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Metabolický bulletin 01_1

Metabolic Bulletin
January – February 2011
Adherence to Diet and Quality of Life in Patients with Phenylketonuria.3 Dietary Treatment of Phenylketonuria: The Effect of Phenylalanine on Reaction Time.4 L-Phenylalanine Concentration in Blood of Phenylketonuria Patients: A Modified EnzymeColorimetric Assay Compared with Amino Acid Analysis, Tandem Mass Spectrometry, and HplcMethods.5 Generalized Seizures Aggravated by Levetiracetam in an Adult Patient with Phenylketonuria.6 Direct Evidence for a Phenylalanine Site in the Regulatory Domain of Phenylalanine Hydroxylase.7 Transition of Young Adults with Phenylketonuria from Pediatric to Adult Care.8 Phenotyping and Treatment of Phenylketonuria.9 Impact of Metabolic Control on Bone Quality in Phenylketonuria and Mild Hyperphenylalaninemia . 9 Lysosomal Enzyme Activities in Phenylketonuria.9 Bone Impairment in Phenylketonuria Is Characterized by Circulating Osteoclast Precursors andActivated T Cell Increase.10 Evidence That L: -Carnitine and Selenium Supplementation Reduces Oxidative Stress inPhenylketonuric Patients.11 High Phenylalanine Levels Directly Affect Mood and Sustained Attention in Adults withPhenylketonuria: A Randomised, Double-Blind, Placebo-Controlled, Crossover Trial.12 Parenting a Child with Phenylketonuria or Galactosemia: Implications for Health-Related Quality ofLife .13 Mild Hyperphenylalaninemia: To Treat or Not to Treat.14 How Individuals with Phenylketonuria Experience Their Illness: An Age-Related Qualitative Study.15 Experience with Hyperphenylalaninemia in a Developing Country: Unusual Clinical Manifestationsand a Novel Gene Mutation.15 Mental and Motor Development and Psychosocial Adjustment of Chinese Children withPhenylketonuria.16 Complete Restoration of Phenylalanine Oxidation in Phenylketonuria Mouse by a Self-Complementary Adeno-Associated Virus Vector.17 A Cross-Sectional Study of Docosahexaenoic Acid Status and Cognitive Outcomes in Females ofReproductive Age with Phenylketonuria.18 Determination of Unconjugated Aromatic Acids in Urine by Capillary Electrophoresis with DualElectrochemical Detection - Potential Application in Fast Diagnosis of Phenylketonuria.19 ADHERENCE TO DIET AND QUALITY OF LIFE IN PATIENTS WITH

Cotugno G; Nicolo R; Cappelletti S; Goffredo B; Dionisi Vici C; Di Ciommo V Acta Paediatr*Division of Metabolic Diseases Bambino Gesu Children's Hospital-- Rome --Italy Division of ChildNeuropsichiatry -- Bambino Gesu Children's Hospital -- Rome --Italy-- Laboratory of Biochemistry --Bambino Gesu Children's Hospital-- Rome --Italy Epidemiology Unit Bambino Gesu -- Children'sHospital -Rome-- Italy AIM: To investigate adherence to dietary treatment and quality of life in patients with
METHODS: In the setting of a tertiary paediatric hospital 41 early--treated patients affected by
phenylketonuria aged more than 3--years--old were enrolled in a cross--sectional study . Three--
days dietary assessment, quality of life questionnaires for patients less than 18 years-old (Child
Health Questionnaire), and Short Form for adults were completed.
RESULTS: Out of 41 patients, 23 (56.1%) were considered adherent to the dietary prescriptions
as their phenylalanine intake was less than prescribed. Phenylalanine intake was significantly inexcess of prescribed if mothers had a lower level of education. Adherence was not correlated withage. Metabolic control was obtained in 41.5-51.2% of the patients depending on the target. Qualityof Life was reduced in children and adolescents. There was no significant correlation betweenadherence and quality of life, except for the domains of Global Health and Family Activities (rho=0.42 and 0.46, respectively). The overall agreement between adherence and metabolic controlvaried according to different targets of metabolic control (51.2-65.9%). CONCLUSIONS: It is necessary to improve the adherence to diet and the Quality of Life in
children and adolescents affected by phenylketonuria.

