Severe hypothyroidism due to atrophic thyroiditis from second year of life influenced developmental outcome.

UNLABELLED: From the second year of life a girl showed an insidious development of clinical hypothyroidism due to a non-goitrous lymphocytic thyroiditis without traceable circulating levels of thyroid antibodies measured by routine immunoassays. The diagnostic delay of this rare variant of atrophic thyroiditis caused persistent neuropsychological deficits. CONCLUSION: Her difficulties with speed of processing and working memory in particular could suggest a frontal deficit, possibly in the dorsolateral prefrontal circuit. This contrasts with findings in congenital hypothyroidism, suggesting a relatively preserved frontal function, and could illustrate different neuropsychological deficits of hypothyroidism at different ages in early childhood.

Congenital hypothyroidism: no adverse effects of high dose thyroxine treatment on adult memory, attention, and behaviour.

BACKGROUND: In congenital hypothyroidism (CH) it has been questioned whether high dose thyroxine replacement therapy has detrimental effects on memory, attention, and behaviour. AIMS: To describe memory, attention, and behaviour problems in young adults with CH, and to study possible negative effects of high dose thyroxine replacement therapy. METHODS: A cohort based follow up study of 49 young adults (mean age 20 years) with early treated CH, and sibling controls (n = 41). RESULTS: Controlled for age and sex, the CH group attained significantly lower scores than sibling controls on some tests of memory (Wechsler Logical Memory part II: 12.9 versus 17.8; difference 5.2, 95% CI 3.6 to 6.8) and attention (Wechsler Freedom From Distractibility factor: 95.6 versus 104.8; difference 9.9, 95% CI 6.4 to 13.4). They rated themselves with more behaviour problems than did sibling controls (52.7 versus 44.7; difference -7.6, 95% CI -11.2 to -4.0) on the Achenbach Self Report. A high thyroxine starting dose, high serum thyroxine treatment levels during the first six childhood years, and high levels at assessment had no adverse effects on outcome measures at age 20. On the contrary, the results suggest better outcome with higher childhood treatment levels. CONCLUSIONS: Long term outcome revealed deficits in some aspects of memory, attention, and behaviour in young adults with CH relative to sibling controls. No adverse effects of high dose thyroxine therapy were found on measures of memory, attention, and behaviour problems.

Evaluation of novel assays in clinical chemistry: quantification of plasma total homocysteine.

BACKGROUND: There is a need for systematic evaluation of methods before their release to the market. We addressed this problem in novel homocysteine assays as part of an European Demonstration Project involving six centers in four countries. METHODS: Two immunological methods for measurement of plasma total homocysteine (P-tHcy), the fluorescence polarization immunoassay (FPIA) and the enzyme immunoassay (EIA), were compared with two comparison methods, HPLC and gas chromatography-mass spectrometry (GC-MS). All laboratories performed the following procedures: (a) familiarization; (b) determination of linearity and precision by analyzing five plasma samples with interrelated concentrations for 20 days; (c) correlation using patients' samples; and (d) assessment of long-term performance. RESULTS: Both immunological methods were linear for P-tHcy between 5 and 45 micromol/L. The intralaboratory imprecision (CV) was <5% for FPIA and <9% for EIA used with a sample processor. The bias was -2% to 3% for FPIA and 2-4% for EIA used with a sample processor. CONCLUSIONS: The immunological methods provide results with little bias compared with HPLC and GC-MS. The imprecision of the assays must be considered in the context of their intended use(s).

Subcellular organization of bile acid amidation in human liver: a key issue in regulating the biosynthesis of bile salts.

