrode were used. Apart from inborn errors of metabolism, we also introduced a screening programme for neuroblastoma in which vaniline mandelic acid (VMA) in urine was estimated and for congenital hypothyroidism were TSH level was assessed. The results of screening are shown in the tables and in the figures. In our opinion the best clinical results are obtained with screening for congenital hypothyroidism and for PKU, since very early detection and treatment in these diseases prevents severe mental retardation. We therefore consider that both these screening programmes should be treated as obligatory examinations in all neonates. Taking into consideration the fact that there are different types of hyperhenylalaninemias, the principles of differential diagnosis are discussed. Molecular genetic investigations, carried out in the NRIMC Department of Genetics proved to be a very important procedure in the verification of diagnosis of different mutations. The authors also discuss the problem of dietary treatment duration in PKU. In our opinion the hypophenyloalanine diet regimen in girls, should not be discontinued during adolescence, since there is the problem of maternal PKU and the

  14. Developer Network

    SciTech Connect

    2012-08-21

    NREL's Developer Network, developer.nrel.gov, provides data that users can access to provide data to their own analyses, mobile and web applications. Developers can retrieve the data through a Web services API (application programming interface). The Developer Network handles overhead of serving up web services such as key management, authentication, analytics, reporting, documentation standards, and throttling in a common architecture, while allowing web services and APIs to be maintained and managed independently.

  15. Faculty Development.

    ERIC Educational Resources Information Center

    Gillan, Bob, Ed.; McFerrin, Karen, Ed.

    This document contains the following papers on faculty development and technology: "Involving Faculty in Faculty Development" (Kristine Blair and Dan Madigan); "Technology Use in Higher Education: A Faculty Development Model" (Jessica Kahn); "A Faculty of Education as a Community of Learners: Growing to Meet the Demands of…

  16. Resume Development.

    ERIC Educational Resources Information Center

    Lorenzen, Elizabeth A.; And Others

    This paper presents a step-by-step guide for developing a resume as part of a job search campaign. The paper presents the following information: purposes of the resume; steps in resume development; resume formats; resume headings; and some "do's and some "don't's." The paper also includes a list of 161 action verbs for use in resume development, a…

  17. Teacher Development.

    ERIC Educational Resources Information Center

    1997

    Eight conference papers on language teacher development are presented, including: "Mosaics of Teacher Development and Socialization" (Andrew Barfield, Paul A. Beaufait, Sean Conley, Tim Murphey, Katsura Haruko), a panel presentation on aspects of and experiments in teacher development; "Questions About Teaching? Answers from…

  18. Instructional Development in Developing Countries.

    ERIC Educational Resources Information Center

    Saba, Farhad

    1984-01-01

    Discussion of conditions that combine to influence the selection and implementation of instructional development as an approach to solving educational problems in developing nations focuses on prevailing traditions, economics, and internal and external politics. (MBR)

  19. Program Development

    SciTech Connect

    Atencio, Julian J.

    2014-05-01

    This presentation covers how to go about developing a human reliability program. In particular, it touches on conceptual thinking, raising awareness in an organization, the actions that go into developing a plan. It emphasizes evaluating all positions, eliminating positions from the pool due to mitigating factors, and keeping the process transparent. It lists components of the process and objectives in process development. It also touches on the role of leadership and the necessity for audit.

  20. KENO developments

    SciTech Connect

    Hollenbach, D.F.; Landers, N.F.; Petrie, L.M.

    1997-06-01

    Modifications and developments to the series of KENO multigroup, criticality safety transport codes are very briefly summarized. Three areas are addressed: (1) modifications to KENO-V.a, (2) development of KENO-VI, (3) modifications to the CSAS4 sequence of the SCALE package, and (4) future work on KENO related programs. Minor changes have been made to KENO-V.a, primarily for maintenance. KENO-VI has been developed and will be released soon. A new search type is being developed in SCALE to allow CSAS4 to do a concentration search on a mixture component.

  1. [Toddler Development.

    ERIC Educational Resources Information Center

    Pawl, Jeree, Ed.

    1991-01-01

    This theme newsletter issue presents seven articles describing toddler behavior and development, services for toddlers, and toddlers with special needs. The first article, "Toddlers: Themes and Variations" (Lois Barclay Murphy and Colleen Small) focuses on variations in toddler development, noting emerging skills, language, and the caregiver role.…

  2. Talent Development.

    ERIC Educational Resources Information Center

    Drum, Jean, Ed.

    1993-01-01

    This theme issue on talent development in students who are gifted or have special talents contains several feature articles, editorials, and a calendar of events. Articles have the following titles and authors: "Talent Development in Education" (John F. Feldhusen) proposes four domains for fostering talent in all youth:…

  3. Developing Computation

    ERIC Educational Resources Information Center

    McIntosh, Alistair

    2004-01-01

    In this article, the author presents the results of a state project that focused on the effect of developing informal written computation processes through Years 2-4. The "developing computation" project was conducted in Tasmania over the two years 2002-2003 and involved nine schools: five government schools, two Catholic schools, and…

  4. Numerical Development

    ERIC Educational Resources Information Center

    Siegler, Robert S.; Braithwaite, David W.

    2016-01-01

    In this review, we attempt to integrate two crucial aspects of numerical development: learning the magnitudes of individual numbers and learning arithmetic. Numerical magnitude development involves gaining increasingly precise knowledge of increasing ranges and types of numbers: from non-symbolic to small symbolic numbers, from smaller to larger…

  5. Child Development

    MedlinePlus

    ... Children™ study. Multimedia & Tools Videos, podcasts and widgets. Child Development: What's New Article: Differences in health care, family, ... and share it with the child’s doctor. More Child Development Basics Developmental Screening Screening for Professionals Positive Parenting ...

  6. Professional Development.

    ERIC Educational Resources Information Center

    Benson, Chris, Ed.

    2000-01-01

    This serial issue contains 12 articles on the theme of "Professional Development," specifically about how teachers in the Bread Loaf Rural Teacher Network (BLRTN) are fostering their own and each other's development as teachers. The BLRTN consists of approximately 260 rural teachers in Alaska, Arizona, Colorado, Georgia, Kentucky,…

  7. Management Development.

    ERIC Educational Resources Information Center

    1997

    This document contains three papers from a symposium on management development. "LMX (Leader-Member Exchange) Theory, Personality Type, and Management Development" (Janet Z. Burns) reports the results of a study on the similarities and differences in personality type (as outlined in the theories of Carl Jung and Isabel Myers) and its relationship…

  8. Staff Development.

    ERIC Educational Resources Information Center

    Reusswig, James, Ed.; Ponzio, Richard, Ed.

    1980-01-01

    Eight essays are presented which reflect current problems, issues, and practices related to the development of teacher and administrator expertise. The authors are school district and public school administrators, faculty of schools of education, and a director of staff development in a state department of education. The topics treated are: (1)…

  9. New insights into tetrahydrobiopterin pharmacodynamics from Pah enu1/2, a mouse model for compound heterozygous tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency.

    PubMed

    Lagler, Florian B; Gersting, Søren W; Zsifkovits, Clemens; Steinbacher, Alice; Eichinger, Anna; Danecka, Marta K; Staudigl, Michael; Fingerhut, Ralph; Glossmann, Hartmut; Muntau, Ania C

    2010-11-15

    Phenylketonuria (PKU), an autosomal recessive disease with phenylalanine hydroxylase (PAH) deficiency, was recently shown to be a protein misfolding disease with loss-of-function. It can be treated by oral application of the natural PAH cofactor tetrahydrobiopterin (BH(4)) that acts as a pharmacological chaperone and rescues enzyme function in vivo. Here we identified Pah(enu1/2) bearing a mild and a severe mutation (V106A/F363S) as a new mouse model for compound heterozygous mild PKU. Although BH(4) treatment has become established in clinical routine, there is substantial lack of knowledge with regard to BH(4) pharmacodynamics and the effect of the genotype on the response to treatment with the natural cofactor. To address these questions we applied an elaborate methodological setup analyzing: (i) blood phenylalanine elimination, (ii) blood phenylalanine/tyrosine ratios, and (iii) kinetics of in vivo phenylalanine oxidation using (13)C-phenylalanine breath tests. We compared pharmacodynamics in wild-type, Pah(enu1/1), and Pah(enu1/2) mice and observed crucial differences in terms of effect size as well as effect kinetics and dose response. Results from in vivo experiments were substantiated in vitro after overexpression of wild-type, V106A, and F263S in COS-7 cells. Pharmacokinetics did not differ between Pah(enu1/1) and Pah(enu1/2) indicating that the differences in pharmacodynamics were not induced by divergent pharmacokinetic behavior of BH(4). In conclusion, our findings show a significant impact of the genotype on the response to BH(4) in PAH deficient mice. This may lead to important consequences concerning the diagnostic and therapeutic management of patients with PAH deficiency underscoring the need for individualized procedures addressing pharmacodynamic aspects.

  10. Individualized long-term outcomes in blood phenylalanine concentrations and dietary phenylalanine tolerance in 11 patients with primary phenylalanine hydroxylase (PAH) deficiency treated with Sapropterin-dihydrochloride.

    PubMed

    Stockler-Ipsiroglu, Sylvia; Yuskiv, Nataliya; Salvarinova, Ramona; Apatean, Delia; Ho, Gloria; Cheng, Barbara; Giezen, Alette; Lillquist, Yolanda; Ueda, Keiko

    2015-03-01

    We analyzed long-term sustainability of improved blood Phenylalanine (Phe) control and changes to dietary Phe tolerance in 11 patients (1 month to 16 years), with various forms of primary PAH deficiency (classic, moderate, severe phenylketonuria [PKU], mild hyperphenylalaninemia [HPA]), who were treated with 15-20mg/kg/d Sapropterin-dihydrochloride during a period of 13-44 months. 7/11 patients had a sustainable, significant reduction of baseline blood Phe concentrations and 6 of them also had an increase in mg/kg/day Phe tolerance. In 2 patients with mild HPA, blood Phe concentrations remained in the physiologic range even after a 22 and 36% increase in mg/kg/day Phe tolerance and an achieved Phe intake at 105% and 268% of the dietary reference intake (DRI) for protein. 2 of these responders had classic PKU. 1 patient with mild HPA who started treatment at 2 months of life, had a significant and sustainable reduction in pretreatment blood Phe concentrations, but no increase in the mg/kg/day Phe tolerance. An increase in Phe tolerance could only be demonstrated when expressing the patient's daily Phe tolerance with the DRI for protein showing an increase from 58% at baseline to 78% of normal DRI at the end of the observation. Long-term follow-up of patients with an initial response to treatment with Sapropterin is essential to determine clinically meaningful outcomes. Phenylalanine tolerance should be expressed in mg/kg/day and/or % of normal DRI to differentiate medical therapy related from physiologic growth related increase in daily Phe intake.

  11. Splicing of phenylalanine hydroxylase (PAH) exon 11 is vulnerable: molecular pathology of mutations in PAH exon 11.

    PubMed

    Heintz, Caroline; Dobrowolski, Steven F; Andersen, Henriette Skovgaard; Demirkol, Mübeccel; Blau, Nenad; Andresen, Brage Storstein

    2012-08-01

    In about 20-30% of phenylketonuria (PKU) patients, phenylalanine (Phe) levels can be controlled by cofactor 6R-tetrahydrobiopterin (BH(4)) administration. The phenylalanine hydroxylase (PAH) genotype has a predictive value concerning BH(4)-response and therefore a correct assessment of the mutation molecular pathology is important. Mutations that disturb the splicing of exons (e.g. interplay between splice site strength and regulatory sequences like exon splicing enhancers (ESEs)/exon splicing silencers (ESSs)) may cause different severity of PKU. In this study, we identified PAH exon 11 as a vulnerable exon and used patient derived lymphoblast cell lines and PAH minigenes to study the molecular defect that impacted pre-mRNA processing. We showed that the c.1144T>C and c.1066-3C>T mutations cause exon 11 skipping, while the c.1139C>T mutation is neutral or slightly beneficial. The c.1144T>C mutation resides in a putative splicing enhancer motif and binding by splicing factors SF2/ASF, SRp20 and SRp40 is disturbed. Additional mutations in potential splicing factor binding sites contributed to elucidate the pathogenesis of mutations in PAH exon 11. We suggest that PAH exon 11 is vulnerable due to a weak 3' splice site and that this makes exon 11 inclusion dependent on an ESE spanning position c.1144. Importantly, this implies that other mutations in exon 11 may affect splicing, since splicing is often determined by a fine balance between several positive and negative splicing regulatory elements distributed throughout the exon. Finally, we identified a pseudoexon in intron 11, which would have pathogenic consequences if activated by mutations or improved splicing conditions. Exonic mutations that disrupt splicing are unlikely to facilitate response to BH(4) and may lead to inconsistent genotype-phenotype correlations. Therefore, recognizing such mutations enhances our ability to predict the BH(4)-response.

  12. Capillary sample

    MedlinePlus

    ... repeat the test with blood drawn from a vein. Alternative Names Blood sample - capillary; Fingerstick; Heelstick Images Phenylketonuria test Phenylketonuria test Capillary sample References Garza ...

  13. Powerstick development

    SciTech Connect

    Borshchevsky, A.; Chmielewski, A.; Chen-Kuo, H.; Bass, J.; Bugby, D.; Pustovalov, A.; Gusev, V.

    1997-12-31

    A device called a Powerstick is being developed to satisfy the requirements of several potential solar system exploration missions. The Powerstick is a small power source consisting of three major components: a space qualified heat source (RHU), a thermopile (thermoelectric converter) and a set of rechargeable batteries. The Powerstick merges several devices developed earlier by the space power programs. The RHU was developed by DOE for the Galileo and Ulysses missions, the thermopile is a combination of the early RTG technology and pace maker technology with new packaging techniques, and a lithium-ion rechargeable battery is currently being developed for space applications. NASA has recently awarded a Small Business Technology Transfer (STTR) contract to Hi-Z Technology, Inc. of San Diego to manufacture a miniaturized thermopile and provide a preliminary design of the Powerstick. JPL`s Solar System Exploration Program funded Powerstick prototype design and fabrication contract with Swales and Associates, Inc. The Swales unit and the Hi-Z thermopile will be integrated at JPL. This integrated prototype with the thermopile, rechargeable batteries and electrical RHU simulator will be tested at JPL. At the same time JPL is pursuing a ruggedized Powerstick development with the Russian company BIAPOS. BIAPOS is to independently design, build and deliver to JPL for testing their own version of the Powerstick. According to the technology development road map for small space sources the American and Russian efforts will lead to the development of an engineering and qualification Powerstick unit by the end of the century.

  14. Sensory development.

    PubMed

    Clark-Gambelunghe, Melinda B; Clark, David A

    2015-04-01

    Sensory development is complex, with both morphologic and neural components. Development of the senses begins in early fetal life, initially with structures and then in-utero stimulation initiates perception. After birth, environmental stimulants accelerate each sensory organ to nearly complete maturity several months after birth. Vision and hearing are the best studied senses and the most crucial for learning. This article focuses on the cranial senses of vision, hearing, smell, and taste. Sensory function, embryogenesis, external and genetic effects, and common malformations that may affect development are discussed, and the corresponding sensory organs are examined and evaluated.

  15. Technology development.

    PubMed

    Gomory, R E

    1983-05-06

    In technology development significant advances are as often the result of a series of evolutionary steps as they are of breakthroughs. This is illustrated by the examples of the steam engine and the computer. Breakthroughs, such as the transistor, are relatively rare, and are often the result of the introduction of new knowledge coming from a quite different area. Technology development is often difficult to predict because of its complexity; practical considerations may far outweigh apparent scientific advantages, and cultural factors enter in at many levels. In a large technological organization problems exist in bringing scientific knowledge to bear on development, but much can be done to obviate these difficulties.

  16. Toddler Development

    MedlinePlus

    ... watch your toddler learn new skills. The normal development of children aged 1-3 includes several areas: Gross motor - walking, running, climbing Fine motor - feeding themselves, drawing Sensory - seeing, hearing, tasting, touching, and smelling Language - saying ...

  17. Leaf Development

    PubMed Central

    2013-01-01

    Leaves are the most important organs for plants. Without leaves, plants cannot capture light energy or synthesize organic compounds via photosynthesis. Without leaves, plants would be unable perceive diverse environmental conditions, particularly those relating to light quality/quantity. Without leaves, plants would not be able to flower because all floral organs are modified leaves. Arabidopsis thaliana is a good model system for analyzing mechanisms of eudicotyledonous, simple-leaf development. The first section of this review provides a brief history of studies on development in Arabidopsis leaves. This history largely coincides with a general history of advancement in understanding of the genetic mechanisms operating during simple-leaf development in angiosperms. In the second section, I outline events in Arabidopsis leaf development, with emphasis on genetic controls. Current knowledge of six important components in these developmental events is summarized in detail, followed by concluding remarks and perspectives. PMID:23864837

  18. Eye development.

    PubMed

    Baker, Nicholas E; Li, Ke; Quiquand, Manon; Ruggiero, Robert; Wang, Lan-Hsin

    2014-06-15

    The eye has been one of the most intensively studied organs in Drosophila. The wealth of knowledge about its development, as well as the reagents that have been developed, and the fact that the eye is dispensable for survival, also make the eye suitable for genetic interaction studies and genetic screens. This article provides a brief overview of the methods developed to image and probe eye development at multiple developmental stages, including live imaging, immunostaining of fixed tissues, in situ hybridizations, and scanning electron microscopy and color photography of adult eyes. Also summarized are genetic approaches that can be performed in the eye, including mosaic analysis and conditional mutation, gene misexpression and knockdown, and forward genetic and modifier screens.

  19. Organisational development.

    PubMed

    2017-03-30

    The aim of the NHS Improvement national leadership and improvement strategy is to encourage leaders at all levels to develop leadership skills in their staff and themselves. It focuses on fostering compassionate, collaborative and inclusive leadership.

  20. Development risks

    SciTech Connect

    Riedy, M.; Desai, S.

    1996-04-01

    Risks associated with hydropower production development in India are discussed in this article. A project prospectus for the development of India`s estimated 84,044 MW(e) hydropower potential is given which accounts for environmental and regulatory concerns. Regulations issued by the Government of Industry regarding private investment in hydropower are outlined, and additional policies which are expected to be instituted are discussed.

