Protein tyrosine phosphatase 1B is a key regulator of IFNAR1 endocytosis and a target for antiviral therapies.

Type 1 interferons (IFN1) elicit antiviral defenses by activating the cognate receptor composed of IFN-α/ß receptor chain 1 (IFNAR1) and IFNAR2. Down-regulation of this receptor occurs through IFN1-stimulated IFNAR1 ubiquitination, which exposes a Y466-based linear endocytic motif within IFNAR1 to recruitment of the adaptin protein-2 complex (AP2) and ensuing receptor endocytosis. Paradoxically, IFN1-induced Janus kinase-mediated phosphorylation of Y466 is expected to decrease its affinity for AP2 and to inhibit the endocytic rate. To explain how IFN1 promotes Y466 phosphorylation yet stimulates IFNAR1 internalization, we proposed that the activity of a protein tyrosine phosphatase (PTP) is required to enable both events by dephosphorylating Y466. An RNAi-based screen identified PTP1B as a specific regulator of IFNAR1 endocytosis stimulated by IFN1, but not by ligand-independent inducers of IFNAR1 ubiquitination. PTP1B is a promising target for treatment of obesity and diabetes; numerous research programs are aimed at identification and characterization of clinically relevant inhibitors of PTP1B. PTP1B is capable of binding and dephosphorylating IFNAR1. Genetic or pharmacologic modulation of PTP1B activity regulated IFN1 signaling in a manner dependent on the integrity of Y466 within IFNAR1 in human cells. These effects were less evident in mouse cells whose IFNAR1 lacks an analogous motif. PTP1B inhibitors robustly augmented the antiviral effects of IFN1 against vesicular stomatitis and hepatitis C viruses in human cells and proved beneficial in feline stomatitis patients. The clinical significance of these findings in the context of using PTP1B inhibitors to increase the therapeutic efficacy of IFN against viral infections is discussed.

Feline Oral Squamous Cell Carcinoma: Clinical Manifestations and Literature Review.

Squamous cell carcinoma (SCC) is the most commonly encountered malignant oral tumor in cats. The etiology of this locally invasive tumor is likely multifactorial. Several risk factors have been identified, including the use of flea collars, and a history of feeding canned food and canned tuna. Clinical signs vary depending on tumor location. The tumor commonly arises from the gingiva and mucosa of the maxilla, mandible, tongue, sublingual area, or tonsillar region. Maxillary SCC commonly presents clinically as an ulcerative lesion, whereas mandibular SCC is commonly proliferative, expansile, and firm. Lingual/sublingual SCC may be ulcerative, necrotic, infiltrative, or proliferative. In general, feline oral SCC is an invasive and malignant neoplasm regardless of its location. Surgery, radiation therapy, chemotherapy and combinations thereof have been attempted with rarely a satisfactory response. Currently, cures are obtained only in a small subset of cats whose tumors are amenable to complete resection, or where resection with microscopic residual disease is followed by definitive radiation therapy. A multimodal treatment approach likely offers the best chance of success. For cats with advanced disease, palliative care may improve patients' quality of life, albeit transiently. Sequelae associated with tumor progression and local tissue destruction often result in euthanasia of feline patients with oral SCC.

Computed tomographic characteristics of odontogenic neoplasms in dogs.

Odontogenic neoplasms are locally invasive oral tumors in dogs. The purpose of this retrospective study was to describe CT characteristics for varying histopathologic types of canine odontogenic neoplasms. A board-certified veterinary radiologist who was unaware of histologic findings reviewed and scored imaging studies. A total of 29 dogs were included in the study. Twenty-three of these dogs had concurrent dental radiographs. The most common CT characteristics for all tumor types were a direct association with or in the region of multiple teeth in 96.4% (27/28), contrast enhancement in 96.3% (26/27), alveolar bone lysis in 93.1% (27/29), and mass-associated tooth displacement in 85.2% (23/27). Mass-associated cyst-like structures were identified in 53.6% (15/28) and were only present in tumors containing odontogenic epithelium. Canine acanthomatous ameloblastomas (n = 15) appeared as extra-osseous (10/15) or intra-osseous (5/15) masses. Intra-osseous canine acanthomatous ameloblastomas were more likely to have mass-associated cyst-like structures and were subjectively more aggressive when compared with extra-osseous canine acanthomatous ameloblastomas. Amyloid-producing odontogenic tumors (n = 3) had subjectively uniform CT imaging characteristics and consisted of round soft tissue and mineral attenuating masses with multiple associated cyst-like structures. Fibromatous epulides of periodontal ligament origin (n = 4) were contrast enhancing extra-osseous masses that were rarely referred for CT examinations and 25% (1/4) were not visible with CT. Other odontogenic tumors were less represented or had more variable CT imaging characteristics. Mass-associated tooth destruction was appreciated more often with dental radiographs and extra-oral tumor extension was identified more often with CT.

