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IntroductionManagement of phenylketonuria (PKU) is mainly achieved through dietary control with limited intake of phenylalanine (Phe) from food, supplemented with low protein (LP) food and a mixture of free synthetic (FS) amino acids (AA) (FSAA). Casein glycomacropeptide (CGMP) is a natural peptide released in whey during cheese making by the action of the enzyme chymosin. Because CGMP in its pure form does not contain Phe, it is nutritionally suitable as a supplement in the diet for PKU when enriched with specific AAs. Lacprodan (R) CGMP-20 (= CGMP) used in this study contained only trace amounts of Phe due to minor presence of other proteins/peptides.ObjectiveThe aims were to address the following questions in a classical PKU mouse model: Study 1, off diet: Can pure CGMP or CGMP supplemented with Large Neutral Amino Acids (LNAA) as a supplement to normal diet significantly lower the content of Phe in the brain compared to a control group on normal diet, and does supplementation of selected LNAA results in significant lower brain Phe level?. Study 2, on diet: Does a combination of CGMP, essential (non-Phe) EAAs and LP diet, provide similar plasma and brain Phe levels, growth and behavioral skills as a formula which alone consist of FSAA, with a similar composition?.Material and methods45 female mice homozygous for the Pah(enu2 )mutation were treated for 12 weeks in five different groups; G1(N-CGMP), fed on Normal (N) casein diet (75%) in combination with CGMP (25%); G2 (N-CGMP-LNAA), fed on Normal (N) casein diet (75%) in combination with CGMP (19,7%) and selected LNAA (5,3% Leu, Tyr and Trp); G3 (N), fed on normal casein diet (100%); G4 (CGMP-EAA-LP), fed on CGMP (70,4%) in combination with essential AA (19,6%) and LP diet; G5 (FSAA-LP), fed on FSAA (100%) and LP diet. The following parameters were measured during the treatment period: Plasma AA profiles including Phe and Tyr, growth, food and water intake and number of teeth

IntroductionManagement of phenylketonuria (PKU) is mainly achieved through dietary control with limited intake of phenylalanine (Phe) from food, supplemented with low protein (LP) food and a mixture of free synthetic (FS) amino acids (AA) (FSAA). Casein glycomacropeptide (CGMP) is a natural peptide released in whey during cheese making by the action of the enzyme chymosin. Because CGMP in its pure form does not contain Phe, it is nutritionally suitable as a supplement in the diet for PKU when enriched with specific AAs. Lacprodan (R) CGMP-20 (= CGMP) used in this study contained only trace amounts of Phe due to minor presence of other proteins/peptides.ObjectiveThe aims were to address the following questions in a classical PKU mouse model: Study 1, off diet: Can pure CGMP or CGMP supplemented with Large Neutral Amino Acids (LNAA) as a supplement to normal diet significantly lower the content of Phe in the brain compared to a control group on normal diet, and does supplementation of selected LNAA results in significant lower brain Phe level?. Study 2, on diet: Does a combination of CGMP, essential (non-Phe) EAAs and LP diet, provide similar plasma and brain Phe levels, growth and behavioral skills as a formula which alone consist of FSAA, with a similar composition?.Material and methods45 female mice homozygous for the Pah(enu2 )mutation were treated for 12 weeks in five different groups; G1(N-CGMP), fed on Normal (N) casein diet (75%) in combination with CGMP (25%); G2 (N-CGMP-LNAA), fed on Normal (N) casein diet (75%) in combination with CGMP (19,7%) and selected LNAA (5,3% Leu, Tyr and Trp); G3 (N), fed on normal casein diet (100%); G4 (CGMP-EAA-LP), fed on CGMP (70,4%) in combination with essential AA (19,6%) and LP diet; G5 (FSAA-LP), fed on FSAA (100%) and LP diet. The following parameters were measured during the treatment period: Plasma AA profiles including Phe and Tyr, growth, food and water intake and number of teeth

Phenylketonuria (PKU) is an autosomal recessive disorder of phenylalanine (Phe) metabolism, causing a build-up of Phe in the body. Treatment consists of a Phe-restricted diet for life and regular determination of blood Phe levels to monitor the intake of Phe. Despite the fact that diet is the cornerstone of treatment, there are no studies examining common knowledge about food items and whether they are allowed as part of the PKU diet. Improving parents’ and patients’ knowledge and competence about the diet enables them to make appropriate food choices. This study validates a food-knowledge questionnaire first developed in Spanish and modified for English speaking populations. The questionnaire potentially helps parents to prepare appropriate meals and healthcare providers to create individualized educational programs about PKU for children and adolescents with this disorder., Vice-Rectorate for Scientific Policy and Research of the Granada University, Fac. de Psicología, TRUE, pub

The project explored biosensors to potentially develop a home health monitor for people with phenylketonuria (PKU). The thesis included studies of biochip design and preparation, design of a reader unit and concept design for on-chip reagent handling. The biosensor comprised anti-phenylalanine antibodies assembled on a gold electrode, when exposed to human serum would produce an electrochemical response. The research found strong evidence for the potential health benefits of such a monitor for a variety of individual situations and concluded that enzymatic methods may present the best opportunity for successful commercialisation.

Previous studies have suggested that cognitive and psychosocial underfunctioning in early-treated adults with PKU may be explained by suboptimal adherence to dietary treatments, however these studies often employ small samples, with different outcome measures, definitions and cut-offs. Samples have also tended to comprise participants with a limited range of blood phenylalanine concentrations, and often individuals who may not have been treated early enough to avoid neurological damage. In this study, we explore the impact of lifetime dietary control, as indicated by blood phenylalanine concentrations in childhood, adolescence and adulthood, on long-term cognitive and psychosocial outcomes in a large sample of adults with PKU who were diagnosed by neonatal screening and commenced on dietary treatment within the first month of life. 154 participants underwent cognitive testing, assessing attention, learning, working memory, language, executive functioning and processing speed. 149 completed measures of psychosocial functioning, documenting educational, occupational, quality of life, emotional and social outcomes which were compared with a group of healthy controls. Many adults with PKU demonstrated cognitive impairments, most frequently affecting processing speed (23%), executive function (20%) and learning (12%). Cognitive outcomes were related to measures of historic metabolic control, but only processing speed was significantly related to phenylalanine concentration at the time of testing after controlling for historic levels. Adults with PKU did not, however, differ from controls in educational, occupational, quality of life or emotional outcomes, or on a measure of family functioning, and showed only minor differences in relationship style. These findings have implications for patient counselling and decisions regarding the management of PKU in adulthood. This article is protected by copyright. All rights reserved.

