Blood-brain barrier phenylalanine transport and individual vulnerability in phenylketonuria

In vivo nuclear magnetic resonance spectroscopy can be used to measure intracerebral phenylalanine (Phe) concentrations in patients with phenylketonuria (PKU). Stationary levels, obtained under free nutrition, as well as time courses after an oral Phe load (100 mg/kg) were investigated in 11 PKU patients and were correlated with the individual clinical outcome. At blood levels around 1.2 mmol/L, brain Phe was 0.41 to 0.73 mmol/L in clinically "typical" patients, but less than 0.15 mmol/L in three untreated, normally intelligent, adult women. Kinetic investigations revealed higher transport Michaelis constants and lower ratios of the brain influx and consumption rates in these women than in the "typical" control patients (Kt,app = 0.45 to 1.10 mmol/L versus 0.10 mmol/L; T(max)/v(met) = 2.55 to 3.19 versus 7.8 to 14.0). Such variations seem to be major causative factors for the individual vulnerability to PKU.     

Use of phenylalanine-to-tyrosine ratio determined by tandem mass spectrometry to improve newborn screening for phenylketonuria of early discharge specimens collected in the first 24 hours

We compared the screening interpretation of fluorometric analytical results for phenylketonuria (PKU) with tandem mass spectrometry (MS/MS) in filter paper blood spots collected from newborns <24 h of age. In MS/MS, both Phe and Tyr are quantified. Two hundred and eight blood spots collected from infants <24 h of age were retrieved from storage from the California newborn screening program. These samples had been categorized on the basis of fluorometric analysis as initial negative, initial positive for hyperphenylalaninemia with negative determination on recall, or initial positive for hyperphenylalaninemia and confirmed on follow up as PKU or variant hyperphenylalaninemia. The retrieved samples were analyzed in a blinded fashion using MS/MS. Correlation analysis of fluorometry vs MS/MS for Phe concentration was high, with a Pearson correlation coefficient of 0.817. When 180 micromol/L was used as the cutoff Phe concentration for MS/MS and 258 micromol/L was used as the cutoff for fluorometry, all infants with confirmed classical PKU and variant hyperphenylalaninemia were detected. MS/MS analysis reduced the number of false-positive results from 91 to 3. Simultaneous quantification of Phe and Tyr by MS/MS with the use of a cutoff Phe/Tyr molar ratio of 2.5 further reduced the number of false positives to 1. Samples from affected infants showed a discernible trend of increasing Phe concentration and Phe/Tyr molar ratio with age of collection. These results demonstrate the utility of MS/MS in the routine PKU screening of early-discharge newborns. MS/MS reduces the false-positive rate of fluorometric screening almost 100-fold because of the improved accuracy and precision of Phe measurement and simultaneous confirmation with the Phe/Tyr molar ratio. In addition to the detection of PKU, MS/MS can also detect other aminoacidopathies and disorders of fatty acid and organic acid metabolism with lower false-positive rates than other methods currently used in newborn screening programs.     

The IQ of heterozygotes for phenylketonuria (PKU). indication of a blood phenylalanine-independent action of the PKU mutant (author's transl)

The IQ of parents of phenylketonuria-(PKU-)affected children is lower than that of parents with histidinemia-affected children (control group). The difference arises almost entirely from the verbal part of the Hamburg-Wechsler test. The IQ of the parents with histidinemia-affected children shows the same distribution as that of the normal population; heterozygosity for this condition does not appear to confer any intellectual advantage. In PKU patients treated at an early age and apparently adequately, a slight, but significant decrease in IQ becomes apparent between the ages of 6 and 8 years. This slight decrease also refers mainly to the verbal IQ. At 4 years of age all PKU patients are tested with Bühler-Hetzer, as well as the Kramer test. There is a significant difference between the results in favour of the Bühler-Hetzer test, which is much less verbal. Since heterozygotes for PKU never show elevated blood phenylalanine levels and, moreover, prenatal tyrosine deficiency, as argued by others, seems highly improbable, it is supposed that the PKU gene has a more direct influence on certain ganglion cells at least, with a consequent slight, but significant lowering of the verbal IQ in heterozygotes and satisfactorily-treated homozygotes for PKU. A slightly increased intracellular phenylalanine concentration in heterozygotes and apparently adequately-treated homozygotes need not to be reflected in raised blood levels and this could be an explanation for the observed IQ lowering. But it should not be overlooked that by far the greatest part of damage in PKU patients is caused by chronic phenylalanine poisoning which is well preventable by correct dietary treatment.     

