RESUMEN

Copper is a ubiquitous trace metal necessary for normal function of a variety of cellular proteins. Intracellular copper metabolism is complex, and only a few of the proteins/genes involved are known. Copper deficiency does not appear to be a clinical problem in dogs. Excess copper accumulation in the liver as a cause of hepatitis and cirrhosis was first demonstrated among Bedlington terriers. Subsequently, copper accumulation in the liver has been shown to occur in several other breeds of dogs. Excess hepatic copper has been found in dogs with normal liver histology, dogs with hepatitis, and dogs with end stage cirrhosis. Evidence is accumulating that copper is a cause of liver disease in breeds of dogs other than Bedlington terriers. Moreover, as more data are accumulated, the copper storage disease appears to have characteristics that are very similar among all of the affected breeds.

Asunto(s)

RESUMEN

Liver tissue samples were reviewed from 35 Doberman Pinschers with chronic active hepatitis in the precirrhotic stage. Thirty dogs had elevated hepatic copper concentrations, and five had normal liver copper concentrations. The earliest changes were inflammation and scar tissue deposition around the small hepatic vein branches. There was also apoptosis of scattered hepatocytes in zone 3. Inflammation consisted of macrophages, lymphocytes, and plasma cells. As the disease progressed, collagen deposition increased around the hepatic veins; in some liver specimens, thin scar tissue septa radiated from the hepatic vein branches, and inflammation spread to include the portal tracts. The sinusoids adjacent to the scar tissue were converted to endothelial-lined, thin-walled vessels. Chronic active hepatitis (commonly referred to as Doberman hepatitis or chronic active hepatitis of Dobermans) is a progressive fibrosis, inflammation and hepatocyte loss beginning among zone 3 hepatocytes around the terminal hepatic vein branches. The histomorphologic changes were the same among those Dobermans with elevated hepatic copper and those with normal hepatic copper. The cause was not determined, but these morphologic studies support the idea of immune-mediated disease.

Asunto(s)

RESUMEN

Liver tissue from 17 West Highland White Terriers (WHWTs) with cirrhosis, subacute bridging necrosis, hepatitis, or massive necrosis were examined for the presence, composition, and distribution of inflammatory foci. Copper analysis was performed on the specimens. The foci of inflammation and necrosis composed a significant part of the lesion in 15 of the samples. The foci were of two types. One, characteristic of idiopathic chronic active hepatitis, consisted of one or two apoptotic hepatocytes attended by lymphocytes and plasma cells. These foci were found primarily in the vicinity of the portal tracts, not associated with centrolobular copper-laden hepatocytes. The other type of focus was characteristic of copper toxicosis. These foci were larger and composed of debris-filled macrophages, lymphocytes, plasma cells, and scattered neutrophils, and on occasion apoptotic hepatocytes were found at the periphery. These foci were always found around the central vein among the copper-laden hepatocytes. Such foci were found only in dogs with copper concentration > 2,000 parts/million on a dry weight basis. These morphologic studies show that clinical liver disease in WHWTs is caused by more than one etiologic agent. Among 17 WHWTs with clinical liver disease, two had copper toxicosis, five had idiopathic chronic active hepatitis, and 10 had hepatic disease of undetermined type.

Asunto(s)

RESUMEN

OBJECTIVE: To determine the effects of peptidyl fluoromethyl ketones on the in vitro activity of purified cathepsins B and L, on tissue cysteine proteinase activity, and on cartilage and bone destruction in experimental arthritis. METHODS: The effects of the fluoroketones on cathepsins B and L in vitro and the effects of oral administration of fluoroketones on ex vivo cysteine proteinase activity in tissue homogenates were determined by measuring the inhibition of fluorogenic substrate cleavage. To determine the effects on arthritis, animals were injected with adjuvant or type II collagen, treated orally with the fluoroketones, and the severity of arthritis was assessed by clinical, histologic, and radiologic methods. RESULTS: All of the fluoroketones tested were potent inhibitors of purified cathepsins B and L activity. Oral administration of the fluoroketones reduced tissue cysteine proteinase activity by up to 77%. In addition, fluoroketone treatment significantly reduced the severity of clinical joint disease and decreased the destruction of articular cartilage and bone. Quantitative analysis of radiographic images indicated that treatment significantly reduced soft tissue changes, periosteal proliferation, and bone erosion, but only partially reduced juxtaarticular osteoporosis. CONCLUSION: These studies suggest that cysteine proteinase inhibitors may limit tissue destruction in diseases such as rheumatoid arthritis.

Asunto(s)

Asunto(s)

RESUMEN

Peptidyl fluoromethyl ketones with the structure carbobenzoxy (Z)-L-phenylalanine-L-alanine-CH2F (MDL 201,053), and its diastereomer Z-L-phenylalanine-D-alanine-CH2F (MDL 201,117), were synthesized and evaluated in vitro for inhibition of purified human cathepsin B. MDL 201,053 was shown to be a potent inhibitor of cathepsin B activity, whereas MDL 201,117 was more than 100-fold less active. In rats with adjuvant induced arthritis, oral administration of MDL 201,053 (13 or 34 mg/kg/day), but not MDL, 201,117 (28 mg/kg/day), significantly decreased the severity of gross clinical arthritis and reduced histologically graded articular cartilage and bone destruction by 76 to 100%. Quantitative image analysis of radiographs indicated that MDL 201,053 treatment significantly reduced bone density changes and inhibited focal bone erosion that normally occur during the course of adjuvant disease. MDL 201,117 had no significant effect on cartilage or bone destruction by any of the evaluation methods used. The effects of MDL 201,053 treatment were dose dependent and treatment was at least partially effective when initiated after the onset of disease. Our studies suggest that inhibitors of cathepsin B may be useful for the treatment of chronic inflammatory joint disease.

