***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Summary Background Pre- and postnatal tissue accretion of long-chain polyunsaturated fatty acids ( LCPUFA ) has been related to visual and cognitive development in healthy children in several studies . Children with phenylketonuria ( PKU ) consume diets with very low contents of preformed LCPUFA . We studied prospect ively the LCPUFA status in infants with PKU without or with LCPUFA supplementation during the first year of life . Subjects and methods Infants with PKU were enrolled at diagnosis ( < 4 weeks of age ) and r and omized double blind to phenylalanine-free amino acid supplements without LCPUFA ( n=11 ) or with both arachidonic ( AA , 0.46 wt% ) and docosahexaenoic acids ( DHA , 0.27 wt% ) ( n=10 ) . At enrolment and again at 1 , 2 , 3 , 4 , 6 , 9 and 12 months , plasma phospholipid fatty acids were measured and dietary intakes were calculated from dietary protocol s. Results Unsupplemented patients showed a marked LCPUFA depletion to levels clearly below those observed in healthy breast-fed infants . In contrast , supplemented infants had stable and higher LCPUFA levels than unsupplemented infants , reaching significant differences for AA values at 3 , 4 and 6 months , and for DHA values at 1 , 3 , 4 , 6 , 9 and 12 months . Plasma phospholipid levels correlated closely with estimated dietary intakes of preformed LCPUFA . Conclusion Low LCPUFA intakes with PKU diets induce marked depletion of AA and particularly of DHA in the first year of life . Thus endogenous synthesis of LCPUFA from precursors supplied by diet seems unable to compensate for low LCPUFA intakes . LCPUFA supplementation of PKU diets during the first year of life effectively enhances LCPUFA status to levels comparable to those of healthy breast-fed infants Cognitive and behavioral effects of temporarily challenging the CNS with elevated levels of phenylalanine in treated phenylketonuria ( PKU ) were investigated in a triple-blind , cross-over study . A high phenylalanine supplement was given over 3 months to sixteen 10- to 16-year-old early and continuously treated children with classical PKU . We used the WISC and Rivermead tests to measure cognitive function and the Rutter Scales to assess disordered behavior . Parents and children guessed at the condition imposed . The Group x Phase interaction for phenylalanine level was statistically significant , but this pattern was not mirrored in the psychological test data , and guessing was r and om . Results suggest that intellectual ability , memory , and conduct are not affected by medium-term hyperphenylalaninaemia in PKU after 10 or more years of treatment Mean of median phenylalanine intakes  of 1- to 6-yr-old treated phenylketonuria patients who were growing normally were evaluated by age , sex , and treatment group assignment . Total daily means of median phenylalanine intakes  of subjects in treatment group 1 were significantly different from those of subjects in treatment group 2 except at the median age of 69 months . Total daily phenylalanine intakes varied from 285 + /- 10 to 453 + /- 30 mg ( mean + /- SEM ) by subjects in treatment group 1 . Total daily phenylalanine intakes of subjects in treatment group 2 varied from 349 + /- 12 to 530 + /- 42 mg ( mean + /- SEM ) . Mean , median phenylalanine intakes by males ranged from 30 mg/kg of body weight by the younger to 23 mg/kg of body weight by the older subjects . Means of median phenylalanine intakes of females varied from 32 mg/kg of body weight by the younger to 21 mg/kg of body weight by the older subjects . No child had a median phenylalanine intake below 10 mg/kg of body weight OBJECTIVE To determine the effects of large neutral amino acid ( LNAA ) supplements on brain and plasma phenylalanine ( Phe ) levels and other metabolites in early treated subjects with classical phenylketonuria ( PKU ) , and to investigate the relationship between these metabolites and neuropsychological performance . METHODS This was a prospect i ve , double blind , cross over study consisting of four two-week phases with a 4 week washout period . Sixteen subjects ( 7 males ) , with classical PKU were recruited into the study and completed all 4 phases . Each phase consisted of either the LNAA supplement or placebo , and either the patient 's usual medical product or not . Subjects were instructed to follow their usual Phe restricted diet , maintain energy intake and complete a 3-day food record during each phase . At the end of each phase , brain Phe and