To extend our knowledge of how the synthesis of free bile acids and bile salts is regulated within the hepatocyte, bile acid-CoA:amino acid N-acyltransferase and bile acid-CoA thioesterase activities were measured in subcellular fractions of human liver homogenates. Some bile acids, both conjugated and unconjugated, have been reported to be natural ligands for the farnesoid X receptor (FXR), an orphan nuclear receptor. The conversion of [(14)C]choloyl-CoA and [(14)C]chenodeoxycholoyl-CoA into the corresponding tauro- and glyco-bile acids or the free bile acids was measured after high-pressure liquid radiochromatography. There was an enrichment of the N-acyltransferase in the cytosolic and the peroxisomal fraction. Bile acid-CoA thioesterase activities were enriched in the cytosolic, peroxisomal, and mitochondrial fractions. The highest amidation activities of both choloyl-CoA and chenodeoxycholoyl-CoA were found in the peroxisomal fraction (15-58 nmol/mg protein/min). The K(m) was higher for glycine than taurine both in cytosol and the peroxisomal fraction.These results show that the peroxisomal de novo synthesis of bile acids is rate limiting for peroxisomal amidation, and the microsomal bile acid-CoA synthetase is rate limiting for the cytosolic amidation. The peroxisomal location may explain the predominance of glyco-bile acids in human bile. Both a cytosolic and a peroxisomal bile acid-CoA thioesterase may influence the intracellular levels of free and conjugated bile acids.

[Children's rights in Norwegian hospitals--are children and parents satisfied?]. / Barns rettigheter i norske sykehus--er barn og foreldre fornøyde?

The rights of children in hospitals in Norway are protected by regulations based on Norwegian legislation. These regulations cover matters such as teaching of hospitalized children, housing of parents, economic rights of parents, and information. We did a questionnaire study among hospitalized children and their parents about their views on how hospitals complied with these regulations. 90 of 131 questionnaires (69%) were returned. There was a considerable gap between what the law demands of continuance in health care during treatment, schooling and information, and what children and parents actually experience. The study shows that the present regulations concerning children's rights in hospitals should be changed. The health authorities should demand documentation from the hospitals as to how the rights of children are ensured in hospitals.

Presence of choloyl- and chenodeoxycholoyl-coenzyme A thioesterase activity in human liver.

In human liver homogenate the formation of bile acid-CoA thioesters is localized both to the microsomal fraction catalysed by an ATP-dependent synthetase and to the peroxisomal fraction catalysed by the thiolase in the last step of the beta-oxidative cleavage of the 5beta-cholestanoyl side chain. The cytosolic bile acid-CoA:amino acid N-acyltransferase catalyse the conjugation of the CoA-activated bile acids with taurine or glycine prior to secretion into bile. The formation of bile acid-CoA esters is considered the rate-limiting step in bile acid amidation. So far, a bile acid-CoA cleaving activity has not been assessed in the research of bile acid amidation in human liver. In this work, a bile acid-CoA cleaving activity has been demonstrated at a rate that may influence the concentration of bile acid-CoA thioesters, free bile acids and amidated bile acids within the hepatocyte. Recently, it was shown that free chenodeoxycholic acid, formed by the thioesterase, is the physiological ligand of the farnesoid X receptor. A multiorganelle distribution of the bile acid-CoA hydrolytic activity was found. In the postnuclear fraction of human liver homogenate, apparent Km and Vmax for the cleavage of choloyl-CoA were 7.7 x 10-5 mol/L and 3.6 nmol x mg-1 x min-1 respectively. The corresponding values for chenodeoxycholoyl-CoA cleavage were 7.1 x 10-5 mol/L and 4.8 nmol x mg-1 x min-1. Hydrolytic activities were detected in the microsomal and the peroxisomal fractions where the bile acid-CoA esters are formed as well as in cytosol housing the N-acyltransferase activity. Compared to the bile acid-CoA synthetase activities, the hydrolytic activities were considerably higher, both in the postnuclear fraction and in the microsomal fraction. The thioesterase activities were in the same range as detected for the N-acyltransferase activities both in the postnuclear fraction and in the cytosolic fraction. The mere presence of thioesterase in microsomes, peroxisomes and cytosol seems counterproductive to bile acid amidation. The thioesterases may have an indirect regulatory function on the bile acid synthesis and are important for the regulation of bile acid synthesis by providing free chenodeoxycholic acid, the most potent activator of the farnesoid X receptor.

Sulphation of lithocholic acid in the colon-carcinoma cell line CaCo-2.