Asunto(s)

Asunto(s)

Asunto(s)

RESUMEN

Histomorphologic, histochemical, and atomic absorption analysis studies were performed on liver tissue from 623 clinically normal purebred and mixed-breed dogs to assess the range of hepatic copper concentrations, the histologic distribution of copper, and the histomorphologic changes associated with the various copper concentrations that were found. Atomic absorption analysis revealed a continuous numerical spectrum ranging from less than 100 parts per million on a dry weight basis (ppm dw) to more than 2,000. No decisive numerical criterion was found that could be used to separate normal from abnormal copper concentrations because of this continuous array. The threshold for histochemical demonstration of copper-containing granules using rhodanine or rubeanic acid staining was 400 ppm dw. At this concentration the copper-containing granules were located in the centrilobular hepatocytes (zone 3 of Rappaport). Copper-containing granules were found in the midzonal and periportal hepatocytes (zones 2 and 1 of Rappaport) in livers with 1,000 ppm dw and higher copper concentrations. The majority of the 623 livers were normal histomorphologically. Multifocal hepatitis characterized by mixed inflammatory cell accumulation and centrilobular distribution was found to be associated with copper concentrations in the range of 2,000 ppm dw or higher. An appropriate upper limit for normal hepatic copper concentration in the dog was not determined based on the present study.

Asunto(s)

RESUMEN

Accidental monensin toxicosis developed in 5 Stone sheep (Ovis dalli stonei), 5 blesbok (Damaliscus dorcas phillipsi), and a Bactrian camel (Camelus bactrianus) at the St Louis Zoological Park. Eight animals died acutely and 1 was euthanatized because of chronic hind limb paresis. All affected animals had clinicopathologic evidence of severe muscle necrosis, serum electrolyte disturbances, and hemoconcentration.

Asunto(s)

Asunto(s)

RESUMEN

The relative susceptibilities of C57BL/6NCR and BALB/cANNCR mice, F344/NCR rats, 2/NCR guineapigs and CR:RGH Syrian hamsters to Bacillus piliformis infection were determined by orally inoculating 20 weanling females from each species with suspensions of B. piliformis spores. Animals from each group were sequentially necropsied over 2 week periods to document the lesions produced. No significant gross or microscopic lesions were observed in the BALB mice or the Fischer rats. Gross and microscopic lesions were observed in the livers and intestines of many guineapigs and hamsters killed 3-14 days after inoculation. A large lesion was observed in the left cardiac ventricle of one C57BL mouse 10 days after inoculation. Warthin-Starry silver-stained tissue sections revealed clusters of B. piliformis within the cytoplasm of intestinal epithelial cells, smooth muscle cells, hepatocytes and myocytes bordering foci of necrosis in the intestines, liver and heart.

Asunto(s)

RESUMEN

Tyzzer's disease was induced experimentally in nonimmunosuppressed, weanling Mystromys albicaudatus by oral inoculation with Bacillus piliformis spores. Focal areas of necrosis bordered by cells containing B. piliformis were observed first in the tunica muscularis of the intestine and in the periportal region of the liver 3 days post-inoculation, in the ventricular myocardium 7 days post-inoculation and in the brainstem 9 days post-inoculation. Healing in the tunica muscularis, liver and myocardium was accompanied by granuloma formation. The findings indicate that Mystromys are susceptible to B. piliformis infection. This is, to our knowledge, the first time brain lesions have been reported in any species following oral inoculation with B. piliformis. Tyzzer's disease should be considered as a possible diagnosis in Mystromys with hepatoenteritis, myocarditis, or indications of central nervous system disorders.

Asunto(s)

Asunto(s)

RESUMEN

An 8-month-old dog admitted for routine castration was found to have ascites. Liver biopsy revealed inflammation, fibrosis, and a copper concentration of 1,300 ppm on a dry weight basis. As cirrhosis developed, the copper concentration decreased without chelator treatment. At necropsy, the dog had cirrhosis, but the hepatic copper concentration was only 730 ppm.

Asunto(s)

RESUMEN

Histologic, histochemical and atomic absorption studies on liver tissue from 71 West Highland white terriers are reported. Twenty-seven dogs had histologically normal liver and copper concentration comparable to mongrel control dogs. Forty-four dogs had hepatic copper concentrations up to 22 times the mean copper concentration found in clinically normal mongrel dogs. Hepatitis, hepatic necrosis and cirrhosis were associated with the increased copper concentration in some dogs. Matings between dogs with high liver copper concentration produced pups with high liver concentration. The copper storage defect is inherited.

Asunto(s)

Asunto(s)

Asunto(s)

RESUMEN

Three different histochemical methods for copper detection were compared. Atomic absorption analysis was used to substantiate the tissue stains. There was good correlation between rhodanine staining and rubeanic acid-stained tissue sections. The orcein reaction for copper-associated protein did not consistently correlate with the methods demonstrating copper. Prolonged staining (72 hours) with rubeanic acid more consistently and clearly detected increased copper in canine livers than did staining with rhodanine. Seventy-two hour staining with rubeanic acid is the method of choice for histochemical detection of copper in canine liver.

Asunto(s)

Asunto(s)