Dawson C; Murphy E; Maritz C; Chan H; Ellerton C; Carpenter RH; Lachmann RH J Inherit Metab Dis*Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, Box 92, QueenSquare, London, WC1N 3BG, UK ABSTRACT
There is no evidence that high phenylalanine (Phe) levels have irreversible effects on the adultbrain. Many adults with phenylketonuria (PKU) no longer follow a protein-restricted diet.
Neuropsychological studies have shown that reaction time in adults with PKU is slower thancontrols. There are no data to show that this is directly related to Phe levels. Another way to assessreaction time is to measure saccadic latency. We have used a portable, head-mountedsaccadometer to measure latency in the outpatient setting. Patients with PKU were split into threegroups: off-diet (Phe>1,200 mumol/l), on-diet (Phe <800 mumol/l) and maternal diet (Phe 100-400 mumol/l ). Reciprocal median latency (RML) was compared between groups. Latency wassignificantly slower in patients who were off-diet than in patients on-diet, on a maternal diet or innormal controls. Reaction times in both diet-treated groups were not significantly different fromnormal controls. In 16 women planning pregnancy we obtained values before and after theycommenced the maternal diet. Stricter control of Phe levels resulted in a significant improvement inreaction times. We conclude that saccadometry is useful in monitoring PKU patients. Adult patientswith PKU not on a protein-restricted diet have significantly slower reaction times than controls. Inaddition, off-diet patients have significantly slower reaction times than on-diet. Paired data showthat effects of Phe levels on reaction time are reversible.

De Silva V; Oldham CD; May SW Clin Chem Lab Med 48(9): 1271-9*School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332, USA BACKGROUND: Phenylketonuria (PKU) is an autosomal recessive disorder caused by an impaired
conversion of L-phenylalanine (Phe) to L-tyrosine, typically resulting from a deficiency in activity ofa hepatic and renal enzyme L-phenylalanine hydroxylase. The disease is characterized by anincreased concentration of Phe and its metabolites in body fluids. METHODS: A modified assay based on an enzymatic-colorimetric methodology was developed for
measuring blood Phe levels in PKU patients; this method is designed for use with undeproteinized
samples and avoids the use of solvents or amphiphilic agents. Thus, the method could be suitable
for incorporation into a simple home-monitoring device.
RESULTS: We report here on a comparison of blood Phe concentrations in PKU patients measured
in undeproteinized plasma using this enzyme colorimetric assay (ECA), with values determined by
amino acid analysis (AAA) of deproteinized samples, and HPLC and tandem mass spectrometry
(MS/MS) analyses of dried blood spot (DBS) eluates. Pearson correlation coefficients of 0.951,
0.976 and 0.988 were obtained when AAA-measured Phe concentrations were compared with the
ECA-, HPLC- or MS/MS-measured values, respectively. A Bland-Altman analysis revealed that mean
Phe concentrations determined using AAA were on average 65 mumol/L lower than values
measured by our ECA. These results may be the result of minimizing the manipulations performed
on the patient sample compared with AAA, HPLC, and MS/MS methods, which involve plasma
deproteinization or DBS elution and derivatization.
CONCLUSIONS: The results reported here confirm that Phe concentrations determined by our
ECA method are comparable to those determined by other widely used methods for a broad rangeof plasma Phe concentrations.

Dericioglu N; Saygi S Metab Brain Dis 25(2): 207-9*Institute of Neurological Sciences and Psichiatry, Hacettepe University, Ankara, Turkeynesedericioglu@yahoo.com ABSTRACT
Phenylketonuria (PKU) is one of the most common inherited metabolic disorders, which ischaracterized by excessive accumulation of phenylalanine (Phe) in tissues. Generalized seizuresoccur in 25% of the patients. Little is known about seizures and their treatment in adult PKUpatients, and information with newer antiepileptic drugs is lacking. Here we report an adult patientwho developed generalized seizures later in life, despite strict dietary control, and whose seizureswere aggravated by levetiracetam (LEV). Convulsions ceased after discontinuation of LEV and thepatient has been seizure free on topiramate 125 mg/day.

