Reduction in DNA damage in brain and peripheral blood lymphocytes of elderly dogs after treatment with dehydroepiandrosterone (DHEA).

Steady state levels of DNA damage are substantial in vertebrate animals as a consequence of exposure to endogenous and environmental mutagens. DNA damage may contribute to organismal senescence and an increased risk for specific age-related diseases. In this study, we determined if treatment with the neuroactive adrenal steroid, dehydroepiandrosterone (DHEA), which exhibits antioxidant and anticarcinogenic properties in rodents, would reduce DNA damage in the brain and peripheral blood lymphocytes (PBLs) of elderly dogs. Elderly male dogs, physiologically equivalent to 59-69-year-old men, were randomly assigned to receive no treatment (n=9 dogs) or DHEA at 100mg/kg PO daily (n=8 dogs). Extent of DNA damage in brain cells and PBLs was measured using alkaline comet assay. The effect of DHEA treatment on the susceptibility of PBLs to H(2)O(2)-induced DNA damage was also measured. We found that elderly male dogs receiving daily DHEA treatment for 7 months had significantly less DNA damage detectable in their brain compared to age-matched control dogs. After 7 months treatment, DHEA-treated dogs also had a significant reduction in DNA damage in PBLs compared to pre-treatment levels. We also found that PBLs of dogs treated with DHEA were more resistant to H(2)O(2)-induced DNA damage than PBLs of untreated dogs. Our results did not show that basal DNA damage in PBLs was strongly correlated with DNA damage within the brain. The results of this study suggest that DHEA supplementation can significantly reduce steady state levels of DNA damage in the mammalian brain. Further evaluation of DHEA as a neuroactive agent and its effects on DNA damage and gene expression in other tissues and species is warranted.

Cisplatin versus cisplatin combined with piroxicam in a canine model of human invasive urinary bladder cancer.

PURPOSE: More than 12,000 people are expected to die from invasive transitional cell carcinoma (TCC) of the urinary bladder each year in the United States, indicating that more effective therapy is needed. Drugs inhibiting cyclooxygenase (cox) have recently been found to have chemopreventive and antitumor activity and may potentiate the effects of chemotherapy. The purpose of this study was to determine whether cisplatin combined with the cox-inhibitor piroxicam would induce remission more frequently than cisplatin alone in a relevant animal model of human invasive TCC. METHODS: Pet dogs with naturally occurring, histopathologically confirmed, measurable TCC of the urinary bladder were randomized to receive cisplatin (60 mg/m2 i.v. every 21 days) or cisplatin (same dosage) combined with piroxicam (0.3 mg/kg orally every 24 h). Complete staging was performed prior to and at 6-week intervals during therapy. RESULTS: After eight dogs had been evaluated in each treatment group, a significant difference in remission rate was noted (Fisher's Exact test, P < 0.004). Tumor responses in the cisplatin/piroxicam group included two complete remissions (CR), four partial remissions (PR), two stable disease (SD), and no progressive disease (PD). Tumor responses to cisplatin alone in eight dogs were no CR, no PR, four SD, and four PD. Six additional dogs were treated with cisplatin/piroxicam, and in total 10 of 14 dogs had remission (two CR, eight PR). Renal toxicity of cisplatin/ piroxicam was frequent and dose limiting. CONCLUSIONS: Cisplatin/piroxicam induced remission more frequently than cisplatin alone in a canine model of human invasive TCC. Strategies to reduce renal toxicity need to be developed prior to evaluation of cisplatin/piroxicam in humans or general use of this treatment in pet dogs.

Coronavirus-associated epizootic catarrhal enteritis in ferrets.

