Pathology and Neurotoxicity in Dogs after Repeat Dose Exposure to a Serotonin 5-HT1B Inhibitor

AZD3783, a cationic amphiphilic drug and a potent inhibitor of the 5-hydroxytryptamine (5-HT_1B) receptor, was explored as a potential treatment for depression. To support clinical trials, repeat dose toxicity studies in rats and dogs were conducted. Here we report toxicity findings in dogs after dosing from 1 to 3 months. In the 1-month study, there were minimal neuronal vacuolation in the brain, a marked increase in liver enzymes accompanied by hepatocellular degeneration/necrosis and phospholipidosis (PLD), and PLD/cholecystitis in the gallbladder of animals dosed at 47 mg/kg/day. In the 3-month study, neurotoxicity resulted in euthanasia of one animal dosed at 30 mg/kg/day after 86 days. Extensive pathologic changes were seen in all animals in retina epithelium (inclusion bodies), brain (neuronal vacuolation, degeneration, or necrosis and nerve fiber degeneration), spinal ganglia (vacuolation, degeneration, or necrosis), as well as sciatic and optic nerves (degeneration). Pigment-laden macrophages were observed in the lung, kidney, liver, gallbladder, bone marrow, gastrointestinal tract, and lymphoid tissues. Also seen were vitrel and retinal hemorrhage in the eyes. A brain concentration and pathology study showed that the concentration of AZD3783 in the brain was approximately 4 times higher than in the plasma after 4 weeks of dosing, however, they were similar in all regions examined, and did not correlate with areas with pathologic findings. Our findings with AZD3783 in dogs have not been reported previously with other CNS compounds that effect through serotonergic pharmacology.     

Dietary inclusion of dehydrated bocaiuva pulp increases the antioxidant potential of quail eggs

The aim of this study was to evaluate dietary supplementation of different levels of dehydrated bocaiuva pulp (DBP) on the productive performance of laying quails, and on lipid oxidation, and quality in their eggs. A total of 120 quails were distributed in a completely randomized design with six treatments (0%, 0.1%, 0.2%, 0.3%, 0.4% and 0.5% of DBP), five replicates and four birds per experimental unit. To evaluate lipid oxidation, the eggs were collected on five consecutive days at the end of the trial and distributed in a completely randomized experimental design in a 6 × 5 factorial scheme (eggs from quails fed different levels of DBP × evaluated fresh and after 7, 14, 21 and 28 days). The antioxidant potential of diets was improved (p < 0.05) when the DBP was added estimated as 2,2'‐azinobis‐3‐ethylbenzothiazolin‐6‐sulfonic acid (ABTS) free radical scavenging capacity. No effect (p > 0.05) was observed on feed intake, hen‐day egg production and feed conversion (kg/kg and kg/dz). There were no changes (p > 0.05) in the egg weight, Haugh unit, yolk index or eggshell percentage. Although no difference was observed (p > 0.05), when comparing each level with the control, a negative linear effect (p < 0.05) on specific gravity was observed. In addition, only the treatment with 0.5% pulp exhibited lower (p < 0.05) eggshell thickness compared with the control (0%). Thiobarbituric acid reactive substances (TBARS) analysis showed that as the dietary pulp level was increased, malondialdehyde content decreased linearly (p < 0.05) in the egg yolks, regardless of the storage period. Inclusion of DBP in the diets had no effect (p > 0.05) on the concentration of conjugated dienes in the eggs. The diets containing DBP showed a potential antioxidant effect, reducing the degree of lipid oxidation in egg yolk. However, no beneficial effects were observed on performance and egg quality.     

