Immunopathogenesis of canine chronic ulcerative stomatitis.

Canine Chronic Ulcerative Stomatitis is a spontaneously occurring inflammatory disease of the oral mucosa. An immune-mediated pathogenesis is suspected though not yet proven. We have recently reported on the clinical and histologic features, and identification of select leukocyte cell populations within the lesion. A clinical and histologic similarity to oral lichen planus of people was proposed. In the present study, these initial observations are extended by examining lesions from 24 dogs with clinical evidence of chronic ulcerative stomatitis. Because dogs with chronic ulcerative stomatitis often have concurrent periodontal disease, we wondered if dental plaque/biofilm may be a common instigator of inflammation in both lesions. We hypothesized that dogs with chronic ulcerative stomatitis would exhibit a spectrum of pathologic changes and phenotype of infiltrating leukocytes that would inform lesion pathogenesis and that these changes would differ from inflammatory phenotypes in periodontitis. Previously we identified chronic ulcerative stomatitis lesions to be rich in FoxP3+ and IL17+ cells. As such, we suspect that these leukocytes play an important role in lesion pathogenesis. The current study confirms the presence of moderate to large numbers of FoxP3+ T cells and IL17+ cells in all ulcerative stomatitis lesions using confocal immunofluorescence. Interestingly, the majority of IL17+ cells were determined to be non-T cells and IL17+ cell frequencies were negatively correlated with severity on the clinical scoring system. Three histologic subtypes of ulcerative stomatitis were determined; lichenoid, deep stomatitis and granulomatous. Periodontitis lesions, like stomatitis lesions, were B cell and plasma cell rich, but otherwise differed from the stomatitis lesions. Direct immunofluorescence results did not support an autoantibody-mediated autoimmune disease process. This investigation contributes to the body of literature regarding leukocyte involvement in canine idiopathic inflammatory disease pathogenesis.

Multifocal discrete osteolysis in a horse with silicate associated osteoporosis.

Silicate associated osteoporosis (SAO) was diagnosed post mortem in an adult horse with the shortest documented exposure to cytotoxic silicates of 2 years. The horse was evaluated for a 6-months history of progressive back tenderness and acute onset of lameness. The horse had a marked (4/5) [American Association of Equine Practitioners scale] left forelimb lameness, moderate (2/5) hindlimb ataxia and weakness, and cervical pain upon palpation. Physical examination did not reveal clinical skeletal deformities or respiratory compromise. Radiographs revealed widespread, discrete, sharply delineated, osteolytic lesions in the skull, vertebral column, ribs, scapulae and middle phalanx (P2) of the left forelimb and a diffuse bronchointerstitial lung pattern. The presumptive clinical diagnosis was widespread, metastatic osteolytic neoplasia. Due to the poor quality of life and grave prognosis, the horse was humanely euthanised. Post mortem examination revealed pulmonary silicosis in the lungs and hilar lymph nodes and osteolytic lesions with numerous, large osteoclasts and disorganised bone remodeling both consistent with SAO. SAO should be included as a differential diagnosis for horses with widespread, multifocal, discrete osteolysis and history of exposure to endemic regions with possible cytotoxic silicate inhalation. Exposure time of 2 years is potentially sufficient to develop SAO.

The nucleoside analog GS-441524 strongly inhibits feline infectious peritonitis (FIP) virus in tissue culture and experimental cat infection studies.

Feline infectious peritonitis (FIP) is a common and highly lethal coronavirus disease of domestic cats. Recent studies of diseases caused by several RNA viruses in people and other species indicate that antiviral therapy may be effective against FIP in cats. The small molecule nucleoside analog GS-441524 is a molecular precursor to a pharmacologically active nucleoside triphosphate molecule. These analogs act as an alternative substrate and RNA-chain terminator of viral RNA dependent RNA polymerase. We determined that GS-441524 was non-toxic in feline cells at concentrations as high as 100 uM and effectively inhibited FIPV replication in cultured CRFK cells and in naturally infected feline peritoneal macrophages at concentrations as low as 1 uM. We determined the pharmacokinetics of GS-441524 in cats in vivo and established a dosage that would sustain effective blood levels for 24 h. In an experimental FIPV infection of cats, GS-441524 treatment caused a rapid reversal of disease signs and return to normality with as little as two weeks of treatment in 10/10 cats and with no apparent toxicity.

Evaluation of P16 expression in canine appendicular osteosarcoma.

