Infradian rhythms in urinary growth hormone excretion.

All studies of urinary GH excretion in normal and disordered growth have revealed marked day to day (infradian) variation. We used serial overnight urinary GH estimations as an indirect measure of endogenous GH secretion in eight normal prepubertal children (aged 3.6-7.3 yr) over 90-365 days to determine whether longer term rhythms in GH output could exist. This study constitutes a first step in examining the potential relationship between GH excretion and growth. Urinary GH was measured by immunoradiometric assay after dialysis, expressed as the total amount excreted (nanograms per night) or as the GH/creatinine ratio (nanograms per mmol), and assessed by pulse counting techniques and time-series analysis. Variability in urinary GH excretion (median coefficient of variation, 46%) was significantly greater than creatinine (median coefficient of variation, 25%; P = 0.003). Additionally, there was marked month by month variation in baseline urinary GH in all children. High frequency pulses of urinary GH were defined in all children, with periods between 3-5 days. In the two children followed for 7 months or more, time-series analysis was also undertaken on urinary GH data divided into weekly series. This revealed significant rhythms present at 2.6 and 4.1 weeks. There were, therefore, three components to urinary GH excretion: long term basal fluctuation (over months), short term pulses (over days), and intermediate rhythms (over weeks). Further work is required to establish the relationship between these patterns of GH excretion and short term growth.

Variability in the urinary excretion of growth hormone in children: a comparison with other urinary proteins.

As a basis for assessment of the clinical validity of urinary GH (uGH) measurements in children, the day-to-day variability in renal handling of GH has been compared with that of albumin, N-acetylglucosaminidase (NAG) and creatinine. Five overnight urine specimens were collected over a 2-week period from 78 healthy children (aged 5-16 years), 20 of normal stature and 58 with growth disorders; ten children were classified as GH-deficient (GHD) and 48 were designated short normal (SN). The variability of excretion of each substance was expressed as a coefficient of variation (C.V.) which was not influenced by expressing the urine results as total mass excreted, concentration, excretion rate or as a ratio to creatinine. There was considerable night-to-night variability in the excretion of all substances (mean C.V. values for all groups: 56% for albumin, 41% for GH, 33% for NAG and 27% for creatinine). No differences were found in the variability of GH excretion between males and females, nor between prepubertal and pubertal subjects. The mean C.V. for uGH excretion ranged from 37% in normal and 35% in SN children to 52% in those with GHD (P < 0.05). Assay variation rather than a change in renal protein handling accounted for the large variations in uGH concentrations of < 5 pg/ml, thus contributing to the high uGH C.V. of the GHD group.(ABSTRACT TRUNCATED AT 250 WORDS)

An immunoradiometric assay for ferritin in the serum of normal subjects and patients with iron deficiency and iron overload.

An immunoradiometric assay for human ferritin has been developed. Concentrations of ferritin in the serum of male and female controls and patients with iron deficiency and iron overload were measured.Male controls were found to have a significantly higher mean concentration of serum ferritin than females. Patients with iron deficiency had significantly lower levels than normals of either sex and patients with iron overload had greatly elevated serum ferritin concentrations. It is thought that the serum ferritin concentration may reflect the iron stores of the body.

Newborn screening for inborn errors of metabolism: a systematic review.

OBJECTIVES. To establish a database of literature and other evidence on neonatal screening programmes and technologies for inborn errors of metabolism. To undertake a systematic review of the data as a basis for evaluation of newborn screening for inborn errors of metabolism. To prepare an objective summary of the evidence on the appropriateness and need for various existing and possible neonatal screening programmes for inborn errors of metabolism in relation to the natural history of these diseases. To identify gaps in existing knowledge and make recommendations for required primary research. To make recommendations for the future development and organisation of neonatal screening for inborn errors of metabolism in the UK. HOW THE RESEARCH WAS CONDUCTED. There were three parts to the research. A systematic review of the literature on inborn errors of metabolism, neonatal screening programmes, new technologies for screening and economic factors. Inclusion and exclusion criteria were applied, and a working database of relevant papers was established. All selected papers were read by two or three experts and were critically appraised using a standard format. Seven criteria for a screening programme, based on the principles formulated by Wilson and Jungner (WHO, 1968), were used to summarise the evidence. These were as follows. Clinically and biochemically well-defined disorder. Known incidence in populations relevant to the UK. Disorder associated with significant morbidity or mortality. Effective treatment available. Period before onset during which intervention improves outcome. Ethical, safe, simple and robust screening test. Cost-effectiveness of screening. A questionnaire which was sent to all newborn screening laboratories in the UK. Site visits to assess new methodologies for newborn screening. The classical definition of an inborn error of metabolism was used (i.e., a monogenic disease resulting in deficient activity in a single enzyme in a pathway of intermediary metabolism). RESEARCH FINDINGS. INBORN ERRORS OF METABOLISM. Phenylketonuria (PKU) (incidence 1:12,000) fulfilled all the screening criteria and could be used as the 'gold standard' against which to review other disorders despite significant variation in methodologies, sample collection and timing of screening and inadequacies in the infrastructure for notification and continued care of identified patients. Of the many disorders of organic acid and fatty acid metabolism, a case can only be made for the introduction of newborn screening for glutaric aciduria type 1 (GA1; estimated incidence 1:40,000) and medium-chain acyl CoA dehydrogenase (MCAD) deficiency (estimated incidence 1:8000-1:15,000). Therapeutic advances for GA1 offer prevention of neurological damage but further investigation is required into the costs and benefits of screening for this disorder. MCAD deficiency is simply and cheaply treatable, preventing possible early death and neurological handicap. Neonatal screening for these diseases is dependent upon the introduction of tandem mass spectrometry (tandem MS). This screening could however also simultaneously detect some other commonly-encountered disorders of organic acid metabolism with a collective incidence of 1:15,000.(ABSTRACT TRUNCATED)

