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.     

Remedies for pseudoreplication

Pseudoreplication is the failure of a statistical analysis to properly incorporate the true structure of randomness present in the data. It has been well documented and studied in the ecological literature but has received little attention in the fisheries literature. Avoiding pseudoreplication in analyses of fisheries data can be difficult due to the complexity of the statistical procedures required. However, recent developments in statistical methodology are decreasing the extent to which pseudoreplication has to be tolerated. Seven examples are given here, beginning with simple design-based remedies and progressing to more challenging examples including the model-based remedies of mixed-effects modelling, generalized linear mixed models, state-space models, and geostatistics.     

Outbreak of Salmonella enterica serotype Newport in a beef cow-calf herd associated with exposure to bovine viral diarrhea virus

CASE DESCRIPTION: Severe disease and death in cows and calves affected 1 of 3 separate groups (A, B, and C) of cattle on a commercial cow-calf operation. CLINICAL FINDINGS: Clinical illness consisting of severe watery and bloody diarrhea, dehydration, weakness, and death affected adult cows and calves in 1 group (group B). Salmonella enterica serotype Newport was recovered from tissues of cows and calves from group B. TREATMENT AND OUTCOME: Despite supportive and antimicrobial treatment of cattle in group B, cow mortality rate attributable to salmonellosis in that group was 7.9% (32/407); calf mortality rate was 14.4% (52/361). None of the cows in Groups A or C died, and the calf mortality rate in those groups was low. Salmonella enterica serotype Newport was recovered from pooled fecal samples subsequently collected from each group of cows. Bovine viral diarrhea virus (BVDV) antigen was identified in an ear notch sample collected from a necropsied calf from group B. Subsequently, ear notch specimens from cattle in all 3 groups were tested for BVDV antigen. A significantly higher proportion of calves persistently infected with BVDV was identified in group B (8/295 [2.7%]), compared with the proportion in groups A and C combined (1/287 [0.3%]). CLINICAL RELEVANCE: Outbreaks of disease attributable to Salmonella Newport infection in beef cattle are unusual. Because of the immunosuppressive nature of BVDV, the possibility of animals persistently infected with BVDV within the herd should be considered during investigation of unusual outbreaks of infectious diseases.     

Influence of the Expert Effect on Cultural Models

We examined hunters’ perceptions of fauna to see if expert hunters and other hunters perceive wildlife abundance similarly. We used cultural consensus analysis (CCA) to assess the knowledge of 25 hunters in the Bolivian Amazon about the abundance of 38 animals. CCA indicated highly shared beliefs among hunters concerning wildlife abundance (average agreement = .62). However, expert hunters (as judged by their reported successful hunts of rare species, having hunted recently, and consuming more game in their diet) perceived more animals as abundant than did non-experts, although they all shared the same model. Since the expert hunters did not always agree on which species was more abundant, they had low cultural knowledge scores in CCA results. These experts may be unwilling to curtail hunting efforts on key species that they perceive to be abundant.     

Multifactorial resistance to transpermethrin in field-collected strains of the tobacco budworm Heliothis virescens F.

The penetration, degradation and excretion of [³H]transpermethrin were examined in susceptible and field-collected pyrethroid-resistant strains of the tobacco budworm Heliothis virescens. No consistent differences in labelled materials excreted or recovered in cuticle rinses were found between the resistant (R) and susceptible (S) larvae. Considerably lower levels of the parent compound were present internally in R compared with S larvae after 24h (P <0.01), clearly identifying a metabolic resistance mechanism in Meloland and Westmorland larvae. Moderate levels of absorbed permethrin accompanied by an absence of poisoning symptoms were observed in certain individuals of both R strains, suggesting a second resistance mechanism. Neurobioassays of R larvae showed a consistently lower sensitivity of the neuromuscular system to pyrethroids when compared with the S larvae, thus confirming the indication from metabolic studies of the additional (site-insensitive) mechanism. Toxicity values suggest a cross-resistance to other pyrethroids.     