OBJECTIVE: To characterize clinical signs and lesions and identify the etiologic agent associated with epizootic catarrhal enteritis in domestic ferrets. DESIGN: Cross-sectional study. ANIMALS: 119 ferrets with epizootic diarrhea of presumed viral cause and 5 control ferrets. PROCEDURE: Clinical records and biopsy or necropsy specimens of ferrets with presumed epizootic catarrhal enteritis were reviewed. Immunohistochemical staining for coronavirus antigen was performed on paraffin-embedded tissues from approximately 10% of affected ferrets to identify viral antigen and determine its distribution. Transmission electron microscopy was performed on fecal samples and sections of jejunum. Virus isolation studies as well as immunofluorescent tests for other similar viruses were performed. RESULTS: Characteristic microscopic lesions consistent with intestinal coronavirus infection (vacuolar degeneration and necrosis of villus enterocytes; villus atrophy, fusion, and blunting; and lymphocytic enteritis) were consistently detected in affected ferrets. Coronavirus particles were identified in feces and jejunal enterocytes by use of transmission electron microscopy. Immunohistochemical staining of jejunal sections revealed coronavirus antigens. Antigen staining was not detected in healthy ferrets or ferrets with other gastrointestinal tract diseases. Virus isolation was unsuccessful, and other similar viruses were not detected. CONCLUSIONS AND CLINICAL RELEVANCE: Results strongly implicate a coronavirus as the causative agent of epizootic catarrhal enteritis in ferrets. Diagnosis may be made on the basis of a combination of historical, clinical, and microscopic findings.

Life expectancy, antagonistic pleiotropy, and the testis of dogs and men.

BACKGROUND: Prostate cancer and benign prostatic hyperplasia are important age-related prostatic diseases that are under the influence of testicular hormones. However, the disparity between male and female life expectancy within the human population cannot be explained solely by the prevalence of prostatic disease-related mortality. The purpose of this paper is to explore the possibility that the testis exerts a detrimental effect on life span. METHODS: First, we review previously published and unpublished data on the influence of the testis on the life span of dogs and men. Aging in pet dogs and men is then discussed in terms of evolutionary theory, emphasizing the significance of a prolonged postreproductive life span and possible consequences of late-acting deleterious genes in these two species. Finally, we present preliminary data that orchiectomy can reduce DNA damage within the brain of elderly male dogs. RESULTS AND CONCLUSIONS Taken together, these observations raise the intriguing possibility that interventions to antagonize the testis might have much broader therapeutic applications that will extend well beyond the treatment of prostate cancer.

Naturally-occurring canine transitional cell carcinoma of the urinary bladder A relevant model of human invasive bladder cancer.

Invasive bladder cancer results in over 10,000 deaths yearly in the United States alone. More effective therapy for invasive bladder cancer is clearly needed. As new cellular and molecular targets for therapy are identified, relevant animal models are needed to test new therapeutic strategies aimed at these targets prior to human clinical trials. The purpose of this review is to characterize spontaneous invasive transitional cell carcinoma of the urinary bladder (TCC) in dogs, to summarize the similarities and differences between canine and human invasive TCC, and to describe how canine TCC could serve as a relevant model of human invasive bladder cancer. Information was summarized from 102 dogs with TCC evaluated and treated at the Purdue University Veterinary Teaching Hospital, from a review of the Veterinary Medical Data Base, and from reports in the literature. Canine TCC was found to be very similar to human invasive bladder cancer in histopathologic characteristics, molecular features, biological behavior including metastasis, response to medical therapy, and prognosis. Differences between canine and human TCC were few, but included gender predilection with a male:female ratio of 2.8:1 in humans versus a male:female ratio of 0.5:1 in dogs. The location of the TCC within the bladder also differed: Most canine TCC was trigonal in location, whereas more than 50% of human TCC was in the lateral and posterior walls of the bladder. Considering the great similarity between invasive bladder cancer in humans and dogs, spontaneous canine TCC can be considered a relevant animal model of human invasive bladder cancer.

Prevalence of gastric ulcers in show horses.

OBJECTIVE: To determine prevalence and risk factors for gastric ulcers in show horses. DESIGN: Field survey. ANIMALS: 50 horses in active training that had been transported to at least 1 event in the 30 days prior to endoscopy. PROCEDURE: Interview of owner, physical examination, serum biochemical analysis, CBC, and gastric endoscopy were performed. RESULTS: Gastric ulceration was detected in 58% of the horses. Horses with a nervous disposition were more likely to have ulceration than quiet or behaviorally normal horses. Horses with gastric ulceration had significantly lower RBC counts and hemoglobin concentrations than those without ulceration. CONCLUSIONS AND CLINICAL RELEVANCE: Show horses have a high prevalence of gastric ulceration. Lower RBC counts and hemoglobin concentrations may be the result of chronic gastric ulceration.