other metabolites were measured by proton magnetic resonance spectroscopy ( MRS ) , and plasma amino acids quantified . A detailed neuropsychological assessment was performed on the same day as the MRS and plasma collection . RESULTS There was no correlation between plasma and brain Phe , but few of the plasma Phe readings were over 1200 micromol/L. Plasma Phe decreased with LNAA supplementation when patients were not taking their medical formula . LNAA supplementation had a specific impact on executive functions particularly in verbal generativity and cognitive flexibility . Measures of attention were better on medical product , with or without LNAA supplements . CONCLUSIONS LNAA supplementation was associated with a trend to a lowering of plasma Phe levels .  LNAA supplementation had a specific impact on executive functions particularly in verbal generativity and flexibility . For individuals already complying with diet and PKU medical product , additional supplementation with LNAA is of limited value . LNAA supplementation may be of benefit to those unable to comply with PKU medical product by reducing plasma Phe , perhaps by competing with Phe at the level of transport across the gut Intelligence and achievement test scores were evaluated for 95 12-year-old children with phenylketonuria who had begun dietary therapy during the neonatal period .  Dietary control of blood phenylalanine below 900 mumol/L was maintained beyond age 10 years in 23 children ; 72 others had blood phenylalanine persistently above that level at ages ranging from 18 months to 10 years .  Test scores at age 12 years were negatively correlated with the age at initiation of diet and with blood phenylalanine levels from ages 4 to 10 years , and positively correlated with parent IQ scores and the age at loss of dietary control . Children who maintained phenylalanine levels below 900 mumol/L beyond age 10 years showed no deficits in test scores , except for arithmetic , the scores of which declined between ages 6 and 12 years in 90 % of the children in this study . These data strongly support a recommendation that dietary restriction of phenylalanine should be maintained through adolescence Phenylketonuria provides a human model for the study of the effect of phenylalanine on brain function . Although irreversible mental retardation is preventable through newborn diagnosis and dietary phenylalanine restriction , controversy exists regarding the effects of increased concentrations of phenylalanine in older patients . We have studied ten older , treated , phenylketonuric patients using a triple-blind , multiple trials , crossover design . Each patient was tested at the end of each of three 1-wk periods of high or low phenylalanine intakes . Tests included a repeatable battery of neuropsychological tests , analysis of plasma amino acids , and measurement of urine amino acids , phenyl organic acids , dopamine , and serotonin . In all 10 patients plasma phenylalanine rose ( 900 - 4,000 microM ) . In 9 of 10 patients there was an inverse relationship between plasma phenylalanine and urine dopamine excretion . When blood phenylalanine was elevated , these patients had prolonged performance times on neuropsychological tests of higher but not lower integrative function . Urinary serotonin fell during phenylalanine loading in six patients . The concentration of phenylacids in the urine was not proportional to the plasma phenylalanine at concentrations below 1.5 mM. In one patient , neither performance time nor dopamine excretion varied as blood phenylalanine rose or fell . We interpret these data as follows : blood phenylalanine above 1.3 mM impairs performance on neuropsychological tests of higher integrative function , this effect is reversible , and one mechanism may involve impaired biogenic amine synthesis Aim : To evaluate the effects of phenylalanine (Phe)‐free essential amino acid ( AA ) tablets enriched in tyrosine and tryptophan on the performance of intellectually disabled adult patients with untreated phenylketonuria ( PKU ) . Methods : Phe‐free AA tablets and placebo tablets were administered to 19 untreated PKU subjects on a normal diet for 6 mo in a prospect i ve double‐blinded crossover study . The adaptive behaviour of the patients was tested prior to the study and at 6 and 12 mo after the start , using a simplified version of the Vinel and Adaptive Behaviour Scale . For each sub‐domain , the patients were rated either “ 0 ” ( for poor performance ) or “ 1 ” ( for good performance ) . Neurological