Li J; Ilangovan U; Daubner SC; Hinck AP; Fitzpatrick PF Arch Biochem Biophys 505(2): 250-5*Department of Biochemistry and Biophysics, Texas A&M University, College Station, 77843-2128,United States ABSTRACT
The hydroxylation of phenylalanine to tyrosine by the liver enzyme phenylalanine hydroxylase isregulated by the level of phenylalanine. Whether there is a distinct allosteric binding site forphenylalanine outside of the active site has been unclear. The enzyme contains an N-terminalregulatory domain that extends through Thr117. The regulatory domain of rat phenylalaninehydroxylase was expressed in Escherichia coli. The purified protein behaves as a dimer on a gelfiltration column. In the presence of phenylalanine, the protein elutes earlier from the column,consistent with a conformational change in the presence of the amino acid. No change in elution isseen in the presence of the non-activating amino acid proline. (1)H-(1)N HSQC NMR spectra wereobtained of the (1)N-labeled protein alone and in the presence of phenylalanine or proline. Asubset of the peaks in the spectrum exhibits chemical shift perturbation in the presence ofphenylalanine, consistent with binding of phenylalanine at a specific site. No change in the NMRspectrum is seen in the presence of proline. These results establish that the regulatory domain ofphenylalanine hydroxylase can bind phenylalanine, consistent with the presence of an allosteric sitefor the amino acid.

Mutze U; Roth A; Weigel JF; Beblo S; Baerwald CG; Buhrdel P; Kiess WJ Inherit Metab Dis*University Hospital for Children and Adolescents, University Hospital, University of Leipzig,Liebigstrasse 20 a, 04103, Leipzig, Germany, Ulrike.Muetze@medizin.uni-leipzig.de BACKGROUND: Transition from pediatric to adult health care is a particularly vulnerable period
forpatients with inborn metabolic diseases. Aim of the present study was to evaluate the current
transition situation of patients with phenylketonuria (PKU) in Leipzig, Germany, by analysis of the
medical care, metabolic control, patients' satisfaction, socio-economic and psychosocial status, in
order to identify areas of weakness and potential improvement.
METHODS: Patients who had been transferred from pediatric to adult medical care between 2005
and 2008 were identified. An interview was performed using a questionnaire. Pediatric case notes
and the present physician's case notes were analyzed retrospectively. Socio-demographic data
were compared to data derived from the annual statistics of the city of Leipzig, Germany in 2008.
RESULTS: seventy two transferred patients were identified and included in the study, 48 patients
responded to the questionnaire, the data of 24 non-responders were analysed retrospectively.
About 90% of the responding patients with PKU were satisfied with the current transition situation.
However, they agreed to several suggestions of improvement. Most specifically an interdisciplinary
appointment before the definite transfer to the adult clinics was asked for. At the time of transition,
most of the patients were in good metabolic control according to current treatment guidelines
(median dried blood phenylalanine concentration 853 mumol/l before versus 690 mumol/l after
transition). Of the interviewed patients 92% were still on a low phenylalanine diet in combination
with the intake of a phenylalanine free amino acid mixture. Of the interviewees 77% carried a
secondary school certificate or a secondary modern school qualification, but only 19% had
achieved senior high school diploma (controls 38.2%). Marital status was comparable with the
population of Leipzig. However, fewer patients with PKU had children (15% versus 37%).
CONCLUSION: Transition of patients with PKU from pediatric to adult care seems to be successful
in Leipzig. Patients were mostly satisfied with the transition situation. Still, some suggestions for
improvements appeared to be desirable. During transition medical care and metabolic control were
stable. However, with regard to psychosocial and socioeconomic data differences to the control
population were detected.
Porta F; Mussa A; Garelli D; Spada M Lancet 377(9764): 465; author reply 466 IMPACT OF METABOLIC CONTROL ON BONE QUALITY IN

