Nontraditional Applications in Clinical Pathology

Jordan, Holly L.; Register, Thomas C.; Tripathi, Niraj; Bolliger, Anne Provencher; Everds, Nancy E.; Zelmanovic, David; Poitout, Florence; Bounous, Denise I.; Wescott, Debra; Ramaiah, Shashi K.

doi:10.1177/0192623314522109

Cited by 15 publications

(11 citation statements)

References 56 publications

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“…NAC, traditionally used as an antioxidant, modulates oxidative stress-mediated liver injury and inflammation of the small intestine [13,14]. Miniature pigs as an experimental model for humans have advantages of similar sensitivity to drugs compared with other non-rodent species and similar anatomical and physiological features [17,22,23]. Dietary supplementation with NAC increased immune cell numbers and decreased the level of TNF-α production compared with CTX treatment alone.…”

Section: Discussionmentioning

confidence: 99%

N-acetylcysteine modulates cyclophosphamide-induced immunosuppression, liver injury, and oxidative stress in miniature pigs

Kang¹,

Shin

Lee

2020

J Anim Sci Technol

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Cyclophosphamide, a cytotoxic anticancer agent, induces immunosuppression and has several adverse effects. N-acetylcysteine alleviates oxidative stress, liver injury, and intestinal tissue damage. The present study examined whether N-acetylcysteine modulates the adverse effects of cyclophosphamide in pigs. Miniature pigs (n = 15) were used as an experimental model to evaluate the effects of N-acetylcysteine treatment on immune reactions, liver injury, and oxidative stress after cyclophosphamide challenge. Corn-soybean meal based dietary treatments were as follows: control diet with either saline injection, cyclophosphamide injection, or 0.5% N-acetylcysteine and cyclophosphamide injection. N-acetylcysteine increased the number of immune cells and decreased TNF-α production after cyclophosphamide injection and decreased TNF-α, IFN-γ, NF-κB, and IL-8 expression and increased IL-10 expression in peripheral blood mononuclear cells. Serum levels of alanine transaminase and aspartate aminotransferase decreased, superoxide dismutase activity increased, and malondialdehyde activity decreased following N-acetylcysteine treatment after cyclophosphamide injection. N-acetylcysteine decreases immunosuppression, liver injury, and oxidative stress in cyclophosphamide-challenged miniature pigs. The present study suggests that N-acetylcysteine has therapeutic application in livestock for modulating immune reactions, liver injury, and oxidative stress.

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Section: Discussionmentioning

confidence: 99%

N-acetylcysteine modulates cyclophosphamide-induced immunosuppression, liver injury, and oxidative stress in miniature pigs

Kang¹,

Shin

Lee

2020

J Anim Sci Technol

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“…Studies of Ossabaw minipigs on the same diet also found no difference in ALT compared to control animals, whereas AST was increased. However, in pigs, GLHD is considered a more reliable marker of acute liver damage, as compared to ALT, which is non-specific in pigs [26]. Also, in human patients with NAFLD, ALT values have not been found to correlate with the degree of histopathological changes [27].…”

Section: Discussionmentioning

confidence: 99%

Experimental non-alcoholic steatohepatitis in Göttingen Minipigs: consequences of high fat-fructose-cholesterol diet and diabetes

