David C. Twedt

Oxidant injury to hepatic mitochondria in patients with Wilson's disease and Bedlington terriers with copper toxicosis

BACKGROUND/AIMS Copper overload leads to liver injury in humans with Wilsons disease and in Bedlington terriers with copper toxicosis; however, the mechanisms of liver injury are poorly understood. This study was undertaken to determine if oxidant (free radical) damage to hepatic mitochondria is involved in naturally occurring copper toxicosis. METHODS Fresh liver samples were obtained at the time of liver transplantation from 3 patients with Wilsons disease, 8 with cholestatic liver disease, and 5 with noncholestatic liver disease and from 8 control livers. Fresh liver was also obtained by open liver biopsy from 4 copper-overloaded and 4 normal Bedlington terriers and from 8 control dogs. Hepatic mitochondria and microsomes (humans only) were isolated, and lipid peroxidation was measured by lipid-conjugated dienes and thiobarbituric acid-reacting substances. In humans, liver alpha-tocopherol content was measured. RESULTS Lipid peroxidation and copper content were significantly increased (P < 0.05) in mitochondria from patients with Wilsons disease and copper-overloaded Bedlington terriers. More modest increases in lipid peroxidation were present in microsomes from patients with Wilsons disease. Mitochondrial copper concentrations correlated strongly with the severity of mitochondrial lipid peroxidation. Hepatic alpha-tocopherol content was decreased significantly in Wilsons disease liver. CONCLUSIONS These data suggest that the hepatic mitochondrion is an important target in hepatic copper toxicity and that oxidant damage to the liver may be involved in the pathogenesis of copper-induced injury.

Efficacy of Ronidazole for Treatment of Feline Tritrichomonas foetus Infection

OBJECTIVES To determine the efficacy of ronidazole (RDZ), tinidazole (TDZ), and metronidazole (MDZ) against Tritrichomonas foetus in vitro and of RDZ for treatment of feline naturally occurring or experimentally induced T. foetus infection. ANIMALS A cat naturally infected with T. foetus infection and diarrhea. Ten specific-pathogen-free (SPF) kittens. PROCEDURE RDZ, TDZ, and MDZ were tested for activity against 3 different feline isolates of T. foetus in vitro. RDZ then was administered to a naturally infected cat at 10 mg/kg PO q24h for 10 days. SPF kittens were infected orogastrically with feline T. foetus and treated with either placebo or RDZ (10 mg/kg PO q12h for 14 days). Cats with relapsing infection or those receiving placebo were treated subsequently with RDZ (either 30 or 50 mg/kg PO q12h for 14 days). Feces were examined for T. foetus by direct microscopy, culture, and polymerase chain reaction (PCR) testing weekly. RESULTS Both RDZ and TDZ killed T. foetus at concentrations >0.1 microg/mL in vitro. In the naturally infected cat, RDZ abolished diarrhea and T. foetus infection for 85 days after treatment, at which time infection and diarrhea relapsed. Retreatment with RDZ eradicated diarrhea and T. foetus infection for over 407 days. In experimentally induced infection, RDZ at 10 mg/kg caused initial improvement, but infection relapsed in all 5 cats 2 to 20 weeks after treatment. At 30 or 50 mg/kg, 10/10 cats were negative for T. foetus infection for follow-up durations of 21 to 30 weeks after treatment. CONCLUSIONS AND CLINICAL RELEVANCE Oral administration of RDZ at 30 to 50 mg/kg q12h for 14 days resolved diarrhea and eradicated infection (on the basis of polymerase chain reaction [PCR] testing) in 1 naturally infected cat and 10 experimentally inoculated cats receiving a different isolate of T. foetus.