Secondary analysis of economic data: a review of cost-benefit studies of neonatal screening for phenylketonuria.

STUDY OBJECTIVE: To estimate the net financial benefit of neonatal screening for phenylketonuria (PKU): by a simple pooling of cost data from the literature; and by a more complex modelling approach. DESIGN: A systematic literature review was conducted to identify papers containing data on the monetary costs and benefits of neonatal screening for PKU. The methodological quality of the studies was appraised, and data were extracted on resource use and expenditure. Monetary data were converted to common currency units, and standardised to UK incidence rates. Net benefits were calculated for median, best case and worst case scenarios, and the effect of excluding poor quality studies and data was tested. The net benefit was also estimated from a model based on data from the literature and assumptions appropriate for the current UK situation. Extensive sensitivity analysis was conducted. MAIN RESULTS: The direct net benefit of screening based on the median costs and benefits from the 13 studies identified was 143,400 Pounds per case detected and treated (39,000 Pounds and 241,800 Pounds for worst case and best case scenarios respectively). The direct net benefit obtained by the modelling approach was lower at 93,400 Pounds per case detected and treated. Screening remained cost saving under sensitivity analysis, except with low residential care costs (less than 12,300 Pounds per annum), or very low incidence rates (less than 1 in 27,000). CONCLUSIONS: The economic literature on PKU screening is of variable quality. The two methods of secondary analysis lead to the same conclusion: that neonatal PKU screening is worthwhile in financial terms alone in the UK, and that it justifies the infrastructure for collecting and testing neonatal blood samples. This result cannot necessarily be extrapolated to other countries.

Neutropenia associated with dual antimalarial chemoprophylaxis--use of bone-marrow culture as an aid in further drug management.

Bone-marrow culture in soft agar was used to determine the cause of neutropenia in a visitor to Tanzania who had been taking both amodiaquine and proguanil for antimalarial prophylaxis. Desethyl-amodiaquine, a major metabolite of amodiaquine (but not amodiaquine itself, proguanil, cycloguanil or chloroquine) was implicated. Supplementary studies using amodiaquine binding techniques supported the notion that the parent compound, amodiaquine, was not the cause of the neutropenia. The bone-marrow culture technique proved useful in deciding further anti-malarial prophylaxis and in formulating the choice of curative antimalarial therapy, should this have proved necessary. The procedure may help in the managing other such patients with presumed drug-induced blood dyscrasias when the choice of appropriate and effective antimalarial drugs is limited.

Determination of chlorpromazine in serum by radioreceptor assay and HPLC.

A radioreceptor assay for chlorpromazine in serum, which is based on binding to dopamine receptors, is described. This method has been postulated to measure all active metabolites as well as the parent drug. We have compared this method with an HPLC method for chlorpromazine. Dopamine-blocking activity, measured in serum samples from schizophrenic patients receiving chlorpromazine, was 1.85-9.1 times higher than serum chlorpromazine level measured by HPLC. The correlation between the two methods was 0.75. Dopamine-blocking activity was related more closely to dose of drug and to serum prolactin level than was serum chlorpromazine level measured by HPLC.

Albumin analysis in serum of haemodialysis patients: discrepancies between bromocresol purple, bromocresol green and electroimmunoassay.

The analysis of serum albumin by bromocresol purple (BCP), by bromocresol green (BCG), and by electroimmunoassay (EIA) has been compared in a mixed group of 100 hospital patients. Good agreement between the immunochemical and BCP methods, but a positive bias with the BCG method led to routine use of the BCP method. In a group of 19 paediatric patients on chronic haemodialysis the mean BCP-albumin was found to be lower than the true albumin, as determined by EIA, whereas the positive bias using the BCG method remained. The difference between BCP-albumin and EIA-albumin in the haemodialysis group varied from 0 to -13 g/L (mean -7.1 g/L) but was effectively constant for most patients over a 3-month period. Possible mechanisms and necessary further investigations are discussed.

Neuroblastoma--when are urinary catecholamines and their metabolites 'normal'?