Experimental infection of cats (Felis catus) with Tritrichomonas foetus isolated from cattle

Tritrichomonas foetus is recognized as the causative agent of venereal trichomoniasis in cattle. It is characterized by embryonic and early fetal death and post-coital pyometra, and feline trichomoniasis, manifest as chronic, large bowel diarrhea. Many of the infected cats are less than 2 years old and specific routes of transmission remain unknown. We recently demonstrated that feline isolates of T. foetus can successfully infect heifers, resulting in pathologic changes similar, but not identical to those previously reported as representative of bovine trichomoniasis. In this study, we experimentally infected six cats less than 1 year of age with a bovine (D-1) isolate of T. foetus and one cat with a feline (AUTf-1) isolate of T. foetus. Within 2 weeks, the cat infected with the feline (AUTf-1) isolate was culture positive for trichomonads in weekly fecal samples. At the end of 5 weeks, only one cat infected with the bovine (D-1) isolate was fecal culture positive for trichomonads. At necropsy, the intestine of each cat was removed and divided into five sections (ileum, cecum, anterior, medial and posterior colon). Contents from each section were collected and cultured. The cat infected with the feline (AUTf-1) isolate was culture positive in the ileum, cecum, medial and posterior colon. Two cats infected with the bovine (D-1) isolate were culture positive in the cecum only. Additionally, each intestinal section was submitted to a pathologist for histopathological examination. The combined results indicate that there are demonstrable differences between the feline (AUTf-1) and bovine (D-1) isolates regarding their infectivity in cats.     

Canine schistosomiasis in Kansas: five cases (2000-2009)

This is a retrospective case series consisting of five dogs diagnosed with schistosomiasis. The purpose of this article is to report the presence of naturally occurring canine schistosomiasis in Kansas and to provide clinical details regarding schistosomiasis. Medical records of dogs diagnosed with schistosomiasis from 2000 to 2009 were reviewed, and information extracted included signalment, history, clinical signs, diagnostic test results, treatment, and outcome. Affected dogs were primarily medium to large breed and young to middle aged. All dogs were considered outdoor dogs, with three having known access to surface water. Common clinical signs included gastrointestinal disease and signs associated with hypercalcemia. Fecal flotation was negative in all dogs in contrast to fecal saline sedimentation and fecal polymerase chain reaction, which were both positive in all dogs in which it was performed. All dogs treated specifically for schistosomiasis fully recovered. This article describes the first reported cases of canine schistosomiasis in the Midwest and the first reported case of intestinal intussusception secondary to schistosomiasis. Recognizing that canine schistosomiasis is present in Kansas and possibly other Midwestern states should prompt veterinarians to perform appropriate diagnostic investigation in suspect animals as the diagnosis is straight forward and relatively inexpensive.     

Evaluation of shock waveform configuration on the defibrillation capacity of implantable cardioverter defibrillators in dogs

BackgroundImplantable cardioverter defibrillators (ICD) are programmed to detect ventricular arrhythmias and terminate them by delivering an electrical shock. A defibrillation threshold (DFT) at least 10 J below the maximum device output is recommended for successful therapy. Shock waveform configuration is a programmable parameter used to achieve a low DFT. It is hypothesized that a fixed-pulse configuration results in lower defibrillation energy requirements than a fixed-tilt configuration.Animals10 mongrel dogs.Materials and methodsICD generator and transvenous lead were surgically implanted. Defibrillation threshold was determined using a protocol guided by the upper limit of vulnerability. Fixed-pulse and fixed-tilt (50%/50%) waveform configurations were tested in a random order. Plasma cardiac troponin I (cTnI) was measured for signs of myocardial injury.ResultsThe experiment was completed in 9 dogs. Overall mean DFT value was 424 ± 88 V (9.2 ± 3.9 J). Mean differences among voltage, energy and impedance at the DFT for fixed-pulse (422 ± 97 V, 9.1 ± 4.2 J, 62.6 ± 13.8 Ω) and fixed-tilt (426 ± 83 V, 9.3 ± 3.8 J, 62.8 ± 18.5 Ω) configurations were not statistically significant (All P > 0.21). Cardiac TnI concentration changed from 0.03 ng/mL (95% CI: 0.02–0.04) at baseline to 0.11 ng/mL (95 CI: 0.08–0.16) after DFT was obtained with the first waveform configuration and 0.19 ng/mL (95% CI: 0.13–0.28) at the end of the study period. There were no significant changes in heart rate, end-tidal CO2 and blood pressure over time (all P > 0.09).ConclusionThe tested ICD device and lead placement reliably produced acceptable DFT values, based on a 10-J safety margin below the maximum device output. A benefit of fixed-pulse configuration could not be demonstrated over the standard fixed-tilt waveform. Signs of acute myocardial damage from repeated high-voltage shocks and episodes of ventricular fibrillation seemed of limited clinical significance.     

