Impact of different doses of ethinyl oestradiol on reduction of final height in constitutionally tall girls

Fifty-two tall girls were treated for constitutionally tall stature with different ethinyl oestradiol (EE) dosages. They were divided into three different treatment groups: group B (100 g EE/day;n=11); group C (300 g;n=25) and group D (500 g;n=16) and compared with an untreated group A (n=21) matched for age, height, bone age (BA) and height prediction. Using the height prediction method TW II, EE treatment reduced final height compared with the untreated girls in a weak dose-dependent manner, 2.3 cm (100 g/day), 3.0 cm (300 g/day), and 3.8 cm (500 g/day). Such a dose dependency was not found on applying the Bayley-Pineau height prediction method (100 g/day: 4.1 cm; 300 g/day: 4.2 cm; 500 g/day: 4.5 cm). However, there was a striking inverse correlation of the BA at the onset of treatment with the height reduction achieved using the TW II method (r: –0.43;P<0.001). Importantly, girls with a BA below 12 years at the onset of treatment experienced a height reduction of more than 6 cm.The EE dose used in the range of 100–500 g/day is not crucial for the amount of height reduction in tall girls. In general high dose EE treatment should be given restrictively, and especially so in girls with a BA (TW2 RUS-ZH) above 12.0 years.     

Effect of selenium supplementation on the distribution of selenium among plasma proteins of a patient with maple syrup urine disease

Selenium (Se) status was studied in a patient with classical maple syrup urine disease (MSUD) receiving Se supplement. The basal plasma Se concentration was 0.06 mol/l increasing to 2.1 mol/l after 40 days of supplementation. When the plasma Se distribution was analysed by gel filtration, a major peak was seen close to the high molecular weight proteins with a second peak in the albumin region. When the Se dose was decreased in a stepwise manner from 50 g/day to 25 g/day and then to 17 g/day plasma Se decreased, but the proportion of plasma Se in the two protein peaks did not change. In a healthy girl not supplemented with Se, the proportion of plasma Se in the albumin region was somewhat lower. In the MSUD patient glutathione peroxidase activity was initially low, and increased ten-fold during Se supplementation. The study indicates that the Se requirement for plasma glutathione peroxidase activity was fulfilled at the lowest dose of Se used and that Se is incorporated into several plasma proteins after supplementation.Abbreviations MSUD maple syrup urine disease - Se selenium     

Inadequate iron availability as a possible cause of low serum carnitine concentrations in patients with phenylketonuria

A previous observation of decreased serum carnitine concentrations in phenylketonuria (PKU) was investigated in 169 patients either on a strict diet (n=107; median: 8.1 years) or off diet (n=62; median: 15.0 years). Fifty-seven metabolically healthy children (median: 8.5 years) served as controls. PKU patients on a strict diet and older than 2 years had significantly lower serum carnitine concentrations (19.4±5.4 mol/l) than those off diet (29.6±6.7 mol/l). PKU patients on diet also had significantly lower concentrations of haemoglobin and serum ferritin than those off diet. A linear correlation existed between total serum carnitine and ferritin concentrations up to 40 g/l (r=0.52;P<0.01). As iron is an essential cofactor of carnitine synthesis we conclude that reduced endogenous carnitine synthesis due to an inadequate availability of iron may be a major cause of low serum carnitine concentrations. The low carnitine content of the strict and highly protein-reduced diet additionally contributes to a decrease in the serum carnitine concentration. Our results show that a further optimization of the PKU diet increasing either iron availability or carnitine intake should be considered.     

