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Biomedical subjects

I Sternlieb

Publications and source records attributed to I Sternlieb.

120 records · Page 7Linked to original sources
PubMedDate not supplied

Hepatic lysosomal copper protein in dogs with an inherited copper toxicosis.

Hepatic copper overload inherited as an autosomal recessive trait in Bedlington Terriers is characterized by the presence of hepatocellular lysosomal granules of unusually high specific gravity and electron density which contain at least two thirds of the total hepatic copper. Fractionation of homogenates of liver from such affected Bedlington Terriers yielded a low-speed pellet which contained the lysosomal granules. This fraction was used for isolation of a copper-binding protein by alkaline-reduction, solubilization, fractional acetone precipitation, and gel filtration. The purified protein yielded a single band on polyacrylamide gel electrophoresis and resembled other metallothioneins in containing 15 cysteine residues and 7 to 8 atoms of copper (but no zinc) per 54 amino acid residues. No methionine, histidine, or any aromatic amino acid was present. The accumulation of this lysosomal copper protein appears to be related to the primary genetic defect which underlies the hepatic copper toxicosis of the Bedlington Terrier.

Animals↗
PubMedDate not supplied

Origins of biliary copper.

We tested the hypothesis that the copper present in bile--the major route of elimination of the metal from the body--is derived exclusively from hepatocytes by administering radiocopper (64Cu or 67Cu)-labeled ionic Cu, desialylated (AsCPN) or intact human ceruloplasmin (CPN), intravenously, to rats with cannulated bile ducts. The rates of appearance and the total amounts of radiolabeled isotope recovered in bile were measured. The three vehicles chosen for the delivery of radiocopper interact differently with hepatocytes: ionic Cu is taken up by a passive process (Schmitt, R. C. et al., Am. J. Physiol. 1983; 244:G183-G191); AsCPN is promptly cleared from the circulation by specific receptor-mediated endocytosis, and CPN largely remains in the circulation for the duration of the experiment. Similar amounts of radiocopper were recovered following injections of ionic Cu (3.1%) or CPN (2%), but substantially larger amounts (8.1%) were excreted after administration of AsCPN. Using an antibody to CPN which reacts also with AsCPN, we found about 70% of the bile radioactivity to be immunoprecipitable following injections of either glycoprotein, indicating that a fraction of these copper proteins had entered the bile essentially unmodified. Our observations indicate that in addition to the lysosomal compartment which catabolizes a portion of the AsCPN in hepatocytes, there appears to be a direct route for AsCPN from hepatocellular sinusoids to the bile canaliculi. Since CPN does not interact significantly with hepatocytes, its presence in bile suggests transcytosis via the biliary epithelium.

Animals↗
PubMedDate not supplied

Wilson's disease: indications for liver transplants.

The clinical course of certain patients with Wilson's disease resembles that of patients with viral or drug-induced fulminant hepatitis lasting only few weeks from recognition of symptoms to severe hepatic insufficiency and death. The disease is complicated by hemolysis and is characterized by hypercupremia. Routine laboratory findings may underestimate the severity of the disease. These patients, as well as patients with decompensated Wilsonian cirrhosis who are not responding to therapy, should be considered as candidates for liver transplants.

Adult↗
PubMedDate not supplied

A prospective clinical trial of D-penicillamine in the treatment of primary biliary cirrhosis.

We conducted a prospective clinical trial to assess the relative efficacy and safety of high- vs. low-dose D-penicillamine in patients with primary biliary cirrhosis. Following clinical tests and liver biopsy diagnostic of primary biliary cirrhosis, 56 patients were randomized to receive either 250 or 750 mg D-penicillamine daily. Patients were monitored with clinical tests and annual liver biopsy. Randomization produced two groups without differences in demographic, clinical or histologic characteristics. During the trial, no differences were seen between the mean change in liver test results in patients in either treatment group. The 11% per year rise of bilirubin in the 750 mg dose group during the first 3 years was not significantly different from the 18% per year rise in the 250 mg dose group. No patient showed improvement on liver biopsy although patients on 750 mg D-penicillamine deteriorated more slowly. Side effects, particularly rash and dysgeusia, were more common in the 750 mg dose group. The frequency and severity of side effects were responsible for the early conclusion of our trial. Twenty-six patients experienced side effects necessitating discontinuation of D-penicillamine. No evidence of increased efficacy was demonstrated by high-dose D-penicillamine therapy, and side effects were observed in patients on 250 mg D-penicillamine daily. With the severity of adverse effects and continued progression of disease, D-penicillamine is not a clinically useful therapy in primary biliary cirrhosis.

Bilirubin↗
PubMedDate not supplied

Transport and intracellular distribution of copper in a human hepatoblastoma cell line, HepG2.

The uptake of radiocopper by HepG2 cells is a saturable, temperature-dependent and cellular energy-independent process with a Vmax of 7.1 +/- 0.2 pmoles min-1 mg protein-1 and an estimated Km of 3.3 +/- 0.5 microM. The rate of copper uptake is reduced at an equimolar concentration of albumin and is unaffected by zinc at a 10-fold molar excess. Approximately 70% of the newly incorporated radiocopper binds to membranes and organelles, while 30% is recovered in the cytosol. The soluble fraction can be resolved into two copper-binding protein peaks. Incubation of HepG2 with nonisotopic copper results in displacement of radiocopper associated with the proteins contained in the lower molecular weight peak. Exposure of the cells to cycloheximide inhibits the incorporation of the isotope into this fraction.

Biological Transport↗
PubMedDate not supplied

Neuropathological findings in penicillamine-treated patients with Wilson's disease.

We report the terminal neurological impairment, amount of penicillamine taken, neuropathology and cerebral copper content of eleven patients with Wilson's disease treated for as long as 17 years. Therapy was accompanied by complete resolution of neurologic symptomatology in five patients and significant improvement in the neuro-psychiatric manifestations in six. Abnormal glial cells were seen in all the brains; gross or micro-cavitary changes were present in the putamina of eight. Of the four sets of observations, there was virtually no correlation between the degree of neurologic dysfunction - if any - in the months before death and either the amount of penicillamine taken or the cerebral copper content. There was, however, a fair degree of correlation between the severity of the neuropathologic findings and cerebral copper content.

Adult↗
PubMedDate not supplied

Penicillamine-induced skin lesions.

D-penicillamine therapy can produce an unusual variety of skin lesions: Some are acute sensitivity reactions; some are caused by metabolic effects of the drug; some are due to autoimmune phenomena or to unknown mechanisms. The type and incidence of side effects depend on the original disease and on penicillamine dosage and duration of treatment.

Adolescent↗
PubMedDate not supplied

Copper toxicosis of the Bedlington terrier.

Inherited copper toxicosis of Bedlington terriers provides a valuable animal model for studying mechanisms of hepatic copper accumulation and toxicity. D-penicillamine may be indicated for preventing and treating this potentially serious disorder.

Aging↗