  1. Leaf Development

    PubMed Central

    Tsukaya, Hirokazu

    2002-01-01

    The shoot system is the basic unit of development of seed plants and is composed of a leaf, a stem, and a lateral bud that differentiates into a lateral shoot. The most specialized organ in angiosperms, the flower, can be considered to be part of the same shoot system since floral organs, such as the sepal, petal, stamen, and carpel, are all modified leaves. Scales, bracts, and certain kinds of needle are also derived from leaves. Thus, an understanding of leaf development is critical to an understanding of shoot development. Moreover, leaves play important roles in photosynthesis, respiration and photoperception. Thus, a full understanding of leaves is directly related to a full understanding of seed plants. The details of leaf development remain unclear. The difficulties encountered in studies of leaf development, in particular in dicotyledonous plants such as Arabidopsis thaliana (L.) Henyn., are derived from the complex process of leaf development, during which the division and elongation of cells occur at the same time and in the same region of the leaf primordium (Maksymowych, 1963; Poethig and Sussex, 1985). Thus, we cannot divide the entire process into unit processes in accordance with the tenets of classical anatomy. Genetic approaches in Arabidopsis, a model plant (Meyerowitz and Pruitt, 1985), have provided a powerful tool for studies of mechanisms of leaf development in dicotyledonous plants, and various aspects of the mechanisms that control leaf development have been revealed in recent developmental and molecular genetic studies of Arabidopsis (for reviews, see Tsukaya, 1995 and 1998; Van Lijsebettens and Clarke, 1998; Sinha, 1999; Van Volkenburgh, 1999; Tsukaya, 2000; Byrne et al., 2001; Dengler and Kang, 2001; Dengler and Tsukaya, 2001; Tsukaya, 2001). In this review, we shall examine the information that is currently available about various mechanisms of leaf development in Arabidopsis. Vascular patterning is also an important factor in the

  2. Sustainable Development

    NASA Astrophysics Data System (ADS)

    Schmandt, Jurgen; Ward, C. H.; Marilu Hastings, Assisted By

    2000-04-01

    Demographers predict that the world population will double during the first half of the 21st century before it will begin to level off. In this volume, a group of prominent authors examine what societal changes must occur to meet this challenge to the natural environment and the transformational changes that we must experience to achieve sustainability. Frances Cairncross, Herman E. Daly, Stephen H. Schneider and others provide a broad discussion of sustainable development. They detail economic and environmental, as well as spiritual and religious, corporate and social, scientific and political factors. Sustainable Development: The Challenge of Transition offers many insightful policy recommendations about how business, government, and individuals must change their current values, priorities, and behavior to meet present and future challenges. It will appeal to scholars and decision makers interested in global change, environmental policy, population growth, and sustainable development, and also to corporate environmental managers.

  3. Superconductor developments

    SciTech Connect

    Larbalestier, D.

    1989-04-05

    I will cover the technology of the new oxide supeconductors and how they might relate to the existing superconductors. Fermilab and the high energy physics community in general have had much to do with the development of the ''old'' superconductors. Bednorz and M/umlt u/ller must be credited with the idea of setting out on the search for the new superconductors.

  4. New Developments

    ERIC Educational Resources Information Center

    Lohmander, Maelis Karlsson, Ed.; Rabusicova, Milada; Einarsdottir, Johanna

    2008-01-01

    The development of early childhood education (ECE) in Europe and beyond is inextricably linked with women's roles and power in society. Towards the end of the nineteenth and beginning of the twentieth century in a context of urbanisation and industrialisation the need for some sort of public childcare became apparent in many countries. Whereas…

  5. New Developments

    ERIC Educational Resources Information Center

    Lohmander, Maelis Karlson; Vandenbroeck, Michel; Pirard, Florence; Peeters, Jan; Alvestad, Marit

    2009-01-01

    New developments and challenges regarding early childhood education (ECE) policy and practice in Norway and in the Flemish and French communities in Belgium are presented in this issue. There are clear differences between the countries when comparing systems they have chosen for ECE. In Belgium, supervision and responsibilities for education,…

  6. Contraceptive Development.

    ERIC Educational Resources Information Center

    Troen, Philip; And Others

    This report provides an overview of research activities and needs in the area of contraceptive development. In a review of the present state, discussions are offered on the effectiveness and drawbacks of oral contraceptives, intrauterine devices, barrier methods, natural family planning, and sterilization. Methods of contraception that are in the…

  7. Algorithm development

    NASA Technical Reports Server (NTRS)

    Barth, Timothy J.; Lomax, Harvard

    1987-01-01

    The past decade has seen considerable activity in algorithm development for the Navier-Stokes equations. This has resulted in a wide variety of useful new techniques. Some examples for the numerical solution of the Navier-Stokes equations are presented, divided into two parts. One is devoted to the incompressible Navier-Stokes equations, and the other to the compressible form.

  8. Trends Developments.

    ERIC Educational Resources Information Center

    ASPBAE Courier Service, 1981

    1981-01-01

    This issue contains extracts from twenty-one country reports and case studies presented to the Unesco Regional Seminar on Adult Education and Development in Bangkok, November 24-December 4, 1980. The excerpts have an emphasis on innovations in adult education in the region. Countries and programs discussed include (1) community…

  9. Flower Development

    PubMed Central

    Alvarez-Buylla, Elena R.; Benítez, Mariana; Corvera-Poiré, Adriana; Chaos Cador, Álvaro; de Folter, Stefan; Gamboa de Buen, Alicia; Garay-Arroyo, Adriana; García-Ponce, Berenice; Jaimes-Miranda, Fabiola; Pérez-Ruiz, Rigoberto V.; Piñeyro-Nelson, Alma; Sánchez-Corrales, Yara E.

    2010-01-01

    Flowers are the most complex structures of plants. Studies of Arabidopsis thaliana, which has typical eudicot flowers, have been fundamental in advancing the structural and molecular understanding of flower development. The main processes and stages of Arabidopsis flower development are summarized to provide a framework in which to interpret the detailed molecular genetic studies of genes assigned functions during flower development and is extended to recent genomics studies uncovering the key regulatory modules involved. Computational models have been used to study the concerted action and dynamics of the gene regulatory module that underlies patterning of the Arabidopsis inflorescence meristem and specification of the primordial cell types during early stages of flower development. This includes the gene combinations that specify sepal, petal, stamen and carpel identity, and genes that interact with them. As a dynamic gene regulatory network this module has been shown to converge to stable multigenic profiles that depend upon the overall network topology and are thus robust, which can explain the canalization of flower organ determination and the overall conservation of the basic flower plan among eudicots. Comparative and evolutionary approaches derived from Arabidopsis studies pave the way to studying the molecular basis of diverse floral morphologies. PMID:22303253

  10. Workforce Development.

    ERIC Educational Resources Information Center

    1999

    This document contains four symposium papers on work force development. "Effects of Two Different Learning Paths on School-to-Work Transition" (Esther Van Der Schoot) discusses a Dutch study documenting that the following items make a difference in the school-to-work transition: learning path, curriculum characteristics, individual…

  11. Gender Development.

    ERIC Educational Resources Information Center

    Golombok, Susan; Fivush, Robyn

    In spite of the loosening ties between reproductive and social roles, the worlds of men and women and boys and girls, are clearly not the same. There is much more to being female or male than the potential to mother or father a child. Gender development does not simply depend on children's relationship with their parents: it results from a complex…

  12. DEVELOP Students

    NASA Technical Reports Server (NTRS)

    2007-01-01

    DEVELOP team members at Stennis Space Center for the summer 2007 term are (from left): front row, students Deirdra Boley, Jason Jones, Lauren Childs, Craig Matthews and Denise Spindel; back row, advisers Cheri Miller of NASA, Kenton Ross of Science Systems and Applications Inc., Andra Johnson of Southern University and Roxzana Moore, SSAI.

  13. Moral Development.

    ERIC Educational Resources Information Center

    Educational Testing Service, Princeton, NJ.

    The 1974 Educational Testing Service (ETS) Measurement Award was presented to J.P. Guilford at the ETS Invitational Conference. Irving Kristol, in "Moral and Ethical Development in a Democratic Society," called for the restoration of authority within our major social institutions, especially schools. Martin Trow examined the effects of the college…

  14. Professional Development.

    ERIC Educational Resources Information Center

    Swanson, Gordon I.; Jervis, Robert

    Resulting in part from a project designed to identify and describe comprehensive programs of excellence in career education, this booklet is the eighth in a series describing current, successful career education practices. A successful career education program is dependent upon professional development. Based on this premise, the monograph: (1)…

  15. Electrifying Development

    NASA Technical Reports Server (NTRS)

    1998-01-01

    With technical assistance from Marshall Space Flight Center and Kennedy Space Center, Protective Cable and Wire developed Lightning Retardant Cable (LRC). LRC improves lightning protection over standard coaxial cable by 100 percent. The LRC design keeps lightning from traveling through the cable, preventing damage to satellites, antennas, and cable systems. LRC is now being used in homes as well as airports.

  16. Faculty Development.

    ERIC Educational Resources Information Center

    O'Hanlon, James; Sayre, Janette S.

    1982-01-01

    Through professional development activities, physical education faculty members can meet important challenges in their field: (1) keep current in their subjects; (2) learn additional skills; (3) take on new tasks; (4) perform old tasks in different ways; (5) increase scholarship; and (6) increase instructional competence. (CJ)

  17. Management Development.

    DTIC Science & Technology

    1972-12-01

    They apply to training in specific skills as well as In broad educational domains; to present job or future career. They should be understood In the...performance by Imparting knowledge, modifying attitudes, or Increasing skills (House, 1967, P. 13). These attempts range from completely formal...the organization. Training or Education? Traditionally, training (management development Included) connoted teaching skills for a specific purpose

  18. Developing ADHD

    ERIC Educational Resources Information Center

    Taylor, Eric

    2009-01-01

    Over the past 50 years the concept of attention deficit/hyperactivity disorder (ADHD) has developed from the notion of a specific form of brain dysfunction to that of a heterogeneous set of related behaviours. The great advances in genetics, neuroimaging and neuropsychiatry have made it one of the best understood forms of complex mental…

  19. Marker development

    SciTech Connect

    Adams, M.R.

    1987-05-01

    This report is to discuss the marker development for radioactive waste disposal sites. The markers must be designed to last 10,000 years, and place no undue burdens on the future generations. Barriers cannot be constructed that preclude human intrusion. Design specifications for surface markers will be discussed, also marker pictograms will also be covered.

  20. New Developments

    ERIC Educational Resources Information Center

    Karlsson-Lohmander, Maelis

    2005-01-01

    A growing number of countries have recognised the importance of high quality early childhood provision for the development of the young child and the impact on economic growth and prosperity. What shapes Early Childhood Education and Care (ECEC) in an expanding Europe of today? Many factors clearly influence policy decisions and program…

  1. Gender Development

    ERIC Educational Resources Information Center

    Owen Blakemore, Judith E.; Berenbaum, Sheri A.; Liben, Lynn S.

    2008-01-01

    This new text offers a unique developmental focus on gender. Gender development is examined from infancy through adolescence, integrating biological, socialization, and cognitive perspectives. The book's current empirical focus is complemented by a lively and readable style that includes anecdotes about children's everyday experiences. The book's…

  2. CAREER DEVELOPMENT

    EPA Science Inventory

    The Baltimore Summit Project on Career Development/PERFORMS Enhancement/360 Evaluations for All has made some progress. We have identified the fact that we cannot change the current Pass/Fail PERFORMS system to a tiered system. The current pass/fail system does not have a mechani...

  3. Oh, Develop

    NASA Technical Reports Server (NTRS)

    Post, Todd

    2003-01-01

    In a mature view of the subject, career development is not simply four years of college or a week at training, culminating in a diploma or a certificate to hang on an office wall. That's why we wanted to take a broad look at career development in this issue of ASK. Take for example, Dr. Gerald Mulenburg s contribution, Fly on the Wall. When Mulenburg and other members of a knowledge-sharing group at Ames were invited to observe an upcoming project review, Mulenburg thought it would be interesting to learn how another project does its reviews. Note that Mulenburg is no fresh out who's never attended a NASA project review. Not only has he been through a fair share of them as the reviewed, he has also been on the other side of the table as a reviewer. This experienced project manager recognizes that at any stage of a career there is room to grow and develop one's repertoire. Too often people associate career development with textbooks and role classroom training, far removed from project life. But classroom training need not be like this, as you'll find in our Special Feature, The Enterprise Project by Wendy Dolci, which sprung out of an APPL Advanced Project Management class in July 2003 at Ames Research Center. In addition to Dolci, some of her classmates contribute to the story. Mike Sander of the Jet Propulsion Laboratory, project manager for the Mars Science Laboratory mission, who provided the assignment on which the story is based, also has a cameo in the story. We think Dolci's story is an inspiring example of what classroom training can be if it's approached imaginatively and made to serve a practical purpose. Another story from Ames, by Frank Larsen, takes a different twist on career development. At the annual Experimental Aircraft Association Fly-in in Oshkosh, Wisconsin, Larsen represented Ames at a NASA booth. While there, Larsen met a colleague from Glenn Research Center. Months later on a project with a quick turnaround, he remembered his colleague from

  4. Yardang Development

    NASA Technical Reports Server (NTRS)

    2004-01-01

    [figure removed for brevity, see original site]

    Released 16 July 2004 The atmosphere of Mars is a dynamic system. Water-ice clouds, fog, and hazes can make imaging the surface from space difficult. Dust storms can grow from local disturbances to global sizes, through which imaging is impossible. Seasonal temperature changes are the usual drivers in cloud and dust storm development and growth.

    Eons of atmospheric dust storm activity has left its mark on the surface of Mars. Dust carried aloft by the wind has settled out on every available surface; sand dunes have been created and moved by centuries of wind; and the effect of continual sand-blasting has modified many regions of Mars, creating yardangs and other unusual surface forms.

    This image illustrates different amounts of yardang development on the large deposit found on the floor of Nicholson Crater. Note the formation of the ridge/trough shape at the bottom part of the main deposit.

    Image information: VIS instrument. Latitude 0.2, Longitude 195.3 East (164.7 West). 19 meter/pixel resolution.

    Note: this THEMIS visual image has not been radiometrically nor geometrically calibrated for this preliminary release. An empirical correction has been performed to remove instrumental effects. A linear shift has been applied in the cross-track and down-track direction to approximate spacecraft and planetary motion. Fully calibrated and geometrically projected images will be released through the Planetary Data System in accordance with Project policies at a later time.

    NASA's Jet Propulsion Laboratory manages the 2001 Mars Odyssey mission for NASA's Office of Space Science, Washington, D.C. The Thermal Emission Imaging System (THEMIS) was developed by Arizona State University, Tempe, in collaboration with Raytheon Santa Barbara Remote Sensing. The THEMIS investigation is led by Dr. Philip Christensen at Arizona State University. Lockheed Martin Astronautics, Denver, is the prime contractor for

  5. Professional development

    NASA Astrophysics Data System (ADS)

    Yoon, Jin Hee; Hartline, Beverly Karplus; Milner-Bolotin, Marina

    2013-03-01

    The three sessions of the professional development workshop series were each designed for a different audience. The purpose of the first session was to help mid-career physicists aspire for and achieve leadership roles. The second session brought together students, postdoctoral fellows, and early-career physicists to help them plan their career goals and navigate the steps important to launching a successful career. The final session sought to increase awareness of the results of physics education research, and how to use them to help students-especially women-learn physics better. The presentations and discussions were valuable for both female and male physicists.

  6. Developing ADHD.

    PubMed

    Taylor, Eric

    2009-01-01

    Over the past 50 years the concept of attention deficit/hyperactivity disorder (ADHD) has developed from the notion of a specific form of brain dysfunction to that of a heterogeneous set of related behaviours. The great advances in genetics, neuroimaging and neuropsychiatry have made it one of the best understood forms of complex mental disturbance--but much remains to be done to translate understanding into practice. More effective treatment may come from identifying and treating more specific components of disorder and by a focus on identifying the factors determining course in the longer term so that they, as well as the core features of disorder, can become targets for intervention.

  7. Bone development

    PubMed Central

    Berendsen, Agnes D.; Olsen, Bjorn R.

    2015-01-01

    The development of the vertebrate skeleton reflects its evolutionary history. Cartilage formation came before biomineralization and a head skeleton evolved before the formation of axial and appendicular skeletal structures. This review describes the processes that result in endochondral and intramembranous ossification, the important roles of growth and transcription factors, and the consequences of mutations in some of the genes involved. Following a summary of the origin of cartilage, muscle, and tendon cell lineages in the axial skeleton, we discuss the role of muscle forces in the formation of skeletal architecture and assembly of musculoskeletal functional units. Finally, ontogenetic patterning of bones in response to mechanical loading is reviewed. PMID:26453494

  8. Energy development

    USGS Publications Warehouse

    Lovich, Jeffrey E.; Jones, L.L.C.; Lovich, R. L.; Halama, K.J.

    2016-01-01

    Large areas of the desert southwest are currently developed or being evaluated for construction of utility-scale renewable energy projects. These projects include numerous solar and wind energy facilities some of which will be massive. Unfortunately, peer-reviewed scientific publications are not yet available to evaluate the potential effects of solar-based utility-scale renewable energy development (USRED) on any species of wildlife, including amphibians and reptiles (herpetofauna). Scientific publications on the effects of wind-based USRED and operation (USREDO) are focused almost exclusively on flying wildlife including birds and bats. To the best of our knowledge the only publications on the effects of wind-based USREDO on herpetofauna are three publications on desert tortoise ecology at a wind energy facility near Palm Springs, California. Those studies suggested that not all effects of USREDO were detrimental in the short-term. However, additional research is required to determine if wind energy operation is compatible with conservation of this long-lived species over longer periods of time.

  9. Process development

    NASA Technical Reports Server (NTRS)

    Bickler, D. B.

    1985-01-01

    An overview is given of seven process development activities which were presented at this session. Pulsed excimer laser processing of photovoltaic cells was presented. A different pulsed excimer laser annealing was described using a 50 w laser. Diffusion barrier research focused on lowering the chemical reactivity of amorphous thin film on silicon. In another effort adherent and conductive films were successfully achieved. Other efforts were aimed at achieving a simultaneous front and back junction. Microwave enhanced plasma deposition experiments were performed. An updated version of the Solar Array Manufacturing Industry Costing Standards (SAMICS) was presented, along with a life cycle cost analysis of high efficiency cells. The last presentation was on the evaluation of the ethyl vinyl acetate encapsulating system.