BACKGROUND: Osteosarcoma (OSA) is a common malignant bone tumor of large breed dogs that occurs at predictable anatomic sites. At the time of initial diagnosis, most affected dogs have occult pulmonary metastases. Even with aggressive surgical treatment combined with chemotherapy, the majority of dogs diagnosed with OSA live less than 1 year from the time of diagnosis. The ability to identify canine OSA cases most responsive to treatment is needed. In humans, OSA is also an aggressive tumor that is histologically and molecularly similar to canine OSA. The expression of the tumor suppressor gene product P16 by human OSA tissue has been linked to a favorable response to chemotherapy. RESULTS: We identified an antibody that binds canine P16 and developed a canine OSA tissue microarray in order to test the hypothesis that P16 expression by canine OSA tissue is predictive of clinical outcome following amputation and chemotherapy. Although statistical significance was not reached, a trend was identified between the lack of canine OSA P16 expression and a shorter disease free interval. CONCLUSIONS: The identification of a molecular marker for canine OSA is an important goal and the results reported here justify a larger study.

Nasal Cavity Masses Resembling Chondro-osseous Respiratory Epithelial Adenomatoid Hamartomas in 3 Dogs.

Chondro-osseous respiratory epithelial adenomatoid hamartomas (COREAHs) are rare tumors in the nasal cavity of people, which have not been described in other species. COREAHs in people are minimally invasive and rarely recur following excision. Histologically, these tumors are composed of disorganized, mature, nasal turbinate tissue that is organized into polypoid growths. These growths are lined by respiratory epithelium, contain glandular elements, and are organized around central cores of chondro-osseous matrix. This report describes 3 cases of dogs with nasal tumors that have histomorphology similar to that of COREAH in people. The tumors were all identified within the nasal cavity and were associated with regional bony lysis of the turbinates and surrounding skull bones, a feature that has not been reported in COREAH in people. There was no evidence of metastasis or extension beyond the nasal cavity in any of the 3 cases.

Pharmacokinetics and pharmacodynamics of suberoylanilide hydroxamic acid in cats.

Suberoylanilide hydroxamic acid (SAHA), or vorinostat, is a histone deacetylase inhibitor approved for use as chemotherapy for lymphoma in humans. The goal of this study was to establish pharmacological parameters of SAHA in cats. Our interest in treating cats with SAHA is twofold: as an anticancer chemotherapeutic and as antilatency therapy for feline retroviral infections. Relying solely on data from studies in other animals would be inappropriate as SAHA is partially metabolized by glucuronidation, which is absent in feline metabolism. SAHA was administered to cats intravenously (2 mg/kg) or orally (250 mg/m², ~17 mg/kg) in a cross-over study design. Clinically, SAHA was well tolerated at these dosages as no abnormalities were noted following administration. The pharmacokinetics of SAHA in cats was found to be similar to that of dogs, but the overall serum drug exposure was much less than that of humans at an equivalent dose. The pharmacodynamic effect of an increase in acetylated histone proteins in blood was detected after both routes of administration. An increased oral dose of 60 mg SAHA/kg administered to one animal resulted in a surprisingly modest increase in peak drug concentration, suggesting possible saturation of absorption kinetics. This study provides a foundation for future studies of the clinical efficacy of SAHA in treating feline disease.

Oral papillary squamous cell carcinoma in twelve dogs.

Papillary squamous cell carcinoma (PSCC) is a distinct histological subtype of oral squamous cell carcinoma (SCC), described in both dogs and man. In dogs, PSCC has long been considered a malignant oral tumour of very young animals, but it has recently been reported to occur in adult dogs as well. The aim of this study was to describe the major clinicopathological characteristics of canine oral PSCC (COPSCC). Twelve dogs diagnosed with COPSCC were included in this retrospective study (1990-2012). The majority (75%) of the dogs were >6 years of age (median age 9 years). All tumours were derived from the gingiva of dentate jaws, with 66.7% affecting the rostral aspects of the jaws. The gross appearance of the lesions varied, with one having an intraosseous component only. The majority (91.7%) of the tumours were advanced lesions (T2 and T3), but no local or distant metastases were noted. Microscopically, two patterns were seen: (1) invasion of bone forming a cup-shaped indentation in the bone or a deeply cavitating cyst within the bone (cavitating pattern), (2) histologically malignant growth, but lack of apparent bone invasion (non-cavitating pattern). The microscopical appearance corresponded to imaging findings in a majority of cases, with cavitating forms presenting with a cyst-like pattern of bone loss or an expansile mass on imaging and non-cavitating forms showing an infiltrative pattern of bone destruction on imaging. These features suggest two distinct biological behaviours of COPSCC.