Hypozincaemia in febrile convulsion

To understand further the role of trace elements in the pathogenesis of febrile convulsions, serum zinc (Zn), copper (Cu), magnesium (Mg) and CSF Zn, Cu, Mg and protein levels were measured by spectrometry in patients with febrile convulsion (n=19), bacterial meningitis (n=9), viral CNS infection (n=16) and in the control groupn=10) which consisted of children with signs of meningeal irritation due to upper respiratory tract infection but normal CSF findings. Samples were obtained within 6 h after admission to hospital. Mean serum and CSF Zn levels in the febrile convulsion group were significantly lower than in the other groups (for serum Zn: 0.66±0.03 mg/l vs 0.98±0.07 mg/l, 1.06±0.08 mg/l, 1.05±0.09 mg/lP<0.05; for CSF Zn: 22.96±1.62 g/l vs 75.47 ±6.9 g/l, 50.32±5.235 g/l, 39.85 ±2.81 g/lP<0.05). A linear relationship was established between serum Zn and CSF Zn levels (P<0.001). Mean CSF Zn, Cu and protein levels in the bacterial meningitis group were significantly higher than in the other groups (for CSF Cu 63.94±6.33 g/l vs 38.77±2.70 g/l, 35.84±3.48 g/l, 33.86±2.88 g/lP<0.05; for CSF protein 0.80 ± 0.12 g/l vs 0.22±0.02 g/l, 0.53±0.08 g/l, 0.19±0.01 g/lP<0.05). In children with meningitis, the elevation of the mean CSF Zn and Cu levels may result from the breakdown of the blood-brain barrier and subsequent leakage of trace elements and protein from serum to CSF. There was no significant difference between the four groups in terms of mean serum Mg and mean CSF Mg levels.Conclusion Serum and CSF Zn levels are decreased in children with febrile seizures. Zinc deprivation may play a role in the pathogenesis of febrile seizures.     

Efficacy and safety of salmeterol in childhood asthma

In children with asthma, twice daily administration of salmeterol 25 g, salmeterol 50 g and salbutamol 200 g were compared in two, 3-month, double-blind, parallel group studies, one using metered dose inhalers (MDIs), the other using dry powder inhalers (Diskhaler, DPIs). Both studies were continued for a further 9 months during which time exacerbation rates, lung function at the clinic and adverse events were monitored. Similarities in design and methodology of the two studies justified a combined analysis. Eight hundred and forty-seven asthmatic children aged between 4 and 16 (mean 10.1) years, requiring inhaled beta₂-agonist treatment were randomised to treatment. After a 2 week run-in when all bronchodilator therapy was withdrawn, 279 patients received salmeterol 25 g bd, 290 patients salmeterol 50 g bd and 278 patients salbutamol 200 g bd. After 3 months' treatment the change from baseline in daily morning and evening peak expiratory flow (PEF) was significantly greater with salmeterol 50 g bd than with salbutamol 200 g bd (P<0.001). Salmeterol 50 g bd was also significantly better than salmeterol 25 g bd at improving mean morning PEF (P=0.017) but both treatments had a similar effect on evening PEF. Analysis of variance showed an interaction between baseline PEF less than 100% predicted normal value and treatment outcome. Analysis of this sub-set of patients with lower lung function revealed similar results to the total population although the improvements in PEF from baseline were greater. Data from both studies, showed that the improvement in lung function was maintained throughout 12 months' treatment. Patients receiving salmeterol 50 g bd had significantly more symptom-free nights (P<0.01) and a higher percentage of rescue bronchodilator-free days (P=0.01). The incidence of asthma exacerbations was evenly distributed between the three treatment groups and there was no evidence of any change in the rate of occurrence of exacerbations over the 12 month period. Adverse events were no different across treatment groups or across age groups and were primarily related to the patients' disease state.     

Adrenocortical reserve of neonates born of long-term,steroid-treated mothers

Since corticosteroids have been shown to be transferred across the human placenta, prolonged administration of these drugs during gestation could be expected to suppress the response of the neonatal adrenal gland. Plasma cortisol levels, before and 30 min after the injection of ACTH (36 g/kg), were determined in six neonates who were exposed in utero to prolonged maternal administration of prednisone. The basal plasma cortisol levels of these neonates (6.15±2.57 g%; mean±SEM) were similar to values obtained in eight healthy neonates (5.19±1.36g%). The increment of cortisol levels after ACTH stimulation (16.4±2.07 g%) of the study patients was larger (P<0.01) than the change (10.3±0.82 g%) observed in six older controls. These results indicate a normal neonatal adrenal reserve after prolonged exposure to corticosteroids during fetal life.     