Porta F; Mussa A; Zanin A; Greggio NA; Burlina A; Spada M J Pediatr Gastroenterol Nutr 52(3): 345-50*Department of Pediatrics, University of Torino, Torino, Italy daggerUnita Operativa ComplessaMalattie Metaboliche Ereditarie, Italy double daggerUOC di Endocrinologia Pediatrica, Dipartimentodi Pediatria, Azienda Ospedaliera Universita di Padova, Padova, Italy OBJECTIVES: A reduction of bone mineral density of unknown etiology has been reported in
phenylketonuria (PKU) by radiological techniques, whereas no data on bone density in mildhyperphenylalaninemia (HPA) are available. We aimed to assess bone condition in PKU and HPA byquantitative ultrasound (QUS), taking into account patients' clinical and biochemical features. PATIENTS AND METHODS: Phalangeal QUS has been used for bone assessment in 78 patients
affected by PKU (n = 42) or mild HPA (n = 36). For each patient, blood phenylalanine
concentrations in the 2 years before the study have been recorded and related to bone
RESULTS: Overall normal bone quality has been observed in the whole study group (AD-SoS
standard deviation score [SDS] 0.25 +/- 1.29; BTT SDS -0.13 +/- 1.08). PKU adolescents (age
older than 15 years, AD-SoS SDS -0.54 +/- 1.33; BTT SDS -0.85 +/- 1.21) and patients with poor
compliance with treatment (blood phenylalanine >10 mg/dL, AD-SoS SDS -0.47 +/- 1.39; BTT SDS
-0.97 +/- 1.14) showedlower BTT SDS with respect to normal population (P = 0.003 and P <
0.001, respectively). Patients with PKU with good compliance with treatment (blood phenylalanine
< 10 mg/dL, AD-SoS SDS 0.65 +/- 1.33; BTT SDS 0.15 +/- 0.94) and patients with mild HPA (AD-
SoS SDS 0.44 +/- 1.06 and BTT SDS 0.19 +/- 0.85) showed normal bone mineral density and
cortical thickness.
CONCLUSIONS: Good compliance with treatment in PKU during adolescence and adulthood is
desirable because diet discontinuation is associated with bone loss. Mild HPA seems not to be
complicated by bone damage.
Porta F; Pagliardini S; Pagliardini V; Dotta A; Mussa A; Spada M Mol Genet Metab BONE IMPAIRMENT IN PHENYLKETONURIA IS CHARACTERIZED BY

Roato I; Porta F; Mussa A; D'Amico L; Fiore L; Garelli D; Spada M; Ferracini R PLoS One 5(11): e14167*Center for Experimental Research and Medical Studies, A.O.U. San Giovanni Battista, Torino, Italyroato78@libero.it BACKGROUND: Phenylketonuria (PKU) is a rare inborn error of metabolism often complicated by
a progressive bone impairment of uncertain etiology, as documented by both ionizing and non-
ionizing techniques.
METHODOLOGY: Peripheral blood mononuclear cell (PBMC) cultures were performed to study
osteoclastogenesis, in the presence or absence of recombinant human monocyte-colony stimulatingfactor (M-CSF) and receptor activator of NFkappaB ligand (RANKL). Flow cytometry was utilized toanalyze osteoclast precursors (OCPs) and T cell phenotype. Tumour necrosis factor alpha (TNF-alpha), RANKL and osteoprotegerin (OPG) were quantified in cell culture supernatants by ELISA.
The effects of RANKFc and anti-TNF-alpha antibodies were also investigated to determine theirability to inhibit osteoclastogenesis. In addition, bone conditions and phenylalanine levels in PKUpatients were clinically evaluated. PRINCIPAL FINDINGS: Several in vitro studies in PKU patients' cells identified a potential
mechanism of bone formation inhibition commonly associated with this disorder. First, PKU patientsdisclosed an increased osteoclastogenesis compared to healthy controls, both in unstimulated andM-CSF/RANKL stimulated PBMC cultures. OCPs and the measured RANKL/OPG ratio were higher inPKU patients compared to healthy controls. The addition of specific antagonist RANKFc causedosteoclastogenesis inhibition, whereas anti-TNF-alpha failed to have this effect. Among PBMCsisolated from PKU patients, activated T cells, expressing CD69, CD25 and RANKL.

