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.     

Upregulated expression of EGF and TGF-α in the proximal respiratory epithelium in the human hypoplastic lung in congenital diaphragmatic hernia

Newborn infants with congenital diaphragmatic hernia (CDH) still have a high mortality rate. Epidermal growth factor (EGF) and transforming growth factor- (TGF-) are peptide growth factors involved in the fetal lung growth and development. The EGF and TGF- have been reported to promote pulmonary branching activity and alveolar type-II pneumocyte proliferation. Epidermal growth factor and TGF- immunoreactivity and mRNA expression in the bronchial and bronchiolar epithelium is maximal during early fetal life and barely detectable in the proximal airways of neonatal lung. The purpose of this study was to determine protein and gene expression of EGF and TGF- in CDH lung in order to elucidate the potential role of these growth factors in the pathogenesis of pulmonary hypoplasia in CDH. Lung tissue specimens were obtained from archival lung tissue from 11 patients with CDH and 5 controls. Indirect immunohistochemistry was performed using ABC method with anti-EGF and anti-TGF- antibodies. In situ hybridization was performed using EGF and TGF- specific digoxigenin-labeled oligonucleotide probes. The most striking difference between hypoplastic CDH lung and control lung was the strong EGF and TGF- mRNA expression and immunoreactivity in the bronchial and bronchiolar epithelium in CDH lung. The upregulated protein and gene expression of EGF and TGF- in the proximal airways in the CDH hypoplastic lung suggests persistence of fetal stage of pulmonary airway development in CDH.     

Familial subluxation of the metacarpophalangeal and proximal interphalangeal joints of the little finger in two consecutive siblings: The “serpentine little finger”

Two consecutive siblings, both males, presented with congenital curly little finger (serpentine finger) caused by subluxations at the metacarpo-phalangeal and the proximal interphalangeal joints. Literature on this phenomenon is scant, and to the best of the authors' knowledge it is probably a new entity. A theory of the possible aetiology is presented.     

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.     

Renal,pancreatic and hepatic dysplasia sequence

A renal, pancreatic and hepatic dysplasia sequene (RPHD sequence) was found in a male premature baby who died a few minutes after birth. Autopsy documented multicystic dysplastic kidneys, a dysplastic pancreas with dilated ducts, cysts, fibrosis and inflammatory infiltrates, prominent portal tracts containing dilated bile ducts and hypoplastic lungs. Other organs were normal. This triad constitutes a dysplastic sequence and was first reported by Ivemark et al. [6] as familial dysplasia of kidneys, liver and pancreas. Since then, this combination of abnormalities has been named polycystic dysplasia [4] and renal-hepatic-pancreatic dysplasia [1], but mostly Ivemark syndrome [8], at the risk of being confused with asplenia-cardiac anomaly syndrome, which was reviewed by Ivemark et al. [5] and also bears Ivemark's name.Abbreviation RHPD renal pancreatic and hepatic dysplasia sequence     

Spondylometaphyseal dysplasia,type VII

Spondylometaphyseal dysplasia was first described by Kozlowski et al. in 1967 as a new dysplastic bone disease, characterized by metaphyseal dysplasia associated with generalized platyspondyly in the vertebral column [1]. Kozlowski et al. have pointed out the autosomal dominant transmission of this disorder at that time. However, later reports showed that the manner of genetic transmission and the degree of the manifestation of the radiological findings could be variable and accordingly seven types of spondylometaphyseal dysplasia were described [2]. In this article, three cases displaying one of the rare forms of spondylometaphyseal dysplasia, type VII are presented and the diagnostic findings as well as the differential diagnostic criteria are discussed.     

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.

