α-aminoadipic aciduria and persistence of fetal haemoglobin in an oligophrenic child

The case of a mentally retarded girl with a number of dysmorphic features, Raynaud's phenomenon, hypotonia and petit mal seizures is presented. Laboratory investigations showed -aminoadipic aciduria and a high level of fetal haemoglobin. Oral l-lysine loading resulted in a marked increase of -aminoadipic acid in blood and urine. After 3 months of pyridoxine medication the increase of -aminoadipic acid in blood and urine during the oral l-lysine loading test was less than in the test before treatment. A normal degradation rate of dl--amino [1-¹⁴C] adipic acid in fibroblasts of the patient, as measured by ¹⁴CO₂ production, did not indicate a primary enzyme defect in the -aminoadipic acid transamination or decarboxylation steps.The persistent HbF could be the result of stress on the erythropoiesis by a secondary induced defect in an early stage of haemoglobin synthesis in which -amino--ketoadipic acid, a structural analogue of -aminoadipic acid, is an intermediate.     

Sisters with α-mannosidosis and systemic lupus erythematosus

Alpha-mannosidosis is an autosomal recessive disorder caused by deficiency of lysosomal -mannosidase (LAMAN). Here, we report two sisters with -mannosidosis who developed systemic lupus erythematosus (SLE). The sisters were both homozygous for a one bp deletion within the LAMAN gene resulting in a truncated gene product. The coincidence of -mannosidosis and SLE are discussed with regard to both clinical and molecular findings. Conclusion:-mannnosidosis may contribute to the onset of systemic lupus erythematosus in predisposed patients.Abbreviations ACR American College of Rheumatology - LAMAN lysosomal -mannosidase - SLE systemic lupus erythematosus     

The unreliability of mean corpuscular volume and mean cellular hemoglobin determinations in the diagnosis of α-thalassemia in newborn infants

Mean corpuscular volume (MCV) and mean cellular hemoglobin (MCH) were determined by means of a Hemalog 8/90 electronic counter in 51 full-term newborn infants with -thalassemia-2 and 15 with -thalassemia-1, as well as in 150 normal newborn infants. The mean MCV and MCH values were 92 fl±06 and 33.26 pg±2.22 in the normal newborn infants, 82 fl±07 and 29.40 pg±2.60 in the -thalassemia-2 subjects, and 73 fl±06 and 26.07 pg±2.05 in the -thalassemia-1 subjects. Four of the 150 normal newborn infants had MCV's<79 fl and MCH's<29.00 pg whereas 5 of the -thalassemic subjects had MCV's>90 fl and MCH's>32.00 pg. We conclude that MCV and MCH determinations are unreliable in the diagnosis of -thalassemia in the neonatal period.     

Serum tumour necrosis factor in newborns at risk for infections

Tumour necrosis factor- (TNF-) is an important mediator in the pathogenesis of Gram-negative shock. In order to assess the role of TNF- as a marker of the severity of infections in the neonates, serum TNF- concentrations were determined at the time of septic work-up in 69 newborns (gestational age: 28–40 weeks). Nine patients had systemic infection (group A), four of them with signs of circulatory failure. Eleven patients had positive cultures of gastric aspiration or placental smears (group B) and 49 patients had completly negative septic work-up. Patients of group A had significantly more elevated serum TNF- levels than patients of group B and C. Within group A, patients with circulatory failure had mean serum TNF- concentration of 2165±817 pg/ml versus 27±8 pg/ml in newborns without shock. Serum TNF- concentrations of more than 15 pg/ml detected systemic infections in eight out of nine patients. The specificity was 98% (1 elevated TNF- concentration out of 60 non infected patients). These data indicate that premature neonates and term newborns are able to produce TNF- when they are infected. Highly elevated TNF- concentrations are found in severe systemic infections causing cardiovascular impairment.     