Sitta A; Vanzin CS; Biancini GB; Manfredini V; de Oliveira AB;Wayhs CA; Ribas GO; Giugliani L;Schwartz IV; Bohrer D; Garcia SC; Wajner M; Vargas CR Cell Mol Neurobiol*Servico de Genetica Medica, HCPA, UFRGS, Rua Ramiro Barcelos, 2350, Porto Alegre, RS, 90035-903, Brazil, angelasitta@yahoo.com.br ABSTRACT
It is well established that the involvement of reactive species in the pathophysiology of severalneurological diseases, including phenylketonuria (PKU), a metabolic genetic disorder biochemicallycharacterized by elevated levels of phenylalanine (Phe). In previous studies, we verified that PKUpatients (treated with a protein-restricted diet supplemented with a special formula not containingL: -carnitine and selenium) presented high lipid and protein oxidative damage as well as areduction of antioxidants when compared to the healthy individuals. Our goal in the present studywas to evaluate the effect of Phe-restricted diet supplemented with L: -carnitine and selenium, twowell-known antioxidant compounds, on oxidative damage in PKU patients. We investigated variousoxidative stress parameters in blood of 18 treated PKU patients before and after 6 months ofsupplementation with a special formula containing L: -carnitine and selenium. It was verified thattreatment with L: -carnitine and selenium was capable of reverting the lipid peroxidation, measuredby thiobarbituric acid-reactive species, and the protein oxidative damage, measured by sulfhydryloxidation, to the levels of controls. Additionally, the reduced activity of glutathione peroxidase wasnormalized by the antioxidant supplementation. It was also verified a significant inverse correlationbetween lipid peroxidation and L: -carnitine blood levels as well as a significant positive correlationbetween glutathione peroxidase activity and blood selenium concentration. In conclusion, ourresults suggest that supplementation of L: -carnitine and selenium is important for PKU patientssince it could help to correct the oxidative stress process which possibly contributes, at least inpart, to the neurological symptoms found in phenylketonuric patients.

Ten Hoedt AE; de Sonneville LM; Francois B; ter Horst NM; Janssen MC; Rubio-Gozalbo ME;Wijburg FA; Hollak CE; Bosch AM J Inherit Metab Dis 34(1): 165-71*Department of Pediatrics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands ABSTRACT
The main debate in the treatment of Phenylketonuria (PKU) is whether adult patients need thestrict phenylalanine (Phe)-restricted diet. Physicians and patients lack evidence-based guidelines tohelp them make well-informed choices. We have carried out the first randomised double-blindplacebo-controlled trial into the effects of short-term elevation of Phe levels on neuropsychologicalfunctions and mood of adults with PKU. Nine continuously treated adults with PKU underwent two4-week supplementation periods: one with Phe, mimicking normal dietary intake, and one withplacebo in randomly allocated order via a randomisation coding list in a double-blind cross-overdesign. A set of neuropsychological tests (Amsterdam Neuropsychological Tasks) was administeredat the end of each study period. In addition, patients and for each patient a friend or relative,completed weekly Profile of Mood States (POMS) questionnaires, evaluating the patients' mood.
Phe levels were measured twice weekly. Mean plasma Phe levels were significantly higher duringPhe supplementation compared with placebo (p = 0.008). Neuropsychological tests demonstratedan impairment in sustained attention during Phe supplementation (p = 0.029). Both patients andtheir friend or relative reported lower scores on the POMS questionnaires during Phesupplementation (p = 0.017 and p = 0.040, respectively). High plasma Phe levels have a directnegative effect on both sustained attention and on mood in adult patients with PKU. A Phe-restricted "diet for life" might be an advisable option for many.

Ten Hoedt AE; Maurice-Stam H; Boelen CC; Rubio-Gozalbo ME; van Spronsen FJ; Wijburg FA;Bosch AM; Grootenhuis MA J Inherit Metab Dis*Department of Pediatrics (H7-270), Academic Medical Center, University of Amsterdam,Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands ABSTRACT
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 disorderreported an even lower HRQoL than parents of children with other chronic disorders. Possibly, theuncertainty about the course of the disease and the limited life expectancy in many metabolicdisorders are important factors in the low parental HRQoL. Therefore, we performed a cross-sectional study in parents of children with phenylketonuria (PKU, OMIM #261600) andgalactosemia (OMIM #230400), metabolic disorders not affecting life expectancy, in order toinvestigate their HRQoL compared to parents of healthy children and to parents of children withother metabolic disorders. A total of 185 parents of children with PKU and galactosemia aged 1-19years completed two questionnaires. Parents of children with PKU or galactosemia reported aHRQoL comparable to parents of healthy children and a significantly better HRQoL than parents ofchildren with other metabolic disorders. Important predictors for parental mental HRQoL were thepsychosocial factors emotional support and loss of friendship. As parental mental functioninginfluences the health, development and adjustment of their children, it is important that treatingphysicians also pay attention to the wellbeing of the parents. The insight that emotional supportand loss of friendship influence the HRQoL of the parents enables treating physicians to providebetter support for these parents.
van Spronsen FJ J Inherit Metab Dis*Beatrix Children's Hospital, Groningen, Netherlands, f.j.van.spronsen@bkk.azg.nl ABSTRACT
One of the issues to be resolved in phenylketonuria is whether patients with mildhyperphenylalaninemia need treatment, or in other words, in what patients treatment needs to bestarted. Do patients need treatment when phenylalanine concentrations in blood are >360mumol/L or >600 mumol/L? This paper reviews the literature on the outcome of untreated patientswith mild hyperphenylalaninemia to try to determine whether outcome is normal. The paperconcludes that there is, in fact, only one paper that can be used to answer this question. Therefore,the question is whether we may rely on one paper to draw conclusions or whether more research isnecessary to determine whether all patients with phenylalanine concentrations >360 mumol/L or allpatients with phenylalanine concentrations >600 mumol/L require treatment.

