Chronic poisoning by copper in tap water: I. Copper intoxications with predominantly gastointestinal symptoms.

Copper can induce acute and chronic intoxications in humans. Copper in tap water has caused a series of severe systemic diseases in Germany in recent years (copper induced liver cirrhosis). Besides cirrhosis, another type of disease with predominantly gastrointestinal symptoms has occurred which likewise appeared to be induced by copper in tap water. - In a retrospective investigation we looked for additional indications and proof that chronic copper poisoning has been the cause of the observed gastrointestinal diseases. All patients suffering from this type of disease had copper plumbing in their houses. - The patients (children and adults) suffered from nausea, vomiting, colic, and diarrhoea. In the group of infants, one refused formula milk (prepared with tap water) and the others suffered from persistent restlessness, unexplainable screaming (especially at night) and/or long lasting diaper rash. - We accept the diagnosis of chronic copper intoxication as the cause of the gastrointestinal symptoms when at least one of the following criteria were fulfilled: 1. first manifestation, remission and relapse of the disease depend on intake and a non-intake of water containing copper, respectively. 2. hypercupric state of the patients (i.e. pathological high concentrations of the non-ceruloplasmin-bound copper in serum and/or elevated copper levels in urine) 3. signs of systemic copper intoxication in the same patient 4. signs of systemic copper intoxication or hypercupric states in members of the patient s family or in his neighbourhood (non-relatives) - We found that the disease can even be caused by copper concentrations below the allowed concentration given by the German Guidelines for Drinking Water (Trinkwasserverordnung). - The data prove that copper in drinking water can cause gastrointestinal diseases and not only the better known systemic diseases (i.e. copper induced liver cirrhosis). Copper poisoning must be considered as a possible cause of chronic gastrointestinal diseases in those countries in which copper plumbing is common.

Chronic poisoning by copper in tap water: II. Copper intoxications with predominantly systemic symptoms.

Copper can induce acute and chronic intoxications in humans. Copper in tap water has caused a series of severe systemic diseases in Germany in recent years (chronic copper poisoning, CCuP). From the clinical point of view it has been difficult to establish the diagnosis on the basis of clinical and laboratory methods. In a retrospective study, we therefore looked for essential clinical signs as well as laboratory findings which might be typical and essential for the diagnosis of CCuP. - We observed that in patients with severe systemic CCuP not only the liver but also several other organs have been the target of copper. As a proof copper overload has been measured. The latter results are presented here. - During or shortly after exposure "free" serum copper (= non-ceruloplasmin-bound copper) was significantly elevated in all patients (range 5.1 to 47.1 micromol/l, or 25.7 to 56.2 % of total serum copper). The normal upper limits in infants according to Salmenperä (8) are: 0.3 micromol/l, or 1.6 % of total serum copper. - Total serum copper was elevated in 14/16 patients: 13.7 to 30.1 micromol/l in sick infants (normal upper level: 12.6 micromol/l), and 17.0 to 27.2 in sick children (normal upper level for children and adults: 21.4 micromol/l). - Urine copper excretion was found elevated in 9/10 patients, with a range of 11 to 456 microg/dl (normal upper level in adults: 15 microg/dl). - Our results show that patients with systemic CCuP are in a "hypercupric" state. The data thus firstly prove that indeed the putative agent copper is found in excess in the patients and secondly show that the estimation of "free" copper in serum and the measurement of copper in urine are reliable diagnostic methods. Elevation of total serum copper (even though not specific) can give a first hint to the diagnosis. - The hypercupric state of systemic CCuP can be differentiated from that of Wilson's disease by (1) normal levels of ceruloplasmin and (2) the observation that values for free copper in serum or urinary copper normalize in an environment without copper in tap water, for instance in a hospital.

Renal function and renotropic effects of secretin in cystic fibrosis.