Underlying and multiple cause mortality in a cohort of workers exposed to aromatic amines.

BACKGROUND: The National Institute for Occupational Safety and Health (NIOSH) has previously conducted studies of bladder cancer incidence and mortality at a synthetic dye plant that manufactured beta-naphthylamine from 1940 through 1979. This report extends the period of mortality follow-up 13 years and analyzes both underlying and nonunderlying causes of death. METHODS: The vital status of each cohort member, as of December 31, 1992, was determined by using the National Death Index and information from the Internal Revenue Service and the U.S. Postal Service. The NIOSH life table analysis system (LTAS) was used to generate person-year-at-risk and the expected numbers of death for 92 categories of death, using several referent rates (U.S. underlying, Georgia underlying, U.S. multiple cause). RESULTS: There were three bladder cancer deaths listed as underlying cause, yielding a standardized mortality ratio (SMR) based on U.S. rates of 2.4 (95% confidence interval (CI) = 0.5, 7.0) and a total of eight bladder cancers listed anywhere on the death certificates (SMR based on multiple cause referent rates = 5.6; 95% CI = 2.4, 11.1). Mortality from esophageal cancer, which had been significantly elevated in the previous study, was no longer significantly elevated (SMR = 2.0; 95% CI = 0.8, 4.1). Mortality from all causes was significantly higher than expected (SMR = 1.5; 95% CI = 1.3, 1.6). CONCLUSIONS: The elevated bladder cancer risk in this cohort was detected by the multiple cause, but not the underlying cause, analysis. Elevated mortality from other causes of death, especially among short-term workers, may be related to regional and lifestyle factors.

Complete fractures of the third metacarpal or metatarsal bone in horses: 25 cases (1980-1996).

OBJECTIVES: To compare treatments of complete fractures of the third metacarpal (MC) or metatarsal (MT) bone in horses and to identify factors that could impact prognosis. DESIGN: Retrospective case series. ANIMALS: 25 horses with fractures of the third MC or MT bone that were treated by use of internal fixation, external coaptation, or both. PROCEDURE: Medical records from the Veterinary Medical Data Base of horses treated for fractures of third MC or MT bone at Texas A&M University from 1980 to 1994 and Purdue University from 1980 to 1996 were reviewed. Information on signalment, results of physical and radiographic examinations, treatment, and outcome were obtained. For horses that had radiographic evidence of healing, long-term follow-up information was obtained by telephone contact with owners or referring veterinarians. RESULTS: Age, sex, weight, and limb affected were not related to outcome; however, affected horses were younger than the general hospital populations. Seventeen horses had open fractures at referral. Infection was the most common complication after surgery, with open fractures more likely to become infected. Nonunion in an infected fracture was the most common reason for postoperative failure (7 horses). Long-term follow-up was available for 16 horses; 11 of these had no complications related to surgical repair. CLINICAL IMPLICATIONS: Fractures of the MC or MT bone are not always associated with a poor prognosis in horses. Proper case selection, rigid fracture stabilization, and efforts to prevent or treat infection will improve success rate.

Host related risk factors for canine osteosarcoma.

A case-control study using the Veterinary Medical Data Base (VMDB) was conducted to test the hypothesis that increasing height and increasing weight are important risk factors for osteosarcoma in dogs. The role of other host factors was also explored. The cases comprised 3062 purebred dogs with histologically or radiographically confirmed osteosarcoma admitted to 24 veterinary teaching hospitals in the United States and Canada between 1980 and 1994. The controls were 3959 purebred dogs with other diagnoses obtained randomly by frequency matching to cases for institution and year of diagnosis. The risk of osteosarcoma rose with increasing age, increasing body weight, increasing standard weight and increasing standard height. Compared with the German Shepherd breed, the highest risk of osteosarcomas was found for large and giant breeds, while small breeds had reduced risks. A twofold excess risk was observed among neutered dogs. Adjustment of risk estimates for standard height adjusted for standard weight, and vice versa, showed a stronger and more consistent association of osteosarcoma with increasing height than increasing weight.