Biotin recycling impairment in phenylketonuric children with seborrheic dermatitis

OBJECTIVE: To investigate the effect of a therapeutic diet on serum biotin levels and to explain the seborrheic dermatitis in phenylketonuric (PKU) patients on a "loose" diet. DESIGN: Forty-seven patients were divided into two groups: group A (n=21) demonstrated good compliance to a special diet and group B (n=26) were on a "loose" diet. Most of the patients in group B (20/26), who suffered from mild seborrheic dermatitis, were requested to return to phenylalanine (Phe)-restricted diet for at least 15 days. Seventy-nine healthy children of comparable age were used as controls. Biotin serum levels and plasma biotinidase activity were measured in patients as well as controls. In addition, biotinidase activity was evaluated in vitro after incubation with various concentrations of Phe. RESULTS: Biotin levels in group A patients (636+/-118 ng/L) were statistically significantly elevated (P < 0.01) compared with those of group B patients before (412+/-184 ng/L) and after (501+/-160 ng/L) 15 days on a Phe-restricted diet, as well as with those of controls (337+/-290 ng/L). Furthermore, biotinidase activities were decreased in group B patients (4.2+/-1.68 nmol/min/L) compared with those of group A patients (6.4+/-0.7 nmol/min/L) and controls (6.10+/-0.8 nmol/min/L). Additionally, biotinidase activities in the patients of group B were restored to normal (5.78+/-0.81 nmol/min/L), with a simultaneous remission of their skin lesions, after 15 days on a Phe-restricted diet. Moreover, the in vitro findings showed a 51% inhibition of biotinidase activity when incubated with Phe (20 mg/dL). CONCLUSIONS: It is suggested that the high biotin levels in group A patients reflect the intake of water-soluble biotin of vegetable origin. In contrast, the low biotinidase activity in group B patients may be attributed to their high Phe plasma levels, which acts as an enzyme inhibitor, as shown by the in vivo and in vitro results. Consequently, the observed seborrheic dermatitis in PKU children (group B) is associated with an impairment of biotin recycling.     

Hyperhomocysteinemia and atherosclerotic vascular disease: pathophysiology, screening, and treatment. off

Hyperhomocysteinemia has recently been identified as an important risk factor for atherosclerotic vascular disease. This article reviews homocysteine metabolism, causes of hyperhomocysteinemia, the pathophysiological findings of this disorder, and epidemiological studies of homocysteine and vascular disease. Screening for hyperhomocysteinemia should be considered for patients at high risk for vascular disease or abnormalities of homocysteine metabolism. For primary prevention of vascular disease, treatment of patients with homocysteine levels of 14 micromol/L or higher should be considered. For secondary prevention, treatment of patients with homocysteine levels of 11 micromol/L or higher should be considered. Treatment is most conveniently administered as a folic acid supplement (400-1000 microg) and a high-potency multivitamin that contains at least 400 microg of folate. Higher doses of folic acid and cyanocobalamin supplements may be required in some patients. Until prospective clinical trial data become available, these conservative recommendations provide a safe, effective, and evidence-based approach to the diagnosis, evaluation, and management of patients with hyperhomocysteinemia.     

Mutation of the phenylalanine hydroxylase gene in the population of central Bohemia. Relation to the clinical picture of phenylketonuria

BACKGROUND: Phenylketonuria (PKU) is an autosomal recessive, disease, heterogeneous at the molecular level, caused by mutations in the gene of phenylalanine hydroxylase (PAH). The objective of the present work was to identify mutations and their frequency in the Central Bohemian and Prague population in relation to the clinical phenotype. METHODS AND RESULTS: The authors analyzed a group of 33 patients from 32 unrelated families. The phenotypic manifestations were classified as non-PKU hyperphenylalaninaemia (non-PKU-HPA), mild and classical PKU. Sixty-six mutant alleles of the PAH gene were analyzed by means of the polymerase chain reaction on a Perkin Elmer (480) apparatus and on PHC Techne. A total of eight mutations linked with five haplotypes were detected. R408W mutation linked with 2.4 haplotype was detected on 53% of mutant alleles. No type of mutation was detected by hitherto published procedures in 27% of mutant alleles. CONCLUSIONS: The finding on the distribution and frequency of mutations indicate a genotypic homogeneity of the PKU population in the Central Bohemian area and Prague and are consistent with hitherto published data from the Czech Republic. The revealed data can be used in prenatal and postnatal DNA diagnosis and genotype classification of PKU.     