In ten cystic fibrosis patients and nine age-matched controls, renal function was determined before and after infusion of secretin. Under baseline conditions creatinine excretion and clearance were significantly elevated, exclusively due to those patients who were homozygous for the DF508 mutation (153 vs 132 ml/min*1.73m2), whereas the glomerular filtration rate, measured by inulin clearance showed no difference. Renal plasma flow and the fractional reabsorption rates of electrolytes were similar in patients and controls. During secretin infusion renal plasma flow increased and the fractional reabsorption rates of electrolytes decreased in both groups. The patients had a increased metabolic clearance (2900 vs 1660 ml/min*m2) and endogenous production rate (9,9 vs 2,5 pmol/min*m2) of of secretin. In conclusion global renal function and electrolyte handling, in particular chloride permeability, are unchanged in cystic fibrosis. Individuals expressing the DF508 genotype showed a selective elevation of creatinine excretion and clearance. The secretion and metabolic clearance of secretin are increased in cystic fibrosis.

Effects of furosemide, captopril and indometacin on the renin-angiotensin system and the renal prostaglandins in anesthetized neonatal piglets.

The effects of the diuretic furosemide (CAS 54-31-9) 1 mg/kg bw i.v., of the angiotensin converting enzyme (ACE) inhibitor captopril (CAS 62571-86-2) 1 mg/kg bw p.o. and the prostaglandin synthesis inhibitor indometacin (CAS 53-86-1) 2 mg/kg bw p.o. on kidney function, salt and water excretion, the excretion of renal prostaglandins PGE2, PGF2a, 6-keto-PGF1a, thromboxane B2 (TXB2) and the plasma renin activity (PRA) were investigated on 29 neonatal piglets. Within 1 h, fuorsemide led to pronounced diuresis and natriuresis, to a rise of the glomerular filtration rate (GFR) (which ist low in neonatal pigs) by 1.8 times, increased the excretion of renal prostaglandins (especially the vasoconstrictor, thromboxane B2 (TXB2 and PGF2a) and raised the PRA significantly. Under captopril, the PRA rose significantly, whereas there was no unequivocal change in the excretion of renal prostaglandins. There was a pronounced decline of the sodium and potassium excretion in the urine with a fall in the concentrations of electrolytes in serum and of the hematocrit. Under indometacin, the excretion of all prostaglandins in the urine declined (this decline was most pronounced for PGE2). There was also a decrease in sodium excretion, whereas there was no significant change in PRA. It can be concluded from the results that the effects of the investigated drugs on the pig neonate kidney is at least partially attributable to an influence on hormonal factors.

[Bromism or chronic bromide poisoning]. / Der Bromismus oder die chronische Bromidintoxikation.

Bromism, the chronic intoxication with bromide is rare and has been almost forgotten. In the recent past bromide is rediscovered as an anticonvulsive drug. The increasing frequency of bromism in children coming to admission induced this report. We describe the cause, the symptoms and the pseudohyperchloremia associated with bromism. If unclarified neurological or psychiatric symptoms are associated with the determination of an elevated serum chloride concentration and a diminished anion gap chronic intoxication with bromide has to be excluded.

Myoadenylate deaminase deficiency with severe rhabdomyolysis.

A 13-year-old Turkish girl was admitted because of recurrent episodes of muscle pain and weakness since the age of 5 years. As an outpatient she developed severe acute rhabdomyolysis (myoglobinuria and increased serum creatine kinase level of 19,000 units/l). The acute rhabdomyolysis and the preceding episodes of muscle pain and weakness had been induced by exercise. There was no increase in plasma ammonia level during ischaemic forearm exercise test and bicycle ergometry. Myoadenylate deaminase deficiency was proven both histochemically and biochemically. The girl was found to be homozygous for the C 34-T mutation of the AMPD1 gene causing primary myoadenylate deaminase deficiency in skeletal muscle. Both parents and her brother were heterozygous for that mutation. Myoadenylate deaminase deficiency has to be considered as a cause of severe rhabdomyolysis.