Use of the urine cortisol: creatinine ratio to monitor treatment response in dogs with pituitary-dependent hyperadrenocorticism.

OBJECTIVE: To determine the usefulness of measuring urine cortisol:creatinine ratio (UCCR) as a means of monitoring response to mitotane treatment in dogs with pituitary-dependent hyperadrenocorticism (PDH). DESIGN: Case series. ANIMALS: 51 clinically normal dogs and 21 dogs with PDH. PROCEDURE: The reference range for the UCCR was determined by measuring the ratio in 51 clinically normal dogs. The usefulness of measuring UCCR in evaluating response of 21 dogs with PDH to treatment with mitotane was evaluated by comparing ACTH-stimulated blood cortisol concentrations with UCCR at the end of the induction phase of treatment (13 dogs) and during the maintenance phase of treatment (21). RESULTS: UCCR was not useful for identifying dogs with inadequate adrenal reserves at the end of the induction phase of treatment or during the maintenance phase. The UCCR was useful for identifying dogs in which control of cortisol secretion was not adequate. CLINICAL IMPLICATIONS: UCCR should not be used for evaluation of dogs during the induction phase of treatment, because the potential consequences of not identifying dogs with inadequate adrenal reserves are great. The UCCR may be useful as an adjunct means of monitoring treatment response during the maintenance phase of treatment. However, the ACTH stimulation test remains a necessary component when monitoring response to treatment in dogs with PDH receiving mitotane.

Feline fibrosarcomas at vaccination sites and non-vaccination sites.

A retrospective study of 195 feline sarcomas diagnosed histologically between July 1988 and June 1994 showed that 170 (87.2%) were fibrosarcomas. Cats with vaccination site (VS) fibrosarcomas were younger (8.6 +/- 3.9 years; median = 8 years) than cats with non-vaccination site (NVS) fibrosarcomas (10.2 +/- 4.7 years; median = 11 years) (P = 0.03), but there was no such association with breed, sex, or "neuter status". Microscopical features more characteristic of VS fibrosarcomas than of NVS fibrosarcomas were (1) subcutaneous location (P < 0.001), (2) necrosis (P < 0.001), (3) inflammatory cell infiltration (P < 0.001), (4) increased mitotic activity (P < 0.02), (5) pleomorphism (P < 0.001), and (6) variability in the density of the extracellular matrix (P < 0.001). When these data were fitted to a logistic regression model, younger age (P = 0.003), subcutaneous location of the fibrosarcoma (P = 0.0002), and the presence of inflammation (P = 0.017) were more characteristic of VS fibrosarcomas than of NVS fibrosarcomas. The study showed that in the absence of any vaccination history, the age of a cat, coupled with certain histological characteristics (e.g., tumour location in skin, and inflammation), may help in distinguishing VS fibrosarcomas from NVS fibrosarcomas. The characteristic histological features of VS fibrosarcomas, such as necrosis, increased mitotic activity and pleomorphism, are those of aggressive tumours.

Interleukin-6 activity in dogs with juvenile polyarteritis syndrome: effect of corticosteroids.

Juvenile polyarteritis syndrome (JPS) is an idiopathic febrile disease in dogs. Elevated serum levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) have been reported in human patients with vasculitis. We investigated whether these cytokines are also elevated in serum of dogs with JPS using sensitive bioassays. Increased levels of IL-6 activity were detected in the serum of 12 acutely ill dogs, whereas the IL-6 activity decreased to low or undetectable levels during convalescence. Treatment of 5 acute JPS dogs with prednisone resulted in a rapid clinical improvement accompanied by a decrease of IL-6 activity. Withdrawal of prednisone treatment caused reappearance of clinical symptoms and high serum IL-6 activity within a few days. TNF activity could not be detected in the samples of normal dogs, convalescent JPS, or acute JPS dogs. These studies support a role for IL-6 in the pathogenesis of JPS.

Pathologic features of naturally occurring juvenile polyarteritis in beagle dogs.