The overproduction of catecholamines and their metabolites is a well recognised feature of neuroblastoma. Published data are scarce for their urinary excretion in children with neuroblastoma and in ill children in whom this diagnosis may be considered. We have determined a graphical upper reference limit for total catecholamines, total metadrenalines and HMMA in urine, expressed as a ratio to the creatinine concentration, for a group of 174 children with neuroblastoma and 704 hospitalised children with other disorders. This graph has been determined by examining the overlap region between the results for the two groups of children and avoids the irregularities caused by statistical outliers. The sensitivity and specificity of the individual tests indicate that total catecholamines is marginally the best single test to perform when trying to diagnose neuroblastoma, with the best clinical sensitivity being achieved by examining both total catecholamines and HMMA. Only two of the 174 children with neuroblastoma would not have been detected using these two tests. Total metadrenalines did not appear to add any further information and could be dropped from the repertoire in favour of the other two measurements.

Longitudinal study of thyroid function in Down's syndrome in the first two decades.

AIMS AND METHODS: Thyroid function tests were initially carried out on 122 children with Down's syndrome aged 6-14 years and then repeated four to six years later in 103 adolescents (85% of the group of 122) when they were aged 10-20 years (median 14.4 years). At the second test two were hypothyroid and two with isolated raised thyroid stimulating hormone (IR-TSH) were receiving thyroxine. RESULTS: At the first test there were 98 (80%) euthyroid children: 83 were retested and four (5%) had IR-TSH. At the first test 24 had IR-TSH: 20 were retested and 14 (70%) had become normal. Seventeen with IR-TSH on initial testing had a thyrotrophin releasing hormone test within three months; TSH had become normal in eight (47%) of these children. There was no association between reported clinical symptoms and IR-TSH, but there were clear symptoms in one of the two with definite hypothyroidism. CONCLUSIONS: The likelihood ratio for a positive result on second testing when raised TSH and positive antibody status on first testing are combined is 20. This suggests initial testing results could be used as a basis to select a subgroup for further testing at say five yearly intervals unless new symptoms emerge in the interim. It also suggests that yearly screening (as recommended by the American Academy of Pediatrics, 2001) is probably not justified in the first 20 years of life.

Acetylcholinesterase activity in rectal biopsies: an assessment of its diagnostic value in Hirschsprung's disease.

Acetylcholinesterase (AChE) activity was measured in rectal suction biopsies from 392 patients investigated for Hirschsprung's disease (HD). Results in HD (2.7-23.7 RU; n = 37) were not clearly differentiated from those in patients without HD (0.6-18.0 RU; n = 355). Sample instability was shown not to be a significant cause of error. From analysis of duplicate biopsies and a consideration of false-negative results, tissue inhomogeneity or incorrect siting of the biopsy appeared likely causes of error. Examination of a number of possible diagnostic decision levels indicated an optimal choice of AChE activity greater than 10 RU with an AChE activity not less than 60% of total cholinesterase activity. At a prevalence of 10%, this decision level resulted in sensitivity of 64.9%, specificity 98.7%, predictive value of positive 85.7%, and predictive value of negative 96.3%. The false positives (n = 4) and false negatives (n = 13) by these criteria were examined to detect possible common features.

Congenital hypothyroidism: increased incidence in Asian families.

Screening in the North West health region of England showed a significantly higher incidence of congenital hypothyroidism in Asian families--1/918 compared with 1/3391 in non-Asians. This could only in part be explained by consanguinity. No differences were found in birth order, season of birth, gestational age, or birth weight between normal infants and those with congenital hypothyroidism. There was a significantly higher incidence of additional congenital abnormalities (9%) and a significantly increased mortality (5%) in infants with congenital hypothyroidism compared with unaffected infants.

Increase in urinary growth hormone excretion in puberty.

During the pubertal years the overnight urinary excretion rate of growth hormone (hGHu) increases to three to four times the prepubertal rate, reaching a peak in girls at 13 years and in boys at 15 years. After puberty the mean rate of overnight hGHu is twice that before puberty.

Effects of fasting and oral premedication on the pH and volume of gastric aspirate in children.

The pH and volume of gastric aspirate were measured immediately after the induction of anaesthesia in 224 healthy children to determine the effects of decreasing the period of fasting and of giving oral premedicants before anaesthesia. Fasting for less than 4 h was found to increase the volume of gastric aspirate and the risk of developing pulmonary aspiration syndrome. Trimeprazine syrup was found to increase the pH of the gastric contents, and decrease the likelihood of the pulmonary aspiration syndrome. There was a significant increase in gastric volume in patients premedicated with temazepam elixir which did not occur in patients given temazepam capsules. These results support the custom of fasting patients for at least 4 h before anaesthesia and indicate that oral premedicants and their vehicles can have significant effects on the stomach.

Blood glucose in anaesthetised children. Comparison of blood glucose concentrations in children fasted for morning and afternoon surgery.

Blood glucose levels were measured immediately after induction of anaesthesia and again intraoperatively in 26 children fasted overnight for operations in the morning and 28 children fasted from 8.00 a.m. for afternoon surgery. The mean post-induction glucose concentration of the afternoon surgery group was significantly lower than that of the morning group. However, no child in either group was hypoglycaemic. Anesthesia and surgery caused significant increases in blood glucose levels. It is concluded that pre-operative fasting is well tolerated in healthy pre-school children, regardless of the timing of surgery.