[Peritoneal dialysis in hemolytic-uremic syndrome following ileocecal resection for invagination in postoperative peritonitis]. / Peritonealdialyse bei hämolytisch-urämischem Syndrom nach Ileozökalresektion wegen Invagination bei postoperativer Peritonitis.

A 3-year-old girl is reported on who underwent laparotomy for ileocaecal intussusception elsewhere one week following severe gastroenteritis. Immediately after surgery, she developed haemolytic-uraemic syndrome with haemolytic anaemia, thrombocytopenia, increase of urea and creatinine and anuria as well as subsequent peritonitis, enterocolitis and sepsis. Following relaparotomy with establishment of ileostomy, peritoneal dialysis for several days was carried out for treatment of the haemolytic-uraemic syndrome. This case demonstrates that the haemolytic-uraemic syndrome can be treated effectively by peritoneal dialysis despite fresh bowel anastomoses, and that simultaneously occurring peritonitis can be managed by intraperitoneal administration of antibiotics via dialysis fluid.

Pyonephrosis in childhood--is ultrasound sufficient for diagnosis?

The validity of ultrasound in the diagnosis of pyonephrosis in infants and children was retrospectively investigated in 14 patients. The disease was unilateral in 13 patients and bilateral in one. The diagnosis was proven by percutaneous nephrostomy in 7 and by operation in 7 patients. Ultrasound was true positive in 9 patients (10 kidneys) and false negative in 5. Large staghorn calculi were present in 2 of the 5 false negative cases. A group of 20 patients with simple hydronephrosis, investigated by percutaneous punctures, served as a control group. There were two false positive cases in this group. The sensitivity of sonography for the diagnosis of pyonephrosis was only 66.7%, which is considerably lower than in previous reports. We therefore recommend early sonographically guided percutaneous puncture of the renal pelvis whenever pyonephrosis is suspected.

Nutritional copper intoxication in three German infants with severe liver cell damage (features of Indian childhood cirrhosis).

Three of the four children of two unrelated German families fell ill in the first year of life with severe hepatopathy leading to death in two of the children so far, after a progressive clinical course and severe hepatic failure. Laboratory and morphological investigations revealed a high concentration of copper in the liver and to a lesser degree in the kidneys and other organs. The liver architecture was severely altered by micronodular cirrhosis with toxic liver cell damage similar to that found in Indian childhood cirrhosis. Epidemiologically, copper intoxication of the drinking water was verified. The drinking water was obtained from wells via copper pipes. The copper content of the drinking water went as high as 3400 micrograms/l in the two families while water taken directly from the well showed normal content but had lowered pH (6.2). Both parents were clinically healthy, as was an older son who had not been exposed to copper intoxication during the first nine months of his life. Therefore, copper intoxication during the perinatal period appears to be a prerequisite for manifestation of the disease.

[Diagnosis and therapy of pyonephrosis in infancy and childhood]. / Diagnostik und Therapie der Pyonephrose im Säuglings- und Kindesalter.

A diagnostic schedule in pyonephrosis was followed in thirteen infants and children. Obstruction of the urinary tract could be demonstrated in 12 patients, non-obstructive pyonephrosis was present in one case. Congenital obstructive malformation of the urinary tract was found in 7 patients, obstruction was acquired in 5. Sonographically, pyonephrosis could be diagnosed in 8 patients (64.3%). Excretory urography (10/13) was helpful in no actual case. Sonographical-guided percutaneous nephrostomies were performed in 5 patients and operative nephrostomies in 4. Emergency-nephrectomies were done in 4 patients. A tap of the renal pelvis is the best way for early diagnosis whenever pyonephrosis is clinically suspected.

Copper storage disease of the liver and chronic dietary copper intoxication in two further German infants mimicking Indian childhood cirrhosis.

