Abstract. Labrador Retrievers with elevated hepatic copper levels have been reported; however, it is unclear whether primary copper-associated hepatitis occurs in this breed. The objective of this study was to determine whether copper-associated hepatitis could be identified in Labradors by reviewing cases from the Diagnostic Center for Population and Animal Health, Michigan State University. Sixteen Labrador Retrievers (3 male, 12 female, and 1 of undetermined sex) between 4 and 11 years old, had multifocal and coalescing, centrilobular hepatitis characterized by macrophages with abundant intracytoplasmic copper and hemosiderin. Other lesions included multifocal, centrilobular and random, pigmented granulomas, hepatocellular necrosis, intrahepatic cholestasis, centrilobular or bridging fibrosis, and occasionally, pseudolobule formation. In rhodanine-stained sections, copper was concentrated in the cytoplasm of centrilobular and midzonal hepatocytes and in macrophages, which is consistent with copper-associated hepatitis. In 12 of the dogs, quantitative liver copper levels were available, and in all but 2 dogs the levels were greater than 2,000 parts per million dry weight (ppm dw). One dog had a liver copper level of 1,990 ppm dw and one dog with advanced hepatic cirrhosis had a level of 1,490 ppm dw. The findings suggest that primary copper-associated hepatitis likely occurs in Labrador Retrievers.

Hydrogen sulfide (H2S), the gas with the odor of rotten eggs, was formally discovered in 1777, over 239 years ago. For many years, it was considered an environmental pollutant and a health concern only in occupational settings. Recently, however, it was discovered that H2S is produced endogenously and plays critical physiological roles as a gasotransmitter. Although at low physiological concentrations it is physiologically beneficial, exposure to high concentrations of H2S is known to cause brain damage, leading to neurodegeneration and long-term neurological sequelae or death. Neurological sequelae include motor, behavioral, and cognitive deficits, which are incapacitating. Currently, there are concerns about accidental or malicious acute mass civilian exposure to H2S. There is a major unmet need for an ideal neuroprotective treatment, for use in the field, in the event of mass civilian exposure to high H2S concentrations. This review focuses on the neuropathology of high acute H2S exposure, knowledge gaps, and the challenges associated with development of effective neuroprotective therapy to counteract H2S-induced neurodegeneration.

Hydrogen sulfide (H S) is a highly neurotoxic gas. It is the second most common cause of gas-induced deaths. Beyond mortality, surviving victims of acute exposure may suffer long-term neurological sequelae. There is a need to develop countermeasures against H S poisoning. However, no translational animal model of H S-induced neurological sequelae exists. Here, we describe a novel mouse model of H S-induced neurotoxicity for translational research. In paradigm I, C57/BL6 mice were exposed to 765 ppm H S for 40 min on day 1, followed by 15-min daily exposures for periods ranging from 1 to 6 days. In paradigm II, mice were exposed once to 1000 ppm H S for 60 minutes. Mice were assessed for behavioral, neurochemical, biochemical, and histopathological changes. H S intoxication caused seizures, dyspnea, respiratory depression, knockdowns, and death. H S-exposed mice showed significant impairment in locomotor and coordinated motor movement activity compared with controls. Histopathology revealed neurodegenerative lesions in the collicular, thalamic, and cortical brain regions. H S significantly increased dopamine and serotonin concentration in several brain regions and caused time-dependent decreases in GABA and glutamate concentrations. Furthermore, H S significantly suppressed cytochrome c oxidase activity and caused significant loss in body weight. Overall, male mice were more sensitive than females. This novel translational mouse model of H S-induced neurotoxicity is reliable, reproducible, and recapitulates acute H S poisoning in humans.

Background and Purpose An urgent need exists to develop therapies for stroke which have high efficacy, long therapeutic time windows and acceptable toxicity. We undertook preclinical investigations of a novel therapeutic approach involving supplementation with carnosine, an endogenous pleiotropic dipeptide. Methods Efficacy and safety of carnosine treatment was evaluated in rat models of permanent or transient middle cerebral artery occlusion. Mechanistic studies used primary neuronal/astrocytic cultures and ex vivo brain homogenates. Results Intravenous treatment with carnosine exhibited robust cerebroprotection in a dose-dependent manner, with long clinically-relevant therapeutic time windows of 6 h and 9 h in transient and permanent models, respectively. Histological outcomes and functional improvements including motor and sensory deficits were sustained at 14 d post-stroke onset. In safety and tolerability assessments, carnosine did not exhibit any evidence of adverse effects or toxicity. Moreover, histological evaluation of organs, complete blood count, coagulation tests and the serum chemistry did not reveal any abnormalities. In primary neuronal cell cultures and ex vivo brain homogenates, carnosine exhibited robust anti-excitotoxic, antioxidant, and mitochondria protecting activity. Conclusion In both permanent and transient ischemic models, carnosine treatment exhibited significant cerebroprotection against histological and functional damage, with wide therapeutic and clinically relevant time windows. Carnosine was well tolerated and exhibited no toxicity. Mechanistic data show that it influences multiple deleterious processes. Taken together, our data suggest that this endogenous pleiotropic dipeptide is a strong candidate for further development as a stroke treatment.