I denna studie undersöks värdet av diagnostik vid sällsynta sjukdomar hos unga individer. Då området är mångfacetterat studeras två fall med olika karaktär. Det första fallet undersöker värdet av screening för den sällsynta sjukdomen fenylketonuri (PKU) bland nyfödda, denna screening har utförts sedan 1960-talet. Det andra fallet fokuserar på en mer modern teknologisk utveckling och utvärderar värdet av införandet av helgenomsekvensering (WGS) som genetiskt test vid sökandet efter sällsynta sjukdomar. Båda fallen använder sig av kostnadseffektivitetsanalys som metod där kostnader respektive hälsoeffekter estimeras för de utvärderade insatserna. Fallen skiljer sig åt med avseende på tillgängliga dataunderlag vilket innebär att tillvägagångssättet för att skatta kostnaderna och hälsoeffekterna är olika i de båda fallen. I fallet med PKU-screening används Markovmodellering där data från olika källor syntetiseras i en simuleringsmodell. I fallet med WGS-testning används i större utsträckning ett insamlat empiriskt datamaterial som utgörs av faktiskt uppmätta sjukvårdskostnader. Resultaten i båda fallen indikerar att de diagnostiska metoderna har en rimlig kostnad i förhållande till hälsoeffekterna. Fall ett åskådliggör att dagens screening för PKU genererar ökade hälsoeffekter till lägre kostnader i jämförelse med att inte screena för PKU. För en kohort på 100 000 nyfödda barn blir den sammanlagda hälsoeffekten en ökning med 73 QALYs och screeningen medför samtidigt en besparing på 53 376 602 kr, sett över ett livstidsperspektiv. Fall två visar att WGS som första genetiskt test i genomsnitt minskar sjukvårdskostnaderna med 15 903 kr per individ jämfört med nuvarande vård och ökar samtidigt chansen till diagnos med 9,5 procentenheter (45,7%). Resultaten bör tolkas med viss försiktighet då de är förknippade med osäkerheter, men kan samtidigt användas som en del av det underlag beslutsfa, This study examines the value of diagnostics in rare diseases in young individuals. As the field is varied, two cases with different character are studied. The first case examines the value of screening for the rare disease phenylketonuria (PKU) among newborns, this screening has been performed since the 1960s. The second case focuses on a more modern technological development and evaluates the value of the introduction of whole genome sequencing (WGS) as a genetic test in the search for rare diseases. Both cases utilize the method of cost-effectiveness analysis where costs and health effects are estimated for the evaluated measures. The cases differ regarding available data, which means that the approach to estimating costs and health effects is different in the two cases. In the case of PKU- screening, Markov modeling is used where data from different sources are synthesized in a simulation model. In the case of WGS-testing, an empirical data material is used to a greater extent, which is based on actually measured healthcare costs. The results in both cases indicate that the diagnostic methods have a reasonable cost in relation to the health effects. Case one illustrates that today's screening for PKU generates increased health effects at lower costs compared to not screening for PKU. For a cohort of 100 000 newborns, the total health effect will be an increase of 73 QALYs and the screening will also result in cost- savings of SEK 53 376 602, seen from a lifetime perspective. Case two shows that WGS used as an initial genetic test on average reduces healthcare costs by SEK 15 903 per individual compared with current care and at the same time increases the chance of diagnosis by 9.5 percentage points (45.7%). The results should be interpreted with some caution as they are associated with some uncertainties, but can still be used as part of the basis on which decision-makers need to make decisions on how health care resources should be prioritized.

Introducción: El ácido docosahexaenoico (DHA) es un ácido graso poliinsaturado de cadena larga (AGPI-CL; LC-PUFA), cuya principal fuente de entrada a nuestro organismo son los alimentos ricos en proteínas de alto valor biológico. Objetivos: Analizar los beneficios de una suplementación con ácidos grasos poliinsaturados de cadena larga (LC-PUFA) en especial el ácido docosahexaenoico, en el tratamiento de la fenilcetonuria y la aciduria glutárica I; evaluando, además, la posible deficiencia de LC-PUFA, en especial el DHA, que existe de partida en esta población a estudio, y/o su causa. Métodos: Se ha realizado una exhaustiva y ordenada revisión de las publicaciones incluidas en la base de datos PUBMED en relación con los ácidos grasos poliinsaturados de cadena larga (LC-PUFA) y la fenilcetonuria (PKU) y la aciduria glutárica 1 (GA-1). Los criterios de inclusión de los estudios analizados fueron: estudios realizados en humanos, que estuvieran publicados en inglés o español y que tuvieran abstract disponible. Únicamente se incluyeron ensayos clínicos, ensayos clínicos aleatorizados y controlados, metaanálisis, revisiones y revisiones sistemáticas. El período de búsqueda fue desde el 01/01/2000 hasta el 01/04/2020. Resultados: Se incluyeron 22 estudios en los que se analizaron los beneficios de una suplementación con ácidos grasos poliinsaturados de cadena larga (LC-PUFA) en especial el ácido docosahexaenoico, en el tratamiento de la fenilcetonuria y la aciduria glutárica I; evaluando, además, la posible deficiencia de LC-PUFA, en especial el DHA, que existe de partida en esta población a estudio, y/o su causa. No existe evidencia en cuanto a la relación de la aciduria glutárica 1 (GA-1) y los ácidos grasos poliinsaturados de cadena larga (LC-PUFA), por lo que es necesario que se investigue al respecto. Existe un déficit de LC-PUFA en la fenilcetonuria (PKU) con dos posibles explicaciones, y la suplementación con LC-PUFA es potencialmente útil y necesaria en estos pacien, Background: Docosahexaenoic acid (DHA) is a long-chain polyunsaturated fatty acid (LC-PUFA; LC-PUFA), whose main sources of entry into our organism are foods rich in proteins of high biological value. Objectives: To analyze the benefits of supplementation with long-chain polyunsaturated fatty acids (LC-PUFA), especially docosahexaenoic acid, in the treatment of phenylketonuria and glutaric aciduria I; evaluating, in addition, the possible deficiency of LC-PUFA, especially DHA, that exists in this study population, and/or its cause. Methods: An exhaustive and orderly review of the publications included in the PUBMED database regarding long-chain polyunsaturated fatty acids (LC-PUFA) and phenylketonuria (PKU) and glutaric aciduria 1 (GA-1) was performed. The inclusion criteria for the studies analyzed were: studies conducted in humans, published in English or Spanish and with available abstracts. Only clinical trials, randomized and controlled clinical trials, meta-analyses, reviews and systematic reviews were included. The search period was from 01/01/2000 to 01/04/2020. Results: 22 studies were included in which the benefits of supplementation with long-chain polyunsaturated fatty acids (LC-PUFA), especially docosahexaenoic acid, in the treatment of phenylketonuria and glutaric aciduria I were analyzed; evaluating, in addition, the possible deficiency of LC-PUFA, especially DHA, that exists in this study population, and/or its cause. There is no evidence regarding the relationship between glutaric aciduria 1 (GA-1) and long-chain polyunsaturated fatty acids (LC-PUFA), so more research is needed. There is a deficit of LC-PUFA in phenylketonuria (PKU) with two possible explanations, and LC-PUFA supplementation is potentially useful and necessary in these patients, since it solves this deficit and seems to have, in general, positive effects on visual evoked potentials. There are no conclusive data on the effect of DHA supplementation on neurodevelopment in PKU patients, Introdución: O ácido docosahexaenoico (DHA) é un acido graxo poliinsaturado de cadena longa (AGPI-CL; LC-PUFA), no que a fonte principal para incorporarse o noso organismo son os alimentos ricos en proteínas de alto valor biolóxico. Obxectivos: Analizar os beneficios dunha suplementación con ácidos graxos poliinsaturados de cadea longa (LC-PUFA), especialmente ácido docosahexaenoico, no tratamento da fenilcetonuria e da aciduria glutárica I; avaliando, ademais, a posible deficiencia de LC-PUFA, especialmente DHA, que inicialmente existe nesta poboación a estudo e / ou a súa causa. Métodos: Realizouse unha revisión exhaustiva e ordenada das publicacións incluídas na base de datos PUBMED en relación aos ácidos graxos poliinsaturados de cadea longa (LC-PUFA) e á fenilcetonuria (PKU) e á aciduria glutárica 1 (GA-1). Os criterios de inclusión dos estudos analizados foron: estudos realizados en humanos, que foron publicados en inglés ou español e que tiñan un resumo dispoñible. Só se incluíron ensaios clínicos, ensaios clínicos aleatorios e controlados, metaanálises, revisións e revisións sistemáticas. O período de busca foi do 01/01/2000 ao 04/01/2020. Resultados: Incluíronse vinte e dous estudos nos que se incluían os beneficios da suplementación con ácidos graxos poliinsaturados de cadea longa (LC-PUFA), especialmente o ácido docosahexaenoico, no tratamento da fenilcetonuria e da aciduria glutárica. avaliando, ademais, a posible deficiencia de LC-PUFA, especialmente DHA, que inicialmente existe nesta poboación de estudo e / ou a súa causa. Non hai evidencias sobre a relación entre a aciduria glutárica 1 (GA-1) e os ácidos graxos poliinsaturados de cadea longa (LC-PUFA), polo que é necesario investigar. Hai un déficit de LC-PUFA en fenilcetonuria (PKU) con dúas explicacións posibles, e a suplementación de LC-PUFA é potencialmente útil e necesaria nestes pacientes, xa que resolve este déficit e parece ter, en xeral, efectos positivos sobre os potenciais visuais evocados.