  10. Nozzle development

    SciTech Connect

    Dodge, F.T.; Dodge, L.G.; Johnson, J.E.

    1989-06-01

    The objective of this program has been the development of experimental techniques and data processing procedures to allow for the characterization of multi-phase fuel nozzles using laboratory tests. Test results were to be used to produce a single value coefficient-of-performance that would predict the performance of the fuel nozzles independent of system application. Several different types of fuel nozzles capable of handling multi-phase fuels have been characterized for: (a) fuel flow rate versus delivery pressure, (b) fuel-air ratio throughout the fuel spray or plume and the effective cone angle of the injector, and (c) fuel drop- or particle-size distribution as a function of fluid properties. Fuel nozzles which have been characterized on both single-phase liquids and multi-phase liquid-solid slurries include a variable-film-thickness nozzle, a commercial coal-water slurry (CWS) nozzle, and four diesel injectors of different geometries (tested on single-phase fluids only). Multi-phase mixtures includes CWS with various coal loadings, surfactant concentrations, and stabilizer concentrations, as well as glass-bead water slurries with stabilizing additives. Single-phase fluids included glycerol-water mixtures to vary the viscosity over a range of 1 to 1500 cP, and alcohol-water mixtures to vary the surface tension from about 22 to 73 dyne/cm. In addition, tests were performed to characterize straight-tube gas-solid nozzles using two differences size distributions of glass beads in air. Standardized procedures have been developed for processing measurements of spray drop-size characteristics and the overall cross-section average drop or particle size. 43 refs., 60 figs., 7 tabs.

  11. Pahenu1 is a mouse model for tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency and promotes analysis of the pharmacological chaperone mechanism in vivo.

    PubMed

    Gersting, Søren W; Lagler, Florian B; Eichinger, Anna; Kemter, Kristina F; Danecka, Marta K; Messing, Dunja D; Staudigl, Michael; Domdey, Katharina A; Zsifkovits, Clemens; Fingerhut, Ralph; Glossmann, Hartmut; Roscher, Adelbert A; Muntau, Ania C

    2010-05-15

    The recent approval of sapropterin dihydrochloride, the synthetic form of 6[R]-l-erythro-5,6,7,8-tetrahydrobiopterin (BH(4)), for the treatment of phenylketonuria (PKU) as the first pharmacological chaperone drug initiated a paradigm change in the treatment of monogenetic diseases. Symptomatic treatment is now replaced by a causal pharmacological therapy correcting misfolding of the defective phenylalanine hydroxylase (PAH) in numerous patients. Here, we disclose BH(4) responsiveness in Pah(enu1), a mouse model for PAH deficiency. Loss of function resulted from loss of PAH, a consequence of misfolding, aggregation, and accelerated degradation of the enzyme. BH(4) attenuated this triad by conformational stabilization augmenting the effective PAH concentration. This led to the rescue of the biochemical phenotype and enzyme function in vivo. Combined in vitro and in vivo analyses revealed a selective pharmaceutical action of BH(4) confined to the pathological metabolic state. Our data provide new molecular-level insights into the mechanisms underlying protein misfolding with loss of function and support a general model of pharmacological chaperone-induced stabilization of protein conformation to correct this intracellular phenotype. Pah(enu1) will be essential for pharmaceutical drug optimization and to design individually tailored therapies.

  12. The interplay between genotype, metabolic state and cofactor treatment governs phenylalanine hydroxylase function and drug response.

    PubMed

    Staudigl, Michael; Gersting, Søren W; Danecka, Marta K; Messing, Dunja D; Woidy, Mathias; Pinkas, Daniel; Kemter, Kristina F; Blau, Nenad; Muntau, Ania C

    2011-07-01

    The discovery of a pharmacological treatment for phenylketonuria (PKU) raised new questions about function and dysfunction of phenylalanine hydroxylase (PAH), the enzyme deficient in this disease. To investigate the interdependence of the genotype, the metabolic state (phenylalanine substrate) and treatment (BH(4) cofactor) in the context of enzyme function in vitro and in vivo, we (i) used a fluorescence-based method for fast enzyme kinetic analyses at an expanded range of phenylalanine and BH(4) concentrations, (ii) depicted PAH function as activity landscapes, (iii) retraced the analyses in eukaryotic cells, and (iv) translated this into the human system by analyzing the outcome of oral BH(4) loading tests. PAH activity landscapes uncovered the optimal working range of recombinant wild-type PAH and provided new insights into PAH kinetics. They demonstrated how mutations might alter enzyme function in the space of varying substrate and cofactor concentrations. Experiments in eukaryotic cells revealed that the availability of the active PAH enzyme depends on the phenylalanine-to-BH(4) ratio. Finally, evaluation of data from BH(4) loading tests indicated that the patient's genotype influences the impact of the metabolic state on drug response. The results allowed for visualization and a better understanding of PAH function in the physiological and pathological state as well as in the therapeutic context of cofactor treatment. Moreover, our data underscore the need for more personalized procedures to safely identify and treat patients with BH(4)-responsive PAH deficiency.

  13. Aspartame: review of safety.

    PubMed

    Butchko, Harriett H; Stargel, W Wayne; Comer, C Phil; Mayhew, Dale A; Benninger, Christian; Blackburn, George L; de Sonneville, Leo M J; Geha, Raif S; Hertelendy, Zsolt; Koestner, Adalbert; Leon, Arthur S; Liepa, George U; McMartin, Kenneth E; Mendenhall, Charles L; Munro, Ian C; Novotny, Edward J; Renwick, Andrew G; Schiffman, Susan S; Schomer, Donald L; Shaywitz, Bennett A; Spiers, Paul A; Tephly, Thomas R; Thomas, John A; Trefz, Friedrich K

    2002-04-01

    Over 20 years have elapsed since aspartame was approved by regulatory agencies as a sweetener and flavor enhancer. The safety of aspartame and its metabolic constituents was established through extensive toxicology studies in laboratory animals, using much greater doses than people could possibly consume. Its safety was further confirmed through studies in several human subpopulations, including healthy infants, children, adolescents, and adults; obese individuals; diabetics; lactating women; and individuals heterozygous (PKUH) for the genetic disease phenylketonuria (PKU) who have a decreased ability to metabolize the essential amino acid, phenylalanine. Several scientific issues continued to be raised after approval, largely as a concern for theoretical toxicity from its metabolic components--the amino acids, aspartate and phenylalanine, and methanol--even though dietary exposure to these components is much greater than from aspartame. Nonetheless, additional research, including evaluations of possible associations between aspartame and headaches, seizures, behavior, cognition, and mood as well as allergic-type reactions and use by potentially sensitive subpopulations, has continued after approval. These findings are reviewed here. The safety testing of aspartame has gone well beyond that required to evaluate the safety of a food additive. When all the research on aspartame, including evaluations in both the premarketing and postmarketing periods, is examined as a whole, it is clear that aspartame is safe, and there are no unresolved questions regarding its safety under conditions of intended use.

  14. Sampling Development

    PubMed Central

    Adolph, Karen E.; Robinson, Scott R.

    2011-01-01

    Research in developmental psychology requires sampling at different time points. Accurate depictions of developmental change provide a foundation for further empirical studies and theories about developmental mechanisms. However, overreliance on widely spaced sampling intervals in cross-sectional and longitudinal designs threatens the validity of the enterprise. This article discusses how to sample development in order to accurately discern the shape of developmental change. The ideal solution is daunting: to summarize behavior over 24-hour intervals and collect daily samples over the critical periods of change. We discuss the magnitude of errors due to undersampling, and the risks associated with oversampling. When daily sampling is not feasible, we offer suggestions for sampling methods that can provide preliminary reference points and provisional sketches of the general shape of a developmental trajectory. Denser sampling then can be applied strategically during periods of enhanced variability, inflections in the rate of developmental change, or in relation to key events or processes that may affect the course of change. Despite the challenges of dense repeated sampling, researchers must take seriously the problem of sampling on a developmental time scale if we are to know the true shape of developmental change. PMID:22140355

  15. Sustainable Development: The Challenge for Community Development.

    ERIC Educational Resources Information Center

    Gamble, Dorothy N.; Weil, Marie O.

    1997-01-01

    Five areas of inquiry shape the sustainable development movement: environmental movement, women's movement, overpopulation concerns, critique of development models, and new indicators of social progress. Community development workers are challenged to prepare local development projects within a sustainable development framework. (SK)

  16. VAP Development: Initiation, Development, Evaluation, and Release

    SciTech Connect

    Jensen, M; Collis, Fast, J; Flynn, C; Mather, J; McFarlane, S; Monroe, J; Sivaraman, C; Xie, S

    2011-02-23

    This white paper provides a plan to formalize the evaluation of newly developed VAPs and a framework for the development of value-added products through four different stages: Initiation, Development, Evaluation, and Release.

  17. Developed-developing country partnerships: benefits to developed countries?

    PubMed

    Syed, Shamsuzzoha B; Dadwal, Viva; Rutter, Paul; Storr, Julie; Hightower, Joyce D; Gooden, Rachel; Carlet, Jean; Bagheri Nejad, Sepideh; Kelley, Edward T; Donaldson, Liam; Pittet, Didier

    2012-06-18

    Developing countries can generate effective solutions for today's global health challenges. This paper reviews relevant literature to construct the case for international cooperation, and in particular, developed-developing country partnerships. Standard database and web-based searches were conducted for publications in English between 1990 and 2010. Studies containing full or partial data relating to international cooperation between developed and developing countries were retained for further analysis. Of 227 articles retained through initial screening, 65 were included in the final analysis. The results were two-fold: some articles pointed to intangible benefits accrued by developed country partners, but the majority of information pointed to developing country innovations that can potentially inform health systems in developed countries. This information spanned all six WHO health system components. Ten key health areas where developed countries have the most to learn from the developing world were identified and include, rural health service delivery; skills substitution; decentralisation of management; creative problem-solving; education in communicable disease control; innovation in mobile phone use; low technology simulation training; local product manufacture; health financing; and social entrepreneurship. While there are no guarantees that innovations from developing country experiences can effectively transfer to developed countries, combined developed-developing country learning processes can potentially generate effective solutions for global health systems. However, the global pool of knowledge in this area is virgin and further work needs to be undertaken to advance understanding of health innovation diffusion. Even more urgently, a standardized method for reporting partnership benefits is needed--this is perhaps the single most immediate need in planning for, and realizing, the full potential of international cooperation between developed and

  18. Developed-developing country partnerships: Benefits to developed countries?

    PubMed Central

    2012-01-01

    Developing countries can generate effective solutions for today’s global health challenges. This paper reviews relevant literature to construct the case for international cooperation, and in particular, developed-developing country partnerships. Standard database and web-based searches were conducted for publications in English between 1990 and 2010. Studies containing full or partial data relating to international cooperation between developed and developing countries were retained for further analysis. Of 227 articles retained through initial screening, 65 were included in the final analysis. The results were two-fold: some articles pointed to intangible benefits accrued by developed country partners, but the majority of information pointed to developing country innovations that can potentially inform health systems in developed countries. This information spanned all six WHO health system components. Ten key health areas where developed countries have the most to learn from the developing world were identified and include, rural health service delivery; skills substitution; decentralisation of management; creative problem-solving; education in communicable disease control; innovation in mobile phone use; low technology simulation training; local product manufacture; health financing; and social entrepreneurship. While there are no guarantees that innovations from developing country experiences can effectively transfer to developed countries, combined developed-developing country learning processes can potentially generate effective solutions for global health systems. However, the global pool of knowledge in this area is virgin and further work needs to be undertaken to advance understanding of health innovation diffusion. Even more urgently, a standardized method for reporting partnership benefits is needed—this is perhaps the single most immediate need in planning for, and realizing, the full potential of international cooperation between developed and

  19. App Development Paradigms for Instructional Developers

    ERIC Educational Resources Information Center

    Luterbach, Kenneth J.; Hubbell, Kenneth R.

    2015-01-01

    To create instructional apps for desktop, laptop and mobile devices, developers must select a development tool. Tool selection is critical and complicated by the large number and variety of app development tools. One important criterion to consider is the type of development environment, which may primarily be visual or symbolic. Those distinct…

  20. Comparing Spiritual Development and Cognitive Development.

    ERIC Educational Resources Information Center

    Love, Patrick G.

    2002-01-01

    Three spiritual development theories and theorists (i.e., Parks, Fowler, and Helminiak) were compared with traditional cognitive development theory and theorists. The analysis reveals both commonalities between the two sets of theories and unique contributions to an understanding of student development on the part of spiritual development theory.…

  1. Entrepreneurial Intentions in Developing and Developed Countries

    ERIC Educational Resources Information Center

    Iakovleva, Tatiana; Kolvereid, Lars; Stephan, Ute

    2011-01-01

    Purpose: This study proposes to use the Theory of Planned Behaviour to predict entrepreneurial intentions among students in five developing and nine developed countries. The purpose is to investigate whether entrepreneurial intention and its antecedents differ between developing and developed countries, and to test the theory in the two groups of…

  2. Child Development and Learning.

    ERIC Educational Resources Information Center

    Johnson, William C., Ed.

    Previously published articles on child development and learning are collected in this textbook for college students. Topics include cognitive development, achievement behavior, and social development. (SBT)

  3. Developing New Academic Developers: Doing before Being?

    ERIC Educational Resources Information Center

    Kensington-Miller, Barbara; Brailsford, Ian; Gossman, Peter

    2012-01-01

    A small group of new academic developers reflected on their induction into the profession and wondered if things could have been done differently. The researchers decided to question the directors of three tertiary academic development units about how they recruited new developers, what skills and competences they looked for and how they inducted…

  4. Genes for super-intelligence?

    PubMed

    Sofaer, J A; Emery, A E

    1981-12-01

    The results of a postal questionnaire distributed to British members of Mensa failed to confirm an association of superior intelligence with torsion dystonia, retinoblastoma, or phenylketonuria, but were consistent with real associations between high IQ and infantile autism, gout, and myopia. Further confirmation of these findings in other populations might well indicate that genes producing these disorders have more or less direct effects on cerebral development and function.

  5. Clean development mechanism: Perspectives from developing countries

    SciTech Connect

    Sari, Agus P.; Meyers, Stephen

    1999-06-01

    This paper addresses the political acceptability and workability of CDM by and in developing countries. At COP-3 in Kyoto in 1997, the general position among developing countries changed from strong rejection of joint implementation to acceptance of CDM. The outgrowth of CDM from a proposal from Brazil to establish a Clean Development Fund gave developing countries a sense of ownership of the idea. More importantly, establishing support for sustainable development as a main goal for CDM overcame the resistance of many developing countries to accept a carbon trading mechanism. The official acceptance of CDM is not a guarantee of continued acceptance, however. Many developing countries expect CDM to facilitate a substantial transfer of technology and other resources to support economic growth. There is concern that Annex I countries may shift official development assistance into CDM in order to gain carbon credits, and that development priorities could suffer as a result. Some fear that private investments could be skewed toward projects that yield carbon credits. Developing country governments are wary regarding the strong role of the private sector envisioned for CDM. Increasing the awareness and capacity of the private sector in developing countries to initiate and implement CDM projects needs to be a high priority. While private sector partnerships will be the main vehicle for resource transfer in CDM, developing country governments want to play a strong role in overseeing and guiding the process so that it best serves their development goals. Most countries feel that establishment of criteria for sustainable development should be left to individual countries. A key issue is how CDM can best support the strengthening of local capacity to sustain and replicate projects that serve both climate change mitigation and sustainable development objectives.There is support among developing countries for commencing CDM as soon as possible. Since official commencement must

  6. FPG Child Development Institute

    MedlinePlus

    ... and 'alternative facts,' science can reliably inform policy. Child development research advises that a sense of security provided ... Development, Teaching, and Learning The Frank Porter Graham Child Development Institute will partner with Zero to Three to ...

  7. Your Child's Development: Newborn

    MedlinePlus

    ... Your 1- to 2-Year-Old Your Child's Development: Newborn KidsHealth > For Parents > Your Child's Development: Newborn ... changed; or goes to sleep ) Movement and Physical Development moves in response to sights and sounds rooting ...

  8. Developing New Models for Collection Development.

    ERIC Educational Resources Information Center

    Stoffle, Carla J.; Fore, Janet; Allen, Barbara

    1999-01-01

    Discusses the need to develop new models for collection development in academic libraries, based on experiences at the University of Arizona. Highlights include changes in the organizational chart; focusing on users' information goals and needs; integrative services; shared resources; interlibrary loans; digital technology; and funding. (LRW)

  9. Curriculum Development: Teacher Involvement in Curriculum Development

    ERIC Educational Resources Information Center

    Alsubaie, Merfat Ayesh

    2016-01-01

    In order for curriculum development to be effective and schools to be successful, teachers must be involved in the development process. An effective curriculum should reflect the philosophy, goals, objectives, learning experiences, instructional resources, and assessments that comprise a specific educational program ("Guide to curriculum…

  10. Child Development Associate. Body Skills Development.

    ERIC Educational Resources Information Center

    Office of Child Development (DHEW), Washington, DC.

    This Child Development Associate (CDA) training module, one of a series of 18, is intended to provide the intern with the knowledge and skills necessary for helping children develop their body skills. The module stipulates competency-based objectives and provides essential information, suggestions, examples and learning activities on three topics…

  11. Developing Teachers: Improving Professional Development for Teachers

    ERIC Educational Resources Information Center

    Coe, Robert; Aloisi, Cesare; Higgins, Steve; Major, Lee Elliot

    2015-01-01

    This document is a summary of the report "What Makes Great Teaching". It argues that improved teacher ­development will positively impact on pupil attainment, particular those from disadvantaged backgrounds. "Developing Teachers" presents five policy recommendations which have been signed by 17 of Britain's leading headteachers…

  12. SIRU development. Volume 1: System development

    NASA Technical Reports Server (NTRS)

    Gilmore, J. P.; Cooper, R. J.

    1973-01-01

    A complete description of the development and initial evaluation of the Strapdown Inertial Reference Unit (SIRU) system is reported. System development documents the system mechanization with the analytic formulation for fault detection and isolation processing structure; the hardware redundancy design and the individual modularity features; the computational structure and facilities; and the initial subsystem evaluation results.