Neutrophil chemotaxis in infants delivered by caesarean section

We evaluated polymorphonuclear leucocyte (PMN) chemotaxis and cortisol levels in cord blood from 15 healthy term infants delivered by caesarean section and from 15 healthy vaginally delivered term infants. Mean neutrophil chemotaxis was significantly higher in infants delivered by caesarean section (78.3±23.4m) than in vaginally delivered infants (57.8±16.6 m;P=0.01). Mean blood cortisol level was significantly lower in infants delivered by caesarean section (9.14±2.76 g/dl) than in infants born by vaginal delivery (20.71±6.98 g/dl;P=0.0001). No relationship was found between PMN chemotaxis and blood cortisol level. The higher neutrophil chemotactic activity observed in infants delivered by caesarean section could be related to general maternal anaesthesia.     

Pharmacodynamics and pharmacokinetics of esmolol,a short-acting β-blocking agent,in children

Summary Esmolol, a short-acting intravenous cardioselective -blocking agent, was evaluated for age-dependent pharmacodynamic and pharmacokinetic features in 17 young patients (6 months to 14 years). A loading dose (500 g/kg/min) alternating with a maintenance dose (25–200 g/kg/min, titrating by 25 g/kg/min every 4 min) was infused until the heart rate or mean arterial pressure decreased 10%. Cardiac index, left ventricular shortening fraction, and systemic vascular resistance were measured at baseline, peak esmolol effect, and recovery. Serum esmolol concentrations were obtained to determine the half-life and the elimination rate constant.Esmolol reduced the heart rate, blood pressure, shortening fraction, and cardiac index in all patients, but it did not change systemic vascular resistance. Maintenance esmolol dose was 118 ±49 g/kg/min, and the half-life was 2.88±2.67 min. Blood pressure and heart rate returned to normal within 2–16 min, but cardiac index and shortening fraction took longer to recover. There were no statistically significant age-dependent pharmacodynamic effects, but blood pressure decreased prior to heart rate and cardiac index took longer to recovery in patients who weighed15kg. The pharmacokinetic profile in young patients was similar to that of older patients, but the half-life was shorter. The only side effeect was transient nausea and vomiting in one patient. Esmolol is a safe and efficacious -blocking agent in young patients.     

Endorphin and cortisol responses to surgical stress in newborns and infants

The beta-endorphin (BE) response to surgical stress in newborns and infants and its relation to pituitary-adrenal dynamics during stress is still unknown. Nine newborns 5 h to 5 days of age, and 5 infants 5 to 10 months old undergoing surgery were studied. All patients were anesthetized with N₂O–O₂ and halothane. Blood samples for BE and cortisol determinations were taken preoperatively and 30 min, 12 h, and 24 h after operation for radioimmunoassay. Both BE and cortisol levels in newborns were not significantly different from those in infants preoperatively (196±85.2 pg/ml vs. 138±47.8 pg/ml for BE and 23.7±17.5 g/dl vs. 10.1±5.6 g/dl for cortisol, P >0.05). At 30 min after operation, no significant increase in BE (220±106 pg/ml) and cortisol (36.1±21.2 g/dl) was found in newborns, while significant increases (BE 493±281 pg/ml, cortisol 43.9±24.2 g/dl) were found in infants compared to preoperative levels (both P <0.05). A significant difference between groups was seen in BE but not cortisol levels 30 min after operation. Both BE and cortisol declined to preoperative values within 24 h after surgery. Our study showed significant BE and cortisol responses to surgical stress in infants, but not in newborns. Factors such as age-related differential responses to the same anesthetic technique, duration of operation, and developmental differences in stress response are considered responsible for the differences.Supported by the Research Grant of Chang Gung Memorial Hospital, CMRP No. 176.     