     

Recurrent,familial Reye-like syndrome with a new complex amino and organic aciduria

Five of 13 siblings from a Jewish-Ashkenazi family suffered from recurrent Reye-like episodes. During attacks, these patients excreted -keto-adipic, -hydroxy-adipic, and -aminoadipic acids, branched-chain keto acids and saccharopine in addition, to lactic, pyruvic, and dicarboxylic acids characteristic of Reye syndrome. The serum concentrations of citrulline and -aminoadipic acid were elevated and carnitine was at the upper limit of the normal range. Serum acetoacetate level was 4–5 times the -hydroxybutyrate level, but the pyruvate/lactate ratio was normal. Notably, plasma ketone bodies were lower than expected from the degree of catabolism. When the patients were symptom-free, no abnormal amino or organic acids in serum or urine were detected. These findings might be interpreted as a functional impairment at three different biochemical sites: fatty acid -oxidation, dehydrogenase complexes of the pyruvic, -ketoglutaric, -ketoadipic, and branched-chain keto acids, and pyruvate carboxylase. We suggest that in this hereditary disorder a toxic substance, exogenously or endogenously derived, interfered at multiple sites in different metabolic pathways.     

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.     

Renal-hepatic-pancreatic dysplasia: An autosomal recessive disorder with renal and hepatic failure

Abstract We report two brothers with renal dysplasia and congenital hepatic fibrosis. One patient died shortly after birth of lung hypoplasia. The second developed end-stage renal failure at 14 months. The hepatic fibrosis progressed to cirrhosis and hepatic failure. Pancreatic function was normal, but increased echogenicity was seen on ultrasound. At age 3 years and 9 months a successful combined liver-kidney transplantation was performed. The features of our patients are compatible with the renal-hepatic-pancreatic dysplasia syndrome.Conclusion Renal-hepatic-pancreatic dysplasia is an autosomal recessive disorder with variable expression. Combined liver-kidney transplantation offers a new therapeutic option.     

Chronopharmacology of hydrocortisone and 9α-fluorhydrocortisone in the treatment for congenital adrenal hyperplasia

The conventional treatment of CAH with hydrocortisone (16–19 mg/m² per day) and 9-F-cortisol (just enough to normalise renin concentrations, started at 07:00 h) was inffective in suppressing the early morning rise of 17-OH-progesterone and in turn androgens in about 20% of our patients. The present work explored the effect of a modified dosage regimen of the drug in five patients. The schedule was: 03:00 h F 33%+9-F-F 33%; 07:00 h F 30%; 12:00 h F 22%+9-F-F 33%; 17:30 h F 15%+9-F-F 33%.Monitored levels of circulating 17-OH-progesterone, testosterone, and individual urinary 17-ketosteroids showed significant improvement, which was not achieved by giving higher or later evening doses. Menarche was induced in two girls (bone age 15 years). The modified dosage schedule offers on the one hand the possibility of better management of CAH, and on the other, cuts down the risk of enhanced Cushing-like effects, which in animal models have been related frequently to dosage schedules not corresponding to the circadian rhythm. The difficulty of administering the drugs at 03:00 h should be overcome by the development of a late-releasing preparation.Abbreviation CAH congenital adrenal hyperplasia This work was presented in part on the 80th Annual Meeting of the Deutsche Gesellschaft für Kinderheilkunde, September 16–19, 1984, in Tübingen     

The oto-onycho-peroneal syndrome

Two male sibs exhibit peculiar dysplasia of the ears, partial aplasia of the nails, and aplasia or hypoplasia of the fibulae. Gross motor development is severely impaired due to contractures of the hip, knee and ankle joints. Minor craniofacial abnormalities and immobility of several interphalangeal joints are also noted in this new syndrome which may be due to a rare recessive allele, probably autosomal.This paper is dedicated to Prof. K. D. Bachmann, Münster, on the occasion of his 60th birthday     

Proximal phocomelia and radial ray aplasia in fetal valproic syndrome

We describe a child with multiple congenital anomalies born to a women treated with valproic acid (1000 mg/day) for post traumatic epilepsy. Defects included the typical dysmorphism of the fetal valproic syndrome, bilateral radial ray aplasia, unilateral proximal phocomelia of the upper limb, kidney hypoplasia and brain atrophy. A direct teratogenic effect of valproic acid is suspected on an experimental basis, and validated by two previous reports of radial defects after valproic acid exposure.     