Effective treatment of cobalamin deficiency with oral cobalamin

Because cobalamin deficiency is routinely treated with parenteral cobalamin, we investigated the efficacy of oral therapy. We randomly assigned 38 newly diagnosed cobalamin deficient patients to receive cyanocobalamin as either 1 mg intramuscularly on days 1, 3, 7, 10, 14, 21, 30, 60, and 90 or 2 mg orally on a daily basis for 120 days. Therapeutic effectiveness was evaluated by measuring hematologic and neurologic improvement and changes in serum levels of cobalamin (normal, 200 to 900 pg/mL) methylmalonic acid (normal, 73 to 271 nmol/L), and homocysteine (normal, 5.1 to 13.9 micromol/L). Five patients were subsequently found to have folate deficiency, which left 18 evaluable patients in the oral group and 15 in the parenteral group. Correction of hematologic and neurologic abnormalities was prompt and indistinguishable between the 2 groups. The mean pretreatment values for serum cobalamin, methylmalonic acid, and homocysteine were, respectively, 93 pg/mL, 3,850 nmol/L, and 37. 2 micromol/L in the oral group and 95 pg/mL, 3,630 nmol/L, and 40.0 micromol/L in the parenteral therapy group. After 4 months of therapy, the respective mean values were 1,005 pg/mL, 169 nmol/L, and 10.6 micromol/L in the oral group and 325 pg/mL, 265 nmol/L, and 12.2 micromol/L in the parenteral group. The higher serum cobalamin and lower serum methylmalonic acid levels at 4 months posttreatment in the oral group versus the parenteral group were significant, with P < .0005 and P < .05, respectively. In cobalamin deficiency, 2 mg of cyanocobalamin administered orally on a daily basis was as effective as 1 mg administered intramuscularly on a monthly basis and may be superior.     

Response monitoring in children with phenylketonuria.

Phenylketonuria (PKU) is characterized by a disruption in the metabolism of phenylalanine and is associated with dopamine deficiency (Diamond, Prevor, Callender, & Druin, 1997) and cerebral white matter abnormalities (e.g., Anderson et al., 2007). From a neuropsychological perspective, prefrontal dysfunction is thought to underlie the deficits in executive abilities observed in individuals with PKU (Christ, Steiner, Grange, Abrams, & White, 2006; Diamond et al., 1997; White, Nortz, Mandernach, Huntington, & Steiner, 2001, 2002). The purpose of our study was to examine a specific aspect of executive ability, response monitoring, as measured by posterror slowing. The authors examined posterror reaction time (RT) in 24 children with well-controlled, early treated PKU and 25 typically developing control children using a go/no-go task. Results showed that RTs of both controls and children with PKU slowed significantly following the commission of errors. The magnitude of posterror slowing, however, was significantly less for children with PKU. These findings indicate deficient response monitoring in children with PKU. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Does impaired growth of PKU patients correlate with the strictness of dietary treatment? National Dutch PKU Steering Committee

To assess whether growth retardation in patients with phenylketonuria (PKU) is related to the strictness of their dietary treatment, the relationship between Z scores for height up to 3 y of age and different indices of dietary control in 103 early treated Dutch PKU patients was studied. As indices of dietary control, the mean phenylalanine (Phe) concentration, the frequency of plasma Phe concentrations < 200 and < 120 micromol/l, and the standard deviation of the individual plasma Phe concentrations were studied. These measures of the dietary control were divided into quartiles. The mean Z score of the studied patients showed a decrease of 0.18/y (SD 0.36). No statistically significant difference between any of the quartiles of the studied indices with growth retardation was found. None of the used indices of dietary control based on plasma Phe concentrations showed a relationship between different degrees of the strictness of dietary treatment with growth retardation in Dutch PKU patients.     

Reliability of potential clinical measures of muscle tone in the elbows of patients after stroke

In order to establish a genotype-phenotype relationship, we have identified both mutant phenylalanine hydroxylase (PAH) genes in 108 phenylketonuria (PKU) patients (27 different alleles, 54 different genotypes). One major group of patients with very high pretreatment phenylalanine values ("classical" PKU) exclusively comprised homozygotes of the PKU mutations I65T, G272X, F299C, Y356X, R408W, IVS12nt1, and compound heterozygotes of various combinations of these alleles with G46S, R261Q, R252W, A259T, R158Q, D143G, R243X, E280K, or Y204C. A second major group of patients with lower phenylalanine values ("mild" PKU) comprised mutations A300S, R408Q, Y414C in various compound heterozygous states, and R261Q, R408Q, Y414C in homozygotes. The phenylalanine values in these groups were non-overlapping. In addition, a smaller group of patients formed the transition between the two main groups. In sib pairs 4 of 15 had discordant pretreatment phenylalanine values. Conclusion: Our results are consistent with the view that allelic heterogeneity at the PAH locus dominates the biochemical phenotype in PKU and that genotype information is able to predict the metabolic phenotype in PKU patients.     