  13. Child Development Associate. Child Growth and Development.

    ERIC Educational Resources Information Center

    Oscar Rose Junior Coll., Midwest City, OK.

    The purpose of this Child Development Associate (CDA) training module, one of a series of 18, is to help the CDA intern understand the factors and principles which affect the total growth and development of children. Early sections of the module stipulate the module's competency-based objectives, define terms, and suggest procedures by which…

  14. Education and Development: A Developing Theme

    NASA Astrophysics Data System (ADS)

    Brock-Utne, Birgit

    2002-03-01

    The following article is based on an analysis of selected examples from the approximately 2500 main articles that have been published in the International Review of Education ( IRE) since its inception in 1931 until the fall of 2001. The scope of the topic is education within developing countries and the promotion of such education by industrialised countries and development agencies. After an introduction on the growth of the concern over education and development over seven decades of the journal, three themes are looked at in some more detail: (1) The discussion on nationalism versus internationalism in education, a theme that bears clear relevance to the field "Education and Development" and has been with the journal from its inception but on which one finds more emphasis in the earlier volumes. (2) The language of instruction in developing countries. This theme has also been with the journal from its inception and it is still much debated. (3) The effects of external aid on the education sector in developing countries. Though massive economic aid in the form of grants or loans to the education sector in developing countries is of more recent nature external influence on the education sector has been there since colonial times.

  15. Options for developing countries in mining development

    SciTech Connect

    Walrond, G.W.; Kumar, R.

    1985-01-01

    This book is a study of the issues that developing countries face in planning and implementing mineral development, taking as case studies Botswana, Sierra Leone, Zambia, Tanzania, Malaysia, Papua New Guinea and the developed states of Quebec and Western Australia. The authors consider the major aspects of the matter including organization and administration; regulation; taxation and surplus distribution; the dynamics of such instruments as royalty, rent resource tax and capital allowances under various cost/price scenarios; and selected mining agreements and their key provisions. They stress throughout the need for foreign investment while maximizing the economic benefits reaped from exhaustible resources.

  16. Geothermal development opportunities in developing countries

    SciTech Connect

    Kenkeremath, D.C.

    1989-11-16

    This report is the proceedings of the Seminar on geothermal development opportunities in developing countries, sponsored by the Geothermal Division of the US Department of Energy and presented by the National Geothermal Association. The overall objectives of the seminar are: (1) Provide sufficient information to the attendees to encourage their interest in undertaking more geothermal projects within selected developing countries, and (2) Demonstrate the technological leadership of US technology and the depth of US industry experience and capabilities to best perform on these projects.

  17. Energy Sources and Development.

    ERIC Educational Resources Information Center

    Crank, Ron

    This instructional unit is one of 10 developed by students on various energy-related areas that deals specifically with energy sources and development. Its objective is for the student to be able to discuss energy sources and development related to the historical perspective, biological development, current aspects, and future expectations…

  18. LGBT Career Development

    ERIC Educational Resources Information Center

    Gedro, Julie

    2007-01-01

    In this paper, I would like to open a conversation with my HRD colleagues about the issues related to Lesbian, Gay, Bisexual and Transgender (LGBT) career development. This paper provides some insights about LGBT career development, analyzing the factors that distinguish LGBT career development from heterosexual career development.

  19. Directions in Staff Development

    ERIC Educational Resources Information Center

    Brew, Angela, Ed.

    This collection of readings is intended to provide a source book on best practices in staff development in higher education within a British context. The 13 papers are grouped into three parts: part 1 presents the educational development tradition which has focused on development of staff as teachers; part 2 considers development of staff in…

  20. Software Development Program.

    ERIC Educational Resources Information Center

    Collin County Community Coll., McKinney, TX.

    The Software Development Program described in this report was developed at Collin County Community College as a pilot associate degree program for the State of Texas. Drawing from an employer needs assessment and a DACUM (Developing a Curriculum) process, the two-year associate in applied science (AAS) program was developed to train scientific…

  1. Rural Development Issues.

    ERIC Educational Resources Information Center

    Economic Research Service (USDA), Washington, DC. Economic Development Div.

    Elements essential to an adequate framework for rural development in the U.S. are a national growth and development policy which includes a rural development strategy and definition of common problems and programmatic actions required to deal with them. Many past federal rural development programs (lacking a federal rural policy focus) have failed…

  2. Agile Software Development

    ERIC Educational Resources Information Center

    Biju, Soly Mathew

    2008-01-01

    Many software development firms are now adopting the agile software development method. This method involves the customer at every level of software development, thus reducing the impact of change in the requirement at a later stage. In this article, the principles of the agile method for software development are explored and there is a focus on…

  3. Your Child's Development: Newborn

    MedlinePlus

    ... Feeding Your 1- to 2-Year-Old Your Child's Development: Newborn KidsHealth > For Parents > Your Child's Development: Newborn Print A A A en español El ... the sole of the foot Social and Emotional Development soothed by a parent's ... When to Talk to Your Doctor Every child develops at his or her own pace, but ...

  4. Quantitative fluorescence detection of phenylalanine in blood spots on filter paper

    NASA Astrophysics Data System (ADS)

    Li, Yuezhi; Liu, Fengjun; Wang, Xuemin; Xu, Gang

    2007-11-01

    Phenylketonuria is a genetic disease, which causes the metabolization disorder of phenylalanine, this disorder would damage the neural system of infants as a result of the accumulation of phenylalanine in blood. Therefore, it is of great importance to diagnose and treat phenylketonuria as early as possible for newborns. The aim of this paper is to develop a fluorescence detection system to measure blood phenylalanine concentration of new-born infants. In this design, a high luminance ultraviolet LED is used for excitation source, and a kind of bifurcated optical fiber assembly is applied for conduction of light. The excitation source is filtered and coupled into quartz fibers of the bifurcated fiber assembly for conduction of light to excite the fluorescence of phenylalanine in blood sample. The collected fluorescence is transmitted along the glass fibers of the assemblies and coupled to a photomultiplier tube. The fluorescence is filtered with 470~500 nm band-pass filter to subdue scattered excitation light and to limit the spectral width of the detected fluorescence. By the comparison with a standard instrument, the new system with low power consumption, low cost and small size is also proven sensitive and accurate, which meets the demand of clinical phenylketonuria screening.

  5. Hanford Site Development Plan

    SciTech Connect

    Hathaway, H.B.; Daly, K.S.; Rinne, C.A.; Seiler, S.W.

    1993-05-01

    The Hanford Site Development Plan (HSDP) provides an overview of land use, infrastructure, and facility requirements to support US Department of Energy (DOE) programs at the Hanford Site. The HSDP`s primary purpose is to inform senior managers and interested parties of development activities and issues that require a commitment of resources to support the Hanford Site. The HSDP provides an existing and future land use plan for the Hanford Site. The HSDP is updated annually in accordance with DOE Order 4320.1B, Site Development Planning, to reflect the mission and overall site development process. Further details about Hanford Site development are defined in individual area development plans.

  6. Hanford Site Development Plan

    SciTech Connect

    Rinne, C.A.; Curry, R.H.; Hagan, J.W.; Seiler, S.W.; Sommer, D.J. ); Yancey, E.F. )

    1990-01-01

    The Hanford Site Development Plan (Site Development Plan) is intended to guide the short- and long-range development and use of the Hanford Site. All acquisition, development, and permanent facility use at the Hanford Site will conform to the approved plan. The Site Development Plan also serves as the base document for all subsequent studies that involve use of facilities at the Site. This revision is an update of a previous plan. The executive summary presents the highlights of the five major topics covered in the Site Development Plan: general site information, existing conditions, planning analysis, Master Plan, and Five-Year Plan. 56 refs., 67 figs., 31 tabs.

  7. DEVELOPING STATE POLICIES SUPPORTIVE OF BIOENERGY DEVELOPMENT

    SciTech Connect

    Kathryn Baskin

    2004-07-28

    Working within the context of the Southern States Biobased Alliance (SSBA) and with officials in each state, the Southern States Energy Board (SSEB) is identifying bioenergy-related policies and programs within each state to determine their impact on the development, deployment or use of bioenergy. In addition, SSEB will determine which policies have impacted industry's efforts to develop, deploy or use biobased technologies or products. As a result, SSEB will work with the Southern States Biobased Alliance to determine how policy changes might address any negative impacts or enhance positive impacts. In addition to analysis of domestic policies and programs, this project will include the development of a U.S.-Brazil Biodiesel Pilot Project. The purpose of this effort is to promote and facilitate the commercialization of biodiesel and bioenergy production and demand in Brazil.

  8. DEVELOPING STATE POLICIES SUPPORTIVE OF BIOENERGY DEVELOPMENT

    SciTech Connect

    Kathryn Baskin

    2004-10-31

    Working within the context of the Southern States Biobased Alliance (SSBA) and with officials in each state, the Southern States Energy Board (SSEB) is identifying bioenergy-related policies and programs within each state to determine their impact on the development, deployment or use of bioenergy. In addition, SSEB will determine which policies have impacted industry's efforts to develop, deploy or use biobased technologies or products. As a result, SSEB will work with the Southern States Biobased Alliance to determine how policy changes might address any negative impacts or enhance positive impacts. In addition to analysis of domestic policies and programs, this project will include the development of a U.S.-Brazil Biodiesel Pilot Project. The purpose of this effort is to promote and facilitate the commercialization of biodiesel and bioenergy production and demand in Brazil.

  9. DEVELOPING STATE POLICIES SUPPORTIVE OF BIOENERGY DEVELOPMENT

    SciTech Connect

    Kathryn Baskin

    2005-04-30

    Working within the context of the Southern States Biobased Alliance (SSBA) and with officials in each state, the Southern States Energy Board (SSEB) is identifying bioenergy-related policies and programs within each state to determine their impact on the development, deployment or use of bioenergy. In addition, SSEB will determine which policies have impacted industry's efforts to develop, deploy or use biobased technologies or products. As a result, SSEB will work with the Southern States Biobased Alliance to determine how policy changes might address any negative impacts or enhance positive impacts. In addition to analysis of domestic policies and programs, this project will include the development of a U.S.-Brazil Biodiesel Pilot Project. The purpose of this effort is to promote and facilitate the commercialization of biodiesel and bioenergy production and demand in Brazil.

  10. DEVELOPING STATE POLICIES SUPPORTIVE OF BIOENERGY DEVELOPMENT

    SciTech Connect

    Kathryn Baskin

    2005-01-31

    Working within the context of the Southern States Biobased Alliance (SSBA) and with officials in each state, the Southern States Energy Board (SSEB) is identifying bioenergy-related policies and programs within each state to determine their impact on the development, deployment or use of bioenergy. In addition, SSEB will determine which policies have impacted industry's efforts to develop, deploy or use biobased technologies or products. As a result, SSEB will work with the Southern States Biobased Alliance to determine how policy changes might address any negative impacts or enhance positive impacts. In addition to analysis of domestic policies and programs, this project will include the development of a U.S.-Brazil Biodiesel Pilot Project. The purpose of this effort is to promote and facilitate the commercialization of biodiesel and bioenergy production and demand in Brazil.

  11. DEVELOPING STATE POLICIES SUPPORTIVE OF BIOENERGY DEVELOPMENT

    SciTech Connect

    Kathryn Baskin

    2003-10-31

    Working within the context of the Southern States Biobased Alliance (SSBA) and with officials in each state, the Southern States Energy Board (SSEB) is identifying bioenergy-related policies and programs within each state to determine their impact on the development, deployment or use of bioenergy. In addition, SSEB will determine which policies have impacted industry's efforts to develop, deploy or use biobased technologies or products. As a result, SSEB will work with the Southern States Biobased Alliance to determine how policy changes might address any negative impacts or enhance positive impacts.

  12. Developing the plan

    NASA Technical Reports Server (NTRS)

    1975-01-01

    The basic sequence in the planning development process is discussed. Alternative ways of satisfying estimated needs, and the selection of an alternative are described along with the development of a plan to implement the selected alternative.

  13. CHP Project Development

    EPA Pesticide Factsheets

    Access information and tools to support the CHP project development process, including identifying if your facility is a good fit for CHP, the steps involved with CHP project development, and policies and incentives supportive of CHP.

  14. Growth and Development

    MedlinePlus

    ... the Classroom What Other Parents Are Reading Your Child's Development (Birth to 3 Years) Feeding Your 1- to ... Tots Understanding Puberty Your Child's Changing Voice Your Child's Development: 1.5 Years (18 Months) Your Child's Growth ...

  15. Robotic Lander Development Project

    NASA Video Gallery

    The Robotic Lander Development Project at the Marshall Center is testing a prototype lander that will aid in the design and development of a new generation of small, smart, versatile robotic lander...

  16. AVOSS Development Approach

    NASA Technical Reports Server (NTRS)

    Hinton, David A.

    1997-01-01

    A concept is presented for development and implementation of prototype Aircraft Vortex Spacing System (AVOSS). The purpose of the AVOSS is to provide dynamical, weather dependent wake vortex separation criteria to ATC facilities with adequate stability and lead time for use in establishing arrival scheduling. This current paper discusses AVOSS development approach. The discussion includes: system model, AVOSS R&D effort scope, major development issues, concept system development process, AVOSS system testing, and concept demonstration.

  17. Coalbed gas development

    SciTech Connect

    Not Available

    1992-01-01

    This book includes: Overview of coalbed gas development; Coalbed gas development in the West Coalbed gas development on Indian lands; Multi-mineral development conflicts; Statutory solutions to ownership disputes; State and local regulation; Environmental regulations; Status of the section 29 tax credit extension; Using the section 29 credit; Leasing coalbed gas prospects; Coalbed gas joint operating agreements and Purchase and sale agreements for coalbed gas properties.

  18. Mechanisms in Plant Development

    SciTech Connect

    Hake, Sarah

    2013-08-21

    This meeting has been held every other year for the past twenty-two years and is the only regularly held meeting focused specifically on plant development. Topics covered included: patterning in developing tissues; short and long distance signaling; differentiation of cell types; the role of epigenetics in development; evolution; growth.

  19. Development Communication Report, 1993.

    ERIC Educational Resources Information Center

    Bosch, Andrea, Ed.

    1993-01-01

    The three 1993 issues of the newsletter "Development Communication Report" focus on the use of communication technologies in developing countries to educate the people about various social issues as well as the field of development communication itself. Agricultural communication is the theme of the first issue which contains the…

  20. Moral Development in Adolescence

    ERIC Educational Resources Information Center

    Hart, Daniel; Carlo, Gustavo

    2005-01-01

    Themes in the papers in this special issue of the "JRA" on moral development are identified. We discuss the intersection of moral development research with policy concerns, the distinctive qualities of moral life in adolescence that warrant investigation, the multiple connotations of "moral", the methods typical of moral development research, and…

  1. Developing Large CAI Packages.

    ERIC Educational Resources Information Center

    Reed, Mary Jac M.; Smith, Lynn H.

    1983-01-01

    When developing large computer-assisted instructional (CAI) courseware packages, it is suggested that there be more attentive planning to the overall package design before actual lesson development is begun. This process has been simplified by modifying the systems approach used to develop single CAI lessons, followed by planning for the…

  2. Curriculum Development in Geomorphology.

    ERIC Educational Resources Information Center

    Gregory, Kenneth J.

    1988-01-01

    Examines the context of present curriculum development in geomorphology and the way in which it has developed in recent years. Discusses the content of the geomorphology curriculum in higher education and the consequences of curriculum development together with a consideration of future trends and their implications. (GEA)

  3. PHOTOGRAPHIC FILM DEVELOPER

    DOEpatents

    Berry, F.G.

    1958-06-24

    S>An improved photographic developer is presented having very high energy development fine grain characteristics and a long shelf life. These characteristics are obtained by the use of aminoacetic acid in the developer, the other constituents of which are: sodium sulfite, hydroquinone, sodiunn borate, boric acid and potassium bromide, 1-phenyl-3-pyrazolidone.

  4. Leadership Development. Symposium 12.

    ERIC Educational Resources Information Center

    2000

    Three presentations are provided from the Academy of Human Resource Development (HRD) 2000 Conference Proceedings. "Leadership Development: A Review of the Theory and Literature" (Susan A. Lynham) has four parts that analyze the leadership development process: the present state of the available body of knowledge on leadership…

  5. Teachers as Course Developers.

    ERIC Educational Resources Information Center

    Graves, Kathleen, Ed.

    The collection of essays on teachers as course developers is designed to help teachers understand how to develop courses or modify existing ones using their own experience and the experiences and theories of others. It attempts to capture this process through the stories of six teachers who have developed courses. Each narrative focuses on a…

  6. World Development Report 1984.

    ERIC Educational Resources Information Center

    World Bank, Washington, DC.

    This report, seventh in a series of annual publications, examines the relationship between population change and development, showing why continuing rapid population growth in developing countries is likely to mean a lower quality of life for millions of people. The first part of the report concludes that the economies of developing countries can…

  7. HRD Professional Development.

    ERIC Educational Resources Information Center

    1999

    These three papers are from a symposium on human resource development (HRD) professional development. "Mentoring as a Tool for Faculty Development: Predicting Positive Outcomes for Mentors" (Ellen J. Mullen, John Van Ast, Harry Grant) describes a study of the relationship between mentoring outcomes and mentoring activities and mentor and mentee…

  8. Marketing Human Resource Development.

    ERIC Educational Resources Information Center

    Frank, Eric, Ed.

    1994-01-01

    Describes three human resource development activities: training, education, and development. Explains marketing from the practitioners's viewpoint in terms of customer orientation; external and internal marketing; and market analysis, research, strategy, and mix. Shows how to design, develop, and implement strategic marketing plans and identify…

  9. Does Educational Development Matter?

    ERIC Educational Resources Information Center

    Knapper, Christopher

    2016-01-01

    This essay provides reflections on the growth and influence of educational development, and the changes in approaches to teaching in universities. It also identifies some areas in which educational development and developers face challenges for the future, including educational technology, leadership and resistance to change.