High levels of bile acids in the colon may correlate with an increased risk of colon cancer, but the underlying mechanisms are not known. Proteoglycan structures have been shown to change when human colon cells differentiate in vitro. The expression of [(35)S]sulphated molecules was used as a phenotypic marker to study the effects of bile acids on the human-colon-carcinoma cell line CaCo-2. [(35)S]sulphated compounds were isolated from the medium of cell fractions of cells metabolically labelled with [(35)S]sulphate in the absence and presence of cholic acid, deoxycholic acid, chenodeoxycholic acid and lithocholic acid (LA). Labelled molecules were analysed by gel chromatography, HPLC and SDS/PAGE in combination with chemical and enzymic methods. The expression of (35)S-labelled proteoglycans was not affected by any of the bile acids tested. However, the level of sulphated metabolites increased 7-18-fold in different experiments during a 22 h labelling period in the presence of an LA concentration of 10 microg/ml (26.6 nmol/ml) compared with controls. Further analyses showed that this was due, at least in part, to the sulphation of LA itself. This sulphation of LA was a rapid process followed by secretion back to the medium. Brefeldin A did not reduce the sulphation of LA, indicating that this conversion takes place in the cytosol, rather than in the Golgi apparatus of the CaCo-2 cells. LA in colon may be sulphated efficiently by the colonocytes to reduce the toxic effects of this particular bile acid. Sulphation may possibly be an important protective mechanism in the colon.

Linear growth in early treated children with congenital hypothyroidism.

Length/height was studied from birth to 6 years of age in 103 children with congenital hypothyroidism identified by the Norwegian or Swedish screening programs. We used the "infancy-childhood-puberty (ICP) growth model". This model describes normal linear growth during the first 3 years of life by an infancy component with the addition of a childhood component, the latter acting from the second half of the first year. In comparison with reference children, children with hypothyroidism had reduced growth from 6 to 12 months, and increased growth after 12 months of age. Mean onset of the childhood component of growth was delayed from 8.1 months (SD 1.9) to 10.4 months (SD 2.2) in girls, and from 8.9 months (SD 2.0) to 11.0 months (SD 2.1) in boys. Age at onset of the childhood component was correlated with age at start of treatment (r = 0.24), and in children with more severe hypothyroidism (pretreatment serum thyroxine < 40 nmol/l) inversely correlated with the L-thyroxine dose at start of treatment (r = -0.40). Change in height standard deviation score from 1 to 3 years of age was correlated with the serum thyroxine concentration at age 1 year (r = 0.30). The delay in the onset of the childhood component of growth and the association with age at start of treatment and initial L-thyroxine dose indicate that thyroid hormones during the first months of life are essential for normal onset of the childhood component of growth, which otherwise is assumed to be growth hormone-dependent.

[The rights of children in hospitals. A questionnaire study of rights of hospitalized children in 14 Norwegian hospitals]. / Forskrift om barn i sykehus. En spørreundersøkelse om barns rettigheter ved 14 norske sykehus.

The rights of children in hospitals in Norway are protected by regulations based on the hospital statute: Regulations covering children in hospital, signed in 1989. These regulations cover matters such as the schooling of hospitalized children, the housing of parents, the economic rights of parents and information. We interviewed hospital management at two different levels of administration to find out how they put these regulations into practice. We found a certain gap between what the law demands and what the hospitals actually provide e.g. with regard to children on adult wards, firm point of contact, activity areas and provisions for education, clarification of parents' duties and respite facilities, reimbursement of expenses and issue of regulations. We conclude that the time has come for hospitals to report on the actions taken to ensure children's rights and for amendment to the law.

Studies on the degradation of [U-3H]-phytanic acid and [U-3H]-pristanic acid in cultured fibroblasts from children with peroxisomal disorders.