A new familial intrauterine growth retardation syndrome the “3-M syndrome”

Two pairs of siblings are described with proportionate dwarfism due to skeletal hypoplasia of prenatal onset. The head size was normal for age and disproportionately large for height. The patients had a characteristic face different from that seen in the Silver-Russell syndrome. The family data are in accordance with autosomal recessive inheritance. In spite of some similarities, the bulk of clinical and genetic evidence suggests that the described intrauterine growth retardation syndrome is different from the Silver-Russell syndrome and presents an apparently new entity which has been designated 3-M syndrome.Supported, in part, by PHS/NIH Grant GM 20 130. Paper No. 1973 from the Genetics Laboratory, University of Wisconsin, Madison. Regarding the term 3-M Syndrome see addendum.     

Tumour necrosis factor in neonatal listeriosis: a case report

A newborn with fatal neonatal listeriosis developed septic shock, neutropenia, thrombocytopenia and profound hypoxaemia due to severe pulmonary hypertension. Tumour necrosis factor , interleukin-1- and interferon- serum concentrations were markedly elevated, suggesting the participation of these cytokines in the aetiopathogenesis of shock induced by Listeria monocytogenes in the neonate.Abbreviations IFN- interferon- - IFN- interferon- - IL-1 interleukin-1 - MPA monocytosis producing agent - TNF- tumour necrosis factor      

Beitrag zur Problematik der Dysplasia renofacialis

Zusammenfassung An Hand eines umfassenden Literaturstudiums werden 170 Beobachtungen mit einer doppelseitigen Nierenagenesie tabellarisch aufgegliedert. Besondere Berücksichtigung erfahren acht Fälle mit einer auffallend langen Überlebenszeit. Über einen eigenen Patienten mit einer Überlebenszeit von 13 Tagen und 2 Std wird ausführlich berichtet. Nach Ausklammerung der in 17% bei Nierenagenesie vorkommenden monströsen Mißbildungen ergab sich folgende klinische und pathologisch-anatomische Konstellation: Agenesie von Nieren und Ureteren bei 100%, typische Gesichtsdysplasie (Potter) bei 82%, Mißbildungen des inneren männlichen und weiblichen Genitale bei 80–100%, Mikrocystis bei 74%, Hypoplasie der Lungen bei 70%, Klumpfüße bei 31%, Deformierungen der Wirbelsäule bei 15%, Analatresie bei 12,5%, fehlgebildetes äußeres Genitale bei 12,5%, Gelenkkontrakturen bei 11,5% der Fälle.Da die gleichen Veränderungen auch bei Nierenhypoplasie, doppelseitiger hochgradiger Cystenniere und Urethraatresie vorkommen, wird die Frage der Eigenständigkeit des Syndromes diskutiert und folgende etwas globale Definition vorgeschlagen: Von einer Dysplasia renofacialis sollte man dann sprechen, wenn bei sogenannter funktioneller Nierenagenesie mit fehlender Urinausscheidung in das Fruchtwasser typische Gesichtsveränderungen in der Regel in Kombination mit einer Lungenhypoplasie beobachtet werden. Verständlicherweise kann über Ätiologie und Pathogenese der Dysplasia renofacialis nach wie vor wenig gesagt werden. Insgesamt müssen wohl zur Zeit exogene Faktoren am ehesten in Erwägung gezogen werden.