Previous studies have suggested that cognitive and psychosocial underfunctioning in early-treated adults with PKU may be explained by suboptimal adherence to dietary treatments, however these studies often employ small samples, with different outcome measures, definitions and cut-offs. Samples have also tended to comprise participants with a limited range of blood phenylalanine concentrations, and often individuals who may not have been treated early enough to avoid neurological damage. In this study, we explore the impact of lifetime dietary control, as indicated by blood phenylalanine concentrations in childhood, adolescence and adulthood, on long-term cognitive and psychosocial outcomes in a large sample of adults with PKU who were diagnosed by neonatal screening and commenced on dietary treatment within the first month of life. 154 participants underwent cognitive testing, assessing attention, learning, working memory, language, executive functioning and processing speed. 149 completed measures of psychosocial functioning, documenting educational, occupational, quality of life, emotional and social outcomes which were compared with a group of healthy controls. Many adults with PKU demonstrated cognitive impairments, most frequently affecting processing speed (23%), executive function (20%) and learning (12%). Cognitive outcomes were related to measures of historic metabolic control, but only processing speed was significantly related to phenylalanine concentration at the time of testing after controlling for historic levels. Adults with PKU did not, however, differ from controls in educational, occupational, quality of life or emotional outcomes, or on a measure of family functioning, and showed only minor differences in relationship style. These findings have implications for patient counselling and decisions regarding the management of PKU in adulthood. This article is protected by copyright. All rights reserved.

I denna studie undersöks värdet av diagnostik vid sällsynta sjukdomar hos unga individer. Då området är mångfacetterat studeras två fall med olika karaktär. Det första fallet undersöker värdet av screening för den sällsynta sjukdomen fenylketonuri (PKU) bland nyfödda, denna screening har utförts sedan 1960-talet. Det andra fallet fokuserar på en mer modern teknologisk utveckling och utvärderar värdet av införandet av helgenomsekvensering (WGS) som genetiskt test vid sökandet efter sällsynta sjukdomar. Båda fallen använder sig av kostnadseffektivitetsanalys som metod där kostnader respektive hälsoeffekter estimeras för de utvärderade insatserna. Fallen skiljer sig åt med avseende på tillgängliga dataunderlag vilket innebär att tillvägagångssättet för att skatta kostnaderna och hälsoeffekterna är olika i de båda fallen. I fallet med PKU-screening används Markovmodellering där data från olika källor syntetiseras i en simuleringsmodell. I fallet med WGS-testning används i större utsträckning ett insamlat empiriskt datamaterial som utgörs av faktiskt uppmätta sjukvårdskostnader. Resultaten i båda fallen indikerar att de diagnostiska metoderna har en rimlig kostnad i förhållande till hälsoeffekterna. Fall ett åskådliggör att dagens screening för PKU genererar ökade hälsoeffekter till lägre kostnader i jämförelse med att inte screena för PKU. För en kohort på 100 000 nyfödda barn blir den sammanlagda hälsoeffekten en ökning med 73 QALYs och screeningen medför samtidigt en besparing på 53 376 602 kr, sett över ett livstidsperspektiv. Fall två visar att WGS som första genetiskt test i genomsnitt minskar sjukvårdskostnaderna med 15 903 kr per individ jämfört med nuvarande vård och ökar samtidigt chansen till diagnos med 9,5 procentenheter (45,7%). Resultaten bör tolkas med viss försiktighet då de är förknippade med osäkerheter, men kan samtidigt användas som en del av det underlag beslutsfa, This study examines the value of diagnostics in rare diseases in young individuals. As the field is varied, two cases with different character are studied. The first case examines the value of screening for the rare disease phenylketonuria (PKU) among newborns, this screening has been performed since the 1960s. The second case focuses on a more modern technological development and evaluates the value of the introduction of whole genome sequencing (WGS) as a genetic test in the search for rare diseases. Both cases utilize the method of cost-effectiveness analysis where costs and health effects are estimated for the evaluated measures. The cases differ regarding available data, which means that the approach to estimating costs and health effects is different in the two cases. In the case of PKU- screening, Markov modeling is used where data from different sources are synthesized in a simulation model. In the case of WGS-testing, an empirical data material is used to a greater extent, which is based on actually measured healthcare costs. The results in both cases indicate that the diagnostic methods have a reasonable cost in relation to the health effects. Case one illustrates that today's screening for PKU generates increased health effects at lower costs compared to not screening for PKU. For a cohort of 100 000 newborns, the total health effect will be an increase of 73 QALYs and the screening will also result in cost- savings of SEK 53 376 602, seen from a lifetime perspective. Case two shows that WGS used as an initial genetic test on average reduces healthcare costs by SEK 15 903 per individual compared with current care and at the same time increases the chance of diagnosis by 9.5 percentage points (45.7%). The results should be interpreted with some caution as they are associated with some uncertainties, but can still be used as part of the basis on which decision-makers need to make decisions on how health care resources should be prioritized.

Routine diagnostic screening of inborn errors of metabolism (IEM) is currently performed by different targeted analyses of known biomarkers. This approach is time-consuming, targets a limited number of biomarkers and will not identify new biomarkers. Untargeted metabolomics generates a global metabolic phenotype and has the potential to overcome these issues. We describe a novel, single platform, untargeted metabolomics method for screening IEM, combining semi-automatic sample preparation with pentafluorophenylpropyl phase (PFPP)-based UHPLC-Orbitrap-MS. We evaluated analytical performance and diagnostic capability of the method by analysing plasma samples of 260 controls and 53 patients with 33 distinct IEM. Analytical reproducibility was excellent, with peak area variation coefficients below 20% for the majority of the metabolites. We illustrate that PFPP-based chromatography enhances identification of isomeric compounds. Ranked z-score plots of metabolites annotated in IEM samples were reviewed by two laboratory specialists experienced in biochemical genetics, resulting in the correct diagnosis in 90% of cases. Thus, our untargeted metabolomics platform is robust and differentiates metabolite patterns of different IEMs from those of controls. We envision that the current approach to diagnose IEM, using numerous tests, will eventually be replaced by untargeted metabolomics methods, which also have the potential to discover novel biomarkers and assist in interpretation of genetic data.