Up till now, errors of phytanic acid metabolism in children with peroxisomal disorders have been estimated by measuring 14CO2 formation from 1-14C-labelled phytanic acid in different systems. In the present work we have incubated both 1-14C- and U-3H-labelled phytanic acid and U-3H-labelled pristanic acid with cultured fibroblasts from healthy children as well as from children with peroxisomal disorders. In cultured fibroblasts from healthy children, [U-3H]-pristanic acid was degraded at a rate 60 times that of [U-3H]-phytanic acid, indicating that the initial degradation of phytanic acid into pristanic acid is the rate-limiting step in the overall conversion. In cultured fibroblasts from children with the Zellweger syndrome and infantile Refsum disease, the degradation of both phytanic acid and pristanic acid, was severely impaired (10-40 and 10-30 times, respectively), but the degradation of pristanic acid was still more than 20 times higher than that of phytanic acid in these disorders. In fibroblasts from a child with rhizomelic chondrodysplasia punctata the rate of degradation of U-3H- and 1-14C-labelled phytanic acid was markedly reduced whereas the rate of degradation of U-3H-labelled pristanic acid was normal. No evidence was obtained for elongation of phytanic or pristanic acid in the different fibroblastic cultures. It is concluded that both the degradation of phytanic acid and pristanic acid may be affected in peroxisomal disorders. The possibility that phytanic acidaemia in these disorders is due to product inhibition of accumulated pristanic acid seems to be excluded. The pristanic acidaemia sometimes seen is likely to be due to dietary pristanic acid rather than to de novo synthesized pristanic acid from accumulated phytanic acid.

[A small-group center. A model trial for activities of a center for rare diseases and syndromes at the National Hospital]. / Smågruppesenteret. En modellutprøvning for Rikshospitalets utadrettede virksomhet for noen sjeldne sykdommer og syndromer.

The Centre for Rare Disorders at the National Hospital is a trial project in connection with the Government's Plan of Action for the disabled. The intention is to establish nationwide facilities which in cooperation with local resources can provide both medical, pedagogical and social services for persons with rare disorders and their families. The work at the centre is based on a life span perspective and the goal is improved coping, independence and better quality of life. The centre gathers, adapts and spreads information on 15 rare disorders. Representatives from the user organisations ensure that the users have a strong influence on the management of the centre. It is hoped that systematic evaluation of the centre's activities will give an answer to the Government and to the host hospital as to whether the intentions and goals will be fulfilled or not during the project period.

Mutations in the iduronate-2-sulfatase gene in five Norwegians with Hunter syndrome.

We have identified the mutations in the iduronate-2-sulfatase (IDS) gene of five unrelated Norwegians with Hunter syndrome by reverse transcription-polymerase chain reaction (RT-PCR) analysis of IDS mRNA followed by single strand conformation polymorphism (SSCP) analysis and cDNA sequencing. One patient had a 5-bp deletion, located at the intron 5/exon 6 junction, that created a new alternative splice site. This expanded the deletion to 9 bp in mRNA, an in-frame deletion of the first 3 codons of exon 6 of the IDS gene. In two patients point mutations were identified, the S333L mutation, which has been reported previously, and A346D (a C-->A transversion at nucleotide 1161/exon 8), which is novel. Two patients had large 3' mRNA rearrangements. The A346D mutation was associated with the mild phenotype, all others with the severe form.

Significance of elevated serum thyrotropin during treatment of congenital hypothyroidism.

Serum thyrotropin concentrations are frequently elevated during treatment of children with congenital hypothyroidism. It is unclear if elevated thyrotropin during early treatment indicates non-optimal treatment. In a cohort of 49 children with congenital hypothyroidism, we studied the decline in serum thyrotropin concentration after initiating L-thyroxine treatment, the relationship between elevated thyrotropin and treatment variables, and non-compliance with the treatment as a possible cause of elevated thyrotropin. The initial mean dose of thyroxine was 8.5 (SD 3.3) micrograms/kg body weight/day: 71% of the serum samples obtained 15-21 days after the start of treatment had serum thyrotropin concentrations < 10 mU/l. Six children had no samples with serum thyrotropin < 10 mU/l during the first 3 months of treatment. These children had a lower thyroxine dose prescribed, and serum thyrotropin was normalized when the dose was sufficiently increased. During treatment, from 6 weeks of age, serum thyrotropin > 10 mU/l was related to a lower dose of thyroxine and lower serum thyroxine, and was not due to non-compliance with treatment.

Skeletal maturation during thyroxine treatment in children with congenital hypothyroidism.