Age-dependency of alpha- and beta-adrenoceptors on thrombocytes and lymphocytes of asthmatic and nonasthmatic children

Among the possible mechanisms which may cause wheezing or asthmatic episodes a genetically determined -adrenoceptor blockade and a hyperresponsiveness of -andrenoceptors has been postulated. Evidence to support this hypothesis stems from an increased bronchial sensitivity to -blockers, a reduced formation of cyclic AMP in response to -adrenergic stimulation and enhanced -adrenergic responses in asthmatic subjects. The recent development of techniques for measuring the specific, high-affinity binding of radiolabeled -and -adrenergic antagonists made it possible to study - and -adrenoceptors in vitro. Based upon the assumption that a change in the number and/or affinity of adrenergic receptors might be a general phenomenon, we have performed - and -receptor binding studies on lymphocytes and platelets from wheezing infants and asthmatic children as well as of infants, children, and adults not suffering from these diseases.Using ¹²⁵[I]-cyanopindolol (ICYP) and ³[H]-yohimbine (HYOH) as highly specific ligands for - and -adrenoceptors, the following results were obtained: (1) Lymphocytes and platelets from control subjects and asthamatics bound similar amounts of ICYP and HYOH and thus showed no differences either in the number or the affinity of - and -adrenoceptors. Lymphocytes and platelets of wheezing and nonwheezing infants also bound the same amounts of the radioligands. (2) In asthmatic children receiving 4×2 puffs salbutamol -adrenoceptor were down-regulated and this may mimic -adrenoceptor blockade. (3) When subjects were divided into four categories according to age (0–5, 5–10, 10–20 years, adults) the number of -adrenoceptor binding sites showed an age-dependent increase. The number and affinity of -adreneceptor binding sites on platelets was neither influenced by age nor disease.It is concluded that the - and -adrenoceptors of wheezing infants and asthmatic children at least on blood cells are normal. However the -adrenoceptors show an age-dependent maturation process, which may account for an unresponsiveness to -adrenoceptor agonists in wheezing infants.Supported by a grant from the Ministerium für Wissenschaft und Forschung, NRWPresented at the 19th Workshop for Pediatric Research, University of Göttingen, March 10–11, 1983     

Effects of immunoglobulin and gamma-interferon on the production of tumour necrosis factor-α and interleukin-1β by peripheral blood monocytes in the acute phase of Kawasaki disease

Abstract In order to study the in vitro effects of intact immunoglobulin (Ig) and gamma-interferon (INF-) in patients with Kawasaki disease, the production of tumour necrosis factor- (TNF-) and interleukin-1 (IL-1) was measured in peripheral blood monocytes (PBM) both before and after intravenous immunoglobulin (IVIG) therapy. Spontaneous production of TNF- and IL-1 both before and after IVIG therapy was significantly higher than in healthy controls. Intact Ig enhanced in vitro the production of TNF- and IL-1 both before and after IVIG therapy approximately 3–4 times as compared to the spontaneous production. INF- did not affect the production of the two cytokines. Ig enhanced IL-1 mRNA expression in PBM of KD by 3–8 times more than that of spontaneous production.Conclusion These results suggest that: (1) the mechanism of action of IVIG therapy in KD is not to cut down the production of inflammatory cytokines such as TNF- and IL-1 andf that (2) the changes of these cytokine levels may be related to the clinical effectiveness of high dose IVIG.     