BACKGROUND: In infants with phenylketonuria (PKU), dietary management is based on lowering and titrating phenylalanine (Phe) intake from breast milk or standard infant formula in combination with a Phe-free infant formula in order to maintain blood Phe levels within target range. Professionals use different methods to feed infants with PKU and our survey aimed to document practices across Europe. METHODS: We sent a cross sectional, survey monkey® questionnaire to European health professionals working in IMD. It contained 31 open and multiple-choice questions. The results were analysed according to different geographical regions. RESULTS: Ninety-five centres from 21 countries responded. Over 60% of centres commenced diet in infants by age 10 days, with 58% of centres implementing newborn screening by day 3 post birth. At diagnosis, infant hospital admission occurred in 61% of metabolic centres, mainly in Eastern, Western and Southern Europe. Breastfeeding fell sharply following diagnosis with only 30% of women still breast feeding at 6 months.53% of centres gave pre-measured Phe-free infant formula before each breast feed and 23% alternated breast feeds with Phe-free infant formula. With standard infant formula feeds, measured amounts were followed by Phe-free infant formula to satiety in 37% of centres (n = 35/95), whereas 44% (n = 42/95) advised mixing both formulas together. Weaning commenced between 17 and 26 weeks in 85% centres, ≥26 weeks in 12% and < 17 weeks in 3%. DISCUSSION: This is the largest European survey completed on PKU infant feeding practices. It is evident that practices varied widely across Europe, and the practicalities of infant feeding in PKU received little focus in the PKU European Guidelines (2017). There are few reports comparing different feeding techniques with blood Phe control, Phe fluctuations and growth. Controlled prospective studies are necessary to assess how different infant feeding practices may influence longer term feeding dev

Background: We aimed to assess the current state of PKU screening and management in the region of southeastern Europe. Methods: A survey was performed involving all identified professionals responsible for the PKU management in the 11 countries from South-Eastern region of Europe (Albania, Bulgaria, Bosnia and Herzegovina, Croatia, Kosovo, Macedonia, Moldova, Montenegro, Romania, Serbia, Slovenia). The questionnaire was designed to assess the characteristics regarding PKU management in three main areas: nation-wide characteristics, PKU screening, and characteristics of the PKU management in the responding centre. It consisted of 56 questions. The distribution and collection of the questionnaires (via e-mail) was taking place from December 2013 to March 2014. Results: Responses from participants from 11 countries were included; the countries cumulative population is approx. 52.5 mio. PKU screening was not yet introduced in 4 of 11 countries. Reported PKU incidences ranged from 1/7325 to 1/39338 (and were not known for 5 countries). National PKU guidelines existed in 5 of 11 countries and 7 of 11 countries had PKU registry (registries included 40 to 194 patients). The number of PKU centers in each country varied from1 to 6. Routine genetic diagnostics was reported in 4 of 11 countries. Most commonly used laboratory method to assess phenylalanine levels was fluorometric. Tetrahydrobiopterine was used in only 2 of 11 countries. Most frequently, pediatricians were caring for the patients. Dietitian was a member of PKU team in only 4 of 11 countries, while regular psychological assessments were performed in 6 of 11 countries. Patient's PKU society existed in 7 of 11 countries. Conclusions: The region of southeastern Europe was facing certain important challenges of PKU screening and management. Neonatal PKU screening should be introduced throughout the region. Furthermore, PKU management was falling behind internationally established standards-of-care in many aspects.

Patients with phenylketonuria (PKU) encompass an 'at risk' group for micronutrient imbalances. Optimal nutrient status is challenging particularly when a substantial proportion of nutrient intake is from non-natural sources. In PKU patients following dietary treatment, supplementation with micronutrients is a necessity and vitamins and minerals should either be added to supplement phenylalanine-free l-amino acids or given separately. In this literature review of papers published since 1990, the prevalence of vitamin and mineral deficiency is described, with reference to age of treatment commencement, type of treatment, dietary compliance, and dietary practices. Biological micronutrient inadequacies have been mainly reported for zinc, selenium, iron, vitamin B12 and folate. The aetiology of these results and possible clinical and biological implications are discussed. In PKU there is not a simple relationship between the dietary intake and nutritional status, and there are many independent and interrelated complex factors that should be considered other than quantitative nutritional intake. © 2013 Elsevier Inc., SCOPUS: re.j, info:eu-repo/semantics/published

Patients with phenylketonuria (PKU) encompass an 'at risk' group for micronutrient imbalances. Optimal nutrient status is challenging particularly when a substantial proportion of nutrient intake is from non-natural sources. In PKU patients following dietary treatment, supplementation with micronutrients is a necessity and vitamins and minerals should either be added to supplement phenylalanine-free l-amino acids or given separately. In this literature review of papers published since 1990, the prevalence of vitamin and mineral deficiency is described, with reference to age of treatment commencement, type of treatment, dietary compliance, and dietary practices. Biological micronutrient inadequacies have been mainly reported for zinc, selenium, iron, vitamin B12 and folate. The aetiology of these results and possible clinical and biological implications are discussed. In PKU there is not a simple relationship between the dietary intake and nutritional status, and there are many independent and interrelated complex factors that should be considered other than quantitative nutritional intake. © 2013 Elsevier Inc., SCOPUS: re.j, info:eu-repo/semantics/published

V diplomové práci je zpracován průběžný audit investiční akce na zahlazení následků hornické činnosti bývalého lomu Chabařovice, která probíhá hydrickou rekultivací. V první části je charakterizován státní podnik Palivový kombinát Ústí, jeho historie a předmět podnikání. Následně je začleněn popis investiční akce na zahlazení následků hornické činnosti bývalého lomu Chabařovice, který zahrnuje i historii Chabařovického lomu, popis současného stavu rekultivace a vyhlídky do budoucnosti. V další části jsou zpracovány skutečně vynaložené investiční náklady ve sledovaném období, které jsou následně porovnány s projektem a následně jsou vyhodnoceny i peněžní toky z investice ve sledovaném období., This thesis deals with a continuous audit investment project to eliminate the effects of mining activities of a former quarry Chabařovice, which is proceeded with hydric recultivation. In the first part there is a characterisation of the state enterprise Palivový kombinát Ústí, its history and a subject of enterprise. Further there is a description of investment projects to eliminate the effects of mining activities of the former quarry Chabařovice, which includes a history of the quarry Chabařovice, description of a current situation of the recultivation and future prospects. In the next part, actual costs in the tracking period are processed and compared with the project, and then cash flows from investing in the tracking period are analysed., Import 04/07/2011

Children with early and continuously treated phenylketonuria (ECT-PKU) remain at risk of developing executive function (EF) deficits. There is some evidence that a high phenylalanine to tyrosine ratio (phe:tyr) is more strongly associated with impaired EF development than high phenylalanine alone. This study examined EF in a sample of 11 adolescents against concurrent and historical levels of phenylalanine, phe:tyr, and tyrosine. Lifetime measures of phe:tyr were more strongly associated with EF than phenylalanine-only measures. Children with a lifetime phe:tyr less than 6 demonstrated normal EF, whereas children who had a lifetime phe:tyr above 6, on average, demonstrated clinically impaired EF.