signs and symptoms and specific behavioural characteristics were recorded monthly by caretakers . Every 6 mo , neurological examination of the patients was performed , and the caretakers were interviewed . The statistical significance of the results was tested by means of the Fisher 's exact and Wilcoxon tests . Results : The most significant changes were an improved concentration and the development of a meaningful smile , which were observed in 44 % and 43 % of the patients on AA tablet treatment , respectively , but not patients on placebo . Other important but less significant changes included increased awareness of external stimuli ( 63 % ) and less self‐injury ( 43 % ) , and 40 % were smiling and laughing occasionally . The mean overall rating increased from an initial value of 6.3 to 10.1 in patients when on AA tablet treatment ( p=0.002 ) , and to 7.0 in patients when on placebo ( p=0.068 ) . The difference between active AA treatment and placebo was statistically significant ( p=0.027 ) Blood phenylalanine concentrations were experimentally increased for 3 months by means of a phenylalanine-complemented amino acid supplement in a group of 16 children aged 10 - 16 years with classical phenylketonuria who had been treated early and who had remained on the restricted diet . Average concentrations achieved during challenge were between 1000 and 1300 µmol/L. Psychological outcome was measured by a neuropsychological battery consisting of tests of verbal and spatial memory , attention and fine motor coordination . A triple-blind , repeated measures , r and omized , crossover design was adopted to control for practice and expectancy effects . Subjects were assessed at baseline and at the end of the first and second phenylalanine manipulation periods . Significant interactions ( ANOVA ) emerged as predicted for phenylalanine concentrations , but similar crossover effects were not found for any of the neuropsychological tests . The results suggested that medium-term hyperphenylalaninaemia in treated PKU is not harmful to psychological functioning in older children and adolescents who have been continuously treated up to and beyond age 10 years , though the susceptibility of executive functions needs to be further research ed . The findings add some weight to the idea that by late childhood the vulnerability of the nervous system to the neurotoxic influence of phenylalanine may be much reduced Nine adolescents with phenylketonuria ( PKU ) , who had been on unrestricted diets for 2 to 11 years , underwent serial neuropsychological testing over two consecutive 4- to 5-week periods during which each was maintained on a low-phe diet supplemented in a triple-blind fashion either with L-phe ( high phe ) or L-alanine ( low phe ) . Assignment to the initial condition was done r and omly , and the alternate condition was substituted at the end of the first 4- to 5-week period . In 6 of 7 subjects with PKU , baseline median choice reaction times ( RTs ) were slower than those of controls matched for age , sex , h and edness , and Full-Scale IQ ( WISC-R ) . A highly significant improvement occurred during the low-phe phases of the study . Results suggest that adolescents with PKU on unrestricted diets have a neuropsychological deficit that is out of proportion to their overall intellectual h and icap . Moreover , this deficit appears to be at least partly reversible by return to dietary phe restriction despite years of hyperphenylalaninemia ABSTRACT . In a group of 9 patients with classical phenylketonuria ( PKU ) aged 15–24 years we examined the effect of  phenylalanine restricted diet on vigilance , as judged by the continuous visual reaction times , and neurotransmitter synthesis , as judged by cerebrospinal fluid ( CSF ) homovanillic acid ( HVA ) and 5‐hydroxyindole acetic acid ( 5‐HIAA ) levels . HVA and 5‐HIAA levels decreased significantly with increase in plasma phenylalanine concentration on free diet ( p<0.01 and p<0.0005 respectively ) . Vigilance improved on phenylalanine restricted diet in 6 of the 7 patients with abnormally long reaction times on free diet . Addition of tyrosine ( 160 mg/kg/24 h ) to the free diet result ed in an increased HVA/5‐HIAA ratio in CSF in the six patients examined . In 14 patients on free diet supplemented with tyrosine  , 
    Output:
    
The results of non-r and omised studies have concluded that a low-phenylalanine diet is effective in reducing blood phenylalanine levels and improving intelligence quotient and neuropsychological outcomes .