Vegni E; Fiori L; Riva E; Giovannini M; Moja EA Child Care Health Dev 36(4): 539-48*Chair of Medical Psychology, San Paolo Hospital, University of Milan, Milan, Italyelena.vegni@unimi.it BACKGROUND: The aim of the study was to explore the illness experience of individuals affected
by phenylketonuria (PKU) and its differences in different patient age groups.
METHODS: A qualitative-interpretative methodology was used through in-depth interviews.
Textual data were explored using the principles of grounded theory.
RESULTS: Forty-seven patients participated in the study, aged from 10 to >25 years old. The
results suggested the age-related PKU experience: (1) a paradox, either to feel normal but isolated
from the social context, or to be different while participating in the convivial aspects of the social
being; and (2) the need for education about the disease tailored to the individual and growing
needs. Specific themes seem to characterize each age range.
CONCLUSIONS: This study constitutes a first attempt at understanding PKU from a non-medical-
biological perspective.

Vela-Amieva M; Ibarra-Gonzalez I; Fernandez-Lainez C; Monroy-Santoyo S J Child Neurol 26(2): 260 MENTAL AND MOTOR DEVELOPMENT AND PSYCHOSOCIAL ADJUSTMENT

Wu W; Sheng D; Shao J; Zhao Z J Paediatr Child Health*Children's Hospital, Zhejiang University School of Medicine, 57 Zhugan Xiang, Hangzhou,Zhejiang, China Aim: This study was designed to evaluate mental and motor development, psychosocial
adjustment (temperament and behavioural problems) in children with phenylketonuria (PKU).
Methods: Twenty-eight Chinese children aged from three to 36 months with early-treated PKU
were evaluated by Bayley Scales of Infant Development (BSID), Peabody Developmental Motor
Scale (PDMS-II), Toddler Temperament Questionnaire (TTQ) and Achenbach's Child Behavior
Checklist (CBCL). The related factors, including blood phenylalanine (Phe) levels, and the socio-
economic status (SES) of the children's family were also explored.
Results: In comparison with healthy control, early-treated PKU children showed no delay in the
mental and motor development. However, they presented higher levels on four of the nine
temperamental dimensions (higher level in activity, more intense in reaction, more negative mood
and more distraction). They also had more behavioural problems in depression, aggression and
destructibility. A lower Phe level and a higher SES of children's family showed a positive effect on
development index, temperamental characteristics and behavioural problems.
Conclusion: Early-treated PKU children were normal in the mental and motor development.
However, they presented higher level on four of the nine temperamental dimensions and had morebehavioural problems. Paediatric control combined with psycho-counselling was suggested foryoung PKU children.