RIVM rapport:Bij screening van pasgeborenen voor aangeboren stofwisselingsziekten wordt in een bloedmonster, verkregen via de hielprik en opgevangen op filtreerpapier, een aantal bloedcomponenten gemeten. Veelal wordt gebruik gemaakt van commercieel verkrijgbare reagentia sets. De fabrikanten kalibreren hun reagentia sets vaak met hun eigen kalibratoren. Bovendien zijn er in de wereld meerdere filtreerpapiersoorten in gebruik, met verschillen in specificaties. Door deze beide oorzaken zijn de uitslagen van verschillende screeningslaboratoria vaak niet goed vergelijkbaar. Dit bemoeilijkt de evaluatie van zulke screeningsprogramma's. De International Society for Neonatal Screening (ISNS) heeft eerder goede ervaringen opgedaan met het laten bereiden van referentiematerialen in filtreerpapierbloed en het overreden van fabrikanten om deze materialen te gebruiken als maatstaf. In 2004 heeft de ISNS aan het RIVM verzocht om een gecombineerd referentiemateriaal te maken voor filtreerpapierbloed met bekende concentraties aan thyrotropine, 17alpha-hydroxyprogesteron, en phenylalanine, merkstoffen die van belang zijn voor de screening op stoornissen in de schildklier, bijnier, respectievelijk eiwitmetabolisme. In dit rapport is de bereiding en evaluatie van dit referentiemateriaal beschreven., Many countries have a screening programme for newborns for congenital metabolic disorders. For this screening several components are measured in dried blood spots collected by a heel stick on filter paper. Most laboratories use commercially available reagent sets for the measurements. Manufacturers of these reagents often calibrate their reagent sets against own calibrators. Moreover several types of filter paper, each with different specifications are in use all over the world. These factors make it difficult to compare results from different screening laboratories and to evaluate such screening programmes. In the past the International Society for Neonatal Screening (ISNS) has been able to persuade manufacturers to use previously prepared dried blood spot reference materials as calibration standards. Having run out of stock, in 2004 the ISNS asked the RIVM to produce a combined reference preparation in filter paper blood with known concentrations of thyrotropine, 17alpha-hydroxyprogesterone and phenylalanine, being the markers of interest for screening on disorders of the thyroid gland, the adrenal gland and amino acid metabolism, respectively. This report describes the production and evaluation of this reference preparation.

RIVM rapport:Bij screening van pasgeborenen voor aangeboren stofwisselingsziekten wordt in een bloedmonster, verkregen via de hielprik en opgevangen op filtreerpapier, een aantal bloedcomponenten gemeten. Veelal wordt gebruik gemaakt van commercieel verkrijgbare reagentia sets. De fabrikanten kalibreren hun reagentia sets vaak met hun eigen kalibratoren. Bovendien zijn er in de wereld meerdere filtreerpapiersoorten in gebruik, met verschillen in specificaties. Door deze beide oorzaken zijn de uitslagen van verschillende screeningslaboratoria vaak niet goed vergelijkbaar. Dit bemoeilijkt de evaluatie van zulke screeningsprogramma's. De International Society for Neonatal Screening (ISNS) heeft eerder goede ervaringen opgedaan met het laten bereiden van referentiematerialen in filtreerpapierbloed en het overreden van fabrikanten om deze materialen te gebruiken als maatstaf. In 2004 heeft de ISNS aan het RIVM verzocht om een gecombineerd referentiemateriaal te maken voor filtreerpapierbloed met bekende concentraties aan thyrotropine, 17alpha-hydroxyprogesteron, en phenylalanine, merkstoffen die van belang zijn voor de screening op stoornissen in de schildklier, bijnier, respectievelijk eiwitmetabolisme. In dit rapport is de bereiding en evaluatie van dit referentiemateriaal beschreven., Many countries have a screening programme for newborns for congenital metabolic disorders. For this screening several components are measured in dried blood spots collected by a heel stick on filter paper. Most laboratories use commercially available reagent sets for the measurements. Manufacturers of these reagents often calibrate their reagent sets against own calibrators. Moreover several types of filter paper, each with different specifications are in use all over the world. These factors make it difficult to compare results from different screening laboratories and to evaluate such screening programmes. In the past the International Society for Neonatal Screening (ISNS) has been able to persuade manufacturers to use previously prepared dried blood spot reference materials as calibration standards. Having run out of stock, in 2004 the ISNS asked the RIVM to produce a combined reference preparation in filter paper blood with known concentrations of thyrotropine, 17alpha-hydroxyprogesterone and phenylalanine, being the markers of interest for screening on disorders of the thyroid gland, the adrenal gland and amino acid metabolism, respectively. This report describes the production and evaluation of this reference preparation.

RIVM rapport:Bij screening van pasgeborenen voor aangeboren stofwisselingsziekten wordt in een bloedmonster, verkregen via de hielprik en opgevangen op filtreerpapier, een aantal bloedcomponenten gemeten. Veelal wordt gebruik gemaakt van commercieel verkrijgbare reagentia sets. De fabrikanten kalibreren hun reagentia sets vaak met hun eigen kalibratoren. Bovendien zijn er in de wereld meerdere filtreerpapiersoorten in gebruik, met verschillen in specificaties. Door deze beide oorzaken zijn de uitslagen van verschillende screeningslaboratoria vaak niet goed vergelijkbaar. Dit bemoeilijkt de evaluatie van zulke screeningsprogramma's. De International Society for Neonatal Screening (ISNS) heeft eerder goede ervaringen opgedaan met het laten bereiden van referentiematerialen in filtreerpapierbloed en het overreden van fabrikanten om deze materialen te gebruiken als maatstaf. In 2004 heeft de ISNS aan het RIVM verzocht om een gecombineerd referentiemateriaal te maken voor filtreerpapierbloed met bekende concentraties aan thyrotropine, 17alpha-hydroxyprogesteron, en phenylalanine, merkstoffen die van belang zijn voor de screening op stoornissen in de schildklier, bijnier, respectievelijk eiwitmetabolisme. In dit rapport is de bereiding en evaluatie van dit referentiemateriaal beschreven., Many countries have a screening programme for newborns for congenital metabolic disorders. For this screening several components are measured in dried blood spots collected by a heel stick on filter paper. Most laboratories use commercially available reagent sets for the measurements. Manufacturers of these reagents often calibrate their reagent sets against own calibrators. Moreover several types of filter paper, each with different specifications are in use all over the world. These factors make it difficult to compare results from different screening laboratories and to evaluate such screening programmes. In the past the International Society for Neonatal Screening (ISNS) has been able to persuade manufacturers to use previously prepared dried blood spot reference materials as calibration standards. Having run out of stock, in 2004 the ISNS asked the RIVM to produce a combined reference preparation in filter paper blood with known concentrations of thyrotropine, 17alpha-hydroxyprogesterone and phenylalanine, being the markers of interest for screening on disorders of the thyroid gland, the adrenal gland and amino acid metabolism, respectively. This report describes the production and evaluation of this reference preparation.