Ganglioneuroma of the brachial plexus in two cockatiels (Nymphicus hollandicus).

Ganglioneuroma involving the brachial plexus, paraspinal ganglia, and cervical-thoracic spinal cord was diagnosed in 2 adult cockatiels (Nymphicus hollandicus). Both birds had a chronic 1-year history of ataxia and perching difficulty. At necropsy, each bird had a unilateral, firm, gelatinous white to tan multilobular mass at the thoracic inlet expanding and partially obliterating the brachial plexus and cervical spinal cord. Histologically, the masses were characterized by a locally infiltrative neoplasm comprised of spindloid cells forming streams and sheets with interspersed distinct neuron cell bodies consistent with ganglion cells. The spindloid cell population was immunohistochemically positive for neurofilament protein in one of the birds.

Increased renal allograft thrombosis in CAPD patients.

In a retrospective analysis of 202 renal transplant procedures in the years 1989-1992 we identified an excess of grafts lost from primary renovascular thrombosis in patients receiving continuous ambulatory peritoneal dialysis (CAPD) compared to haemodialysis (HD) patients (9 CAPD versus 0 HD, Chi-squared = 9.63; P < 0.01). All graft losses from thrombosis occurred within 16 days of surgery. Possible predisposing causes were identified in three patients. Donor age was greater in CAPD patients losing their kidneys from thrombosis compared to the overall CAPD group [mean (SD) years, 43.0(12.9) versus 29.1(15.8); P = 0.01] whereas no significant difference in haematocrit, platelet count, antibody status, cyclosporin use, peroperative hypotension, primary diagnosis, smoking, or diabetes mellitus was found. Data from the EDTA registry for 1990-91 show that graft loss from primary renovascular thrombosis in UK-treated patients was reported in 7.1% of CAPD recipients compared with 1.8% in haemodialysis. We suggest that CAPD patients are at greater risk of graft loss from renovascular thrombosis than HD patients and may require more intensive fluid and anticoagulant treatment in the perioperative period.

Renal replacement therapy in multiple myeloma and systemic amyloidosis.

Renal failure frequently complicates both multiple myeloma and systemic amyloidosis. Renal replacement therapy (RRT) may be poorly tolerated and its role in such patients is not clearly defined. Of fifty patients (26 males and 24 females) referred to a single centre because of renal failure associated with multiple myeloma or systemic amyloidosis 37 progressed to end-stage renal failure and 30 of these patients received RRT. Nine patients have been treated by CAPD, 13 by haemodialysis, and 8 patients have required both forms of dialysis. Overall one year and two year survival rates were 66% and 57% respectively. The median duration on RRT was 7.5 months (range 1-96 months) with a 51% one year, and a 46% two year survival rate. Of 7 patients with amyloidosis who underwent renal transplantation, 3 died within 6 months of transplantation. Undiagnosed cardiac involvement contributed to this early mortality. We conclude that renal replacement therapy is appropriate for some patients with multiple myeloma and systemic amyloidosis who develop endstage renal failure. Careful assessment and selection of patients is necessary prior to renal transplantation.

Localization of a biologically important epitope on toxic-shock-syndrome toxin-1.

A monoclonal antibody, designated B-14, inhibits the nonspecific T lymphocyte mitogenicity of toxic-shock-syndrome toxin-1 (TSST-1), and the antibody binds to an internal cyanogen bromide (CNBr) fragment (Mr, 14,000) of the toxin. The epitope recognized by B-14 was further localized to include a decapeptide at the NH2-terminus of the CNBr fragment. The decapeptide inhibited the ELISA and western blot reactivity of B-14 with TSST-1, although it was approximately 10,000-fold less effective than the native toxin. The peptide also inhibited the capacity of B-14 to block TSST-1-induced mitogenicity. A conjugate, consisting of decapeptide4-ovalbumin, was used to hyperimmunize three rabbits. Serum from these rabbits reacted specifically with intact TSST-1 in ELISA and western blots and partially neutralized toxin mitogenicity; however, the serum did not prevent fever and enhancement of susceptibility to endotoxin shock typically seen in rabbits after administration of TSST-1.