Familial clustering of infantile cirrhosis in Northern Germany: A clue to the etiology of idiopathic copper toxicosis.

Two cases of infantile liver cirrhosis of unknown origin occurred in a circumscribed rural area of Northern Germany. Both children had increased dietary copper exposure. The search for additional cases of what appeared to be idiopathic copper toxicosis (ICT) revealed a cluster of affected infants in this region, raising questions about the relative importance of genetic and environmental factors that are considered to be etiologic. We gathered clinical and pathologic data concerning the patients, analyzed the pedigrees of affected families, and searched for possible environmental factors contributing to the pathologic process. We encountered 8 cases of infantile liver cirrhosis in 5 families in Emsland, a circumscribed and predominantly rural area of Northern Germany; ICT was definitely proven in 2 cases. Clinical presentation and liver pathology in 6 additional cases were consistent with the diagnosis of ICT. Pedigrees of affected families revealed complex relationships with occasional consanguinity of parents, suggesting autosomal recessive inheritance. The households were served by private wells with water of low pH flowing through copper pipes, suggesting the possibility of increased alimentary copper exposure. These findings support earlier conclusions that ICT develops when an infant with a genetic predisposition is exposed to a copper-enriched diet.

Stearic acid oxidation in the Alaskan red-backed vole: effects of cold and norepinephrine.

Saturated fatty acids constitute a considerable energy reserve that could convey survival value under chronic cold exposure. It was investigated whether acclimation to cold was associated with a change in the ability of a small microtine rodent, the red-backed vole (Clethrionomys rutilis), to increase the use of saturated fatty acids during thermogenesis. The C-14 labeled stearic acid, a typical saturated fatty acid (FA), was used to determine the rate of utilization through oxidation. In warm acclimated (WA, 20 degrees C) and cold acclimated (CA, 5 degrees C) voles, acute cold exposure (WA at 5 degrees C, -2 degrees; CA at -5 degrees C) and norepinephrine (NE) injection increased metabolic rate (VO2, VCO2) and mobilization of lipid reserves. Acute cold exposure increased percent blood stearate oxidized in a linear fashion with both metabolic rate and stearate concentration in both WA and CA voles. The CA voles at 5 degrees C had increased stearate irreversible loss (1.5x) and oxidation rate (2x) compared to WA voles at 20 degrees C. The CA voles at -5 degrees C increased stearate irreversible loss and oxidation linearly with metabolic rate and blood stearate concentration. In CA voles the contribution made by stearate oxidation to VCO2, increased with the level of cold exposure and NE injection. In contrast, for WA voles stearate irreversible loss and the contribution made by stearate oxidation to VCO2 were unaffected by acute cold exposure. Thus, cold acclimation involves: (1) a modest increase (1.5x) in the use of stearate as a fuel substrate; and (2) a greater stearate oxidation and contribution to overall metabolism during acute cold exposure (-5 degrees C).

Proteinuria and other renal functions in Wilson's disease.

Renal lesions have repeatedly been described in Wilson's disease (WD). We investigated the excretion of total protein, albumin, low (LMW) and high molecular weight (HMW) proteins, N-acetyl-beta-D-glucosaminidase (NAG), and calcium, as well as creatinine clearance, in 24-h urine samples of 41 patients with WD aged 6-37 (mean 17) years who had been treated for a period of 0-15 (mean 4.5) years with D-penicillamine (900 mg/day). The amount of all protein excreted was significantly increased compared with controls, 39% of patients presenting with total proteinuria more than two standard deviations from the mean of controls. The changes in protein excretion depended on the duration of treatment. LMW proteinuria was elevated almost exclusively in the first 2 years after the start of treatment, indicating early tubular damage. This is supported by an initially high excretion of beta 2-microglobulin, NAG, and calcium. Increased excretion of HMW proteins, including albumin, persisted over longer periods, which suggests glomerular injury in some patients, possibly related to the use of D-penicillamine. Creatinine clearance remained roughly within normal limits. We propose that renal function should regularly be checked in patients with WD.

Functional comparison of PML-type and archetype strains of JC virus.