Intelligence in mild atypical phenylketonuria

In 82 children with mild phenylketonuria (PKU) (blood phenylalanine (Phe) concentrations consistently below 900 mol/l throughout follow up) the relationship between intelligence at age 4 (IQ by Stanford-Binet) and average blood Phe concentrations from birth to 4 years was examined. Of the 82 children 24 had received no treatment. In the group as a whole, and in the 24 untreated subjects alone, mean IQs were significantly below population norms, with deficits of approximately 4.5 points and 9 points respectively. After allowing for social class IQ fell progressively by approximately 6 points for each 100 mol/l rise in mean Phe concentrations in both the treated and untreated subjects. This relationship resembled that previously reported in early treated children with more severe forms of PKU, except that the scale of the relationship was even greater. We conclude that all children whose blood Phe concentrations reach 400 mol/l or above should receive a low Phe diet, at least during the pre-school years, and that the aim should be to control blood Phe levels below 400 mol/l throughout early childhood in all forms of PKU.     

Serum iron,serum transferrin and transferrin saturation in healthy children without iron deficiency

Serum iron, serum transferrin and transferrin saturation were studied in 253 healthy, non-anaemic children 4, 8 and 13 years old, and in 60 healthy, non-anaemic adults having serum ferritin values 15 g/l. One hundred and ninety-six children had serum ferritin values 15 g/l (i.e. replete iron stores), 35 had intermediate ferritin values from 10–14 g/l and 22 had ferritin values <10 g/l (i.e. depleted iron stores). Iron replete children showed a gradual rise in serum iron and transferrin saturation values with age. Serum iron and transferrin saturation values were lower (P<0.001, P<0.0001) and transferrin values high (P<0.0001) in iron replete children compared to adults. Iron replete children had a 2.5 centile transferrin saturation value of 5%; 19.9% of these children had saturation values <15% and 8.2% had values <10%. In iron depleted children a transferrin saturation value <7% yielded the highest diagnostic efficiency as regards exhausted iron stores, although with a low predictive value of a positive test. The transferrin saturation is unsuitable as a single diagnostic criterion in the evaluation of iron deficiency in children and should always be combined with other indicators of iron status.     

Hemoglobin and serum ferritin levels in mothers and infants at birth

Hemoglobin levels and serum ferritin concentrations were measured in cord blood and maternal blood taken a few hours before birth. Maternal serum ferritin levels were 29.1±18.6 g/l which is lower than values given for normal adult women. Serum ferritin levels in cord blood were 144.4±73.2 g/l which is higher than levels in normal adult men. No correlation was found between newborn hemoglobin and serum ferritin levels, or between newborn birth weight and serum ferritin levels.     

Urinary excretion of 17-hydroxypregnanolones in patients with different forms of congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency

To improve diagnostic criteria in different (classical salt-wasting (SW), classical simple virilizing (SV) and non classical late onset (LO)) forms of congential adrenal hyperplasia (CAH) due to steroid 21-hydroxylase deficiency, we investigated the urinary excretion of 17-hydroxypregnanolones (17OH-PO(5) and (5), 15-hydroxypregnanolone(15OH-PO), pregnanetriol(PT) and 11-oxo-pregnanetriol (11-O-PT) compared to hydrocortisone metabolities During the 1st month of life newborn infants with CAH-SW excreted from barely detectable to very large amounts of 17OH-PO(5), 15OH-PO and PT, and, in 12 of 14 cases, also 11-O-PT in their urines. From the 1st to the 28th day of life, cortisol metabolites were virtually absent in urines of CAH-SW infants. This was in contrast of 36 healthy newborn infants. We measured the excretion of 17OH-PO(5) in children with CAH of whom 19 patients with CAH-SV had a median 17OH-PO(5) excretion of 1110 g/day (range: 152–5515). In 21patients with CAH-LO, median excretion of 17OH-PO(5) was 294g/day (range: 66–1273). Besides the conventional metabolites of 17-hydroxyprogesterone (17OH-PO(5), PT and 11-O-PT),no 17OH-PO(5) was detected in the urines of 14 patients with precocious pubarche, in 14 patients with virilization of unknown origin and in 94 healthy children of comparable age. The ratio of 17OH-PO(5) to tetrahydrocortisone (THE) discriminated between CAH-SV and CAH-LO from the 1st to the 18th year of age. The determination of urinary 17OH-PO(5) is an excellent diagnostic method in CAH-SV as well as CAH-LO.     