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A contribution to the problem of dysplasia renofacialis

Summary Based on a comprehensive study of the literature, 170 cases of bilateral kidney agenesia have been evaluated. Special attention was paid to eight cases with an unusually long survival period. An extensive report is given on a patient in this hospital, whose survival time was 13 days and two hours. Not counting the 17 per cent of cases with monstrous deformities which were found in kidney agenesia, the following clinical and pathologic-anatomical findings were obtained: agenesia of the kidneys and ureters in 100 per cent; typical facial dysplasia (Potter) in 82 per cent; deformities of the internal male and female genital organs in 80 to 100 per cent; microcystis in 74 per cent; hypoplasia of the lungs in 70 per cent; club foot in 31 per cent, deformities of the spine in 15 per cent; analatresia in 12.5 per cent; malformation of the external genital organs in 12.5 per cent; contracted joints in 11.5 per cent of the cases.Since similar changes are also observed in kidney hypoplasia, bilateral advanced cystic kidney, and urethraatresia, the question was raised whether dysplasia renofacialis should be regarded as a syndrom in its own right; the following, some-what far-reaching, definition was proposed: A case should only be described as dysplasia renofacialis if in the presence of a so-called functional renal agenesia (no secretion of urine into the amniotic fluid), typical facial changes are observed which usually go together with a hypoplasia of the lungs. It is of course still impossible to say anything about the etiology and pathogenesis of dysplasia renofacialis. However, the overall impression is that exogenic factors are probably responsible for its occurrence.

     

Reduced-antigen-content-diphtheria-tetanus-acellular-pertussis and inactivated polio vaccine as a booster for adolescents 10 to 14 years of age

High rates of pertussis disease in adolescents suggest that additional boosting against pertussis would be beneficial. A combined acellular-pertussis-containing booster vaccine (dTpa-IPV; Boostrix Polio, n =440) was compared to separately administered dTpa (Boostrix) and inactivated polio virus (IPV; Imovax Polio^®, n =219), and to DTPa-IPV (Infanrix IPV, n =111) vaccine in a partially blind, randomised controlled trial in 10–14 year olds. One month after vaccination, seroprotection/seropositivity rates for all antigens were similar for all groups. Although pertussis and diphtheria antibody geometric mean antibody concentrations were higher after DTPa-IPV, all subjects had protective antibodies against diphtheria, tetanus and polio, and at least 97% had a vaccine response to pertussis antigens. Reactogenicity of dTpa-IPV was comparable to dTpa + IPV, but dTpa-IPV was generally better tolerated than DTPa-IPV. Conclusion:The combined reduced-antigen-content-diphtheria-tetanus-acellular-pertussis and IPV vaccine is immunogenic and well tolerated when administered to adolescents and could be used to improve the control of pertussis disease in this age group.     

Polysomnographic studies and home monitoring of siblings of SIDS victims and of infants with no family history of sudden infant death

We report preliminary results of a prospective study conducted to prevent sudden death in asymptomatic infants. From 1977–1984, 3658 infants were studied polygraphically. There were 923 siblings of SIDS victims and 2735 infants with no personal of family history of SIDS. The infants were studied at 8 weeks of age. Polygraphic risk factors were defined by central apnoeas longer than 15s; periodic breathing above 5% sleep time; or obstructive apnoeas above 3s. In 937 infants risk factors were seen and a second study was requested 4 weeks later. Out of 891 infants re-studied at 12 weeks, 153 still presented some risk factors and were selected for a home monitoring programme; 150 families agreed to monitor their infants at home with a cardiorespiratory monitor with the alarms set at 20s apnoea, and 50 beats per min bradycardia. Repeated alarms were reported for 97/150 (65%) infants; 48/150 (32%) infants were stimulated and 8/150 (5.3%) were resuscitated on at least one occasion. No death occurred during monitoring, which could be interrupted before the end of the first year of life in all infants. In the group of 3459 infants with normal results and not monitored, three siblings (0.35%) and one infant without history (0.04%) died of SIDS. Of the infants with abnormal polygraphic results, one sibling not returned for the second recording, and two out of three infants for whom the parents refused monitoring, died of SIDS. It is concluded that the programme, may prevent the death of some infants, but that the outcome of a child with normal results cannot be foreseen.Abbreviation SIDS sudden infant death syndrome     