Die α-Amylase-Aktivität im Harn gesunder Schulkinder

Zusammenfassung Durch die Einführung der Mikro- und Ultramikromethode von Street u. Close zur Bestimmung der -Amylase-Aktivität in die klinischen Laboratorien wurde die Überarbeitung der bisherigen Normalwerte dieses Enzyms in den einzelnen Altersklassen und Körperflüssigkeiten erforderlich.In dieser Studie wurden 210 Schulkinder im Alter zwischen 6 und 12 Jahren auf ihre -Amylase-Ausscheidung im Harn untersucht. Der Test wurde unter Standardbedingungen an einer Greifswalder Oberschule mit einer dreistündigen Sammelperiode zwischen 7.45 Uhr und 10.45 Uhr durchgeführt. Wie schon in früheren Untersuchungen konnte auch an diesem Probandengut ein altersbezogener Anstieg der -Amylase-Aktivität und der Gesamtausscheidung der -Amylase mit dem Harn in der Zeiteinheit innerhalb zweier Altersklassen festgestellt werden. Geschlechtsgebundene Differenzen wurden nicht gefunden.Der Normalbereich der -Amylase-Aktivität im Harn für Schulkinder im Alter zwischen 6 und 12 Jahren wurde zwischen 40 und 250 SCE pro 100 ml Harn und die Gesamtausscheidung innerhalb von 3 Std mit 25-200 SCE bestimmt. Es besteht eine Korrelation zwischen der -Amylase-Ausscheidung mit dem Harn und dem spezifischen Gewicht des Harns. Die eigenen Befunde werden mit neueren Angaben der Literatur verglichen und interpretiert.

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The -amylase activity in the urine of healthy school children

Summary The introduction of new laboratory methods requires a review of the normal values. The micro- and ultra micro method for the determination of -amylase activity by Street and Close, already used successfully by many laboratories, allows the determination of enzyme activity in many biological fluids but calls for a re-assessment of the so-called normal values. In this study the results of determinations done on 210 school children are presented. The tests were perfomed with urine samples from a three hour period, collected under standard conditions. An exact statement of the quantity of -amylase excreted with the urine per unit of time was thus made possible.The 210 children belonged to two age-groups: either 7–8 or 11–12 years old. The three parameters determined from the three hour sample were: Quantity, specific weight, and -amylase activity. We were able to confirm our own earlier findings that the enzyme activity increases with age, in both, activity and quantity. Significant sex-dependent differences were not observed. The normal range of values of -amylase concentration in urine was found to be between 40 and 250 SCU (Street-Close Units) per 100 ml urine and the total excretion within three hours ranged from 25-200 SCU. A correlation between -amylase concentration and specific weight of the urine was not observed. This form of test implies an improvement of the diagnostic possibilities.

     

α-l-Iduronidase activity in leukocytes: Diagnosis of homozygotes and heterozygotes of the Hurler syndrome

The activity of -l-iduronidase was determined in leukocytes from two patients with the Hurler syndrome, five obligatory heterozygotes, one patient with the Hunter syndrome, and ten normal individuals. It was found that the determination of -l-iduronidase in leukocytes was a useful method for differential diagnosis between the Hurler and Hunter syndromes. Heterozygotes of the Hurler syndrome showed approximately 50% level of -l-iduronidase activity in leukocytes as compared with that of normal individuals.This suggests that the determination of -l-iduronidase activity may be available for the carrier detection of the Hurler syndrome.     

α-Amylase activity in sweat and serum of patients with cystic fibrosis of the pancreas

The hypothesis by Doggett and Harrison, according to which -amylase is the pathogenic factor of the exocrinopathy in cystic fibrosis (C.F.), is investigated. No elevation of -amylase in sweat and serum of C.F. patients, as compared with controls of similar age, is observed. It is concluded that the C.F. factor cannot be identified with -amylase.This work is part of a doctor's thesis.     

Familiärer mangel und α 1

Zusammenfassung Es wird über zwei Kinder aus zwei Familien mit Mangel an ₁ berichtet. Homozygote Defektträger wiesen etwa 15–25%, heterozygote 50–75% des mittleren normalen Serumspiegels auf. Unter 100 Blutspendern fanden sich 5 mit erniedrigten ₁ wie bei heterozygoten Defektträgern.Klinische Auswirkungen des Gendefektes waren im Kindesalter nicht zu erkennen, insbesondere keine Enthemmung der Fibrinolyse.

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₁ deficiency in two families

Two children from two different families with ₁ deficiency are described. Deficient subjects had 15–25% of normal serum ₁ levels in case of homozygosity and 50–75% in case of heterozygosity. Among one hundred healthy blood donors five had serum ₁ levels below 150 mg% corresponding to the levels found in heterozygous deficiency carriers.In the two children described the gene defect had no clinical consequence; fibrinolysis, in particular was not increased.