Serum ferritin and iron status of children in the Faroe Islands

Iron status was assessed by measurement of serum ferritin (S-ferritin), transferrin saturation and haemoglobin (Hb) in 270 healthy Faroese children (153 , 117 ) 4, 8 and 13 years old. There were no significant differences between the three variables in boys and girls. Geometric mean S-ferritin increased from 16 g/l in 4-year-old children to 21 g/l in 8-year-old (P<0.01) and 25 g/l in 13-year-old children (P<0.05). Likewise Hb displayed a gradual increase with age (P<0.001); the arithmetic mean Hb was 129 g/l in 4-year-old, 137 g/l in 8-year-old, and 143 g/l in 13-year-old children. Depleted iron stores (i.e. S-ferritin<12 g/l) were present in 21.5% of 4-year-old, and in 12.7% of 8 and 13-year-old children. Latent iron deficiency (i.e. S-ferritin<10 g/l and transferrin saturation<10%) was found in 3.1% of 4-year-old and in 0.5% of 8 to 13-year-old children. None of the children had iron deficiency anaemia. A high dietary intake of animal protein probably explains the low prevalence of iron deficiency.     

Amine im menschlichen Stuhl

Zusammenfassung Die p- und m-Tyraminausscheidung wurde quantitativ im Stuhl von Neugeborenen, Säuglingen und Schulkindern unter verschiedenen Kostformen untersucht. Der p-Tyramingehalt von normalen Säuglingsstühlen (Naßgewicht) lag zwischen 0,030–0,460 Mol/g Stuhl, der normaler Stühle von Schulkindern zwischen 0,005 und 0,102 Mol/g Stuhl. m-Tyramin ließ sich in Säuglingsstühlen nicht nachweisen. Die Konzentration im Stuhl von Schulkindern überschritt sicher nicht 0,008 Mol/g Stuhl.

---

Summary The excretion of para- and meta-tyramine in faeces was estimated in newborns, infants, and children during the application of various diets. The p-tyramine content of normal stools of infants (wet weight) amounted 0.030–0.460 moles per gr. faeces and that of children 0.005–0.102 moles per gr. m-Tyramine was not detected in the faeces of infants. If this substance is found at all in faeces of children it does not exceed 0.008 moles per gr. of faeces.

---

---

Mit Unterstützung durch die Deutsche Forschungsgemeinschaft.     

Differential effects of oestrogen treatment on the proportionality of growth in tall girls

We studied the differential inhibitory effects of conjugated oestrogens on lower leg length and standing height increments in 17 excessively tall girls compared to a control group of 17 tall healthy untreated girls. Standing height, lower leg length and body weight were recorded at weekly or monthly intervals. Standing height velocity dropped from 150 m/day to 122 m/day, whereas daily weight gain increased from 17 to 48 g/day during oestrogen treatment. The oestrogen induced decrease of standing height velocity could be explained by a marked inhibition of lower leg growth velocity from 42 m/day to 30 m/day (native data) or 35 m/day to 8 m/day (data corrected for weight gain) (P<0.001), whereas no differences of trunk growth velocity could be detected. Thus, the findings strongly suggest that pharmacological doses of oestrogens only affect epiphyseal growth.     