  10. Collection Development Project.

    ERIC Educational Resources Information Center

    Nuby, Mary

    Undertaken to provide data on the current status of collection development in selected academic libraries, this study also analyzed the structure of the collection development function at Chicago Academic Library Council (CALC) institutions and outlined a formal collection development policy for Chicago State University's Douglas Library.…

  11. Folk Media in Development.

    ERIC Educational Resources Information Center

    Instructional Technology Report, 1975

    1975-01-01

    This issue is dedicated to folk media. Using Indonesia for his case study, Dr. Nat Colletta analyzes traditional culture as a medium for development. Juan Diaz Bordenave expresses doubts about adapting folk media to development objectives; Susan Hostetler and Arthur Gillette report on uses of the theater to promote development objectives; and…

  12. Prodder's Development Annual, 1988.

    ERIC Educational Resources Information Center

    van der Kooy, R. J. W., Ed.

    This collection of reports examines the current state of development in southern Africa, in general, and in South Africa, in particular. The introduction, "A Development Perspective of Southern Africa" (R. J. W. van der Kooy), briefly reviews the history of southern African development, and discusses purposes, approaches, and progress.…

  13. Terrorism, Governance, and Development

    DTIC Science & Technology

    2016-01-13

    science research on national security issues. A primary objective was to develop better theories about the impact of aid programs on terrorist and...SUBJECT TERMS Terrorism, counterinsurgency, economics, development, foreign aid , governance, insurgent, national security, political science, political...9 • Optimal Scale and Design of Development and Military Aid

  14. Essays on Child Development in Developing Countries

    ERIC Educational Resources Information Center

    Humpage, Sarah Davidson

    2013-01-01

    This dissertation presents the results of three field experiments implemented to evaluate the effectiveness of strategies to improve the health or education of children in developing countries. In Guatemala, community health workers at randomly selected clinics were given patient tracking lists to improve their ability to remind parents when their…

  15. Dental Curriculum Development in Developing Countries.

    ERIC Educational Resources Information Center

    Phantumvanit, Prathip

    1996-01-01

    Since establishment of formal dental education in Southeast Asia, changes stemming from research and technology have led to dental curriculum changes. Development of the dental curriculum can be divided into three phases: disease oriented; health oriented; and community oriented. Evolution of these phases is traced in the dental curricula of Laos,…

  16. Initiation of vascular development.

    PubMed

    Ohashi-Ito, Kyoko; Fukuda, Hiroo

    2014-06-01

    The initiation of vascular development occurs during embryogenesis and the development of lateral organs, such as lateral roots and leaves. Understanding the mechanism underlying the initiation of vascular development has been an important goal of plant biologists. Auxin flow is a crucial factor involved in the initiation of vascular development. In addition, recent studies have identified key factors that regulate the establishment of vascular initial cells in embryos and roots. In this review, we summarize the recent findings in this field and discuss the initiation of vascular development.

  17. Geothermal development attitudes surveyed

    SciTech Connect

    Not Available

    1986-01-01

    The State of Hawaii has conducted several surveys on public opinion towards the development of geothermal energy. The latest poll was designed to: measure public opinion in the County of Hawaii relevant to geothermal development for electrical power supplied to Island of Hawaii residents only; measure public opinion in the County of Hawaii relevant to geothermal development of electricity to be exported for use on Oahu; and identify barriers to, and opportunities for energy conservation programs, including geothermal development. In general, the residents of the County of Hawaii favor some form of geothermal development. Issues on geothermal development of concern to the public were similar to those mentioned in the 1982 study. Basically, the issues amount to a trade-off between the economic advantages and the environmental problems of geothermal development. The strong points in favor of development include a perceived need for more energy, a strong preference for alternate energy forms over petroleum, perceived benefits for the local economy and the employment rates, and the possibility that development may reduce or contain utility bills. On the other hand, it appears that geothermal development will cause health problems for those who live near the wells, be hazardous to flora and fauna in the Puna area, and create noise and odor above tolerable levels. These are oversimplified statements of the reasons behind both support and opposition for geothermal development.

  18. Site Development Planning Handbook

    SciTech Connect

    1981-01-01

    The Handbook provides facility managers and site planners at DOE organizations responsible for planning site developments and facilities utilization a step-by-step planning checklist to ensure that planners at each site are focusing on Department-wide goals and objectives. It begins with a brief discussion of a site development-by-objectives program design to promote, recognize, and implement opportunities for improvements in site utilization through planning. Additional information is included on: assembling existing data, plans, programs, and procedures; establishing realistic objectives; identifying site problems, opportunities; and development needs; determining priorities among development needs; developing short and long-range plans; choosing the right development solutions and meeting minimum legal site restrictions; presenting the plan; implementing elements of the plan; monitoring and reporting plan status; and modifying development program plans. (MCW)

  19. Phenylalanine hydroxylase deficiency.

    PubMed

    Mitchell, John J; Trakadis, Yannis J; Scriver, Charles R

    2011-08-01

    Phenylalanine hydroxylase deficiency is an autosomal recessive disorder that results in intolerance to the dietary intake of the essential amino acid phenylalanine. It occurs in approximately 1:15,000 individuals. Deficiency of this enzyme produces a spectrum of disorders including classic phenylketonuria, mild phenylketonuria, and mild hyperphenylalaninemia. Classic phenylketonuria is caused by a complete or near-complete deficiency of phenylalanine hydroxylase activity and without dietary restriction of phenylalanine most children will develop profound and irreversible intellectual disability. Mild phenylketonuria and mild hyperphenylalaninemia are associated with lower risk of impaired cognitive development in the absence of treatment. Phenylalanine hydroxylase deficiency can be diagnosed by newborn screening based on detection of the presence of hyperphenylalaninemia using the Guthrie microbial inhibition assay or other assays on a blood spot obtained from a heel prick. Since the introduction of newborn screening, the major neurologic consequences of hyperphenylalaninemia have been largely eradicated. Affected individuals can lead normal lives. However, recent data suggest that homeostasis is not fully restored with current therapy. Treated individuals have a higher incidence of neuropsychological problems. The mainstay of treatment for hyperphenylalaninemia involves a low-protein diet and use of a phenylalanine-free medical formula. This treatment must commence as soon as possible after birth and should continue for life. Regular monitoring of plasma phenylalanine and tyrosine concentrations is necessary. Targets of plasma phenylalanine of 120-360 μmol/L (2-6 mg/dL) in the first decade of life are essential for optimal outcome. Phenylalanine targets in adolescence and adulthood are less clear. A significant proportion of patients with phenylketonuria may benefit from adjuvant therapy with 6R-tetrahydrobiopterin stereoisomer. Special consideration must be

  20. Development. The decade of the developing brain.

    PubMed

    Jessell, T M; Sanes, J R

    2000-10-01

    Our understanding of neural development has advanced dramatically over the past decade. Significant insights have now been obtained into seven fundamental developmental processes: first, induction of the neural plate; second, regionalization of the neural tube along the dorsoventral and anteroposterior axes; third, generation of neurons and glia from multipotential precursors; fourth, apoptotic cell death; fifth, migration of neurons; sixth, guidance of axons to their targets; and seventh, formation of synapses.

  1. The activity of wild type and mutant phenylalanine hydroxylase with respect to the C-oxidation of phenylalanine and the S-oxidation of S-carboxymethyl-L-cysteine.

    PubMed

    Steventon, Glyn B; Mitchell, Stephen C; Pérez, Belen; Desviat, Lourdes R; Ugarte, Magdalena

    2009-01-01

    The involvement of the enzyme, phenylalanine hydroxylase (PAH), in the S-oxidation of S-carboxymethyl-L-cysteine (SCMC) is now firmly established in man and rat. However, the underlying role of the molecular genetics of PAH in dictating and influencing the S-oxidation polymorphism of SCMC metabolism is as yet unknown. In this work we report that the S-oxidation of SCMC was dramatically reduced in the tetrahydrobiopterin (BH(4)) responsive mutant PAH proteins (I65T, R68S, R261Q, V388M and Y414C) with these enzymes possessing between 1.2% and 2.0% of the wild type PAH activity when SCMC was used as substrate. These same mutant proteins express between 23% and 76% of the wild type PAH activity when phenylalanine was used as the substrate. The PAH mutant proteins (R158Q, I174T and R408W) that result in the classical phenylketonuria (PKU) phenotype expressing 0.2-1.8% of the wild type PAH activity when using phenylalanine as substrate were found to have <0.1% of the wild type PAH activity when SCMC was used as the substrate. Mutations that result in PAH proteins retaining some residual PAH activity with phenylalanine as substrate have <2.0% residual activity when SCMC was used as a substrate. This investigation has led to the hypothesis that the S-oxidation polymorphism in man is a consequence of an individual carrying one mutant PAH allele which has resulted in the loss of the ability of the residual PAH protein to undertake the S-oxidation of SCMC in vivo.

  2. Fast clinical molecular diagnosis of hyperphenylalaninemia using next-generation sequencing-based on a custom AmpliSeq™ panel and Ion Torrent PGM sequencing.

    PubMed

    Cao, Yan-yan; Qu, Yu-jin; Song, Fang; Zhang, Ting; Bai, Jin-li; Jin, Yu-wei; Wang, Hong

    2014-12-01

    Hyperphenylalaninemia (HPA) can be classified into phenylketonuria (PKU) and tetrahydrobiopterin deficiency (BH4D), according to the defect of enzyme activity, both of which vary substantially in severity, treatment, and prognosis of the disease. To set up a fast and comprehensive assay in order to achieve early etiological diagnosis and differential diagnosis for children with HPA, we designed a custom AmpliSeq™ panel for the sequencing of coding DNA sequence (CDS), flanking introns, 5' untranslated region (UTR) and 3' UTR from five HPA-causing genes (PAH, PTS, QDPR, GCH1, and PCBD1) using the Ion Torrent Personal Genome Machine (PGM) Sequencer. A standard group of 15 samples with previously known DNA sequences and a test group of 37 HPA patients with unknown mutations were used for assay validation and application, respectively. All variations were confirmed by Sanger sequencing. In the standard group, all the known mutations were detected and were consistent with the results of previous Sanger sequencing. In the test group, we identified mutations in 71 of 74 alleles, with a mutation detection rate of 95.9%. We also found a frame shift deletion p.Ile25Metfs*13 in PAH that was previously unreported. In addition, 1 of 37 in the test group was inconsistent with either the molecular diagnosis or clinical diagnosis by traditional differential methods. In conclusion, our comprehensive assay based on a custom AmpliSeq™ panel and Ion Torrent PGM sequencing has wider coverage, higher throughput, is much faster, and more efficient when compared with the traditional molecular detection method for HPA patients, which could meet the medical need for individualized diagnosis and treatment.

  3. Development of mammalian ovary.

    PubMed

    Smith, Peter; Wilhelm, Dagmar; Rodgers, Raymond J

    2014-06-01

    Pre-natal and early post-natal ovarian development has become a field of increasing importance over recent years. The full effects of perturbations of ovarian development on adult fertility, through environmental changes or genetic anomalies, are only now being truly appreciated. Mitigation of these perturbations requires an understanding of the processes involved in the development of the ovary. Herein, we review some recent findings from mice, sheep, and cattle on the key events involved in ovarian development. We discuss the key process of germ cell migration, ovigerous cord formation, meiosis, and follicle formation and activation. We also review the key contributions of mesonephric cells to ovarian development and propose roles for these cells. Finally, we discuss polycystic ovary syndrome, premature ovarian failure, and pre-natal undernutrition; three key areas in which perturbations to ovarian development appear to have major effects on post-natal fertility.

  4. Aquaporins in Fetal Development.

    PubMed

    Martínez, Nora; Damiano, Alicia E

    2017-01-01

    Water homeostasis during fetal development is of crucial physiologic importance. The successful formation and development of the placenta is critical to maintain normal fetal growth and homeostasis. The expression of several aquaporins (AQPs ) was found from blastocyst stages to term placenta and fetal membranes. Therefore, AQPs are proposed to play important roles in normal pregnancy, fetal growth, and homeostasis of amniotic fluid volume, and water handling in other organs. However, the functional importance of AQPs in fetal development remains to be elucidated.

  5. Fusion development and technology

    SciTech Connect

    Montgomery, D.B.

    1992-01-01

    This report discusses the following: superconducting magnet technology; high field superconductors; advanced magnetic system and divertor development; poloidal field coils; gyrotron development; commercial reactor studies--aries; ITER physics: alpha physics and alcator R D for ITER; lower hybrid current drive and heating in the ITER device; ITER superconducting PF scenario and magnet analysis; ITER systems studies; and safety, environmental and economic factors in fusion development.

  6. Thallium Mercury Laser Development

    DTIC Science & Technology

    1981-01-01

    THALLIUM MERCURY LASER DEVELOPMENT C. S. Liu and D. W. Feldman FINAL REPORT (PHASE III) (Period between Feb. 1, 1980 and Jan. 31, 1981) 0 Contract No...Pittsburgh, Pennsylvania 15235 Approved for public release;IDistribution Unlimited 1/i;THALLIUM MERCURY LASER DEVELOPMENT * , , IS C. S./Liu tRD. W /eldman...9 ’ t4 THALLIUM MERCURY LASER DEVELOPMENT C. S. Liu and D. W. Feldman Westinghouse R&D Center Pittsburgh, Pennsylvania 15235 1

  7. Blind shaft development

    SciTech Connect

    Fiscor, S.

    2009-02-15

    The article discusses how Shaft Drillers International (SDI) is breaking new ground in shaft development and ground stabilization. Techniques of blind shaft drilling and raise bore shaft development developed by SDI are briefly explained. An associated company, Coastal Drilling East, deals with all types of ground improvement such as pre-grouting work for shafts, grouting of poor soil and water leaks into the mine. 3 photos.

  8. NASA develops Space Station

    NASA Technical Reports Server (NTRS)

    Freitag, R. F.

    1985-01-01

    The NASA Space Station program's planning stage began in 1982, with a view to development funding in FY1987 and initial operations within a decade. An initial cost of $8 billion is projected for the continuously habitable, Space Shuttle-dependent system, not including either operational or scientific and commercial payload-development costs. As a customer-oriented facility, the Space Station will be available to foreign countries irrespective of their participation in the development phase.

  9. Renewable energy project development

    SciTech Connect

    Ohi, J.

    1996-12-31

    The author presents this paper with three main thrusts. The first is to discuss the implementation of renewable energy options in China, the second is to identify the key project development steps necessary to implement such programs, and finally is to develop recommendations in the form of key issues which must be addressed in developing such a program, and key technical assistance needs which must be addressed to make such a program practical.

  10. Processes and process development

    NASA Astrophysics Data System (ADS)

    Hwang, H. L.

    1986-02-01

    Silicon material research in the Republic of China (ROC) parallels its development in the electronic industry. A brief outline of the historical development in ROC silicon material research is given. Emphasis is placed on the recent Silane Project managed by the National Science Council, ROC, including project objectives, task forces, and recent accomplishments. An introduction is also given to industrialization of the key technologies developed in this project.

  11. Thallium Mercury Laser Development.

    DTIC Science & Technology

    1980-04-17

    AD-A9 840 WESTINGHOUSE RESEARCH AND DEVELOPMENT CENTER PITTSBU--ETC F/A 20/5 THALLIUM MERCURY LASER DEVELOPMENT .(U) APR 80 C S LIU, D W FELDMAN, J L...PACK NO001I78-C-0131 lIlrt A nEQE-WOTFX-R NL THALLIUM MERCURY LASER DEVELOPMENT C. S. Liu, D. W. Feldman and J. L. Pack FINAL REPORT (PHASE II...PERIOD COVERED Thallium Mercury Laser Development -T- Final Report (Phase II) Feb. 1, 1979 to Jan. 31, 1980 77a. w-atF. -REPORT NUMBER _,___C2-OTEX

  12. Exploration Technology Development & Demonstration

    NASA Video Gallery

    Chris Moore delivers a presentation from the Exploration Technology Development & Demonstration (ETDD) study team on May 25, 2010, at the NASA Exploration Enterprise Workshop held in Galveston, TX....

  13. Developing Good Practices

    ERIC Educational Resources Information Center

    Fox, Sharon E.

    1972-01-01

    Discusses some good oral reading concepts that teachers should consider when developing new classroom practices, including: round robin reading, silent reading before oral reading, shared reading, etc. (NL)

  14. Halbach Magnetic Rotor Development

    NASA Technical Reports Server (NTRS)

    Gallo, Christopher A.

    2008-01-01

    The NASA John H. Glenn Research Center has a wealth of experience in Halbach array technology through the Fundamental Aeronautics Program. The goals of the program include improving aircraft efficiency, reliability, and safety. The concept of a Halbach magnetically levitated electric aircraft motor will help reduce harmful emissions, reduce the Nation s dependence on fossil fuels, increase efficiency and reliability, reduce maintenance and decrease operating noise levels. Experimental hardware systems were developed in the GRC Engineering Development Division to validate the basic principles described herein and the theoretical work that was performed. A number of Halbach Magnetic rotors have been developed and tested under this program. A separate test hardware setup was developed to characterize each of the rotors. A second hardware setup was developed to test the levitation characteristics of the rotors. Each system focused around a unique Halbach array rotor. Each rotor required original design and fabrication techniques. A 4 in. diameter rotor was developed to test the radial levitation effects for use as a magnetic bearing. To show scalability from the 4 in. rotor, a 1 in. rotor was developed to also test radial levitation effects. The next rotor to be developed was 20 in. in diameter again to show scalability from the 4 in. rotor. An axial rotor was developed to determine the force that could be generated to position the rotor axially while it is rotating. With both radial and axial magnetic bearings, the rotor would be completely suspended magnetically. The purpose of this report is to document the development of a series of Halbach magnetic rotors to be used in testing. The design, fabrication and assembly of the rotors will be discussed as well as the hardware developed to test the rotors.

  15. Population, environment and development.

    PubMed

    Karkal, M

    1994-06-01

    Western development models label subsistence economies, which do not participate in the market economy on a grand scale and do not consume commodities produced for and distributed through the market, to be poor. Yet, subsistence does not always indicate a low quality of life. The Western development process has destroyed wholesome and sustainable lifestyles. In India, the Green Revolution caused many small farmers to lose their land. In comparison to traditional economies, industrial economies have longer technological chains dependent on higher energy and resource inputs and exclude large numbers of people without power to buy goods. Further, they generate new and artificial needs, necessitating increased production of industrial goods and services. They erode resource bases for survival. This erosion is marginalizing people who were traditionally in nature's economy. Developed countries did not deliver 0.15% of their GNP to development projects in developing countries as promised. The US made population growth in these countries its cause. The UN and other multinational agencies during 1962-1972, at the US's request, began to support population and family planning programs in developing countries. These countries opposed the 1st draft at the 1974 Bucharest Population Conference, but by the conference in Mexico City, most supported the need for family planning. Yet, the US politicized this conference and had a greater say in the recommendations than did developing countries. Structural adjustments and external debt repayments required of developing countries in the 1980s set them back. In fact, the number of developing countries increased from 31 to 42. The UN recognizes the right to development, but social inequalities are barriers to this right. If environmental degradation continues, poverty will only increase. Women's groups are playing a great role in preparations for the International Conference on Population and Development in Cairo in September 1994.