Isolates of the human polyomavirus JC can be grouped as either PML-type or archetype strains primarily on the basis of divergence in their regulatory regions. Only PML-type viruses have so far been found to be associated with the human demyelinating disease progressive multifocal leukoencephalopathy. Here we have compared the functional properties of archetype and PML-type regulatory regions with regard to DNA replication and viral gene expression. No significant differences could be detected between archetype and PML-type regions in their ability to direct episomal DNA replication in the presence of JC virus T antigen. When viral gene expression was examined, early- and late-gene promoters from all PML-type strains exhibited a significantly higher activity in glial than in nonglial cells. Surprisingly, archetype strain promoters were also preferentially active in glial cells, although this effect was less pronounced than in PML-type strains. Furthermore, all promoters from archetype strains reacted to the presence of viral T antigen or the glial transcription factor Tst-1/Oct6 in a manner similar to the promoters of the PML-type viral strain Mad-1. Interestingly, T antigen and Tst-1/Oct6 were found to function in a species-specific and cell-type-specific manner, respectively. We concluded from our experiments that the differences in the regulatory regions cannot account for the different biology of archetype and PML-type viral strains.

Late diagnosis of Wilson's disease in a case without onset of symptoms.

Wilson's disease (WD) was diagnosed on the basis of a liver biopsy, blood investigations and a radio copper test in a 60-year-old, neurologically normal female with uncharacteristic gastrointestinal complaints. Since this patient never developed symptoms indicative for WD this case suggests the possibility of a subclinical course of untreated WD.

[Fibrosing alveolitis in a 7-year-old girl with autoimmune hemolytic anemia and autoimmune hepatitis]. / Fibrosierende Alveolitis bei einem sieben Jahre alten Mädchen mit autoimmunhämolytischer Anämie und Autoimmunhepatitis.

A Coombs-positive haemolytic anaemia with proof of heat autoagglutinins and autoantibodies against cell nuclei was diagnosed in a girl, now 7 1/2 years of age, in the sixth month of her life as a sequel to jaundice. Shortly afterwards liver biopsy yielded a confirmed diagnosis of giant cell hepatitis. The signs of the disease receded under treatment with decortin and imurek. An attempt to discontinue the medication at 5 1/2 years of age resulted in a histologically confirmed recurrence of autoimmune hepatitis. When the patient was 5 years old, the x-ray revealed a mainly interstitial pneumonia; at 6 years of age, bronchiectases in the region of the left lower lobe were confirmed by bronchography. Resection of the lower lobe was performed after occurrence of atelectasis. Histopathological findings confirmed fibrotic alveolitis associated with giant cells. Based on the overall clinical course and the histological and immunological findings, autoimmune etiology of fibrotic alveolitis must be discussed. Progression of the disease could be avoided during the past 6 months by intensifying the immunosuppressive prednisolone therapy.

Thermoregulation, growth, and reproduction in Alaskan collared lemmings: role of short day and cold.

To assess factors controlling seasonal thermoregulatory and reproductive changes, collared lemmings (Dicrostonyx groenlandicus) were exposed for 16 wk to long day (LD, 22 h light: 2 h dark) and warm (15 +/- 3 degrees C), LD and cold (1 +/- 0.5 degrees C), short day (SD, 4 h light: 20 h dark) and warm, SD and cold or acclimatized to outdoor winter conditions (OUT). Hair length and color, body mass, and food intake were monitored weekly. Resting metabolic rates (RMR) and nonshivering thermogenesis (NST) were estimated several times by measuring oxygen consumption before and after norepinephrine injections. Body composition and reproductive condition were determined at the end of the experiment. SD and OUT groups had a 15.8% lower (P less than 0.01) RMR at 7 degrees C than the LD groups. Lower thermal conductance in SD and OUT animals appears due to molt to white winter pelage, which occurred by week 3 in SD but not in LD groups. Neither SD, cold, nor OUT altered NST or reproductive morphology. SD-exposed lemmings showed 19.2% greater growth than those in LD, resulting primarily from a 29.2 and 15.0% increase in lean and ash components, respectively. Cold exposure increased food intake by 34.7%. Results suggest that the pineal gland, which mediates SD effects, may influence molt and growth but not NST or reproductive morphology.

Alteration of the lung parenchyma associated with autoimmune hepatitis.