Abstract. This study was conducted with 3 objectives in mind: first, to identify the toxic fraction (aqueous or organic) in leaves and flowers; second, to identify diagnostic marker(s) of toxicosis in cats; and, third, to evaluate the morphologic effects of intoxication. The study was conducted in 2 phases. Phase 1 was to identify which extract, organic or aqueous, was nephrotoxic and also to determine the appropriate dose for use in the phase 2 studies. Results indicated that only the aqueous extracts of leaves and flowers were nephrotoxic and pancreotoxic. To identify the proximate toxic compound, cats in the phase 2 study were orally exposed to subfractions of the aqueous flower extract, 1 subfraction per cat. Results confirmed vomiting, depression, polyuria, polydipsia, azotemia, glucosuria, proteinuria, and isosthenuria as toxic effects of the Easter lily plant. Another significant finding in serum was elevated creatinine kinase. Significant histologic kidney changes included acute necrosis of proximal convoluted tubules and degeneration of pancreatic acinar cells. Renal ultrastructural changes included swollen mitochondria, megamitochondria, edema, and lipidosis. Subfraction IIa 3 of the aqueous floral extract contained most of the toxic compound(s). These studies reproduced the clinical disease, identified the most toxic fraction of the Easter lily, and helped characterize the clinical pathology, histopathology, and ultrastructural pathology associated with the disease.

No abstract

Abstract. Lead poisoning in cattle and other food animals is of public health significance because of the potential for human exposure to lead through ingestion of contaminated meat and milk products derived from lead-poisoned animals. In Michigan, lead poisoning in livestock is a reportable disease, and positive cattle are quarantined until they test negative (Ͻ0.05 ppm blood lead). There is surprisingly little information on blood lead kinetics in cattle. The half-life has been variably reported as 9 weeks and 1-2 months. Because these data did not fit those obtained from cases received at the Michigan State University Animal Health Diagnostic Laboratory, a retrospective study was conducted to review all cases of accidental lead poisoning in cattle between 1990 and 1998. This information is needed to estimate when quarantined lead-poisoned cattle can be released. The results showed that the half-life of blood lead was quite variable and ranged from 48 to 2,507 days. The shortest half-lives (48, 56, and 57 days) were found in a lactating herd of 20-month-old heifers. The longest half-life, 2,507 days, was found in a 9-month-old castrated bull, which ingested a discarded automobile battery. Of the 24 animals monitored, only 8/24 (33%) had half-lives between 6 and 14 weeks. In conclusion, the half-life of blood lead is difficult to predict in accidental cases of cattle poisoning.Lead is the most common cause of heavy metal poisoning in cattle. 1,3,7 The disease is characterized by neurologic signs, which include depression, ataxia, blindness, and seizures. [1][2][3] The most severely affected animals die within 24 hours of initial onset of clinical signs, but death may occur up to about 2 weeks postexposure. Sources of lead exposure in cattle include discarded automobile batteries, paint, solder, greases, asphalt, and roofing materials. 4 Younger animals usually Ͻ5 months old, which lick foreign objects out of curiosity, are most frequently affected. Most incidences of lead poisoning occur following single ingestions of large amounts of lead-containing materials.There is a significant public health food safety concern over consumption of animal products derived from lead-poisoned cattle. The human population most sensitive to lead exposure is children Ͻ3 years old. 5,12 Although the most significant source of lead exposure in this segment of the population is not food related, public health officials are nonetheless concerned about protecting the public from lead of food origin. The US Food and Drug Administration action level of lead is 0.25 ppm in canned foods, and 0.08 ppm in fruits and beverages. 12 Meat and milk products from lead-intoxicated cattle could be a source of lead for children and the general population. Liver and kidney usually contain the highest amounts of lead within days of exposure before it is redistributed for storage in bones. 6,10 From the Animal Health Diagnostic Laboratory, Michigan State University, PO Box 30076, Lansing, MI 48909-7576, and the Michigan Department of Agriculture, PO B...

Pamidronate disodium is a potentially useful drug to reduce CCF-induced toxicosis and other causes of hypercalcemia associated with increased bone resorption in dogs.