     

Accumulation of pristanic acid (2, 6, 10, 14 tetramethylpentadecanoic acid) in the plasma of patients with generalised peroxisomal dysfunction

The plasma of some patients with biochemical evidence of a generalised peroxisomal dysfunction (GPD) show greatly increased levels of phytanic acid as well as its -oxidation product, pristanic acid (2, 6, 10, 14-tetramethylpentadecanoic acid). Increased amounts of 14- and 16- carbon branched chain fatty acids are also found in some of these patients. As pristanic acid is present in normal or near-normal amounts in classical Refsum disease and rhizomelic chondrodysplasia, two disorders characterised by deficiencies in phytanic acid oxidation, we speculate that its accumulation is not secondary to a defect in the -oxidation of phytanic acid, but is indicative of a block in the peroxisomal -oxidation of pristanic acid. The finding of phytanic acid, as well as a number of its metabolites in patients with inherited defects in peroxisomal biogenesis indicates that a number of the steps in phytanic acid degradation may be confined to peroxisomes.Abbreviations GPD generalised peroxisomal dysfunction - VLCFA very long chain fatty acids - THCA 3, 7, 12-trihydroxy-5-cholestan-26-oic acid - br branched chain fatty acid - ALD adrenoleukodystrophy - DHAPAT dihydroxyacetone phosphate acyltransferase     

Increased expression of EGFR and TGF-α in segmental renal dysplasia in duplex kidney

Renal dysplasia (RD) is a disorganised development of renal parenchyma that results in a deficit of functional renal tissue. It is known that the epidermal growth factor (EGF) and the transforming growth factor- (TGF-) enhance renal cell proliferation, migration and differentiation during kidney development through binding to the same EGF receptor (EGFR). The aim of the study was to analyse the expression of TGF- and EGFR in the dysplastic kidney. The specimens of dysplstic upper poles duplex kidneys were surgically resected from 19 patients. Indirect immunohistochemistry was performed using the ABC method employing antibodies against EGFR and TGF-, and gene expression using primers specific to the human genes. There was absent or weak EGFR and TGF- immunoreactivity in normal kidney tissue. In dysplastic kidneys, there was strong TGF- and EGFR immunoreactivity in the epithelium of primitive tubules and strong EGFR immunoreactivity in the connective tissue around the primitive tubules. Our findings of markedly increased local expression of EGFR and TGF- in primitive tubules suggest that EGFR and TGF- may play an important role in altering renal morphogenesis resulting in renal dysplasia.     

Fetal bile acids in congenital biliary atresia —production in the liver and clinical significance

The 1-hydroxy bile acids have been said to be fetal bile acids. These bile acids were evaluated in eight patients with congenital biliary atresia (CBA) using gas chromatography-mass spectrometry. At the time of operation 1,3,7,12-tetrahydroxy-5-cholan-24-oic acid (CA-1-ol) and 1,3,7-trihydroxy-5-cholan-24-oic acid (CDCA-1-ol) were 0.46 ± 34 g/ml and 0.72 ± 0.45 g/ml, respectively, which was significantly higher than in the control group. The percentage CA-1-ol of total bile acids showed a tendency to decrease as age advanced. The grade of hepatic fibrosis ranged from F₂ to F₃ and the values and percentages of CA-1-ol and CDCA-1-ol were relatively higher in F₂ than F₃ patients. The percentage of total bile acids gradually increased in patients without sufficient bile flow but fell sharply after Kasai's procedure in the patients with sufficient bile flow. It appears that fetal bile acids are produced in the livers of CBA patients in the same way as in fetal liver, and that production continues in patients without good bile secretion even after Kasai's procedure. These results suggest that these hydroxylases are reactivated in CBA patients.     