The clinical history, radiological and histomorphological alterations of the lung parenchyma associated with chronic active autoimmune hepatitis are described. A 6-month-old female infant developed chronic active autoimmune hepatitis associated with autoimmune haemolytic anaemia. She was treated with immunosuppressive drugs, including steroids, for more than 6 years and developed symptoms and radiological signs of interstitial pneumonitis 4 years after onset of the autoimmune hepatitis. Associated bronchiectasis was detected 1 year later. No abnormalities of lung defence mechanisms could be demonstrated. Resection of the sixth left segment and of the basal parts of the left lower lobe revealed honeycombing with changes in the lung parenchyma which included chronic interstitial pneumonitis with multinucleate giant cells, seen predominantly in the distal airways, marked diffuse interstitial mononuclear infiltrates and mild diffuse interstitial fibrosis as well as bronchiectasis and organizing pneumonia. Granulomatous lesions, angiitis and necrotic areas were absent. Immunohistochemistry for immunoglobulins was negative for IgA, IgG and IgM and positive for IgD in the multinucleate giant cells. A strong positive reaction to HLA-DR-specific monoclonal antibody was noted, whereas no specific sugar receptors (endogenous lectins) could be detected by use of biotinylated glyconeoproteins.

[D-penicillamine-induced IgA deficiency in the therapy of Wilson's disease]. / D-Penicillamin-induzierter IgA-Mangel bei der Therapie der Wilsonschen Erkrankung.

Serum IgA deficiency was first noted in a 10 year old boy 8 months after the onset of D-penicillamine therapy. Special immunological examinations revealed a deficiency of the secretory component of IgA while cellular functions of T- and B-lymphocytes were normal. The patient showed discrete clinical signs compatible with IgA deficiency. Regular control of patients with Morbus Wilson and D-penicillamine treatment should include measurement of serum immunoglobulin levels.

[Clinical aspects, results of diagnostic pulmonary function tests and biochemical parameters in children with homozygote alpha-1-antitrypsin deficiency]. / Klinik, lungenfunktionsdiagnostische und biochemische Parameter bei Kindern mit homozygotem Alpha-1-Antitrypsinmangel.

The clinical course and pulmonary function tests of individuals with severe Alpha-1-Antitrypsin (Alpha-1-AT) deficiency reveal a marked interindividual variability. 4 patients with PI type ZZ and 2 patients with PI type SZ had been identified by neonatal cholestasis. None had pulmonary symptoms at a mean age of 13 (range 9-16) years. Lung function tests disclosed signs of incipient pulmonary emphysema in one girl. Bronchial hyperreactivity had led to the diagnosis of Alpha-1 AT-deficiency (PI type ZZ) in another girl at the age of 7 years. The biochemical analysis of the serum of three children (two PI ZZ and one PI SZ) revealed additional protease inhibitors that may be effective as compensatory mechanisms. The lack of those protective factors as well as the presence of environmental hazards may contribute to the increased risk of emphysema in individual patients.

Fanconi-Bickel syndrome.

Clinical, biochemical, functional and morphological data are presented in nine infants, children and adults, with Fanconi-Bickel syndrome. Long-term follow-up studies show severe growth retardation, partly compensated for by late onset of puberty. Glomerular filtration rate is normal or slightly decreased. Renal tubular dysfunction is characterized by a specific pattern of impaired proximal tubular transport mechanisms, with marked impairment of glucose transport. The utilization of glucose and galactose is defective, whereas fructose metabolism seems to be normal. Glycogenosis of the liver may be an epiphenomenon. Glycogen accumulation in the kidney is limited to the proximal tubule, with maximal levels in the straight part. The Fanconi-Bickel syndrome is a defined clinical entity which is distinguished from other inherited metabolic diseases by complex defects of renal tubular transport and other forms of glycogenosis.

[Sonographic and computerized tomography study of congenital choledochal cyst]. / Sonographische und computertomographische Diagnostik einer kongenitalen Choledochuszyste.

In the neonatal period ultrasound and hepatobiliary functional scintigraphy are used to diagnose choledochal cysts. Initial sonography demonstrates hepatobiliary anatomy, hepatobiliary function is assessed by subsequent scintigraphy. The diagnosis can be confirmed by additional computed tomography as shown in this case report.

[Liver cirrhosis in childhood--etiology, diagnosis and conservative therapy]. / Leberzirrhosen im Kindesalter--Atiologie, Diagnostik und konservative Therapie.

Liver cirrhosis is relatively rare in children as compared to adults; frequently it is diagnosed too late. Biliary cirrhosis of early childhood is often the result of neonatal cholestatic syndromes. Beyond infancy, cirrhosis as a consequence of chronic active autoimmune hepatitis or of Wilson's disease may be prevented, if causal therapy is begun in time. Hence paediatricians should exclude both diseases in all children with elevated transaminases and clinical features of a liver disorder.