Effect of Sample Quality on the Sensitivity of Endoscopic Biopsy for Detecting Gastric and Duodenal Lesions in Dogs and Cats

BACKGROUND The quality of histopathology slides of endoscopic biopsies from different laboratories varies, but the effect of biopsy quality on outcome is unknown. HYPOTHESIS The ability to demonstrate a histologic lesion in the stomach or duodenum of a dog or cat is affected by the quality of endoscopic biopsy samples submitted. More endoscopic samples are needed to find a lesion in poor-quality tissue specimens. ANIMALS Tissues from 99 dogs and 51 cats were examined as clinical cases at 8 veterinary institutions or practices in 5 countries. METHODS Histopathology slides from sequential cases that underwent endoscopic biopsy were submitted by participating institutions. Quality of the histologic section of tissue (inadequate, marginal, adequate), type of lesion (lymphangiectasia, crypt lesion, villus blunting, cellular infiltrate), and severity of lesion (normal, mild, moderate, severe) were determined. Sensitivity of different quality tissue samples for finding different lesions was determined. RESULTS Fewer samples were required from dogs for diagnosis as the quality of the sample improved from inadequate to marginal to adequate. Duodenal lesions in cats displayed the same trend except for moderate duodenal infiltrates for which quality of tissue sample made no difference. Gastric lesions in dogs and mild gastric lesions in cats had the same trend, whereas the number of tissue samples needed to diagnose moderately severe gastric lesions in cats was not affected by the quality of tissue sample. CONCLUSIONS AND CLINICAL IMPORTANCE The quality of endoscopically obtained tissue samples has a profound effect on their sensitivity for identifying certain lesions, and there are differences between biopsies of canine and feline tissues.

WSAVA Standards for Clinical and Histological Diagnosis of Canine and Feline Liver Diseases

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A Multi-Institutional Study Evaluating the Diagnostic Utility of the Spec cPL™ and SNAP® cPL™ in Clinical Acute Pancreatitis in 84 Dogs

BACKGROUND Pancreas-specific lipase is reported to aid in diagnosing acute pancreatitis (AP) in dogs but has not been rigorously evaluated clinically. HYPOTHESIS/OBJECTIVES To describe variability of disease in dogs with suspected clinical AP, and to evaluate accuracy of 2 pancreatic-specific lipase immunoassays, Spec cPL (SPEC) and SNAP cPL (SNAP), in diagnosing clinical AP. We hypothesized that SPEC and SNAP provide better diagnostic accuracy than serum amylase or total lipase. ANIMALS A total of 84 dogs; 27 without AP and 57 with clinical signs associated with AP. METHODS Multicenter study. Dogs were prospectively enrolled based upon initial history and physical examination, then retrospectively classified into groups according to the likelihood of having clinical AP by a consensus of experts blinded to SPEC and SNAP results. Bayesian latent class analyses were used to estimate the diagnostic accuracy of SPEC and SNAP. RESULTS The estimates for test sensitivities and specificities, respectively, ranged between 91.5-94.1% and 71.1-77.5% for SNAP, 86.5-93.6% and 66.3-77.0% for SPEC (cutoff value of 200 μg/L), 71.7-77.8% and 80.5-88.0% for SPEC (cutoff value of 400 μg/L), and were 52.4-56.0% and 76.7-80.6% for amylase, and 43.4-53.6% and 89.3-92.5% for lipase. CONCLUSIONS AND CLINICAL IMPORTANCE SNAP and SPEC have higher sensitivity for diagnosing clinical AP than does measurement of serum amylase or lipase activity. A positive SPEC or SNAP has a good positive predictive value (PPV) in populations likely to have AP and a good negative predictive value (NPV) when there is low prevalence of disease.

Thoracoscopic correction of persistent right aortic arch in a dog.

A 15-week-old, male intact, miniature schnauzer presented for signs consistent with persistent right aortic arch (PRAA). Esophagram and esophagoscopy confirmed this diagnosis. Following selective intubation, the constricting ligamentum arteriosum was visualized and completely resected via thoracoscopy. No complications were noted with this procedure. Advantages of thoracoscopy for management of persistent right aortic arch observed in this case were better visualization of the ligamentum arteriosum, minor postoperative discomfort, and minimal intraoperative hypothermia. Therefore, thoracoscopy is a potential alternative to intercostal thoracotomy for correction of PRAA.