The kinin system in rhinitis and asthma

During detailed visual function testing, pattern-reversal visual evoked potentials (VEP), generated by different spatial frequencies (3 c/d, 1 c/d and 0.6 c/d) and visual contrasts (100% and 10%) were recorded in 21 adolescent and young adult phenylketonuric (PKU) patients (11 females and 10 males; mean age 14.8 years, range 9-22.8) on and off diet. In 14 of the 21 patients, disease had been detected at neonatal screening and in 7 later. Ten age-matched healthy subjects acted as controls. Recordings in more than 40% of eyes in the whole group and 30% of eyes in the screening subgroup showed a prolonged P100 latency. All visual pattern stimuli elicited a significantly longer P100 latency in PKU patients than in controls. VEP latencies to 3 c/d, 1 c/d and 1 c/d with 10% contrast--but not to 0.6 c/d--were longer in patients off diet than in patients on diet. No differences were found between VEP latencies in early- and later-detected subjects. To study the link between biochemical variables and VEP latencies, we envisaged either a linear relationship between recent exposure to phenylalanine (Phe) and VEP abnormalities or a threshold model considering phenylalanine (Phe) concentrations among the factors influencing VEP latencies. The correlation analysis detected an association between plasma Phe concentrations and abnormal VEP latencies, predicting that plasma Phe concentrations > 901 mumol/L would prolong VEP latencies to 1 c/d; concentrations > 879 mumol/L would prolong latencies to 3 c/d; and concentrations > 898 mumol/L would prolong latencies to 1 c/d with 10% contrast.     

Timing is everything: Executive functions in children exposed to elevated levels of phenylalanine.

This study addresses how the timing of a known biological insult affects the developmental progression of executive functions. The sample consisted of children exposed to elevated levels of phenylalanine, either postnatally, as in phenylketonuria (PKU; n = 46), or prenatally, as in maternal PKU (n = 15). Nonhyperphenylalaninemic siblings of children with PKU (n = 18) served as controls. Results indicated that elevated levels of phenylalanine are toxic to the neurological systems that manage executive functions and cognitive tempo. This toxicity is dose dependent, with higher levels of phenylalanine being more detrimental. Executive function difficulties noted in PKU are consistent with attention deficit hyperactivity disorder (ADHD)-inattentive type, whereas maternal PKU offspring had executive function difficulties consistent with ADHD-combined type. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Phenylketonuria. The in vivo hydroxylation rate of phenylalanine into tyrosine is decreased

In phenylketonuria (PKU), the enzyme phenylalanine hydroxylase is deficient, resulting in a decreased conversion of phenylalanine (Phe) into tyrosine (Tyr). The severity of the disease is expressed as the tolerance for Phe at 5 yr of age. In PKU patients it is assumed that the decreased conversion of Phe into Tyr is directly correlated with the tolerance for Phe. We investigated this correlation by an in vivo stable isotope study. The in vivo residual hydroxylation was quantitated using a primed continuous infusion of L-[ring- 2H5]Phe and L-[1-13C]Tyr and the determination of the isotopic enrichments of L-[ring-2H5]Phe, L-[ring-2H4]Tyr, and L-[1-13C]Tyr in plasma. Previous reports by Thompson and coworkers (Thompson, G.N., and D. Halliday. 1990. J. Clin. Invest. 86:317-322; Thompson, G.N., J.H. Walter, J.V. Leonard, and D. Halliday. 1990. Metabolism. 39:799-807; Treacy, E., J.J. Pitt, K. Seller, G.N. Thompson, S. Ramus, and R.G.H. Cotton. 1996. J. Inherited Metab. Dis. 19:595- 602), applying the same technique, showed normal in vivo hydroxylation rates of Phe in almost all PKU patients. Therefore, our study was divided up in two parts. First, the method was re-evaluated. Second, the correlation between the in vivo hydroxylation of Phe and the tolerance for Phe was tested in seven classical PKU patients. Very low (0.13- 0.95 micromol/kg per hour) and normal (4.11 and 6.33 micromol/kg per hour) conversion rates were found in patients and controls, respectively. Performing the infusion study twice in the same patient and wash-out studies of the labels at the end of the experiment in a patient and control showed that the method is applicable in PKU patients and gives consistent data. No significant correlation was observed between the in vivo hydroxylation rates and the tolerances. The results of this study, therefore, showed that within the group of patients with classical PKU, the tolerance does not depend on the in vivo hydroxylation.     