Eighteen young Beagle dogs (eight males and 10 females), ages 6-40 months, with canine juvenile polyarteritis syndrome (CJPS), a naturally occurring vasculitis and perivasculitis of unknown etiology, were necropsied, and their tissues were examined by histopathologic and histochemical methods. The condition is characterized by recurring episodes of an acute onset of fever (> 40 C) and neck pain that persist for 3-7 days. The major histopathologic alterations were a systemic vasculitis and perivasculitis. During the febrile, painful period of CJPS, the vascular lesions ranged from a histiocytic-lymphocytic periarterial infiltration to transmural arterial inflammation with concomitant fibrinoid necrosis and vascular thrombosis. Massive periarterial accumulations of inflammatory cells were common and often extended into adjacent tissues. The small- to medium-sized muscular arteries of the heart, cranial mediastinum, and cervical spinal meninges were consistently involved. Vasculitis occasionally occurred in other organ systems. The vascular lesions in dogs examined during clinically normal periods consisted of intimal and medial fibrosis, ruptured elastic laminae, and mild perivasculitis; these lesions were probably related to previous episodes of vasculitis. Eight dogs that had experienced repeated acute episodes also developed splenic, hepatic, and renal amyloidosis. The clinical signs, laboratory abnormalities, and the vascular lesions suggest that the condition may be immune-system mediated. CJPS may serve as a naturally occurring animal model of human immune-system-mediated vasculitides such as polyarteritis nodosa, infantile polyarteritis, and Kawasaki disease.

Treatment of nonregenerative anemia with human gamma-globulin in dogs.

Five dogs with nonregenerative anemia were treated with human immunoglobulin as a 12-hour IV infusion, at dosages ranging from 0.5 to 1.5 g/kg of body weight. All dogs had a rapid response to treatment, with reticulocytosis within 1 to 4 days and a substantial increase in hematocrit within 3 to 8 days of treatment. In 2 of 5 dogs, the hematocrit returned to values within reference range and remained in the reference range for 8 to 14 months after treatment, despite discontinuing or tapering prednisone treatment to a low dose. In 3 of 5 dogs, the hematocrit did not return to the reference range. In 1 of these 3 dogs, the hematocrit remained at the new, increased value (26 to 28%) for 248 days after treatment, at which time the dog was euthanatized. In the other 2 dogs, the hematocrit had decreased to pretreatment values by 52 days after treatment. Retreatment of these 2 dogs resulted in a similar, but blunted, response to human immunoglobulin. Human immunoglobulin may be an effective treatment for some dogs with immune-mediated anemia that fail to respond to conventional treatment.

Osteoid osteoma of the hamate: report of a case and review of the literature.

There are 7 reported patients with osteoid osteoma of the hamate. Only 1 of these has involved the hook of the hamate. This article reports the second patient with osteoid osteoma involving the hook of the hamate. The clinical features, the diagnostic problems, and the management of this lesion are reviewed.

Pet ownership protects against the risks and consequences of coronary heart disease.

Despite decreasing coronary heart disease mortality among both men and women, this disease still remains the leading cause of death in the United States. In addition to known physiologic factors, such as hypertension, smoking, and elevated plasma cholesterol, psychosocial factors including anxiety, marital status, and social isolation have been shown to contribute to the risk of coronary heart disease. There is increasing evidence suggesting that pet ownership causes measurable short term psychological and physiological effects in people, including reduction of blood pressure and mitigation of psychological indicators of anxiety. There is also evidence that pet ownership is associated with clinically significant health effects in people, including improved survival after a coronary event. We hypothesize that pet ownership, though its ability to positively influence psychosocial risk factors, results in a lowered risk of coronary heart disease and increased survival after a coronary event if it occurs, and that increased pet ownership would further reduce mortality from coronary heart disease.

A technique for the treatment of neuroma in-continuity.

A surgical technique for the management of a neuroma in-continuity, in which motor function is preserved and sensory function is reconstructed with nerve grafting, is presented. Tedious and potentially damaging dissection within the neuroma in-continuity is avoided. The functioning motor fascicles are identified proximal and distal to the injury site with electrical nerve stimulation eliciting muscle contraction. These motor fascicles are preserved. The electrically silent and nonfunctioning sensory fascicles are divided proximal and distal to the neuroma and reconstructed with autogenous nerve grafts. These nerve grafts bypass the functioning motor portion of the neuroma in-continuity.