Evaluation of twelve-hour preprandial and two-hour postprandial serum bile acids concentrations for diagnosis of hepatobiliary disease in dogs

In samples collected from 170 dogs suspected of having hepatobiliary disease, preprandial serum bile acids (PRSBA) and postprandial serum bile acids (POSBA) concentrations were measured, using a spectrophotometric enzymatic method. Dogs were assigned to 8 disease groups and 1 control group on the basis of hepatic histopathologic findings. Pre- and postprandial SBA concentrations and results of routine biochemical analyses (including total bilirubin, albumin, and BUN concentrations, and serum alkaline phosphatase (ALP), alanine transaminase (ALT), and aspartate transaminase (AST) activities) were expressed, using 4 indices: sensitivity, specificity, positive predictive value, and negative predictive value. Single tests and combinations of tests in series were evaluated. For diagnosis of hepatobiliary disease, the specificity of PRSBA was 100% at values greater than 20 mumol/L and of POSBA was 100% at values greater than 25 mumol/L. Test combinations with the best sensitivity for diagnosing the following diseases were: PRSBA-POSBA for cirrhosis, portosystemic vascular anomaly, and glucocorticoid hepatopathy; PRSBA-POSBA or PRSBA-ALP for cholestasis; PRSBA-POSBA or ALT-AST for chronic hepatitis; PRSBA-ALT for hepatic necrosis and passive congestion; and PRSBA-ALP for neoplasia. Test combinations with the overall highest sensitivity and positive predictive value for the fewest number of tests were PRSBA-POSBA, and either PRSBA or POSBA combined with an enzyme activity (ALT, AST, or ALP). The overall test efficacy for PRSBA vs POSBA was nearly identical: for PRSBA, it was 82.4%, and for POSBA, it was 82.3%. On the basis of the results of this study, PRSBA greater than 20 mumol/L or POSBA greater than 25 mumol/L (measured by use of an enzymatic procedure) indicates histopathologic abnormalities of the hepatobiliary system or portosystemic vascular anastomosis. Seemingly, determination of SBA concentrations can be used to indicate the propriety for hepatic biopsy. Pre- and postprandial serum bile acids concentrations should be evaluated in conjunction with routinely used hepatobiliary screening tests for best diagnostic advantage.     

Evaluation of Canine Red Blood Cells Stored in a Saline, Adenine, and Glucose Solution for 35 Days

An additive solution for the storage of red blood cells was evaluated for use in dogs. Blood collected from 6 dogs was processed into packed red blood cells and stored for 35 days in the additive solution Nutricel (Miles, Inc, Pharmaceutical Division, West Haven, CT). Packed red blood cells stored in citrate-phosphate-dextrose-adenine (CPDA-1; Fenwal Laboratories, Baxter Health Care Corp, Deerfield, IL) also were evaluated for comparison. Red blood cell 2,3-diphosphoglycerate (2,3-DPG) concentration, adenosine triphosphate (ATP) concentration, percentage hemolysis, and pH were determined. The red blood cell post-transfusion viability (PTV) after 35 days of storage was assessed with both single-labeled chromium 51 (⁵¹Cr) and double-labeled technetium 99m/chromium 51 (^99mTc/⁵¹Cr) techniques. Mean ATP concentration and percentage hemolysis of the cells stored in Nutricel were 1.1 μmol/g hemoglobin (Hb) and 0.28% respectively and did not differ significantly (P < .05) from the values of 1.0 μmol/g Hb and 0.33% from the CPDA-1-stored red blood cells. The mean pH of red blood cells stored in Nutricel was 6.19, which was significantly lower than the pH of 6.47 for cells stored in CPDA-1. The mean 2,3-DPG concentration of red blood cells stored in Nutricel was significantly higher at 10.1 μmol/g Hb than the 2,3-DPG concentration of 3.4μmol/g Hb for cells stored in CPDA-1. The mean PTV of canine red blood cells stored in Nutricel for 35 days was 85% with ⁵¹Cr and 90% with ^99mTc/⁵¹Cr. This was significantly higher than the mean PTVs of 38% and 36% for the CPDA-1 stored cells as assessed with ⁵¹Cr and ^99mTc/⁵¹Cr techniques, respectively. It was concluded that 35-day-old canine red blood cells stored in Nutricel are of acceptable quality for transfusion purposes.     

Treatment in the field of 27 horses with epiglottic entrapment

Twenty-seven horses were treated for epiglottic entrapment by using an oral, hand-assisted bistoury knife technique, under general anaesthesia; 26 of them returned successfully to racing, but one developed a permanently displaced soft palate. After the surgery 13 of the horses had an increased handicap rating and 13 had a decreased rating.