A severe copper storage disease of the liver with micronodular cirrhosis resembling Indian childhood cirrhosis (ICC) was found in two siblings of a German family leading to death in one infant at the age of 13 months. The fatal outcome correlated with severe ballooning of hepatocytes and excessive formation of Mallory bodies. The copper content of the liver was 698 micrograms per gramme wet weight (control 5 micrograms) in the living patient and 2154 micrograms per gramme dry weight (controls 39, 54 micrograms) in the dead infant. In both cases copper was stored not only in hepatocytes but also to a high degree in mesenchymal cells. Chronic contamination of drinking water supplied from a well via copper pipes could be verified as the cause of copper intoxication, lending further support to ICC as an environmental, acquired disorder. Accumulation of exogenic copper already very early in infancy appears most important for the development of the disease, as both the parents and one child not exposed to copper intoxication during the first 9 months of its life are clinically healthy.

[Active chickenpox vaccination of children with acute leukemia or other neoplastic diseases]. / Aktive Varizellenimpfung bei Kindern mit akuter Leukämie oder anderen neoplastischen Erkrankungen.

26 patients with acute leukemia and other malignancies susceptible to varicella were vaccinated during maintenance chemotherapy. Vaccination was done with OKA strain of live attenuated varicella vaccine developed by Takahashi 1974. All recipients showed no adverse clinical reactions. There was no spread of vaccine virus to others. Seroconversion was 94% in seronegative patients. In those having low antibody titers before vaccination in 56% booster effect was demonstrable. None of the seroconverted recipients contracted varicella in spite of documented contact exposure. Vaccine zoster was not observed. The results suggest that in immunocompromised children live varicella vaccination has a protective effect against varicella infection which has a described mortality rate up 7% in this patients.

Active immunization against varicella of children with acute leukaemia or other malignancies on maintenance chemotherapy.

Twenty-six patients with acute leukaemia and other malignancies susceptible to varicella were vaccinated with the Oka-strain live attenuated varicella vaccine during maintenance chemotherapy. All recipients showed no adverse clinical reactions. There was no spread of vaccine virus. Seroconversion was 94% in seronegative patients. Among those having low antibody titres before vaccination, a booster effect was demonstrable in 56%. None of the seroconverted recipients contracted varicella despite documented contact exposure. No case of herpes zoster occurred. The results suggest that, in immunocompromised children, live varicella vaccination has a protective effect against varicella infection which may result in a mortality rate of up to 7% in these patients.

Modulation of lymphoproliferation by human growth hormone.

This study was designed to investigate the capacity of human growth hormone (hGH) to induce proliferation of human peripheral blood lymphocytes (PBL) and its effect on lectin-induced lymphoproliferation, as measured by [3H]-thymidine (3H-TdR) incorporation into lymphocyte DNA. We observed that hGH itself induced lymphoproliferation. Maximal responses were reached with 50 ng/ml after 4 days and 25 ng/ml after 7 days. Anti-hGH-antiserum completely blocked the stimulatory capacity of hGH. Further evidence for the specificity of the effect was obtained by the finding that no other hormone present in the hGH preparation produced any effect on lymphocyte cultures. In contrast to its stimulatory capacity, hGH reduced the proliferative response of PBL to phytohaemagglutinin (PHA). This effect was also neutralized by anti-hgH-antiserum. These results show a direct stimulatory effect of hGH on PBL and a regulatory effect of the hormone on lectin-induced lymphoproliferation.

[Improved prognosis in Wilms' tumor due to adjuvant combination drug therapy]. / Verbesserte Prognose beim Wilms-Tumor durch adjuvante Kombinationschemotherapie.

78 children with Wilms' tumor stage I--IV diagnosed since 1960 are presented. There were two groups of patients: one group consisting of 35 patients which received adjuvant chemotherapy for 1 year, the other group consisting of 43 patients which received no chemotherapy. Surgical excision and irradiation was identical in both groups. The prognosis was greatly improved by adjuvant chemotherapy: 4-year survival rates increased from 25 to 69%. Late side effects from radiation and chemotherapy were noted: 15/78 patients suffered from scoliosis and all patients treated by chemotherapy had a decreased lymphotoxin activity over years. The following factors appear to be related to prognosis: the extent of disease in patients determined by better techniques, histopathology of the tumor, and the nature of treatment.