et al. 2019

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Background Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in humans, and ranges from steatosis to non-alcoholic steatohepatitis (NASH), the latter with risk of progression to cirrhosis. The Göttingen Minipig has been used in studies of obesity and diabetes, but liver changes have not been described. The aim of this study was to characterize hepatic changes in Göttingen Minipigs with or without diabetes, fed a diet high in fat, fructose, and cholesterol to see if liver alterations resemble features of human NAFLD/NASH. Methods Fifty-four male castrated minipigs (age 6 to 7 months) were distributed into four groups and diet-fed for 13 months. Groups were: lean controls fed standard diet (SD, n = 8), a group fed high fat/fructose/cholesterol diet (FFC, n = 16), a group fed high fat/fructose/cholesterol diet but changed to standard diet after 7 months (diet normalization, FFC/SD, n = 16), and a streptozotocin-induced diabetic group fed high fat/fructose/cholesterol diet (FFC DIA , n = 14). At termination, blood samples for analyses of circulating biomarkers and liver tissue for histopathological assessment and analyses of lipids and glycogen content were collected. Results In comparison with SD and FFC/SD, FFC and FFC DIA pigs developed hepatomegaly with increased content of cholesterol, whereas no difference in triglyceride content was found. FFC and FFC DIA groups had increased values of circulating total cholesterol and triglycerides and the hepatic circulating markers alkaline phosphatase and glutamate dehydrogenase. In the histopathological evaluation, fibrosis (mainly located periportally) and inflammation along with cytoplasmic alterations (characterized by hepatocytes with pale, granulated cytoplasm) were found in FFC and FFC DIA groups compared to SD and FFC/SD. Interestingly, FFC/SD also had fibrosis, a feature not seen in SD. Only two FFC and three FFC DIA pigs had > 5% steatosis, and no hepatocellular ballooning or Mallory–Denk bodies were found in any of the pigs. Conclusions Fibrosis, inflammation and cytoplasmic alterations were characteristic features in the livers of FCC and FFC DIA pigs. Overall, diabetes did not exacerbate the hepatic changes compared to FFC. The limited presence of the key human-relevant pathological hepatic findings of steatosis and hepatocellular ballooning and the variation in the model, limits its use in preclinical research without further optimisation.

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“…Urinalysis in rabbits is not recommended for pivotal ocular toxicity studies since rabbit urine usually has a thick consistency due to the presence of mucus, sex gland secretions, and calcium carbonate crystals making voided samples often unsuitable for analysis. 84 In the author's experience, handling and procedures (intraocular injections, ocular examinations, and blood collections) in ocular toxicity studies of rabbits can occasionally elevate routine acute phase response clinical pathology parameters, including C-reactive protein and creatine kinase, and exacerbate the frequency and severity of myocardial inflammatory cell infiltrates. These effects are similar to that seen in with handling and study-related procedures such as blood collection and intramuscular injection in female NZW rabbits and included elevated stress biomarkers (norepinephrine, epinephrine, cortisol, and corticosterone) and cardiac troponin I.…”

Section: Systemic In-life Parametersmentioning

confidence: 99%

Selected Aspects of Ocular Toxicity Studies With a Focus on High-Quality Pathology Reports: A Pathology/Toxicology Consultant’s Perspective

Short¹

2020

Toxicol Pathol

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Ocular toxicity studies are the bedrock of nonclinical ocular drug and drug–device development, and there has been an evolution in experience, technologies, and challenges to address that ensures safe clinical trials and marketing authorization. The expectations of a well-designed ocular toxicity study and the generation of a coherent, integrative ocular toxicology report and subreports are high, and this article provides a pathology/toxicology consultant’s perspective on achieving that goal. The first objective is to cover selected aspects of study designs for ocular toxicity studies including considerations for contract research organization selection, minipig species selection, unilateral versus bilateral dosing, and in-life parameters based on fit-for-purpose study objectives. The main objective is a focus on a high-quality ocular pathology report that includes ocular histology procedures to meet regulatory expectations and a report narrative and tables that correlate microscopic findings with key ophthalmic findings and presents a clear interpretation of test article-, vehicle-, and procedure-related ocular and extraocular findings with identification of adversity and a pathology peer review. The last objective covers considerations for a high-quality ophthalmology report, which in concert with a high-quality pathology report, will pave the way for a best quality toxicology report for an ocular toxicity study.

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Nontraditional Applications in Clinical Pathology

Cited by 15 publications

References 56 publications

N-acetylcysteine modulates cyclophosphamide-induced immunosuppression, liver injury, and oxidative stress in miniature pigs

N-acetylcysteine modulates cyclophosphamide-induced immunosuppression, liver injury, and oxidative stress in miniature pigs

Experimental non-alcoholic steatohepatitis in Göttingen Minipigs: consequences of high fat-fructose-cholesterol diet and diabetes

Selected Aspects of Ocular Toxicity Studies With a Focus on High-Quality Pathology Reports: A Pathology/Toxicology Consultant’s Perspective

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