The aim of this investigation was to study if bone age development (assessed by the Greulich & Pyle atlas) was related to L-thyroxine treatment in 47 children with congenital hypothyroidism, treated early and according to general recommendations. In spite of frequent delay in skeletal maturation at diagnosis, the delay in mean bone age at a mean chronological age of 1.5 years was slight (0.5 months), and 30% of the variation in bone age SD score (SDS) at 1.5 years was accounted for by the dose of L-thyroxine and serum thyroxine during the first year. The children with a bone age within +/- 1 SDS had a prescribed mean dose of L-thyroxine per kg body weight from 3 to 12 months of age of 5.4 +/- 1.7 micrograms/kg/day, and their mean serum thyroxine concentration during the first year was 175 +/- 29 nmol/l. We conclude that bone age at 1.5 years of age was positively correlated with the dose of L-thyroxine and the serum thyroxine concentrations during the first year. This supports the general use of bone age assessments as a complement to other treatment variables in the follow-up of children with congenital hypothyroidism.

Influence of human plasma or serum albumin on ADP- or vasopressin-induced calcium increases in human platelets.

By focusing the consequences of loading platelets with the fluorescent calcium indicator, fura-2, in buffer or plasma the influences of plasma constituents on calcium responses in blood platelets has been worked out. Proteins were removed from the pre-incubation medium before agonist stimulation and measurement of intracellular calcium concentration [Ca2+]i. We found that moderate amounts (1-33%, v/v) of plasma added to the buffer during pre-incubation stimulated the mobilization of cytoplasmic calcium, delta[Ca2+]i, and reduced the time from agonist stimulation to peak level of [Ca2+]i in platelets stimulated with ADP or arginine vasopressin A8VP. With the buffer used, calcium response was restored by addition of 33% (v/v) plasma to the same level as found for unwashed platelets in the platelet rich plasma (cf. methods). The presence of human serum albumin during the pre-incubation also influenced the calcium response, but not to the same extent as plasma. From a resting level of 73 +/- 10 nmol l-1, addition of 0.4 mumol l-1 ADP increased the [Ca2+]i by 24 +/- 13 nmol l-1 (n = 20), 65 +/- 30 nmol l-1 (n = 5), and 144 +/- 44 nmol l-1 (n = 22) in platelets pre-incubated with buffer, 5 gl-1 albumin, and 33% (v/v) plasma, respectively. The corresponding values after stimulation with 0.05 mumol l-1 A8VP were 49 +/- 34 nmol l-1, 105 +/- 27 nmol l-1, and 170 +/- 39 nmol l-1, (n = 7). In platelets incubated in buffer only, the delta t from stimulation with 0.4 mumol l-1 ADP was 18.9s.(ABSTRACT TRUNCATED AT 250 WORDS)

Peroxisomal chain-shortening of thromboxane B2: evidence for impaired degradation of thromboxane B2 in Zellweger syndrome.

We have shown that rat liver peroxisomes can chain-shorten prostaglandins to dinor- and tetranor-metabolites. In a recent in vivo study we could demonstrate that peroxisomes are of major importance for chain-shortening of prostaglandin F2 alpha in humans (1991, Diczfalusy et al. J. Clin. Invest. 88:978-984). This was shown by identifying the major urinary metabolites of radiolabeled prostaglandin F2 alpha given intravenously to a patient lacking functional peroxisomes (Zellweger syndrome). In the present investigation we have studied the peroxisomal chain-shortening of thromboxane B2, a compound structurally related to prostaglandins. Isolated rat liver peroxisomes oxidized thromboxane B2 to a chain-shortened metabolite in an NAD(+)-dependent reaction. The metabolite was identified as 9,11,15-trihydroxy-2,3,4,5-tetranor-thromb-13-enoic acid (tetranor-thromboxane B1). The urinary excretion of the major beta-oxidized metabolites of thromboxane B2 and prostacyclin was determined in three Zellweger patients and six age-matched controls. The controls excreted on an average 1.7 and 1.1 ng/mg creatinine of 2,3-dinorthromboxane B2 and 2,3-dinor-6-keto-prostaglandin F1 alpha, respectively. In none of the three Zellweger patients could these dinor-metabolites be detected, i.e., the urinary excretion was less than 0.2 ng/mg creatinine. This shows that peroxisomes play an important role in the degradation of the carboxyl side chain of thromboxane B2 in vivo.

Growth and nutrition in 10 girls with Rett syndrome.