Interhemispheric transfer in children with early-treated phenylketonuria

Phenylketonuria (PKU) is a genetic disorder of amino acid metabolism that is associated with brain catecholamine depletion and deficient myelination. Although neuropsychological deficits have been documented in children with early-treated PKU (ETPKU), no study to date has examined possible effects of impaired myelination in this population. In the present study, interhemispheric transfer time was assessed for 14 children with ETPKU, 22 children with attention deficit-hyperactivity disorder, and 48 normal children, using a manual reaction time paradigm previously validated with callosal agenesis patients (Milner, 1982). Children with ETPKU demonstrated slowed interhemispheric transfer from the left to the right hemisphere as compared with the two other groups. The magnitude of slowing was correlated with age and phenylalanine levels at birth. Results support the hypothesis that abnormal myelination disrupts the development of interhemispheric connections in ETPKU, and suggest that left hemisphere projections may be particularly susceptible to such disruption.     

Bioavailability of rifampicin, isoniazid and pyrazinamide from fixed-dose combination capsules

Due to the observation of severe neurological symptoms in single patients as well as brain imaging, neuropsychological and neurophysiological abnormalities, the long-term prognosis of treated phenylketonuria is still under discussion. We investigated the neurological outcome of 57 (24 male, 33 female) patients with phenylketonuria (diet onset < 3 months) at a mean age of 23.6 (17-33) years in comparison to control subjects. Methods used were a clinical-neurological examination, tests for fine motor abilities, IQ test (WAIS-R), a neuropsychological attention task and MRI (30 patients only). Tremor was increased in the patients (28%) compared to controls (15%). Fine motor abilities were significantly reduced in three areas: hand-wrist steadiness, finger-hand dexterity and hand-wrist speed. Tremor as well as reduced fine motor skills were not associated with treatment-related variables, e.g. diet onset, strictness of biochemical control or amount of MRI white matter change. IQ was lower in patients (mean 97.6) compared to matched control subjects (mean 105.5). IQ at 12 years was correlated with biochemical control from birth up to the age of 12 and remained stable up to adult age, independent of biochemical control after 12 years of age. In contrast to the other outcome parameters, the performance in a neuropsychological attention task was influenced by the concurrent plasma phenylalanine concentration. Specific late-onset neurological impairment was not identified in this sample of early-treated adults with phenylketonuria. CONCLUSION: Careful neurological investigation revealed subtle symptoms of brain damage even after early-initiated treatment in adult patients with phenylketonuria. At present it cannot be excluded that further neurological deterioration could emerge later in life. Thus, patients with phenylketonuria - either on or off diet - should be monitored throughout life.     

Antifungal prophylaxis with itraconazole in neutropenic patients with acute leukaemia

The efficacy of antifungal prophylaxis with itraconazole capsules and its serum concentrations were evaluated in patients intensively treated for acute leukaemia. A consecutive group of patients without systemic antifungal prophylaxis (January 1993 to August 1994, period 1) was compared with another consecutive group of patients (period 2) who received itraconazole capsules (September 1994 to April 1995 400 mg/day, from May 1995 onwards 600 mg/day). All patients admitted with acute leukaemia and standard or high-dose chemotherapy were included into the study. Clinical endpoint was mortality from proven fungal infection. Seventy-six patients and 148 courses of cytotoxic chemotherapy were analysed in the control group as well as 47 patients and 112 treatment courses in the intervention group. Antifungal prophylaxis led to a significant decrease of mortality from invasive fungal infections (8.8%-0.9%, P = 0.005). The median trough concentration of itraconazole of all measurements was 520 ng/ml (range 230-793) in patients who received 400 mg/day and 760 ng/ml (370-1200) in patients receiving a dosage of 600 mg/day (P = 0.002). These findings suggest that itraconazole is an effective drug for antifungal prophylaxis but also that a considerable number of patients do not reach the desired trough levels (>500 ng/ml) with itraconazole capsules.     