  16. Information for Agricultural Development.

    ERIC Educational Resources Information Center

    Kaungamno, E. E.

    This paper describes the major international agricultural information services, sources, and systems; outlines the existing information situation in Tanzania as it relates to problems of agricultural development; and reviews the improvements in information provision resources required to support the process of agricultural development in Tanzania.…

  17. Successful Community Development Strategies.

    ERIC Educational Resources Information Center

    Johnson, Thomas G.

    This paper sketches several successful community economic development programs that have implications for rural education. Case studies are used to discuss community characteristics that contribute to development success. In Virginia, a Community Certification Program offers statewide business recruitment services to communities that meet program…

  18. Metals technology development plan

    SciTech Connect

    Betts, W.S.

    1987-03-01

    This document presents the plan for the metals technology development required to support the design of the MHTGR within the US National Gas-Cooled Reactor Program. Besides descriptions of the required technology development, cost estimates, and schedules, the plan also includes the associated design functions and design requirements.

  19. Why Professional Development Matters

    ERIC Educational Resources Information Center

    Mizell, Hayes

    2010-01-01

    Professional development refers to many types of educational experiences related to an individual's work. Doctors, lawyers, educators, accountants, engineers, and people in a wide variety of professions and businesses participate in professional development to learn and apply new knowledge and skills that will improve their performance on the job.…

  20. Developing Our Water Resources

    ERIC Educational Resources Information Center

    Volker, Adriaan

    1977-01-01

    Only very recently developed as a refined scientific discipline, hydrology has to cope with a complexity of problems concerning the present and future management of a vital natural resource, water. This article examines available water supplies and the problems and prospects of water resource development. (Author/MA)

  1. Women and World Development.

    ERIC Educational Resources Information Center

    Tinker, Irene, Ed.; Bramsen, Michele Bo., Ed.

    The book presents background papers and an overview of the proceedings of the American Association of Science Seminar on Women in Development held in Mexico City in June 1975. The objectives of the seminar were to show how and why development programs fail to reach women and to emphasize the waste of human potential that has resulted. An…

  2. Language and Development.

    ERIC Educational Resources Information Center

    Crooks, Tony, Ed.; Crewes, Geoffrey, Ed.

    A selection of papers presented at an international conference on the role of language in economic and social development includes: "Changing Paradigms: The Project Approach" (John McGovern); "Team Development of ELT Projects: A Case Study" (William M. Martin, Lynn P. Balabanis); "The Roles of Insiders and Outsiders in…

  3. Data Centric Development Methodology

    ERIC Educational Resources Information Center

    Khoury, Fadi E.

    2012-01-01

    Data centric applications, an important effort of software development in large organizations, have been mostly adopting a software methodology, such as a waterfall or Rational Unified Process, as the framework for its development. These methodologies could work on structural, procedural, or object oriented based applications, but fails to capture…

  4. Rural Development Strategies.

    ERIC Educational Resources Information Center

    Sears, David W., Ed.; Reid, J. Norman, Ed.

    This book seeks to provide a basis for reexamining rural development policy by presenting comprehensive and current information on the effectiveness of various rural policy approaches. An introduction that defines development terminology and discusses changing policy needs is followed by 13 chapters that represent the best recent research…

  5. WIPP marker development

    SciTech Connect

    1994-04-01

    This article discusses the development of permanent, passive markers for the Waste Isolation Pilot Plant (WIPP) and presents some preliminary concepts in drawings and a table of components for the markers. The panel, convened by Sandia National Laboratories, was charged with developing design characteristics for permanent markers and judging the efficacy of markers in deterring inadvertent human intrusion. 6 figs., 2 tabs.

  6. Action in Development

    ERIC Educational Resources Information Center

    von Hofsten, Claes

    2007-01-01

    It is argued that cognitive development has to be understood in the functional perspective provided by actions. Actions reflect all aspects of cognitive development including the motives of the child, the problems to be solved, and the constraints and possibilities of the child's body and sensorimotor system. Actions are directed into the future…

  7. Towards ``Astronomy for Development''

    NASA Astrophysics Data System (ADS)

    Govender, Kevin

    2016-10-01

    The ambition of the IAU's decadal strategic plan is to use astronomy to stimulate development globally. The Office of Astronomy for Development was established in 2011 to implement this visionary plan. This talk will reflect on the past, present and future activities of the office, and describe the status of implementation of the plan at this halfway point in the 2010- decade.

  8. Developing Sustainable Leadership

    ERIC Educational Resources Information Center

    Davies, Brent, Ed.

    2007-01-01

    Developing and sustaining leaders is a major challenge for all those involved in education today. This book contains a collection of essays from recognized authors to provide insights, frameworks and ideas on how to sustain school leaders and develop values-based leadership. It also offers guidance on countering short-term management solutions,…

  9. Early Developments, 1998.

    ERIC Educational Resources Information Center

    Little, Loyd, Ed.

    1998-01-01

    This document consists of the two 1998 issues of a journal reporting new research in early child development conducted by the Frank Porter Graham Child Development Center at the University of North Carolina at Chapel Hill. In the Spring 1998 issue, articles highlight the Center's diverse cross-cultural projects and global research, training and…

  10. Technical Assistance to Developers

    SciTech Connect

    Rockward, Tommy; Borup, Rodney L.; Garzon, Fernando H.; Mukundan, Rangachary; Spernjak, Dusan

    2012-07-17

    This task supports the allowance of technical assistance to fuel-cell component and system developers as directed by the DOE. This task includes testing of novel materials and participation in the further development and validation of single cell test protocols. This task also covers technical assistance to DOE Working Groups, the U.S. Council for Automotive Research (USCAR) and the USCAR/DOE Driving Research and Innovation for Vehicle efficiency and Energy sustainability (U.S. Drive) Fuel Cell Technology Team. Assistance includes technical validation of new fuel cell materials and methods, single cell fuel cell testing to support the development of targets and test protocols, and regular advisory participation in other working groups and reviews. This assistance is made available to PEM fuel cell developers by request and DOE Approval. The objectives are to: (1) Support technically, as directed by DOE, fuel cell component and system developers; (2) Assess fuel cell materials and components and give feedback to developers; (3) Assist the DOE Durability Working Group with the development of various new material durability Testing protocols; and (4) Provide support to the U.S. Council for Automotive Research (USCAR) and the USCAR/DOE Fuel Cell Technology Team. FY2012 specific technical objectives are: (1) Evaluate novel MPL materials; (2) Develop of startup/ shutdown protocol; (3) Test the impact of hydrophobic treatment on graphite bi-polar plates; (4) Perform complete diagnostics on metal bi-polar plates for corrosion; and (5) Participate and lead efforts in the DOE Working Groups.

  11. Environment and Alternative Development.

    ERIC Educational Resources Information Center

    Kothari, Rajni

    Stressing the global dimension to the adversary relationship between economic development and environmental conservation, this monograph examines the philosophical, historical, cultural, and ethnic underpinnings of modern science and technology. In addition, the monograph spells out policy implications of an alternative concept of development and…

  12. Sandia microelectronics development

    SciTech Connect

    Weaver, H.T.

    1997-02-01

    An overview of the operations of Sandia`s Microelectronics Development Lab (MDL) is to develop radiation hardened IC, but techniques used for IC processing have been applied to a variety of related technologies such as micromechanics, smart sensors, and packaging.

  13. Youth Development: Maori Styles

    ERIC Educational Resources Information Center

    Ware, Felicity; Walsh-Tapiata, Wheturangi

    2010-01-01

    Despite the innovative approach of the Youth Development Strategy Aotearoa and the applicability of its Rangatahi Development Package, the diverse realities and experiences of Maori youth are still presenting unique challenges to national policy in Aotearoa New Zealand. A Maori youth research approach that utilised a combination of action research…

  14. Wind Economic Development (Postcard)

    SciTech Connect

    Not Available

    2011-08-01

    The U.S. Department of Energy's Wind Powering America initiative provides information on the economic development benefits of wind energy. This postcard is a marketing piece that stakeholders can provide to interested parties; it will guide them to the economic development benefits section on the Wind Powering America website.

  15. Leadership and Management Development.

    ERIC Educational Resources Information Center

    1996

    This document contains four papers presented at a symposium on leadership and management development moderated by Mark Porter at the 1996 conference of the Academy of Human Resource Development (AHRD). "Expanding Formative Experiences: A Critical Dimension of Leadership Deportment" (Gary D. Geroy, Jackie L. Jankovich) advocates focusing…

  16. Pathways of Language Development.

    ERIC Educational Resources Information Center

    Australian Council for Educational Research, Hawthorn.

    Prepared by teachers for teachers, this practical classroom guide offers a process of monitoring language development and planning for development within a whole language framework, supported by a compendium of appropriate practice to be drawn on when needed. The guide (1) emphasizes the interdependence of reading, writing, talking, and listening;…

  17. Development Communication Report, 1991.

    ERIC Educational Resources Information Center

    Development Communication Report, 1991

    1991-01-01

    The four 1991 issues of the newsletter "Development Communication Report" are primarily concerned with the use of communication technologies in developing countries to educate the people. Evaluation is the theme of the first issue, which contains the following articles: "Evaluating Communication Programs: Means and Ends,""Making a Splash: How…

  18. Developing Successful Global Leaders

    ERIC Educational Resources Information Center

    Training, 2011

    2011-01-01

    Everyone seems to agree the world desperately needs strong leaders who can manage a global workforce and all the inherent challenges that go with it. That's a big part of the raison d'etre for global leadership development programs. But are today's organizations fully utilizing these programs to develop global leaders, and, if so, are they…

  19. Compassion and Moral Development.

    ERIC Educational Resources Information Center

    Susky, John E.

    1979-01-01

    Critiquing Skinner's and Kohlberg's moral development theories as inadequate, the author asserts that affective development (compassion, empathy, caring) is necessary to moral action. While saying that schools are limited in their ability to provide moral education, he outlines qualities of an educational environment which could facilitate moral…

  20. Physical Development: Thinking Physically

    ERIC Educational Resources Information Center

    Strickland, Erik

    2005-01-01

    Children grow and develop physically according to their own experiences, characteristics, and abilities. Physical development is so important and the environment should allow each child to find her space in the sunshine. This can be done by: (1) creating the right outdoor environment; (2) allowing children time to use it; (3) encouraging movement…

  1. Promoting Literacy Development

    ERIC Educational Resources Information Center

    Coleman, Rhoda; Goldenberg, Claude

    2011-01-01

    A fundamental challenge facing students who are English Learners (ELs) is the interplay of oral language development--speaking and understanding a language--and literacy development--learning to read and write the language. This interplay is especially challenging because each of those developmental processes is complex in and of itself, and each…

  2. Authentic Professional Development

    ERIC Educational Resources Information Center

    Kenneson, Paula M.

    1999-01-01

    Choosing Higher Options in Community Education (CHOICE) Alternative School is devoted to professional development. This report documents the need for and planning of sustained and supported professional development for 4 staff members at the CHOICE Alternative School in Jamestown, New York. There was no focused plan or vision for staff development…

  3. Understanding Teacher Development.

    ERIC Educational Resources Information Center

    Hargreaves, Andy, Ed.; Fullan, Michael G., Ed.

    The 12 chapters in this book interpret teacher development in relation to self-development, teacher reflection, teacher biographies, cultures of teaching, teacher careers, teachers' work, gender identity, and classroom practice. The collection begins with an introductory chapter (Andy Hargreaves and Michael G. Fullan) and continues with 11…

  4. Strengthening Evaluation for Development

    ERIC Educational Resources Information Center

    Ofir, Zenda

    2013-01-01

    Although some argue that distinctions between "evaluation" and "development evaluation" are increasingly superfluous, it is important to recognize that some distinctions still matter. The severe vulnerabilities and power asymmetries inherent in most developing country systems and societies make the task of evaluation…

  5. Child Development and Playgrounds.

    ERIC Educational Resources Information Center

    Frost, Joe L.

    Four major issues are explored in this study of child development research and its implications for children's playgrounds: (1) theories and philosophies of play; (2) the historical evolution of playgrounds; (3) research on child development, play, and playgrounds; and (4) creating playgrounds that meet children's developmental needs. Discussion…

  6. Reference Model Development

    SciTech Connect

    Jepsen, Richard

    2011-11-02

    Presentation from the 2011 Water Peer Review in which principal investigator discusses project progress to develop a representative set of Reference Models (RM) for the MHK industry to develop baseline cost of energy (COE) and evaluate key cost component/system reduction pathways.

  7. Career Development in Denmark.

    ERIC Educational Resources Information Center

    Plant, Peter

    Decentralization is the main feature of Danish governmental structures and the education and training system. The National Council on Educational and Vocational Guidance coordinates the career development field. Local and regional career development committees are organized under this judicial umbrella. Career education takes place as early as…

  8. Supporting Character Development.

    ERIC Educational Resources Information Center

    Janas, Monica; Nabors, Martha C.

    2002-01-01

    Identifies strategies early childhood educators can use to create an environment that encourages character development in young children. Provides reflective checklists for specific areas of character development and character education addressed: (1) content; (2) communication; (3) clarification; (4) community; (5) critical thinking; (6) context;…

  9. Developing Open Courses.

    ERIC Educational Resources Information Center

    Parer, Michael S., Ed.

    This collection of 13 articles contains the reflections of experienced course developers on a particular course that illustrates the process of constructing flagship distance education programs. "Educational Developers in Action--A Series of Tales from the Mud" (Michael Parer) is an introduction that discusses the technology of distance…

  10. Development of IVF Children.

    ERIC Educational Resources Information Center

    van Balen, Frank

    1998-01-01

    Examines physical and psychological development of children conceived through in vitro fertilization (IVF), focusing on questions related to risk of congenital defects or mental retardation and impact on the parent-child relationship. Concludes that no serious problems have arisen concerning the physical and psychological development of IVF…

  11. Hemovigilance in developing countries.

    PubMed

    Ayob, Yasmin

    2010-01-01

    Hemovigilance like quality systems and audits has become an integral part of the Blood Transfusion Service (BTS) in the developed world and has contributed greatly to the development of the blood service. However developing countries are still grappling with donor recruitment and efforts towards sufficiency and safety of the blood supply. In these countries the BTS is generally fragmented and a national hemovigilance program would be difficult to implement. However a few developing countries have an effective and sustainable blood program that can deliver equitable, safe and sufficient blood supply to the nation. Different models of hemovigilance program have been introduced with variable success. There are deficiencies but the data collected provided important information that can be presented to the health authorities for effective interventions. Hemovigilance program modeled from developed countries require expertise and resources that are not available in many developing countries. Whatever resources that are available should be utilized to correct deficiencies that are already apparent and obvious. Besides there are other tools that can be used to monitor the blood program in the developing countries depending on the need and the resources available. More importantly the data collected should be accurate and are used and taken into consideration in formulating guidelines, standards and policies and to affect appropriate interventions. Any surveillance program should be introduced in a stepwise manner as the blood transfusion service develops.

  12. Development. Courier No. 26.

    ERIC Educational Resources Information Center

    ASPBAE Courier Service, 1982

    1982-01-01

    This journal contains a series of articles dealing with the theme of development in Asia and rural Indonesia. Included in the journal are the following articles: "Nonformal Education in Rural Areas of Developing Countries," by members of the Rural Project Team from the Centre for Continuing Education at Australian National University;…

  13. Bicultural Social Development

    ERIC Educational Resources Information Center

    Padilla, Amado M.

    2006-01-01

    The conditions that result in bicultural social development among Latino children and adolescents represent the central focus of this article. The literature surrounding bicultural development is reviewed from four perspectives: (a) immigrant children and adolescents, (b) second generation Latinos or the offspring of immigrants, (c) later…

  14. Contemporary Career Development Issues.

    ERIC Educational Resources Information Center

    Morrison, Robert F., Ed.; Adams, Jerome, Ed.

    This book provides practical guidance and examples for human resource development (HRD) specialists to use in the evaluation of their current career development programs and the design of new ones. "Issues in the Management of Careers" (Jerome Adams) provides a summary of each chapter and points out specific questions the chapter can answer.…

  15. Steps in Intrauterine Development.

    ERIC Educational Resources Information Center

    Barra, H. Gensini; And Others

    1996-01-01

    Recognizing the importance of health care during the perinatal period, the topic for this issue of "Children in the Tropics" is prenatal development; this issue is intended for health educators for use in educating their clients about prenatal development, health care during pregnancy, labor and delivery, and the needs of the mother and…

  16. Individual and Family Development.

    ERIC Educational Resources Information Center

    Carlson, Jean; Simpson, Elizabeth

    This curriculum guide, in working paper form, for a semester-long three-credit course in individual and family development is one of nine technical core courses in an associate degree consumer/family manager program. The course studies individual and family development through the life cycle. Emphasis is on the relationship of basic needs to the…

  17. Towards "Astronomy for Development"

    NASA Astrophysics Data System (ADS)

    Govender, Kevindran

    2015-08-01

    The ambition of the IAU's decadal strategic plan is to use astronomy to stimulate development globally. The Office of Astronomy for Development was established in 2011 to implement this visionary plan. This talk will reflect on the past, present and future activities of the office, and describe the status of implementation of the plan at this halfway point in the 2010-2020 decade.

  18. Energy for development

    SciTech Connect

    Not Available

    1987-01-01

    Expanding upon their analysis in energy for a sustainable world, the authors propose ways to overcome obstacles to energy efficiency and to increase the use of bioenergy in developing countries. The authors assess the stake of the elite classes in energy efficiency development, size up the unique problems of the rural poor, and define an enlarged role for the international assistance community.