A Quantitative Polymerase Chain Reaction Assay for the Detection and Quantification of Epizootic Epitheliotropic Disease Virus (EEDV; Salmonid Herpesvirus 3)

Epizootic epitheliotropic disease virus (EEDV; salmonid herpesvirus [SalHV3]; family Alloherpesviridae) causes a systemic disease of juvenile and yearling Lake Trout Salvelinus namaycush. No cell lines are currently available for the culture and propagation of EEDV, so primary diagnosis is limited to PCR and electron microscopy. To better understand the pervasiveness of EEDV (carrier or latent state of infection) in domesticated and wild Lake Trout populations, we developed a sensitive TaqMan quantitative PCR (qPCR) assay to detect the presence of the EEDV terminase gene in Lake Trout tissues. This assay was able to detect a linear standard curve over nine logs of plasmid dilution and was sensitive enough to detect single-digit copies of EEDV. The efficiency of the PCR assay was 99.4 ± 0.06% (mean ± SD), with a 95% confidence limit of 0.0296 (R² = 0.994). Methods were successfully applied to collect preliminary data from a number of species and water bodies in the states of Pennsylvania, New York, and Vermont, indicating that EEDV is more common in wild fish than previously known. In addition, through the development of this qPCR assay, we detected EEDV in a new salmonid species, the Cisco Coregonus artedi. The qPCR assay was unexpectedly able to detect two additional herpesviruses, the Atlantic Salmon papillomatosis virus (ASPV; SalHV4) and the Namaycush herpesvirus (NamHV; SalHV5), which both share high sequence identity with the EEDV terminase gene. With these unexpected findings, we subsequently designed three primer sets to confirm initial TaqMan qPCR assay positives and to differentiate among EEDV, ASPV, and NamHV by detecting the glycoprotein genes via SYBR Green qPCR.

Received April 20, 2015; accepted November 10, 2015     

Theileria buffeli infection of a Michigan cow confirmed by small subunit ribosomal RNA gene analysis

Theileria buffeli, generally a benign parasite of cattle, has been reported in animals from Texas, Missouri and North Carolina. To date, there have been no reports of the parasite in cattle residing in northern portions of the US. An 8-year-old cow (Maine Anjou x Angus cross-bred) in Michigan presented with hemoglobinuria and a packed cell volume of 9. Blood films stained with Giemsa showed numerous intraerythrocytic parasites morphologically consistent with T. buffeli. The parasite was confirmed to be T. buffeli by SSU rRNA gene sequence analysis (SSU rRNA sequence, Type A). This represents the first report of this parasite in an animal in Michigan.     

Intracranial Lesions in Dogs With Hemangiosarcoma

A retrospective analysis of 85 dogs with hemangiosarcoma (HSA) that underwent complete necropsy, including gross examination of the brain, was conducted. Grossly identifiable intracranial lesions were present in 17 dogs. Twelve of 85 dogs (14.2%) had brain metastases. Four of 85 dogs (4.7%) had hemorrhagic lesions and/or ischemic necrosis without identifiable tumor. One dog had a primary central nervous system tumor. Signs of intracranial disease were present in six of 85 dogs (7.1%) with HSA; four had brain metastases and two had nonneoplastic lesions. Metastases had a propensity for cerebrum and gray matter. Dogs with brain metastases had more widely disseminated disease than dogs without brain metastases (P less than 0.001). Dogs with pulmonary metastases were at greater risk for developing brain metastases than dogs without pulmonary metastases (odds ratio = 8.31). Although thoracic radiography accurately identified ten of 12 dogs (83%) with pulmonary metastases, too few cases were available to assess the applicability/accuracy of thoracic radiography in predicting the presence or absence of brain metastases in dogs with malignancy and signs of intracranial disease.     

Equine protozoal myeloencephalitis caused by Neospora hughesi in an adult horse in Saskatchewan

A protozoal parasite identified as Neospora hughesi was found in inflammatory lesions in the central nervous system of a Canadian-born adult horse presented with neurological signs. This is believed to be the first case of equine protozoal myeloencephalitis (EPM) caused by Neospora hughesi in a horse outside of the United States.