Evaluation of prognostic criteria in extrahepatic bile duct atresia

Extrahepatic bile duct atresias must be classified into four histopathological groups according to the characteristic numerical, metrical, and morphological alterations of the interlobular bile ducts. A prospective study based on an observation period of 5 and more years included 43 patients with extrahepatic biliary atresia. It showed that prognosis is generally dependent on three factors: (1) the duration of cholestasis; (2) the structure of the bile ducts in the praehilaeren Versclussplatte; and (3) the histopathologically defined features of the interlobular bile ducts. The total diameter of all bile duct structures in the praehilaeren Verschlussplatte is unmistakably the most significant finding. A total diameter of more than 400 m indicates a favorable prognostic subtype, while a total diameter of less than 400 m is unfavorable. Even if the prognostically favorable type of finding is present, the ultimate prognosis is determined by the histopathological features of the interlobular bile ducts. Therefore, four characteristic groups must be taken into consideration when evaluating prognosis.     

Evaluation of delta-aminolaevulinic acid excretion in random urine samples of children

Urinary delta-aminolaevulinic acid (-ALA) excretion was evaluated in random urine samples of 191 healthy children, aged 2–14 years, with blood lead levels <0.8 mol/l (mean ± SD: 0.34±0.13), erythrocyte zinc-protoporphyrin <70 mol/mol haem (mean ± SD: 50.4±8.0) and blood haemoglobin >6.8 mmol/l (mean ± SD: 8.2±0.5). It was found that uncorrected -ALA concentration and -ALA/creatinine ratio are age-dependent, whereas the ratio of -ALA/logarithm of creatinine concentration (mean ± SD: 55.3±13.5 mol/log mmol) is independent of age and sex. The authors recommend the use of this parameter for the assessment of -ALA excretion in random urine samples in children     

Gastric secretory function in coeliac disease

Volume, total titrable acidity, total proteolytic activity and pepsin activity have been determined in 14 coeliac patients and in 8 controls of comparable ages and body weights.Basal secretion (B. O.), total outputs (T. O.) and peak outputs (P. O.) after pentagastrin injection have been determined. Peak outputs (values 60 min/kg) of these parameters are as follows: volume 5.0±1.7 ml in coeliacs, 4.3±1.2 ml in controls; total titrable acidity 406.1±155.0 mEq in patients, 296.1±182.4 in controls; total proteolytic activity 962.1±501.1 Eq in coeliacs, 569.6±272.2 in controls; pepsin activity 789.1±521.8 Eq in patients, 447.6±150.4 in controls.     

Die p-Tyramin-Ausscheidung im Urin

Zusammenfassung Die Ausscheidung von freiem p-Tyramin im Urin wurde bei Kindern verschiedener Altersklassen fluorimetrisch nach der Methode von Oates bestimmt.Die Ausscheidung der Säuglinge betrug 1,97±0,75 g/mg Kreatinin, die der Kleinkinder 1,18±0,77 g/mg Kreatinin. Die p-Tyraminausscheidung von unreifen und reifen Neugeborenen schwankte stärker; ihre Ausscheidung lag aber in derselben Größnordnung, wenn keine Hypertyrosinämie vorlag.Bei Kindern mit Eiweißverwertungsstörungen des Darmes (Mucoviscidose und Cöliakie) war die Ausscheidung mit 3,16±1,98 g/mg Kreatinin signifikant erhöht. Keine Erhöhung der p-Tyraminausscheidung fand sich bei Säuglingen mit Toxikose auf dem Boden einer Enteritis.Die Ergebnisse werden im Rahmen der heutigen Kenntnisse über die Bildung und Ausscheidung von p-Tyramin diskutiert.

---

Summary The urinary excretion of p-tyramine was fluorometrically estimated in children of different ages according to the method of Oates.The amount excreted was 1.97±0.77 g per mg. creatinine in infants and 1.18±0.77 g per mg. creatinine in children. If there is no hypertyrosinaemia in immature and mature newborns the excretion of p-tyramine fluctuates to a greater extent especially in the range of lower limits.Children with desturbed protein digestion (cystic fibrosis and coeliac disease) had a significantly increased excretion of p-tyramine (3.16±1.98 g per mg. creatinine). No elevation of p-tyramine excretory rates was in infants with severe enteritis. The results are discussed together with our present-day knowledge on synthesis and excretion of p-tyramine.

---

---

Mit Unterstützung durch die Deutsche Forschungsgemeinschaft.