Veränderungen von Produktion und Metabolismus des Cortisol bei gesunden Säuglingen nach dreitägiger Depot-ACTH-Gabe

Zusammenfassung Es wird über die Harnausscheidung von Pregnan-3-17-20-triol und Pregnan-3-20-diol nach einer dreitägigen Belastung mit Depot-ACTH bei gesunden Säuglingen berichtet.Die Basalmittelwerte liegen für Pregnantriol zwischen 33 und 37 g/d, für Pregnandiol zwischen 70 und 81 g/d. Nach ACTH kommt es zu einer Zunahme der Ausscheidungsgröße beider Substanzen, wobei sich das Verhältnis für Pregnantriol zu Pregnandiol gegenüber den Basalwerten umkehrt.Diese Umkehrung wird einerseits als Ausdruck einer intensiven Ausnutzung der für die beiden letzten Stufen der Cortisolsynthese maßgeblichen Hydroxylasen aufgefaßt, andererseits auf Grund der deutlichen Zunahme der Pregnantriolausscheidung eine funktionelle Limitierung der C-11-und C-21-Hydroxylase zur Diskussion gestellt.Die gegenüber der des Pregnantriol niedrige Pregnandiolausscheidung ergibt einen Hinweis, daß möglicherweise die Limitierung der enzymatischen Aktivität bei der Differenzierung der einzelnen Corticosteroide im Laufe der Umwandlungen in Richtung Endprodukt zunimmt.

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Summary In this paper we report about the urinary excretion of Pregnan-3-17-20-triol and Pregnan-3-20-diol in infants between 4 and 8 months after a three-day load-test with ACTH-depot.The basal mean-values are between 33 to 37 g/die of Pregnantriol and between 70 to 81 g/die of Pregnandiol. After ACTH-load there is an increase of the excretion of both substances whereas the ratio of Pregnantriol and Pregnandiol gets reciprocal. We consider this beeing a sign of an intensive utilization of the hydroxylating enzymes involved in the two last steps of cortisol synthesis. On the other hand it is possible that there is a functional limit in the activity of C-11-and C-21-hydroxylating enzymes regarding the clear increase of Pregnantriolexcretion.The relatively low values of Pregnandiol opposite to these of Pregnantriol may refer to the possibility that the limitation of the enzyme activities increases in way of performing the different corticosteroids.

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Die Arbeit wurde mit Unterstützung durch die Deutsche Forschungsgemeinschaft durchgeführt.     

Klinische,pathologische und biochemische Untersuchungen in einem Fall von infantiler generalisierter Gangliosidose (GM1-Mucolipidose)

Zusammenfassung Schilderung eines Falles von infantiler generalisierter Gangliosidose infolge Fehlens der -Galaktosidase. Dabei werden das Gangliosid G_M1 und ein Keratan-ähnliches Mucopolysaccharid in Ganglienzellen, Leber, Milz, Niere und Knochenmark gespeichert. Die Eltern des Kindes sind blutsverwandt. Bei einem unter der Geburt verstorbenen Geschwisterkind konnten zwar die gleichen morphologischen Speicherphänomene, nicht jedoch der Enzymdefekt nachgewiesen werden. Auffällig ist die Steigerung der Aktivität der -N-Acetyl-Hexosaminidase bei dem Geschwisterkind und in Fibroblasten der Eltern.

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Clinical, pathological, and biochemical investigations in a case of infantile generalized gangliosidosis (G_M1-mucolipidosis)

Report on a case of infantile generalized gangliosidosis due to deficiency of -galactosidase. There is accumulation of ganglioside G_M1 and a Keratanlike mucopolysaccharide in the brain and viscera. The parents are consanguineous. In a sibling who died during delivery the same morphological phenomena of storage were found but no enzyme deficiency. The activity of -N-acetyl-hexosaminidase was elevated in the sibling and in fibroblasts of both parents.

Herrn Prof. Dr. Dr. H. Mai zum 70. Geburtstag