Cross-sectional and retrospective data on growth and anthropometric outcome, feeding problems and dietary intake are presented for 10 girls between three and 16 years of age with Rett syndrome. All girls had birth weight and length within the normal range for gestational age and development was considered normal until six to 24 months of age. The girls presented a fall off in linear growth during the first two years of life and at the time of study, all but one had height and/or weight for height below the 2.5th percentile of healthy children. The girls had good appetite but could not eat by themselves and oral-motor dysfunctions were common. The mean energy intake was 66.9% of the US recommendations according to age and 107.8% of the recommendations according to body weight. The intakes of thiamin, vitamin D, calcium and iron were considered low. None was anaemic. Different nutritional intervention strategies should be investigated to reduce and, if possible, prevent malnutrition and wasting in girls with Rett syndrome.

Feeding problems in children with congenital heart disease: the impact on energy intake and growth outcome.

Cross-sectional data on growth outcome, upper-arm measurements and energy intake have been analysed according to the presence or absence of early feeding problems and poor appetite in 40 children (0.9-13 years) with congenital heart disease (CHD). At the time of study, refusal to eat or poor appetite was reported as a significant problem in 19 children and subnormal height and/or weight were recorded in 11 children. The children ate considerably less calories than recommended for healthy children. The cross-sectional analyses showed that children with poor appetite had significantly (P less than 0.05 and P less than 0.01) lower outcome values of growth and upper-arm measurements than their disabled counterparts with no feeding problems and good appetite. Children with feeding problems also tended to eat less than children without feeding problems. For most parents (65%) feeding of infants and children with CHD involves difficulties, time and anxiety. This study has shown that the parents' experience about feeding problems may be a good predictor for low growth outcome and low voluntary food intake of the child. Whenever feeding problems are reported, nutritional intervention should be offered in order to increase the caloric intake of the child and to develop a sound feeding relationship in the family.

Energy and nutrient intakes of disabled children: do feeding problems make a difference?

We examined the effect of feeding problems and alternative feeding practices on the energy and nutrient intakes of disabled children. Subjects were 221 disabled children aged 1 to 16 years from seven diagnostic groups: a 4-day food record was obtained for 166 children. The children's energy and nutrient intakes were examined in relation to the presence or absence of four feeding problems (gross motor/self-feeding impairment, oral-motor dysfunction, lack of appetite, food aversions) and two alternate feeding practices (prolonged assisted feeding and use of pureed foods). Cross-sectional analyses showed that children with feeding problems or alternative feeding practices had lower energy and nutrient intakes than did children without these factors. The presence of oral-motor dysfunction or prolonged assisted feeding significantly reduced relative energy intake. In general, differences in energy and nutrient intakes between children with and without other feeding problems or practices were small, and few statistically significant differences were found. The findings indicate that some feeding problems may reduce food intake in disabled children, although this effect is lessened by the conscientious efforts of parents. Parents and families of disabled children should receive dietary counseling to prevent deteriorative effects on the physical growth and health of children with long-standing feeding problems.

The impact of feeding problems on growth and energy intake in children with cerebral palsy.

Retrospective data on growth and cross-sectional data on growth outcome, anthropometric measurements and energy intake have been analysed according to the presence or absence of feeding problems in 42 children with cerebral palsy (CP) between 1 and 13 years of age. The mean age for boys and girls was 5.1 and 5.9 years, respectively. The study revealed a high frequency of feeding problems (50%) and growth retardation (48%) in the group. The results of weight for height, triceps skinfold thickness and energy intake indicate that 15% of the children were undernourished at the time of study. The cross-sectional analyses showed that children with feeding problems at the time of study (n = 22) had significantly lower height for age, weight for height, triceps skinfold thickness and upper-arm circumference than children without problems (P less than 0.05). Children with feeding problems also tended to have lower energy intake, but the differences were not significant. The feeding problems were most frequent among the severely disabled children. This study has shown that the presence of feeding problems is one important predictor of low growth outcome in children with CP. When parents report on feeding problems, feeding evaluation, training and nutritional intervention should be offered immediately. This is important for alleviating the heavy care-load for parents and health-workers and for some children it may be necessary to maintain an acceptable nutritional state.