RIVM rapport:Inleiding. In Nederland worden baby's gescreend voor drie aandoeningen: adrenogenitaal syndroom, congenitale hypothyreoidie en phenylketonurie. Hiertoe wordt bij voorkeur de 4e levensdag en uiterlijk op dag 7 hielprikbloed verzameld op filtreerpapier en geanalyseerd in een van de 5 screeningslaboratoria. De screeningsprocedure is in detail beschreven in het 'Draaiboek neonatale screening'. Om een aantal aspecten van de uitvoering van de hielprik procedure te kunnen evalueren werden van 10.000 setjes demografische en andere gegevens geanalyseerd per categorie uitvoerder van de hielprik, per entadministratie en per laboratorium. Resultaten. 1) Op ongeveer 10% van de setjes ontbrak een of meer van de in te vullen gegevens, zoals: uitvoerder hielprik (3.6%), geboortegewicht (1.3%), zwangerschapsduur (3.6%). 2) Op dag 4 was slechts 50% van de hielprikken uitgevoerd met grote verschillen tussen categorieen uitvoerders; op dag 7 was 98% geprikt. 3) Er was een groot verschil tussen categorie6n uitvoerders in setjes met onvoldoende of onbetrouwbaar bloed (OV): verloskundigen, wijkverpleegkundigen en kraamcentra 0.4%, kraamzorg 0.6%, ziekenhuizen 1.4% en huisartsen 2.3%. De ziekenhuizen voeren slechts 18% van de hielprikken uit, maar zijn verantwoordelijk voor ruim 39% van de OV. 4) De bezorging van de setjes door de TPG-Post laat te wensen over en vooral in de regio's Noord-West en Noord-Oost Nederland. Op dag 3 na de hielprik is slechts 79% van alle setjes in het laboratorium ontvangen. 5) De uitvoering van de analyses en de rapportage van de resultaten door de laboratoria waren adequaat en conform het 'Draaiboek neonatale screening' en conform de afspraken die het RIVM met de screeningslaboratoria heeft gemaakt., In the Netherlands neonates are screened for congenital adrenal hyperplasia, congenital hypothyroidism and phenylketonurea. Blood is collected on filter paper according to the heelstick procedure, preferably the fourth day after birth but at least on the seventh day, and analysed in one of the five screening laboratories. To evaluate the performance of the heelstick procedure, demographic and other data of 10.000 heelstick sets were collected and analysed per category of administrator (performer) of the heelstick procedure, per provincial vaccination administrative body and per screening laboratory for the period of 5 to 20 March 2001. Results: 1) In approximately 10% of the samples one or more of tpieces of important data was/were not provided: performer (3.6%), birth weight (1.3%) and gestational age (3.6%). 2) Only 50% of the heelpricks were carried out on day 4 after birth; the 50% showd large differences between categories of performers. A total of 98% of the heel pricks were performed on day 7. 3) The percentage of samples with 'insufficient' or 'unreliable blood' (UB) varied widely between categories of performers: i.e. midwives, local nurses, 0.4%, maternity care workers, 0.6%, hospitals, 1.4% and general practitioners, 2.3%. Hospitals, performing only 18% of the heel pricks, were responsible for 39% of all UB. 4) Three days after the heelprick, only 79% of all sets had reached the laboratory. Mail delivery by the Dutch postal service was slow, especially in the northwest and northeast region. 5) The laboratories carried out the analyses and reported the results on time and according to the national protocol on neonatal screening.

RIVM rapport:Inleiding. In Nederland worden baby's gescreend voor drie aandoeningen: adrenogenitaal syndroom, congenitale hypothyreoidie en phenylketonurie. Hiertoe wordt bij voorkeur de 4e levensdag en uiterlijk op dag 7 hielprikbloed verzameld op filtreerpapier en geanalyseerd in een van de 5 screeningslaboratoria. De screeningsprocedure is in detail beschreven in het 'Draaiboek neonatale screening'. Om een aantal aspecten van de uitvoering van de hielprik procedure te kunnen evalueren werden van 10.000 setjes demografische en andere gegevens geanalyseerd per categorie uitvoerder van de hielprik, per entadministratie en per laboratorium. Resultaten. 1) Op ongeveer 10% van de setjes ontbrak een of meer van de in te vullen gegevens, zoals: uitvoerder hielprik (3.6%), geboortegewicht (1.3%), zwangerschapsduur (3.6%). 2) Op dag 4 was slechts 50% van de hielprikken uitgevoerd met grote verschillen tussen categorieen uitvoerders; op dag 7 was 98% geprikt. 3) Er was een groot verschil tussen categorie6n uitvoerders in setjes met onvoldoende of onbetrouwbaar bloed (OV): verloskundigen, wijkverpleegkundigen en kraamcentra 0.4%, kraamzorg 0.6%, ziekenhuizen 1.4% en huisartsen 2.3%. De ziekenhuizen voeren slechts 18% van de hielprikken uit, maar zijn verantwoordelijk voor ruim 39% van de OV. 4) De bezorging van de setjes door de TPG-Post laat te wensen over en vooral in de regio's Noord-West en Noord-Oost Nederland. Op dag 3 na de hielprik is slechts 79% van alle setjes in het laboratorium ontvangen. 5) De uitvoering van de analyses en de rapportage van de resultaten door de laboratoria waren adequaat en conform het 'Draaiboek neonatale screening' en conform de afspraken die het RIVM met de screeningslaboratoria heeft gemaakt., In the Netherlands neonates are screened for congenital adrenal hyperplasia, congenital hypothyroidism and phenylketonurea. Blood is collected on filter paper according to the heelstick procedure, preferably the fourth day after birth but at least on the seventh day, and analysed in one of the five screening laboratories. To evaluate the performance of the heelstick procedure, demographic and other data of 10.000 heelstick sets were collected and analysed per category of administrator (performer) of the heelstick procedure, per provincial vaccination administrative body and per screening laboratory for the period of 5 to 20 March 2001. Results: 1) In approximately 10% of the samples one or more of tpieces of important data was/were not provided: performer (3.6%), birth weight (1.3%) and gestational age (3.6%). 2) Only 50% of the heelpricks were carried out on day 4 after birth; the 50% showd large differences between categories of performers. A total of 98% of the heel pricks were performed on day 7. 3) The percentage of samples with 'insufficient' or 'unreliable blood' (UB) varied widely between categories of performers: i.e. midwives, local nurses, 0.4%, maternity care workers, 0.6%, hospitals, 1.4% and general practitioners, 2.3%. Hospitals, performing only 18% of the heel pricks, were responsible for 39% of all UB. 4) Three days after the heelprick, only 79% of all sets had reached the laboratory. Mail delivery by the Dutch postal service was slow, especially in the northwest and northeast region. 5) The laboratories carried out the analyses and reported the results on time and according to the national protocol on neonatal screening.