Cholic acid,chenodeoxycholic acid,alpha-1-fetoprotein and alpha-1-antitrypsin serum concentrations in breast-fed infants with prolonged jaundice

Thirteen breast-fed one-month-old infants with prolonged jaundice not due to known causes were included in this study. All infants were investigated at one and twelve months of age. Serum concentrations of total (TB) and conjugated bilirubin (CB), aspartate (ASAT) and alanine aminotransferase (ALAT), alkaline phosphatase (AP), -1-antitrypsin (-1-AT), -1-fetoprotein (AFP) and the two primary bile acids; cholic (CA) and chenodeoxycholic acid (CDCA) were determined at both ages. The Pi-phenotype of -1-AT was determined at the age of twelve months. The serum concentrations of TB, CB, AP and AFP were elevated at the age of one month but were normal at the age of twelve months. No changes in the serum concentrations of ASAT or ALAT were observed between one and twelve months of age, and the values were within the reference ranges. The serum concentrations of -1-AT were within the reference range at both ages. Two infants were heterozygous for MZ, and they had normal serum -1-AT concentrations. The serum concentrations of CA and CDCA were elevated at the age of one month and were still significantly elevated at the age of twelve months indicating that the infants had slight cholestasis at the age of one month, and that the cholestasis had largely subsided by the end of the first year of life.     

Proliferation of intrahepatic bile-duct epithelium in biliary atresia

Proliferating cell nuclear antigen (PCNA) and transforming growth factor (TGF) are considered as markers of cell proliferation. The expression of PCNA and TGF was evaluated immunohistochemically using anti-PCNA antibody and TGF in 31 patients with biliary atresia (BA) (15 jaundice-free and 16 with persistent jaundice) and 6 control infants. The labeling indices (LI) for PCNA- and TGF-positive bile-duct epithelium in BA were 14.1±14.0% and 51.4±33.7%, respectively, which was significantly higher than in the controls (P <0.01). In BA, the number of PCNA-immunoreactive cells was higher in the peripheral bile ductules than in the central bile ducts of the portal tract (P <0.01). LI was not related to patient age at the time of hepatic portoenterostomy in two groups divided at the age of 60 days. Patients in the persistent jaundice group had greater expression of PCNA and TGF (21.7±16.0% and 76.9±20.7%, respectively) compared to those in the jaundice-free group (6.0±2.7% and 24.3±20.9%, P <0.001). PCNA and TGF expression in the bile-duct epithelium of the portal tract was closely related to prognosis in BA patients, and thus could be useful as a prognostic marker.     

Peritoneal dialysis in maple-syrup-urine disease: Studies on branched-chain amino and keto acids

We report biochemical data on a child with MSUD who underwent peritoneal dialysis for severe metabolic imbalance. In confirmation of earlier data, the BCKA/BCAA ratios in blood had been found to be fairly stable in this patient during long-term dietary therapy.The child became comatose at comparatively low levels of leucine and KICA (ca. 2 mM each). At this time the blood/cerebrospinal fluid ratio for BCAA's and BCKA's was markedly diminished. During peritoneal dialysis, peritoneal clearance was highest for KIVA, but less for MEVA and BCAA's (40–50% or urea clearance), and least for the allegedly most toxic metabolite, KICA. The differences for BCKA's may be due to their differential protein binding. Given these individual differences, 1.8 to 8.7 initial plasma volumes were cleared in 14h with 24.21 of dialysis fluid. In the same time, urinary excretion of BCAA's and BCKA's was much less efficient.The data are discussed with regard to the pathobiochemical significance of high tissue levels of branched chain acids. A quantitative comparison between peritoneal dialysis and exchange transfusion is not yet possible.Abbreviations BCAA's branched-chain -amino acids - BCKA's branched-chain -keto acids - KICA -keto-isocaproic acid - KIVA -keto-isovalerio acid - MEVA -keto--methyl-n-valeric acid - MSUD maple syrup urine disease With support of the Landesamt für Forschung des Ministeriums für Wissenschaft und Forschung des Landes Nordrhein-Westfalen. U.L. was supported by Deutsche Forschungsgemeinschaft, Bad Godesberg, G.F.R. (DFG La 201, Schwerpunkt Biochemische Humangenetik and SFB 33 Nervensystem und biologische Information)     

Intrahepatic hematoma: hepatic lesion in a newborn with high α-fetoprotein level

Hepatic hematomas are relatively common in fetuses and neonates; most are subcapsular in location. Sometimes their imaging features can be non-specific, so differentiation from other aggressive lesions like hepatoblastoma can be difficult, especially if there is a concurrent high -fetoprotein level. We report a case of intrahepatic hematoma with a rising -fetoprotein level.     