  19. Bridging the Development Gap.

    DTIC Science & Technology

    1999-11-01

    Bridging the Development Gap is contractual cooperative agreement between Mercury Computer Systems, Inc. and DARPA. This program was developed...processing, interfacing with I/O devices, memory constraints, as well as real-time throughput and latency challenges. Mercury has bridged the indicated

  20. Jamaica: A Development Perspective.

    ERIC Educational Resources Information Center

    Scott, Rosalind; And Others

    Jamaica is known mainly as a tourist playground and the home of Reggae music. This Jamaican teaching unit dispels stereotypes and shows Jamaica for what it really is--an economically-troubled, developing nation. The unit illustrates the challenges this island nation is facing in its struggle toward economic development. Contents are: Teacher…

  1. Handbook of Moral Development

    ERIC Educational Resources Information Center

    Killen, Melanie; Smetana, Judith

    2006-01-01

    The psychological study of moral development has expanded greatly, both in terms of the diversity of theoretical perspectives that are represented in the field, as well as in the range of topics that have been studied. This "Handbook of Moral Development" represents the diversity and multidisciplinary influences on current theorizing about the…

  2. Early Developments, 2002.

    ERIC Educational Resources Information Center

    Winton, Pam, Ed.; Buysse, Virginia, Ed.

    2002-01-01

    This document consists of the three 2002 issues of a journal reporting new research in early child development conducted by the Frank Porter Graham Child Development Center (FPG) at the University of North Carolina at Chapel Hill. Articles in the Winter 2002 issue highlight some current work at FPG on factors that enhance or inhibit social and…

  3. Early Developments, 2000.

    ERIC Educational Resources Information Center

    Little, Loyd, Ed.

    2000-01-01

    This document consists of the three 2000 issues of a journal reporting new research in early child development conducted by the Frank Porter Graham Child Development Center at the University of North Carolina at Chapel Hill. Articles in the spring 2000 issue focus on a follow-up study of the Abecedarian Project, children of depressed mothers,…

  4. Cleanroom software development

    NASA Technical Reports Server (NTRS)

    Dyer, M.; Mills, H. D.

    1981-01-01

    The 'cleanroom' software development process is a technical and organizational approach to developing software with certifiable reliability. Key ideas behind the process are well structured software specifications, randomized testing methods and the introduction of statistical controls; but the main point is to deny entry for defects during the development of software. This latter point suggests the use of the term 'cleanroom' in analogy to the defect prevention controls used in the manufacturing of high technology hardware. In the 'cleanroom', the entire software development process is embedded within a formal statistical design, in contrast to executing selected tests and appealing to the randomness of operational settings for drawing statistical inferences. Instead, random testing is introduced as a part of the statistical design itself so that when development and testing are completed, statistical inferences are made about the operation of the system.

  5. Lightweight Mirror Developments

    NASA Astrophysics Data System (ADS)

    Genet, Russell; Aurigema, Andrew; Badger, Steve; Bartels, Mel; Brodhacker, K. Lisa; Canestrari, Rodolfo; Chen, Peter; Connelley, Mike; Davis, David; Ghigo, Mauro; Jones, Greg; Liu, Tong; Mendex, Eric; Pareschi, Giovanni; Richardson, Terry; Rowe, David; Schmidt, Josh; Shah, Kiran; Villasenor, Efrain

    2009-05-01

    One goal of the Alt-Az Initiative is the development of transportable 1.5 meter class research telescopes. To this end, several Initiative members are developing lightweight, low cost, primary mirrors. Both multiple and single mirror telescope configurations are being considered. Thin meniscus mirrors are being slumped, and approaches for actively correcting these thin mirrors are being investigated. Sandwich mirrors with glass spacers and others with Foamglas cores are under development. Nanocomposite, polyurethane, and glass replica mirrors, which do not require optical grinding or figuring during production, are being evaluated. Finally, spin-cast polymer mirrors are being explored. Although several of these mirror developments are still very experimental, and some may only be useful in optically undemanding applications such as on-axis aperture near IR photometry or low resolution spectroscopy, it is our hope that these efforts will enable the development of transportable, low cost, lightweight, 1.5 meter class telescopes.

  6. [Sustainable development: a contradiction].

    PubMed

    Daly, H E

    1991-01-01

    Economists are very much interested in theories of impossibility, especially in those that demonstrate that it is impossible for the world economy to increase to the point of solving poverty and the environmental degradation. In its physical aspects, the economy is an open subsystem of the terrestrial ecosystem, which is finite in material resources. As the economic subsystem grows, it incorporates an increasing proportion of the total ecosystem. For this reason, development is not sustainable. The term sustainable development, as it applies to the economy, is a contradiction. The economists claim that the growth of the gross national product is a combination of quantitative and qualitative increase and is not subject to the laws of physics. They are right to some degree, because growth means natural material increase by assimilating accretion, while development denotes expansion to slowly realize the opportunities for a state of conditions that are more, bigger, or better. When something grows, size increases. However, when something develops, different things happen. The terrestrial ecosystem develops but does not grow. Its subsystem, the economy, can continue to develop. Thus, sustainable development means development without growth, qualitative improvement which maintains the interchange of material-energy found within regenerative capacities of the ecosystem. In fact, the term sustainable development utilizes as a synonym the contradiction of sustainable growth. Politically, it is very difficult to admit that growth has its limits. The earth will not tolerate the multiplication of grain harvests 64 times only because in the last centuries a culture has developed that depends on exponential growth for its economic stability. The growth of agricultural plants is not sustainable. For plants there is a limit that the earth can support, as there is a limit for humans and cars, with dire consequences for those who ignore this fact.

  7. Liga developer apparatus system

    DOEpatents

    Boehme, Dale R.; Bankert, Michelle A.; Christenson, Todd R.

    2003-01-01

    A system to fabricate precise, high aspect ratio polymeric molds by photolithograpic process is described. The molds for producing micro-scale parts from engineering materials by the LIGA process. The invention is a developer system for developing a PMMA photoresist having exposed patterns comprising features having both very small sizes, and very high aspect ratios. The developer system of the present invention comprises a developer tank, an intermediate rinse tank and a final rinse tank, each tank having a source of high frequency sonic agitation, temperature control, and continuous filtration. It has been found that by moving a patterned wafer, through a specific sequence of developer/rinse solutions, where an intermediate rinse solution completes development of those portions of the exposed resist left undeveloped after the development solution, by agitating the solutions with a source of high frequency sonic vibration, and by adjusting and closely controlling the temperatures and continuously filtering and recirculating these solutions, it is possible to maintain the kinetic dissolution of the exposed PMMA polymer as the rate limiting step.

  8. The development of colliders

    SciTech Connect

    Sessler, A.M.

    1993-02-01

    Don Kerst, Gersh Budker, and Bruno Touschek were the individuals, and the motivating force, which brought about the development of colliders, while the laboratories at which it happened were Stanford, MURA, the Cambridge Electron Accelerator, Orsay, Frascati, CERN, and Novosibirsk. These laboratories supported, during many years, this rather speculative activity. Of course, many hundreds of physicists contributed to the development of colliders but the men who started it, set it in the right direction, and forcefully made it happen, were Don, Gersh, and Bruno. Don was instrumental in the development of proton-proton colliders, while Bruno and Gersh spearheaded the development of electron-positron colliders. In this brief review of the history, I will sketch the development of the concepts, the experiments, and the technological developments which made possible the development of colliders. It may look as if the emphasis is on theoretical concepts, but that is really not the case, for in this field -- the physics of beams -- the theory and experiment go hand in hand; theoretical understanding and advances are almost always motivated by the need to explain experimental results or the desire to construct better experimental devices.

  9. Developing Astronomy in Cuba

    NASA Astrophysics Data System (ADS)

    Rodriguez Taboada, R. E.

    2006-08-01

    Introduction Beginning from a brief historical introduction the up to day situation is presented and the topics relevant to Astronomy development analyzed from the view point of a person actually working in Astrophysics. Arising from national needs, Astronomical Calculations is the only "native-born" branch of astronomy in Cuba. Cuba was an observational platform capable to provide the Soviet Union with the 24 hours solar patrol needed by its Space Agency System to protect the men in orbit. This was the beginning of a very fruitful development of solar research in Cuba. Russia installed the instruments, trained the people to operate them, and gives the academic environment to develop the scientific work in solar physics, space weather, and related topics. What about Stellar Astronomy? The Cuban astro-climate is not good to develop an observational base. We are trying to develop stellar astronomy in collaboration with institutions capable to provide both, the academic and technical environment; but to continue developing Stellar Astronomy we need to influence the public opinion and convince people they need groups working in Astronomy. How to do that? Publishing. Giving conferences talking about OUR work, not only like spectators of the science. Showing science is culture in modern times. Showing projects in Astronomy can be cheap. ¡This is very important! Astronomy is not a luxury. Real possibilities I consider the Virtual Observatory concept the more appropriate in the near future, but it is necessary to have a connectivity level that is not commonly provided in Cuba, and to train the people. Concluding remarks From my experience "engagement" is the key word for Astronomy development in developing countries. Astronomy can not be developed without an appropriate academic environment, and we have not it. It is not "only" about financial resources, it is about "real collaboration" with a mature partner and common research goals.

  10. [Mitochondrial and oocyte development].

    PubMed

    Deng, Wei-Ping; Ren, Zhao-Rui

    2007-12-01

    Oocyte development and maturation is a complicated process. The nuclear maturation and cytoplasmic maturation must synchronize which can ensure normal oocyte fertilization and following development. Mitochondrial is the most important cellular organell in cytoplasm, and the variation of its distribution during oocyte maturation, the capacity of OXPHOS generating ATP as well as the content or copy number or transcription level of mitochondrial DNA play an important role in oocyte development and maturation. Therefore, the studies on the variation of mitochondrial distribution, function and mitochondrial DNA could enhance our understanding of the physiology of reproduction and provide new insight to solve the difficulties of assisted reproduction as well as cloning embryo technology.

  11. Imaging in drug development.

    PubMed

    Nairne, James; Iveson, Peter B; Meijer, Andreas

    2015-01-01

    Imaging has played an important part in the diagnosis of disease and development of the understanding of the underlying disease mechanisms and is now poised to make an impact in the development of new pharmaceuticals. This chapter discusses the underlying technologies that make the field ready for this challenge. In particular, the potentials of magnetic resonance imaging and functional magnetic resonance imaging are outlined, including the new methods developed to provide additional information from the scans carried out. The field of nuclear medicine has seen a rapid increase in interest as advances in radiochemistry have enabled a wide range of new radiotracers to be synthesised.

  12. Democracy and economic development.

    PubMed

    Rao, V

    1985-01-01

    This discussion explains why democracy as is generally understood may not be suitable to meet the challenges of a developing economy and how democratic institutions generally fail to respond to the immediate demands of a population impatient to raise its level of living. It defines the terms economic development and democracy, reviews some theoretical models of democracy which have been proposed in economic theory, proposes an approach to the process of economic development, and considers problems of development. Economic development is a process which calls for huge investments in personnel and material. Such investment programs imply cuts in current consumption that would be painful at the low levels of living that exist in almost all developing societies. Governments need to resort to strong measures, and they must enforce them vigorously in order to marshal the surpluses required for investment. If such measures were put to a popular vote, they would certainly be defeated. Mainstream economic theory assumes the virtues of a market system and the decisions arrived at by the interaction of market forces. This is the economic equivalent of democracy. Yet, mainstream economic theory devotes little attention to the conditions under which a market system generates a just solution. The democratic developing countries have all inherited a class society, with a highly skewed distribution of income. The wealthy minority often seeks to preserve its privileged position and to enjoy the benefits of development. It even seeks the help of the judiciary to preserve the sanctity of private property and to assure that its patterns of conspicuous consumption can continue. This is done in the name of democratic rights. Many developing societies are burdened with outmoded traditions and value systems that are incompatible with the production relations of the new society they hope to achieve. The international exchange of resources is believed by some to be an attempt to control the

  13. Photovoltaic development in Argentina

    SciTech Connect

    Godfrin, E.M.; Duran, J.C.; Frigerio, A.; Moragues, J.A.

    1994-12-31

    A critical assessment of the photovoltaic program in Argentina is presented. Research and development activities on photovoltaic cells as well as industrial and technological development are still in the initial stages. Activities accomplished by the Atomic Energy Commission (CNEA) and the Institute of Technology Development for the Chemical industry (INTEC) are briefly described. The evolution of photovoltaic installations in Argentina is analyzed and accumulative data up to 1993 are given. A summary of the potential market for photovoltaic systems in the short and medium term is presented.

  14. Crew procedures development techniques

    NASA Technical Reports Server (NTRS)

    Arbet, J. D.; Benbow, R. L.; Hawk, M. L.; Mangiaracina, A. A.; Mcgavern, J. L.; Spangler, M. C.

    1975-01-01

    The study developed requirements, designed, developed, checked out and demonstrated the Procedures Generation Program (PGP). The PGP is a digital computer program which provides a computerized means of developing flight crew procedures based on crew action in the shuttle procedures simulator. In addition, it provides a real time display of procedures, difference procedures, performance data and performance evaluation data. Reconstruction of displays is possible post-run. Data may be copied, stored on magnetic tape and transferred to the document processor for editing and documentation distribution.

  15. Engrailed and tectum development.

    PubMed

    Omi, Minoru; Nakamura, Harukazu

    2015-02-01

    The optic tectum is a visual center of nonmammalian vertebrates derived from the mesencephalon. In this review, function of Engrailed (En) in tectum development is reviewed. En plays crucial roles at three steps of tectum development. First, Engrailed is expressed in the mesencephalon and the metencephalon and essential for the regionalization of the mesencephalon. En is expressed in a gradient of caudal-to-rostral in the tectum primordial, and regulates the rostrocaudal polarity of the tectum. In the advanced stage of tectum development, En is expressed in a lamina-specific manner and it is suggested that En regulates cell migration in the tectal laminar formation.

  16. Beam Instrument Development System

    SciTech Connect

    DOOLITTLE, LAWRENCE; HUANG, GANG; DU, QIANG; SERRANO, CARLOS

    2016-01-08

    Beam Instrumentation Development System (BIDS) is a collection of common support libraries and modules developed during a series of Low-Level Radio Frequency (LLRF) control and timing/synchronization projects. BIDS includes a collection of Hardware Description Language (HDL) libraries and software libraries. The BIDS can be used for the development of any FPGA-based system, such as LLRF controllers. HDL code in this library is generic and supports common Digital Signal Processing (DSP) functions, FPGA-specific drivers (high-speed serial link wrappers, clock generation, etc.), ADC/DAC drivers, Ethernet MAC implementation, etc.

  17. CNS development: an overview

    NASA Technical Reports Server (NTRS)

    Nowakowski, R. S.; Hayes, N. L.

    1999-01-01

    The basic principles of the development of the central nervous system (CNS) are reviewed, and their implications for both normal and abnormal development of the brain are discussed. The goals of this review are (a) to provide a set of concepts to aid in understanding the variety of complex processes that occur during CNS development, (b) to illustrate how these concepts contribute to our knowledge of the normal anatomy of the adult brain, and (c) to provide a basis for understanding how modifications of normal developmental processes by traumatic injury, by environmental or experiential influences, or by genetic variations may lead to modifications in the resultant structure and function of the adult CNS.

  18. SP-100 program developments

    NASA Technical Reports Server (NTRS)

    Schnyer, A. D.; Sholtis, J. A., Jr.; Wahlquist, E. J.; Verga, R. L.; Wiley, R. L.

    1985-01-01

    An update is provided on the status of the Sp-100 Space Reactor Power Program. The historical background that led to the program is reviewed and the overall program objectives and development approach are discussed. The results of the mission studies identify applications for which space nuclear power is desirable and even essential. Results of a series of technology feasibility experiments are expected to significantly improve the earlier technology data base for engineering development. The conclusion is reached that a nuclear reactor space power system can be developed by the early 1990s to meet emerging mission performance requirements.

  19. Furlable spacecraft antenna development

    NASA Technical Reports Server (NTRS)

    Oliver, R. E.; Wilson, A. H.

    1972-01-01

    The development of large furlable spacecraft antennas using conical main reflectors is described. Two basic antenna configurations which utilize conical main reflectors have been conceived and are under development. In the conical-Gregorian configuration each ray experiences two reflections in traveling from the feed center to the aperture plane. In the Quadreflex (four reflection) configuration, each ray experiences four reflections, one at each of two subreflector surfaces and two at the main conical reflector surface. The RF gain measurements obtained from 6-ft and 30-in. models of the conical-Gregorian and Quadreflex concepts respectively were sufficiently encouraging to warrant further development of the concepts.

  20. Human pancreas development.

    PubMed

    Jennings, Rachel E; Berry, Andrew A; Strutt, James P; Gerrard, David T; Hanley, Neil A

    2015-09-15

    A wealth of data and comprehensive reviews exist on pancreas development in mammals, primarily mice, and other vertebrates. By contrast, human pancreatic development has been less comprehensively reviewed. Here, we draw together those studies conducted directly in human embryonic and fetal tissue to provide an overview of what is known about human pancreatic development. We discuss the relevance of this work to manufacturing insulin-secreting β-cells from pluripotent stem cells and to different aspects of diabetes, especially permanent neonatal diabetes, and its underlying causes.

  1. Space station structures development

    NASA Technical Reports Server (NTRS)

    Teller, V. B.

    1986-01-01

    A study of three interrelated tasks focusing on deployable Space Station truss structures is discussed. Task 1, the development of an alternate deployment system for linear truss, resulted in the preliminary design of an in-space reloadable linear motor deployer. Task 2, advanced composites deployable truss development, resulted in the testing and evaluation of composite materials for struts used in a deployable linear truss. Task 3, assembly of structures in space/erectable structures, resulted in the preliminary design of Space Station pressurized module support structures. An independent, redundant support system was developed for the common United States modules.

  2. Textile technology development

    NASA Technical Reports Server (NTRS)

    Shah, Bharat M.

    1995-01-01

    The objectives of this report were to evaluate and select resin systems for Resin Transfer Molding (RTM) and Powder Towpreg Material, to develop and evaluate advanced textile processes by comparing 2-D and 3-D braiding for fuselage frame applications and develop window belt and side panel structural design concepts, to evaluate textile material properties, and to develop low cost manufacturing and tooling processes for the automated manufacturing of fuselage primary structures. This research was in support of the NASA and Langley Research Center (LaRc) Advanced Composite Structural Concepts and Materials Technologies for Primary Aircraft Structures program.