RIVM rapport:Op initiatief van Prof. J.L. Dhondt (Frankrijk) werd op 13 en 14 januari 1996 een werkgroep bijeengeroepen, bestaande uit wetenschappelijke experts en fabrikanten van kits voor de bepaling van phenylalanine. Het doel van de werkgroep was consensus te bereiken over de wijze waarop bloedvlekkalibratoren voor phenylalanine moeten worden gemaakt. Er bleek een duidelijke behoefte te bestaan aan een 'Europees Standaardpreparaat voor phenylalanine in bloedvlekken'. Deze 'European Working Standard for Phenylalanine in bloodspots' (EWS-Phe-01) werd bereid door het RIVM in Bilthoven. In totaal werden 178 bloedvlekkaarten gemaakt met bloedvlekken waarvan de phenylalanineconcentratie werd vastgesteld op 55, 175, 295, 535 en 775 mumol/l. De lineariteit van de verschillende kalibratoren en de homogeniteit van de batch zijn goed. Uit een bewaarexperiment bij verschillende temperaturen, kan op basis van de tot nog toe verkregen resultaten worden afgeleid, dat de batch tenminste 24 weken stabiel is. Additionele data zullen na 1 en 2 jaar worden verkregen. De drie deelnemende fabrikanten van kits voor de bepaling van phenylalanine hebben inmiddels hun kalibratoren geijkt ten opzichte van de EWS-Phe-01. De voorlopige resultaten zien er veelbelovend uit: de onderlinge verschillen in meetuitkomsten zijn veel kleiner geworden., On initiative of Prof. J.L. Dhondt (France) a workshop with scientific experts and manufacturers of kits for phenylalanine measurement was arranged in Paris on January 13 and 14, 1996. The aim of the meeting was to reach consensus about the way bloodspot calibrators for phenylalanine should be prepared. An urgent need was noted for a 'Standard preparation for phenylalanine in bloodspots' against which manufacturers of kits for phenylalanine could calibrate their own bloodspot calibrators. This 'European Working Standard for Phenylalanine in bloodspots' (EWS-Phe-01) was prepared by the RIVM (Bilthoven). A total of 178 bloodspot cards were prepared with assigned phenylalanine concentrations of 55, 175, 295, 535 and 775 mumol/l. The linearity of the bloodspot calibrators and the homogeneity of the batch were good. Preliminary results of a storage experiment at different temperatures indicate that the bloodspot calibrators are stable for at least 24 weeks. Additional data will be available after 1 and 2 years. The preliminary results of the recalibration of the calibrators for phenylalanine against EWS-Phe-01 by the three participating manufacturers of kits for phenylalanine are very promising: the differences in measuring levels have been very much decreased.

RIVM rapport:Op initiatief van Prof. J.L. Dhondt (Frankrijk) werd op 13 en 14 januari 1996 een werkgroep bijeengeroepen, bestaande uit wetenschappelijke experts en fabrikanten van kits voor de bepaling van phenylalanine. Het doel van de werkgroep was consensus te bereiken over de wijze waarop bloedvlekkalibratoren voor phenylalanine moeten worden gemaakt. Er bleek een duidelijke behoefte te bestaan aan een 'Europees Standaardpreparaat voor phenylalanine in bloedvlekken'. Deze 'European Working Standard for Phenylalanine in bloodspots' (EWS-Phe-01) werd bereid door het RIVM in Bilthoven. In totaal werden 178 bloedvlekkaarten gemaakt met bloedvlekken waarvan de phenylalanineconcentratie werd vastgesteld op 55, 175, 295, 535 en 775 mumol/l. De lineariteit van de verschillende kalibratoren en de homogeniteit van de batch zijn goed. Uit een bewaarexperiment bij verschillende temperaturen, kan op basis van de tot nog toe verkregen resultaten worden afgeleid, dat de batch tenminste 24 weken stabiel is. Additionele data zullen na 1 en 2 jaar worden verkregen. De drie deelnemende fabrikanten van kits voor de bepaling van phenylalanine hebben inmiddels hun kalibratoren geijkt ten opzichte van de EWS-Phe-01. De voorlopige resultaten zien er veelbelovend uit: de onderlinge verschillen in meetuitkomsten zijn veel kleiner geworden., On initiative of Prof. J.L. Dhondt (France) a workshop with scientific experts and manufacturers of kits for phenylalanine measurement was arranged in Paris on January 13 and 14, 1996. The aim of the meeting was to reach consensus about the way bloodspot calibrators for phenylalanine should be prepared. An urgent need was noted for a 'Standard preparation for phenylalanine in bloodspots' against which manufacturers of kits for phenylalanine could calibrate their own bloodspot calibrators. This 'European Working Standard for Phenylalanine in bloodspots' (EWS-Phe-01) was prepared by the RIVM (Bilthoven). A total of 178 bloodspot cards were prepared with assigned phenylalanine concentrations of 55, 175, 295, 535 and 775 mumol/l. The linearity of the bloodspot calibrators and the homogeneity of the batch were good. Preliminary results of a storage experiment at different temperatures indicate that the bloodspot calibrators are stable for at least 24 weeks. Additional data will be available after 1 and 2 years. The preliminary results of the recalibration of the calibrators for phenylalanine against EWS-Phe-01 by the three participating manufacturers of kits for phenylalanine are very promising: the differences in measuring levels have been very much decreased.

RIVM rapport:Op initiatief van Prof. J.L. Dhondt (Frankrijk) werd op 13 en 14 januari 1996 een werkgroep bijeengeroepen, bestaande uit wetenschappelijke experts en fabrikanten van kits voor de bepaling van phenylalanine. Het doel van de werkgroep was consensus te bereiken over de wijze waarop bloedvlekkalibratoren voor phenylalanine moeten worden gemaakt. Er bleek een duidelijke behoefte te bestaan aan een 'Europees Standaardpreparaat voor phenylalanine in bloedvlekken'. Deze 'European Working Standard for Phenylalanine in bloodspots' (EWS-Phe-01) werd bereid door het RIVM in Bilthoven. In totaal werden 178 bloedvlekkaarten gemaakt met bloedvlekken waarvan de phenylalanineconcentratie werd vastgesteld op 55, 175, 295, 535 en 775 mumol/l. De lineariteit van de verschillende kalibratoren en de homogeniteit van de batch zijn goed. Uit een bewaarexperiment bij verschillende temperaturen, kan op basis van de tot nog toe verkregen resultaten worden afgeleid, dat de batch tenminste 24 weken stabiel is. Additionele data zullen na 1 en 2 jaar worden verkregen. De drie deelnemende fabrikanten van kits voor de bepaling van phenylalanine hebben inmiddels hun kalibratoren geijkt ten opzichte van de EWS-Phe-01. De voorlopige resultaten zien er veelbelovend uit: de onderlinge verschillen in meetuitkomsten zijn veel kleiner geworden., On initiative of Prof. J.L. Dhondt (France) a workshop with scientific experts and manufacturers of kits for phenylalanine measurement was arranged in Paris on January 13 and 14, 1996. The aim of the meeting was to reach consensus about the way bloodspot calibrators for phenylalanine should be prepared. An urgent need was noted for a 'Standard preparation for phenylalanine in bloodspots' against which manufacturers of kits for phenylalanine could calibrate their own bloodspot calibrators. This 'European Working Standard for Phenylalanine in bloodspots' (EWS-Phe-01) was prepared by the RIVM (Bilthoven). A total of 178 bloodspot cards were prepared with assigned phenylalanine concentrations of 55, 175, 295, 535 and 775 mumol/l. The linearity of the bloodspot calibrators and the homogeneity of the batch were good. Preliminary results of a storage experiment at different temperatures indicate that the bloodspot calibrators are stable for at least 24 weeks. Additional data will be available after 1 and 2 years. The preliminary results of the recalibration of the calibrators for phenylalanine against EWS-Phe-01 by the three participating manufacturers of kits for phenylalanine are very promising: the differences in measuring levels have been very much decreased.