Effects of cold, short day and melatonin on thermogenesis, body weight and reproductive organs in Alaskan red-backed voles.

This study examined whether cold, short day or melatonin causes reproductive regression and stimulates nonshivering thermogenesis in a subarctic rodent Clethrionomys rutilus. Red-backed voles born and raised at 23 degrees C and 22 h light per day (LD 22:2) at Fairbanks, Alaska (65 degrees N) were exposed in one of six groups to: 1) long day (LD 22:2), 23 degrees C, injected daily with melatonin or saline 2 h before lights out, 2) long day, 3 degrees C, injected daily with melatonin or saline, 3) short day (LD 8:16), 23 degrees C or 3 degrees C. Voles were tested for nonshivering thermogenesis (NST) prior to and after 8 wk exposure. Body weight, testes weight and female reproductive tract weight were assessed after 8 wk in long day and 12 wk in short day. NST was not altered by short day or melatonin but cold (3 degrees C) caused an increase in NST which was similar in long day and short day. Body weight of males and females was not affected by short day but was decreased by melatonin. Short day did not alter mean testes weight (about 20% voles regressed) but reduced mean female reproductive tract weight (more than 40% voles regressed). Melatonin reduced testes weight and female reproductive tract weight (more than 50% of voles of both sexes regressed). The results suggest that in northern red-backed voles: the pineal does not mediate seasonal changes in thermogenic capacity, the pineal may mediate reduction of body weight and regression of reproductive organs but, in addition to day-length, other cues or factors may be important, populations may exhibit variability in sensitivity of reproduction to photoperiod which could allow for opportunistic breeding.

Increased beta-adrenergic receptors in brown fat of winter-acclimatized Alaskan voles.

To assess a possible mechanism for the enhanced thermogenesis of cold-acclimated and winter-acclimatized red-backed voles (Clethrionomys rutilus), beta-adrenergic receptors of brown fat were characterized by specific binding of (-)-[3H]-dihydroalprenolol [( 3H]DHA) to isolated brown fat membranes from 23 degrees C-acclimated controls, cold-acclimated (5 wk or 5 mo at 5 degrees C), wild summer, and winter-acclimatized voles. Scatchard analysis to determine the equilibrium dissociation constant (Kd) and the maximum number of binding sites (Bmax) for control brown fat membranes gave a Kd of 4.45 nM [3H]DHA and Bmax of 249 fmol [3H]DHA bound per milligram of protein. beta-Adrenergic agonists competed for specific binding sites with an order of potency typical of the beta 1 subtype of adrenergic receptors: (-)-isoproterenol greater than (-)-norepinephrine greater than or equal to (-)-epinephrine. After cold acclimation for 5 wk or 5 mo, the Kd and Bmax for adrenergic binding sites were similar to those of controls. Brown fat mass was 1.5 times greater than that of controls after 5 wk cold acclimation but similar to controls after 5 mo cold acclimation. Winter voles had 1.7 times higher Bmax and 1.6 times more brown fat than summer voles. Thus seasonal acclimatization to winter in red-backed voles appears to involve an increase in beta-adrenergic receptors in brown fat, but cold acclimation does not. The results suggest quantitative and possibly qualitative differences in neural and hormonal stimulation of brown fat between cold acclimation and winter acclimatization in voles.

[Special problems of virus hepatitis B in pediatrics (author's transl)]. / Specielle Probleme der Virushepatitis B in der Pädiatrie.

Virus hepatitis B occurs less frequently in infants and children than in adults; a subclinical and chronic course of this disease however seems to occur more often in childhood. Especially after oral infection the growing organism does not seem to be capable of building up a cellular immune response sufficient to eliminate the virus. If a woman becomes infected with hepatitis B during the last trimester of pregnancy of or immediately before delivery, the newborn has a chance of 80% to become infected during birth himself. This so called vertical transmission may be compared to a large transfusion of HBs-Ag-positive blood. Infection of the neonates will lead in most cases to a probably life-long HBs-Ag-carrier status. A fulminant, that is to say lethal course of acute hepatitis B in early infancy was found mostly in cases, where the mothers were carriers of high titer HBs-Ag without clinical symptoms whatsoever. For that reason immediate immune prophylaxis with anti HBs-globuline is mandatory in newborns with neonatal hepatitis B infection, whose mothers are HBs-Ag-positive.