Maleylated-BSA induces hydrolysis of PIP2, fluxes of Ca2+, NF-kappaB binding, and transcription of the TNF-alpha gene in murine macrophages

Magnetic resonance imaging brain scans and neuropsychological assessments of 17 children who met the NIH consensus diagnostic criteria for neurofibromatosis Type 1 were carried out in order to determine if there is a relationship between presence of high intensity signal abnormalities on MRI scans and nonverbal cognitive deficits. Cranial MRI scans in 10 patients (58.8%) demonstrated high intensity signal abnormalities, most frequently in the cerebral peduncles. Fifteen patients had nonverbal cognitive deficits (88.2%), including difficulty judging the orientation of lines, matching complex visual stimulus configurations, recalling pictures of faces, as well as copying and drawing from memory a complex geometric figure. There was not a significant association between nonverbal neuropsychological deficits and presence of high intensity signal abnormalities on MRI scans, possibly because the location of these hyperintense abnormalities was typically below the level of the basal ganglia. These findings suggest that the high intensity signal lesions seen on the MRI scans of children with neurofibromatosis Type 1 do not predict or explain their nonverbal cognitive deficits.     

Parental problem-solving skills, stress, and dietary compliance in phenylketonuria.

Parents of 30 children with phenylketonuria (PKU) who were classified as being in good dietary control (compliant, measured as within the medically acceptable range of blood phenylalanine levels of 2–20 mg) or poor dietary control (noncompliant, measured as either below or above medically acceptable 2–20 mg blood phenylalanine levels) engaged in verbal and written problem-solving situations under conditions of both high and low time-pressure induced stress. Overall, compliant parents gave higher quality verbal and written problem-solving solutions than noncompliant parents. Stress reduced the quality of problem solving in both compliant and noncompliant parents, but even under high stress, compliant parents demonstrated better problem-solving abilities than noncompliant parents. The potential importance of these findings for preventive intervention in PKU families is discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Prenatal diagnosis of de novo interstitial 16q deletion in a fetus associated with sonographic findings of prominent coronal sutures, a prominent frontal bone, and shortening of the long bones

Ursodeoxycholic acid (UDCA) has been shown to have beneficial effects on patients with primary biliary cirrhosis, suggesting that UDCA has immunomodulating effects. We investigated the effect of UDCA in patients with autoimmune hepatitis (AIH) which is characterized by immunological abnormalities. Eight patients with type 1 AIH were treated with 600 mg of UDCA per day for 2 years. Based on the criteria of the International Autoimmune Hepatitis Group, five patients were diagnosed as definite and three as probable type 1 AIH. Liver function tests were performed every 4 weeks, before and during UDCA therapy and the serum levels of anti-nuclear antibodies (ANA), smooth muscle antibodies (SMA), immunoglobulin G and gamma globulin were determined every 3 months. The levels of serum aspartate aminotransferase and alanine aminotransferase significantly decreased from 154 +/- 24 IU/L and 170 +/- 17 IU/L before UDCA therapy to 31 +/- 3 IU/L and 25 +/- 5 IU/L (P < 0.001) after 1 year of treatment and 28 +/- 2 IU/L and 23 +/- 4 IU/L (P < 0.001) after 2 years of treatment. After 2 years of treatment, the levels of serum immunoglobulin G and gamma globulin significantly decreased (P < 0.05) and ANA titres (5/8 patients) were reduced and SMA (3/5 patients) became negative. Furthermore, hepatic histopathological changes of four patients were assessed after 1 year of treatment, and an improvement of intrahepatic inflammation, but not fibrosis, was observed. In conclusion, these results suggest that UDCA has a beneficial therapeutic effect in patients with type 1 autoimmune hepatitis.     

Receiver operating characteristic plots to evaluate Guthrie, Wallac, and Isolab phenylalanine kit performance for newborn phenylketonuria screening

We used ROC plots to evaluate the clinical performance of the Guthrie, Wallac, and Isolab assays for newborn phenylketonuria (PKU) screening and assessed the screening discriminatory power of these three assays by the area under the ROC plot, Youden's J index, and the likelihood ratio. The use of these plots not only allows us to pinpoint the exact cutoff value in screening, but also provides a direct comparison of these three different assays in clinical outcome performance. The optimum cutoff for the newborn PKU screening is a blood phenylalanine concentration of 0.30, 0.27, and 0.18 mmol/L for the Guthrie, Wallac, and Isolab assays, respectively. We conclude that the Wallac and Isolab kits, like the Guthrie assay, are suitable for newborn PKU screening.