RIVM rapport:Het gegevensbestand over de periode juni-december 1983 van de screening op CHT binnen het RIVM werd doorzocht op een aantal criteria. Dit omvatte onder andere de categorieen inzenders, de intervallen tussen geboortedatum en prikdatum en tussen prikdatum en bepalingsdatum, en de mate van invullen van formulieren. De voornaamste zijn: 1. De in het Draaiboek aanbevolen termijn van 6e tot 9e levensdag wordt gemiddeld slechts in 60-70% van de geboorten aangehouden. 2. De hielprikkaarten zijn langer onderweg dan nodig is. 3. Het invullen van alle gegevens van de pasgeborene laat te wensen over, met name de zwangerschapsduur wordt zeer vaak niet ingevuld. Hierdoor wordt het functioneren van de gewijzigde procedure bemoeilijkt en neemt de hoeveelheid administratief werk toe.

Het gegevensbestand over de periode juni-december 1983 van de screening op CHT binnen het RIVM werd doorzocht op een aantal criteria. Dit omvatte onder andere de categorieen inzenders, de intervallen tussen geboortedatum en prikdatum en tussen prikdatum en bepalingsdatum, en de mate van invullen van formulieren. De voornaamste zijn: 1. De in het Draaiboek aanbevolen termijn van 6e tot 9e levensdag wordt gemiddeld slechts in 60-70% van de geboorten aangehouden. 2. De hielprikkaarten zijn langer onderweg dan nodig is. 3. Het invullen van alle gegevens van de pasgeborene laat te wensen over, met name de zwangerschapsduur wordt zeer vaak niet ingevuld. Hierdoor wordt het functioneren van de gewijzigde procedure bemoeilijkt en neemt de hoeveelheid administratief werk toe.

RIVM rapport:Het gegevensbestand over de periode juni-december 1983 van de screening op CHT binnen het RIVM werd doorzocht op een aantal criteria. Dit omvatte onder andere de categorieen inzenders, de intervallen tussen geboortedatum en prikdatum en tussen prikdatum en bepalingsdatum, en de mate van invullen van formulieren. De voornaamste zijn: 1. De in het Draaiboek aanbevolen termijn van 6e tot 9e levensdag wordt gemiddeld slechts in 60-70% van de geboorten aangehouden. 2. De hielprikkaarten zijn langer onderweg dan nodig is. 3. Het invullen van alle gegevens van de pasgeborene laat te wensen over, met name de zwangerschapsduur wordt zeer vaak niet ingevuld. Hierdoor wordt het functioneren van de gewijzigde procedure bemoeilijkt en neemt de hoeveelheid administratief werk toe.

RIVM rapport:Het gegevensbestand over de periode juni-december 1983 van de screening op CHT binnen het RIVM werd doorzocht op een aantal criteria. Dit omvatte onder andere de categorieen inzenders, de intervallen tussen geboortedatum en prikdatum en tussen prikdatum en bepalingsdatum, en de mate van invullen van formulieren. De voornaamste zijn: 1. De in het Draaiboek aanbevolen termijn van 6e tot 9e levensdag wordt gemiddeld slechts in 60-70% van de geboorten aangehouden. 2. De hielprikkaarten zijn langer onderweg dan nodig is. 3. Het invullen van alle gegevens van de pasgeborene laat te wensen over, met name de zwangerschapsduur wordt zeer vaak niet ingevuld. Hierdoor wordt het functioneren van de gewijzigde procedure bemoeilijkt en neemt de hoeveelheid administratief werk toe.

Professor Gösta Samuelsons samlade trycksaker; 58

Professor Gösta Samuelsons samlade trycksaker; 38

La fenilcetonuria (PKU) es un error innato del metabolismo que se presenta por una alteración genética, producida por deficiencia de la enzima fenilalanina hidroxilasa (FAH), que como consecuencia genera el acumulo de fenilalanina (FA) en sangre, lo que afecta principalmente el sistema nervioso y deja daños irreversibles. Actualmente se manejan dos tratamientos para esta patología, el primero es farmacológico donde se utiliza la sapropterina, un cofactor de la enzima FAH que se le brinda a pacientes que tienen respuesta a tetrahidrobiopterina (BH4); por lo general las personas que presentan una clasificación leve de PKU tienen una buena respuesta. El segundo tratamiento es el nutricional que tiene como principal objetivo evitar el acumulo de FA en sangre por medio del control del aporte de la proteína de origen natural, lo que requiere la intervención de un Nutricionista Dietista. En ese sentido el objetivo del trabajo fue elaborar un protocolo de valoración y tratamiento nutricional para pacientes con PKU, basado en la revisión de literatura, donde se examinaron artículos, guías y protocolos disponibles. Se encontró que en Colombia no se cuenta con literatura propia para el manejo nutricional de los pacientes con esta patología tan compleja y poco común. Por lo anterior, se elaboraron las fases 1 y 2 para la implementación de un protocolo institucional que brinde herramientas estandarizadas a los profesionales del área de nutrición vinculados con la Clínica de Errores Innatos del metabolismo (CEIM) del Hospital Universitario San Ignacio (HUSI). Además, se elaboró una herramienta de educación nutricional para los pacientes con PKU que consiste en un recetario con diversas preparaciones con un bajo aporte de FA. También se incluyó una clasificación de alimentos en método de semaforización así como una lista de alimentos con el aporte de fenilalanina y Tirosina, para facilitarle al paciente la adherencia al tratamiento. Por medio del protocolo se espera que los Nutric

Aunque actualmente se reconoce que la acumulación de fenilalanina es la causante de los síntomas característicos de la fenilcetonuria (PKU), la relación entre la gravedad de la enfermedad y las concentraciones de aminoácidos aún no se comprenden debido a la falta de modelos experimentales no murinos. Debido a esto, en el presente estudio se caracterizó bioquímica y metabólicamente los fibroblastos gingivales (control) y los fibroblastos PKU para analizar su utilidad como modelo biológico para el estudio de la PKU. Se realizaron curvas de proliferación celular en presencia de tratamientos con exceso de fenilalanina y tirosina, cuantificaciones de los dos aminoácidos evaluados y metabolómica del medio de cultivo por medio de cromatografía de gases asociada a espectrometría de masas (GC/MS). Los resultados obtenidos muestran que los fibroblastos PKU no pueden metabolizar la fenilalanina a tirosina en comparación con los fibroblastos control, lo que resulta en la acumulación intracelular de la fenilalanina y, consecuentemente, a una activación de la ruta alterna del metabolismo de este aminoácido que lleva a la excreción de productos metabólicos propios de esa vía. Adicionalmente, se evidenciaron diferencias en la proliferación celular entre los fibroblastos evaluados, en todos los tratamientos anteriormente mencionados. Lo anterior, sugiere que hay una relación entre el balance de aminoácidos y el funcionamiento de los transportadores LAT1 y LAT2. Por otra parte, se realizó la comparación de los perfiles metabólicos del medio de cultivo de los fibroblastos control y PKU, encontrando que el metabolismo energético se encuentra más favorecido en los fibroblastos gingivales en comparación con los PKU. Teniendo en cuenta los resultados obtenidos, se evidenció que los fibroblastos PKU presentan perfiles bioquímicos y metabólicos similares a los reportados para la enfermedad, lo que permitiría emplearlos como modelo biológico para el estudio de la fenilcetonuria.