S-adenosylmethionine (SAMe) in a feline acetaminophen model of oxidative injury

S-adenosylmethionine (SAMe) is reported to have hepatoprotective and antioxidant functions. Acetaminophen (paracetamol) was used to induce oxidative damage in cats, and to then determine the effect of SAMe treatment on erythrocyte morphology, PCV, liver histopathology, thiobarbituate reacting substances (TBARS), reduced glutathione (GSH), and oxidised glutathione (GSSG). Cats receiving acetaminophen had a significant increase in methemoglobin and Heinz body production. A significant effect for the interaction of time and treatment was found for Heinz body production and changes in PCV. No significant changes were found in blood or hepatic TBARS. Blood GSH increased significantly in all cats, while the blood GSH:GSSG ratio tended to increase the most in cats given acetaminophen only. The hepatic GSH:GSSG ratio tended to increase in cats given SAMe and decrease in cats given acetaminophen, but this effect was not significant. SAMe protected erythrocytes from oxidative damage by limiting Heinz body formation and erythrocyte destruction and maybe useful in treating acetaminophen toxicity.

Effect of maropitant, a neurokinin 1 receptor antagonist, on anesthetic requirements during noxious visceral stimulation of the ovary in dogs

OBJECTIVE To determine the anesthetic-sparing effect of maropitant, a neurokinin 1 receptor antagonist, during noxious visceral stimulation of the ovary and ovarian ligament in dogs. ANIMALS Eight 1-year-old female dogs. PROCEDURES Dogs were anesthetized with sevoflurane. Following instrumentation and stabilization, the right ovary and ovarian ligament were accessed by use of laparoscopy. The ovary was stimulated with a traction force of 6.61 N. The minimum alveolar concentration (MAC) was determined before and after 2 doses of maropitant. RESULTS The sevoflurane MAC value was 2.12 ± 0.4% during stimulation without treatment (control). Administration of maropitant (1 mg/kg, IV, followed by 30 μg/kg/h, IV) decreased the sevoflurane MAC to 1.61 ± 0.4% (24% decrease). A higher maropitant dose (5 mg/kg, IV, followed by 150 μg/kg/h, IV) decreased the MAC to 1.48 ± 0.4% (30% decrease). CONCLUSIONS AND CLINICAL RELEVANCE Maropitant decreased the anesthetic requirements during visceral stimulation of the ovary and ovarian ligament in dogs. Results suggest the potential role for neurokinin 1 receptor antagonists to manage ovarian and visceral pain.

Effect of Tissue Processing on Assessment of Endoscopic Intestinal Biopsies in Dogs and Cats

BACKGROUND Prior studies failed to detect significant association between hypoalbuminemia and small intestinal lesions. HYPOTHESIS Use of pictorial templates will enhance consistency of interpathologist interpretation and identification of intestinal lesions associated with hypoalbuminemia. ANIMALS Tissues from 62 dogs and 25 cats examined as clinical cases at 7 referral veterinary practices in 4 countries. METHODS Retrospective, observational study. Histopathology slides from sequential cases undergoing endoscopic biopsy were examined by 4 pathologists by pictorial templates. Changes for 9 microscopic features were recorded as normal, mild, moderate or severe, and 2- and 4-point scales were tested for consistency of interpretation. Logistic regression models determined odds ratios (OR) of histologic lesions being associated with hypoalbuminemia while kappa statistics determined agreement between pathologists on histologic lesions. RESULTS There was poor agreement (kappa = -0.013 to 0.3) between pathologists, and institution of origin of slides had effect (kappa = 1.0 for 3 of 4 lesions on slides from Institution 5) on agreement between pathologists on selected histologic features. Using 2 point as opposed to 4-point grading scale increased agreement between pathologists (maximum kappa = 0.69 using 4-point scale versus maximum kappa = 1.0 using 2-point scale). Significant association (P = .019- .04; 95% OR = 3.14-10.84) between lacteal dilation and hypoalbuminemia was found by 3 pathologists. CONCLUSIONS AND CLINICAL IMPORTANCE Substantial inconsistency between pathologists remains despite use of pictorial template because of differences in slide processing. Distinguishing between mild and moderate lesions might be important source of the disagreement among pathologists.

Copper-Associated Hepatopathies in Dogs

Copper-associated hepatotoxicity in certain breeds has been identified for almost 20 years, and the list of affected breeds is growing. The importance for copper analysis of liver specimens is emphasized by the realization that copper accumulation occurs in many hepatic disease states, and it may become pathologic. Many treatment possibilities exist. It is important that therapy be tailored to the needs of the animal and the severity of accumulation. To determine efficacy of treatment and when an endpoint has been reached, follow-up liver biopsies are essential.