Induction of a lymphotoxin-like mediator in peripheral blood and synovial fluid lymphocytes by incubation with synovial fluid from patients with rheumatoid arthritis.

A significantly increased spontaneous cell-mediated cytotoxicity (SCMC) has been reported in synovial fluid lymphocytes (SFL) as compared to peripheral blood lymphocytes (PBL) of patients with rheumatoid arthritis (RA) and that of normal controls [1-3]. To determine whether this increased SCMC activity is due to the production of a lymphokine and related to the production of a lymphotoxin(LT)-like mediator, PBL from normal controls and PBL and SFL from RA patients were incubated either with a human melanoma cell line (IGR 3) or with cell-free synovial fluid (SF) from RA patients. The SF and the cell-free supernatants of the different cultures were tested for LT activity by estimation of inhibition of DNA synthesis of HeLa cell monolayers and they were added to a SCMC assay system using normal PBL and IGR 3 as target. In the supernatants from cocultures of either PBL from controls or PBL and SFL from RA patients with IGR 3 cells, there was no significant difference in LT activity. An LT-like mediator was observed in the supernatants of all lymphocytes cocultured with SF, whereas SF alone and supernatants of lymphocytes alone exhibited little or no LT activity. In a control experiment, LT induction was not observed when normal lymphocytes were cultured with the serum of RA patients. Absorption of the culture supernatants with an insolubilised goat anti-human Ig did not remove LT activity. The demonstrated release of an LT-like mediator from lymphocytes incubated with SF might be one contributing mechanism to the inflammatory joint reaction in RA patients.

A comparison of the antiproliferative and antiviral activities of alpha-, beta- and gamma-interferons: description of a unified assay for comparing both effects simultaneously.

An assay system is described which allows simultaneous measurement of antiviral (AV) and antiproliferative (AP) activities of various interferons (IFNs) with the same indicator cells and tests one biological function, i.e. the reduction of DNA synthesis. Human IFN-alpha, -beta, and -gamma preparations were investigated for their respective AV and AP activities. In repeated independent experiments the AP:AV ratio was found to be constant for each IFN preparation. However, striking difference in the AP:AV ratios was found between the preparations, being highest in IFN-gamma and lowest in IFN-alpha. The validity of this assay was substantiated by the observation that the AP activity of the IFNs is not influenced by virus once the cells are protected by sufficient amounts of IFN and that the score of the microscopically assessed cytopathic effect (CPE) strongly correlates with the reduction of [3H]TdR uptake in the cultures. The AP:AV ratio of a Corynebacterium parvum induced IFN resembled that of the IFN-alpha-reference, suggesting that contrary to previous reports, the C. parvum induced is of alpha type. It is suggested that the assay system presented here provides a simple means not only of comparing AP and AV ratios of various IFNs but also of characterizing IFNs of unknown type.

Antibody incubation of human marrow graft for prevention graft versus host disease.

An in vitro incubation of incompatible donor bone marrow by xenogenic anti-T-cell globulin (ATG) suppressed an otherwise lethal GvH reaction in animal models. An application of this principle to clinical bone marrow transplantation was successfully tried in three patients with acute lymphoblastic leukemia. Preparation of the specific anti-human T-cell globulin (ATCG-H) was carried out by absorption of anti-human thymocyte globulin with liver-kidney homogenate, chronic lymphocytic leukemia cells of B-cell type, and erythrocytes. Subsequent testing revealed that the serum still reacted with human T-cells but no longer reduced the number of colony-forming units in culture (CFU-C). All three bone marrow recipients were treated by chemotherapeutic conditioning and total body irradiation followed by grafting of in vitro treated bone marrow from HLA-identical siblings. The transplantation of the bone marrow was well tolerated and no major side effects were encountered. No patient so far (24, 7, 6 months) has shown any signs of GvHD. The in vitro pretransplantation treatment of bone marrow with anti T-globulin may be a new approach to the prevention for GvHD in man.