Elastase α1 proteinase inhibitor complex,granulocyte count,ratio of immature to total granulocyte count,and C-reactive protein in neonatal septicaemiaproteinase inhibitor complex,granulocyte count,ratio of immature to total granulocyte count,and C-reactive protein in neonatal septicaemia

In a prospective study elastase ₁-proteinase inhibitor (E₁PI), polymorphonuclear (PMN) count, the immature to total neutrophil count ratio (I/T ratio), and C-reactive protein (CRP) were analysed in 74 patients (76 cases) with neonatal septicaemia at the time of initial clinical symptoms. At that early stage of the disease, 94% of the patients had abnormal values for E₁PI, 71% for I/T ratio, 61% for PMN count, and only 54% for CRP. PMN count was a poor indicator of septicaemia. Neutropenia, present in 26% of all patients, was related to normal E₁PI in only 4 patients. The combined use of E₁ and I/T ratio was the most sensitive indicator. In all patients irrespective of causative bacteria or disease onset at least one of these parameters was elevated. In early-onset septicaemia (n=31), normal CRP values occurred significantly more often (63%) than in late-onset sepsis (33%). Even in five of the seven fatal cases, initial CRP measurements were normal. The sensitivity of PMN count and I/T ratio did not differ significantly between early-and late-onset septicaemia. Laboratory changes observed in 18 newborns during the first 3 days of the septic episode show that the rate of pathological values for E₁PI and I/T ratio was highest at the time of initial clinical symptoms and decreased on days 2 and 3. In contrast, CRP reached maximal values as late as day 2 (88% abnormal values), followed by a decrease on day 3. We conclude that the use of E₁PI may improve the laboratory detection of neonatal septicaemia especially if used in combination with I/T ratio.     

Treatment of an aggressive haemangiomatous lesion with alpha-interferon

We report an infant who presented with an aggressive haemangiomatous lesion of the right thigh that was treated successfully with -interferon.     

Cytokines predict coronary aneurysm formation in Kawasaki disease patients

In this study, we measured serially the serum levels of cytokines including interleukin-6 (IL-6), IL-8, soluble IL-2 receptor (sIL-2R) and tumour necrosis factor (TNF-) in 60 patients with Kawasaki disease (KD) and evaluated the clinical significance of these cytokines in predicting coronary aneurysm formation. Of the 60 patients, 12 were complicated with coronary aneurysm. Blood samples were collected within the 1st week after onset of fever, then once a week for the 1st month, and once a month for another 5 months. The serum levels of IL-6, IL-8, sIL-2R and TNF were measured using an ELISA or RIA method. Our results show that the changes in serum IL-6 and IL-8 were faster than those of sIL-2R and TNF. Within the 1st week, the serum levels of IL-6 and IL-8 were significantly higher in the patients with than in those without coronary aneurysm (P<0.001). In addition, the serum levels of IL-6 and IL-8 obtained in the 1st week were highly correlated (P<0.001) with those of C-reactive protein and erythrocyte sedimentation rate, and the serum levels of sIL-2R and TNF were also increased at the 1st week reaching the highest level in the 2nd week. In the 2nd week, the serum levels of sIL-2R and TNF were significantly higher in the patients with than in those without coronary aneurysm (P<0.05). These findings suggest that the serum levels of IL-6 and IL-8 obtained in the 1st week may serve as useful parameters in predicting coronary aneurysm formation in KD patients.