  3. Fetal Health and Development

    MedlinePlus

    ... fetus grows and develops. There are specific prenatal tests to monitor both the mother's health and fetal health during each trimester. With modern technology, health professionals can Detect birth defects Identify problems ...

  4. Algorithm-development activities

    NASA Technical Reports Server (NTRS)

    Carder, Kendall L.

    1994-01-01

    The task of algorithm-development activities at USF continues. The algorithm for determining chlorophyll alpha concentration, (Chl alpha) and gelbstoff absorption coefficient for SeaWiFS and MODIS-N radiance data is our current priority.

  5. Education and Development

    ERIC Educational Resources Information Center

    Ki-Zerbo, Joseph

    1972-01-01

    The school in an underdeveloped country is a reflection and a fruit of the surrounding underdevelopment. Reform and development involve economics, communications (languages), curriculum, orientation and attitude changes, nationalism, and require international cooperation. (JB)

  6. Physics for development

    NASA Astrophysics Data System (ADS)

    Chetty, Nithaya; Connell, Simon; Bawa, Ahmed C.

    2007-11-01

    South Africa has recognized the importance of science in the development of its society, in moving away from its apartheid past and striving to eradicate poverty. Opportunities abound in its growing programme of physics research.

  7. Environments for Development

    ERIC Educational Resources Information Center

    Grabinski, C. Joanne

    2005-01-01

    This chapter considers Robert Kegan's concept of holding environments, as well as six steps necessary for creation of new or adaptation of existing learning environments that facilitate adult development across the life course.

  8. Developments in Serials: 1977

    ERIC Educational Resources Information Center

    James, John R.

    1978-01-01

    Discusses issues and developments relating to several aspects of serials, including economics and acquisitions; bibliographic control; automation; education; serials literature and bibliographies; and copyrights. A bibliography is included. (Author/MBR)

  9. Toddler Growth and Development

    MedlinePlus

    ... changes. Is your toddler due for a check-up? See the AAP Schedule of Well-Child Care Visits . ​​ Toddler Growth & Development Physical Skills Walks alone Pulls toys behind when walking Begins to run Stands ...

  10. Fiber Optics Instrumentation Development

    NASA Technical Reports Server (NTRS)

    Chan, Patrick Hon Man; Parker, Allen R., Jr.; Richards, W. Lance

    2010-01-01

    This is a general presentation of fiber optics instrumentation development work being conducted at NASA Dryden for the past 10 years and recent achievements in the field of fiber optics strain sensors.

  11. Space Development Grid Portal

    NASA Technical Reports Server (NTRS)

    Vaziri, Arsi

    2004-01-01

    This viewgraph presentation provides information on the development of a portal to provide secure and distributed grid computing for Payload Operations Integrated Center and Mission Control Center ground services.

  12. The Career Development Workshop

    ERIC Educational Resources Information Center

    Marsh, P. J.

    1973-01-01

    This article describes a career planning workshop for managers and its purpose is to support and accelerate the process of individual development without organizational coercion or manipulation. (Author/RK)

  13. Advanced Interconnect Development

    SciTech Connect

    Yang, Z.G.; Maupin, G.; Simner, S.; Singh, P.; Stevenson, J.; Xia, G.

    2005-01-27

    The objectives of this project are to develop cost-effective, optimized materials for intermediate temperature SOFC interconnect and interconnect/electrode interface applications and identify and understand degradation processes in interconnects and at their interfaces with electrodes.

  14. Developing Friendship and Intimacy.

    ERIC Educational Resources Information Center

    Maslow, Abraham H.

    1991-01-01

    Presents previously unpublished paper written by Abraham Maslow in April 1968 in which Maslow speculates on the issue that society had become pathologically individualistic and needed to develop better means of facilitating close relationships among people. (Author/ABL)

  15. Managing Ada development

    NASA Technical Reports Server (NTRS)

    Green, James R.

    1986-01-01

    The Ada programming language was developed under the sponsorship of the Department of Defense to address the soaring costs associated with software development and maintenance. Ada is powerful, and yet to take full advantage of its power, it is sufficiently complex and different from current programming approaches that there is considerable risk associated with committing a program to be done in Ada. There are also few programs of any substantial size that have been implemented using Ada that may be studied to determine those management methods that resulted in a successful Ada project. The items presented are the author's opinions which have been formed as a result of going through an experience software development. The difficulties faced, risks assumed, management methods applied, and lessons learned, and most importantly, the techniques that were successful are all valuable sources of management information for those managers ready to assume major Ada developments projects.

  16. Women's Career Development Patterns.

    ERIC Educational Resources Information Center

    Schreiber, Pamela J.

    1998-01-01

    Women's career development is characterized by balance of work and family, career interruptions, and diverse career paths. Alternative work arrangements such as flexible schedules, telecommuting, and entrepreneurial opportunities may offer women more options for work. (SK)

  17. Geoscientists for international development

    USGS Publications Warehouse

    Hastings, David A.

    1980-01-01

    Professional societies are usually concerned with the advancement of scientific knowledge, but a relative newcomer to the international scene has a different focus - geoscience development in the Third World. David Hastings, a member of AGID, explains.

  18. Patterns of Gender Development

    PubMed Central

    Martin, Carol Lynn; Ruble, Diane N.

    2013-01-01

    A comprehensive theory of gender development must describe and explain long-term developmental patterning and changes and how gender is experienced in the short term. This review considers multiple views on gender patterning, illustrated with contemporary research. First, because developmental research involves understanding normative patterns of change with age, several theoretically important topics illustrate gender development: how children come to recognize gender distinctions and understand stereotypes, and the emergence of prejudice and sexism. Second, developmental researchers study the stability of individual differences over time, which elucidates developmental processes. We review stability in two domains—sex segregation and activities/interests. Finally, a new approach advances understanding of developmental patterns, based on dynamic systems theory. Dynamic systems theory is a metatheoretical framework for studying stability and change, which developed from the study of complex and nonlinear systems in physics and mathematics. Some major features and examples show how dynamic approaches have been and could be applied in studying gender development. PMID:19575615

  19. Gravity and embryonic development

    NASA Technical Reports Server (NTRS)

    Young, R. S.

    1976-01-01

    The relationship between the developing embryo (both plant and animal) and a gravitational field has long been contemplated. The difficulty in designing critical experiments on the surface of the earth because of its background of 1 g, has been an obstacle to a resolution of the problem. Biological responses to gravity (particularly in plants) are obvious in many cases; however, the influence of gravity as an environmental input to the developing embryo is not as obvious and has proven to be extremely difficult to define. In spite of this, over the years numerous attempts have been made using a variety of embryonic materials to come to grips with the role of gravity in development. Three research tools are available: the centrifuge, the clinostat, and the orbiting spacecraft. Experimental results are now available from all three sources. Some tenuous conclusions are drawn, and an attempt at a unifying theory of gravitational influence on embryonic development is made.

  20. Implementing sustainable development

    SciTech Connect

    Loran, B.

    1997-08-01

    Criteria for the implementation of sustainable development are presented. These criteria are derived systematically from a definition of desirable goals, a comparison with the present situation, and an identification of available means to achieve the desired results. A revision of the standards used to measure a country status level (national standards) is found to be a key element. The present situation involves a largely unchecked population expansion in locations least suited to accommodate it, lack of energy and resource use plans, and national standards based on development, or growth. A sustainable development, on the other hand, requires stabilized population and energy and resource use, and national standards moving away from growth and accepting quality of life in its place. Examples of specific applications to different cultural environments and references to pertinent studies are provided, showing that sustainable development is a concrete possibility, once the basic criteria identified are recognized as desirable goals and receive gradual acceptance.

  1. Cascade Distillation System Development

    NASA Technical Reports Server (NTRS)

    Callahan, Michael R.; Sargushingh, Miriam; Shull, Sarah

    2014-01-01

    NASA's Advanced Exploration Systems (AES) Life Support System (LSS) Project is chartered with de-veloping advanced life support systems that will ena-ble NASA human exploration beyond low Earth orbit (LEO). The goal of AES is to increase the affordabil-ity of long-duration life support missions, and to re-duce the risk associated with integrating and infusing new enabling technologies required to ensure mission success. Because of the robust nature of distillation systems, the AES LSS Project is pursuing develop-ment of the Cascade Distillation Subsystem (CDS) as part of its technology portfolio. Currently, the system is being developed into a flight forward Generation 2.0 design.

  2. Clinical vaccine development

    PubMed Central

    2015-01-01

    Vaccination is regarded as one of the biggest triumphs in the history of medicine. We are living in the most successful period of vaccine development. The accumulation of multidisciplinary knowledge and the investment of massive funding have enabled the development of vaccines against many infectious diseases as well as other diseases including malignant tumors. The paradigm of clinical vaccine evaluation and licensure has also been modernized based on scientific improvements and historical experience. However, there remain a number of hurdles to overcome. Continuous efforts are focused on increasing the efficacy and reducing the risks related to vaccine use. Cutting-edge knowledge about immunology and microbiology is being rapidly translated to vaccine development. Thus, physicians and others involved in the clinical development of vaccines should have sufficient understanding of the recent developmental trends in vaccination and the diseases of interest. PMID:25648742

  3. Migrant remittances and development.

    PubMed

    Russell, S S

    1992-01-01

    Income remittances from migrant workers to countries of origin are central to the links between migration and development. Multiple, complex, and diverse forces, however, affect the flow of remittances. Factors may include the number and characteristics of workers abroad; levels and types of economic activity in sending and host countries; differential wage, exchange, and interest rates; political risk; and the facility for transferring funds. These factors then shape personal decisions made by migrants and their families regarding remittances, after which any longer-range development consequences of remittances may result. Debate rages over the effects of remittances on development. This paper therefore reviews papers on the measurement of remittances and gives recent findings on the volume and direction of flows. It continues by considering evidence on the uses of remittances and their consequences for development, and closes with a discussion of policy options for increasing and channeling remittance flows.

  4. Online Staff Development.

    ERIC Educational Resources Information Center

    Pease, Pamela S.; Magnuson, Peter

    2003-01-01

    Describes the benefits for principals of online staff development for teachers. Sources of online courses and training include local and state departments of education, professional associations, colleges and universities, online universities, and commercial suppliers. (PKP)

  5. JPRS report, nuclear developments

    SciTech Connect

    1991-03-28

    This report contains articles concerning the nuclear developments of the following countries: (1) China; (2) Japan, North Korea, South Korea; (3) Bulgaria; (4) Argentina, Brazil, Honduras; (5) India, Iran, Pakistan, Syria; (6) Soviet Union; and (7) France, Germany, Turkey.

  6. ECOSYSTEM GROWTH AND DEVELOPMENT

    EPA Science Inventory

    Thermodynamically, ecosystem growth and development is the process by which energy throughflow and stored biomass increase. Several proposed hypotheses describe the natural tendencies that occur as an ecosystem matures, and here, we consider five: minimum entropy production, maxi...

  7. NASA balloon technology developments

    NASA Astrophysics Data System (ADS)

    Fairbrother, D. A.

    The National Aeronautics and Space Administration (NASA) Balloon Program has been, and will continue to be, committed to improving the capabilities of balloons to support science missions. Fundamental to vehicle improvement is a program of technology development that will enable improved flight performance throughout the next decade. The program's technology thrust areas include: materials, vehicle design & development, structural analysis, operations & support systems, performance modeling and planetary balloons. Building on the foundations of the 18-year research and development program, a technology roadmap has been generated which identifies specific areas of interest to NASA and the vision of future developments. The major components of the roadmap are: vehicle systems, ballooncraft systems, operational and safety support systems, and planetary vehicles. Current technology activities include nanocomposite balloon films, a new balloon designed to lift 3600 kgs to 36 km, a balloon rotation rate study and Mars pumpkin balloon investigations. The technology roadmap, as well as specific projects and recent advancements, will be presented.

  8. NASA Balloon Technology Developments

    NASA Technical Reports Server (NTRS)

    Fairbrother, D. A.

    2004-01-01

    The National Aeronautics and Space Administration (NASA) Balloon Program has been, and will continue to be, committed to improving the capabilities of balloons to support science missions. Fundamental to vehicle improvement is a program of technology development that will enable improved flight performance throughout the next decade. The program s technology thrust areas include: materials, vehicle design & development, structural analysis, operations & support systems, performance modeling and planetary balloons. Building on the foundations of the 18-year research and development program, a technology roadmap has been generated which identifies specific areas of interest to NASA and the vision of future developments. The major components of the roadmap are: vehicle systems, balloon-craft systems, operational and safety support systems, and planetary vehicles. Current technology activities include nanocomposite balloon films, a new balloon designed to lift 3600 kgs to 36 km, a balloon rotation rate study and Mars pumpkin balloon investigations. The technology roadmap, as well as specific projects and recent advancements, will be presented.

  9. Organizational Development and Evaluation.

    ERIC Educational Resources Information Center

    Patton, Michael Quinn

    1999-01-01

    Explores some opportunities open to evaluators as practitioners of organizational development and the advantages and competencies evaluators can bring to such initiatives. Presents eight examples of such opportunities. (SLD)

  10. Element-ary Development.

    ERIC Educational Resources Information Center

    Schamp, Homer W., Jr.

    1989-01-01

    Describes the historic development of the periodic table from the four-element theory to the Lavoisier's table. Presents a table listing the old and new names of chemicals and the Lavoisier's table of elements. Lists two references. (YP)

  11. Catalyzing RE Project Development

    SciTech Connect

    Anderson, Kate; Elgqvist, Emma; Walker, Andy; Cutler, Dylan; Olis, Dan; DiOrio, Nick; Simpkins, Travis

    2016-09-01

    This poster details how screenings done with REopt - NREL's software modeling platform for energy systems integration and optimization - are helping to catalyze the development of hundreds of megawatts of renewable energy.

  12. Consulting in Collection Development.

    ERIC Educational Resources Information Center

    Ash, Lee

    1980-01-01

    Considers the role of the consultant in the areas of library collection development and weeding, and offers suggestions on determining the need for a consultant, obtaining one, and what to do when the consultant arrives. (FM)

  13. Advanced Hydrogen Turbine Development

    SciTech Connect

    Marra, John

    2015-09-30

    Under the sponsorship of the U.S. Department of Energy (DOE) National Energy Technology Laboratories, Siemens has completed the Advanced Hydrogen Turbine Development Program to develop an advanced gas turbine for incorporation into future coal-based Integrated Gasification Combined Cycle (IGCC) plants. All the scheduled DOE Milestones were completed and significant technical progress was made in the development of new technologies and concepts. Advanced computer simulations and modeling, as well as subscale, full scale laboratory, rig and engine testing were utilized to evaluate and select concepts for further development. Program Requirements of: A 3 to 5 percentage point improvement in overall plant combined cycle efficiency when compared to the reference baseline plant; 20 to 30 percent reduction in overall plant capital cost when compared to the reference baseline plant; and NOx emissions of 2 PPM out of the stack. were all met. The program was completed on schedule and within the allotted budget

  14. Initial Hardware Development Schedule

    NASA Technical Reports Server (NTRS)

    Culpepper, William X.

    1991-01-01

    The hardware development schedule for the Common Lunar Lander's (CLLs) tracking system is presented. Among the topics covered are the following: historical perspective, solution options, industry contacts, and the rationale for selection.

  15. Solar energy emplacement developer

    NASA Technical Reports Server (NTRS)

    Mortensen, Michael; Sauls, Bob

    1991-01-01

    A preliminary design was developed for a Lunar Power System (LPS) composed of photovoltaic arrays and microwave reflectors fabricated from lunar materials. The LPS will collect solar energy on the surface of the Moon, transform it into microwave energy, and beam it back to Earth where it will be converted into usable energy. The Solar Energy Emplacement Developer (SEED) proposed will use a similar sort of solar energy collection and dispersement to power the systems that will construct the LPS.

  16. Mandible and Tongue Development

    PubMed Central

    Parada, Carolina; Chai, Yang

    2016-01-01

    The tongue and mandible have common origins. They arise simultaneously from the mandibular arch and are coordinated in their development and growth, which is evident from several clinical conditions such as Pierre Robin sequence. Here, we review in detail the molecular networks controlling both mandible and tongue development. We also discuss their mechanical relationship and evolution as well as the potential for stem cell-based therapies for disorders affecting these organs. PMID:26589920

  17. Probabilistic Model Development

    NASA Technical Reports Server (NTRS)

    Adam, James H., Jr.

    2010-01-01

    Objective: Develop a Probabilistic Model for the Solar Energetic Particle Environment. Develop a tool to provide a reference solar particle radiation environment that: 1) Will not be exceeded at a user-specified confidence level; 2) Will provide reference environments for: a) Peak flux; b) Event-integrated fluence; and c) Mission-integrated fluence. The reference environments will consist of: a) Elemental energy spectra; b) For protons, helium and heavier ions.

  18. Development of TOPS

    NASA Astrophysics Data System (ADS)

    Tanaka, Yoshiyuki; Tsugiishi, Shigemi

    The off-line patent and utility model information management system at Teijin Ltd. had been developed and operated since 1980. To achieve efficient business management through office automation and to get ready for easy access to electronic document delivery so-called Paperless project being developed by Japan Patent Office, the system was reviewed and new online system was constructed in 1985. The paper describes its details.

  19. Federal Drug Development Programs.

    DTIC Science & Technology

    1981-07-17

    of Child 1971 6.7 0 Health and Human Development Caries National Institute of Dental 1971 0.6 0 ( tooth decay ) Research Sickle cell National Heart...industry was marketed in the late 1960s. The caries ( tooth decay ) drug development program was started in 1971 by the National Institute of Dental...Malaria/tropical diseases 280,000 Vaccines 60 Epilepsy 4,400 Antivirals 50 Contraceptives 2,800 Caries ( tooth decay ) 300 Sickle cell anemia 25 Narcotic

  20. Review: 1991 industry developments

    SciTech Connect

    1992-01-01

    This is NUEXCO`s annual summary of the previous year`s (1991) events. There are reviews of major nuclear developments in each continent, as well as international developments. Specific topics include fuels, waste management, new facilities, and decommissioning. Nuclear activities in the following countries are noted: South Africa, Yemen, Lithuania, Latvia, Estonia, Namibia, France, Japan, Taiwan, China, Korea, India, Pakistan, Federal Republic of Germany, Spain, Hungary, Kazakhstan, Italy, Czechoslovakia, United Kingdom, Switzerland, Canada, USA, Argentina, Brazil, and Uraguay.