Yagi H; Ogura T; Mizukami H; Urabe M; Hamada H; Yoshikawa H; Ozawa K; Kume A J Gene Med*Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University,Shimotsuke, Japan; Department of Obstetrics and Gynecology, Institute of Clinical Medicine,University of Tsukuba, Tsukuba, Japan BACKGROUND: Classical phenylketonuria (PKU) arises from a deficiency of phenylalanine
hydroxylase (PAH) that catalyzes phenylalanine (Phe) oxidation in the liver. Lack of PAH activity
causes massive hyperphenylalaninemia and consequently severe brain damage. Preclinical studies
showed that conventional adeno-associated virus (AAV) vectors could correct
hyperphenylalaninemia in a mouse model of PKU, while limitations such as very large dose
requirement and relative inefficiency in female animals were recognized.
METHODS: An AAV8-pseudotyped vector was constructed with a self-complementary AAV (scAAV)
genome for efficient liver transduction and expression. Following vector injection to PKU mice,blood Phe was periodically measured by an enzymatic fluorometric assay. In vivo Phe oxidation wasevaluated by a noninvasive breath test using [1-(13) C]Phe. Vector copy number in the host tissueswas determined by quantitative polymerase chain reaction. RESULTS: A single injection of 1 x 10(11) - 1 x 10(12) particles of the scAAV8 vector resulted in
reduction of blood Phe to normal or near-normal level for more than 1 year in both genders. Thetreated animals showed normal level of in vivo Phe oxidation. The presence of > 1 copy of vectorDNA per diploid genome in the liver was associated with normal blood Phe in the AAV-treated PKUmice. CONCLUSION: Complete phenotypic correction of PKU mice was achieved by the scAAV8 vector
for the longest duration reported to date. The vector overcame the female-specific disadvantage inAAV-mediated liver transduction, thus it offers a promising platform of long-lasting gene therapyfor PKU. Copyright (c) 2011 John Wiley & Sons, Ltd.

Yi SH; Kable JA; Evatt ML; Singh RH J Inherit Metab Dis*Nutrition & Health Sciences Program of the Graduate Division of Biological & Biomedical Sciences,Emory University, Atlanta, GA, USA ABSTRACT
Diet therapy for phenylketonuria (PKU) requires restricted phenylalanine (Phe) intake, with themajority of protein and other nutrients coming from synthetic medical food. The fatty aciddocosahexaenoic acid (DHA) is important in brain development and function; however, there arereports of low blood DHA concentrations in people treated for PKU. Although the implications ofthis low blood DHA are unclear, subtle cognitive deficits have been reported in those treated earlyand continuously for PKU. For this study, we investigated the relationship between DHA status andcognitive performance in 41 females 12 years and older with PKU. Participants were attending thebaseline visit of a research-based camp or a supplementation trial. We assessed the domains ofverbal ability, processing speed, and executive function using standardized tests, and theproportions of DHA in plasma and red blood cell (RBC) total lipids using gas chromatography/massspectrometry. Percent plasma and RBC total lipid DHA were significantly lower in the participantscompared with laboratory controls (P < .001), and participants consumed no appreciable DHAaccording to diet records. Plasma and RBC DHA both negatively correlated with plasma Phe (P < .
02), and performance on the verbal ability task positively correlated with RBC DHA controlling forplasma Phe (R = .32, P = .03). The relationship between DHA and domains related to verbalability, such as learning and memory, should be confirmed in a controlled trial. Domains ofprocessing speed and executive function may require a larger sample size to clarify any associationwith DHA.

Zhang DL; Li WL; Zhang JB; Tang WR; Chen XF; Cao KW; Chu QC; Ye JN Electrophoresis 31(17): 2989-96*Department of Chemistry, East China Normal University, Shanghai, P. R. China ABSTRACT
A novel method of CE coupled with dual electrochemical detection has been developed for thedetermination of pathological metabolites of phenylalanine in urine samples. Factors influencing theseparation and detection were examined and optimized. Five aromatic acid metabolites and amajor coexisting interfering compound uric acid could be well separated within 23 min at aseparation voltage of 16 kV using a 35 mmol/L SDS/60 mmol/L H(3)BO(3)-Na(2)B(4)O(7) runningbuffer (pH 8.2). Highly linear response was obtained for these five biomarker compounds overthree orders of magnitude with detection limits ranging from 6.6 to 0.064 mug/mL (S/N=3). Theaverage recovery and RSD were within the range of 92.6-121.0 and 1.0-12.0%, respectively. Theproposed method has been used to detect the unconjugated aromatic acids simultaneously in urinesamples with the advantages of obtaining more information about target analytes and avoidingredundant measurements and high assay cost, thus could find potential applications involvingassays of biomarker compounds for the purpose of fast diagnose of some metabolic diseasesincluding phenylketonuria.

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