Assessment of apical periodontitis in dogs and humans: a review.

Veterinary dentists commonly encounter apical periodontitis in dogs. An overview of the disease is presented, concentrating on pathogenesis and mechanisms of healing. Assessment modalities are reviewed and interpretations of treatment success and failure are discussed. The limitations of readily available diagnostic equipment are illustrated. The benefits of identifying the causative agent and resultant pathosis should not be overlooked. Well-designed clinical studies evaluating various methods of long-term follow-up for apical periodontitis in dogs are needed.

Polyamine inhibitors for treatment of feline oral squamous cell carcinoma: a proof-of-concept study.

This study assessed proof-of-concept for use of polyamine inhibitor 2-diluoromethylornithine (DFMO) as a treatment for oral squamous cell carcinoma (SCC) in client-owned cats. Polyamine levels in tumor tissue and normal oral mucosa were quantified before and after treatment. DFMO was administered orally to 14 client-owned cats with histologically confirmed oral SCC. Patients were monitored for gastrointestinal, dermatologic, auditory, hematological, and biochemical abnormalities. Total polyamine levels in tumor tissue decreased after treatment, as did the specific polyamine putrescine in both tumor tissue and normal mucosa. Ototoxicity was observed in 5 of 6 cats receiving pre- and post-treatment brainstem auditory evoked potential tests. Subclinical thrombocytopenia was observed in 6 of 14 cats. One cat showed mild post-anesthetic tremors that resolved without treatment. Oral administration of DFMO at doses used in this study resulted in significantly decreased tumor polyamine levels without life-threatening clinical or hematological toxicities. Further studies are warranted to explore pathophysiology of polyamine biochemistry and use of polyamine inhibitors in treatment of cats with oral SCC.

Orofacial manifestations of high-rise syndrome in cats: a retrospective study of 84 cases.

Medical records of cats with high-rise trauma were reviewed to document the prevalence and clinical manifestations of orofacial injury. Cats were presented over a 10-year period from January 2000 to December 2009. Signalment, weight, number of stories fallen, and survival data were recorded in 84 cats and physical examination findings were obtained from 83 cats. Fourteen of these cats were examined by veterinarians of the Dentistry and Oral Surgery Service. Mean age was 37-months. Mean distance fallen was 2.65 stories, and in the majority of cases the substrate the cat fell on was not recorded Overall, survival was 94.0% when including euthanasia as a cause of death and 98.8% when excluding euthanized patients. Orofacial findings included bilateral epistaxis, hard palate fracture +/- tear of palatal soft tissue, palatal soft tissue bruising, mandibular fracture, mandibular symphyseal separation, tongue injury, facial soft tissue injury, dental trauma, and other oral soft tissue injury. Sixty-six percent of cats suffered some degree of orofacial injury. The population was analyzed for the prevalence of each type of injury. An oronasal fistula was seen in one cat as a complication of an untreated hard palate fracture. Possible etiology of the injuries and treatment options are discussed.

Essential considerations for equine oral examination, diagnosis, and treatment.

Equine dentistry should no longer be thought of as art over science. To be an effective equine dental clinician requires considerable investment in knowledge beyond the basic veterinary degree. It requires current scientific dental knowledge and adherence to the fundamental principles of medicine, dentistry, and surgery. Knowledge and principles will provide clinicians with the necessary information to make more evidence-based decisions as the scientific literature continues to evolve. Diagnosis and therapy should be seen as journeys with a destination, keeping in mind the values of the Hippocratic oath. Equine dentistry no longer needs to be seen as hard physical work with considerable risk to all involved. There is a demand for providers of equine dental care to be appropriately trained veterinarians and for veterinarians to further develop the science of equine dentistry. The rewards to the horse, client, and clinician are likely to be evident to those who make the investment.

Oral examination results in rescued ferrets: clinical findings.

Ferrets have increased in popularity as pets, and a growing number are seen in companion animal practice. Domestic ferrets are commonly used as animal models for research of human oral conditions. The present study evaluated the prevalence of oral pathology in rescued ferrets which - to the authors' knowledge - has not yet been described in the scientific literature. Conscious oral examination was performed on 63 ferrets, of which 49 underwent general anesthesia for further examination. The most common clinical findings included malocclusion of mandibular second incisor teeth (95.2%); extrusion of canine teeth (93.7%); and abrasion and attrition of teeth (76.2%). Tooth fractures were exclusively associated with canine teeth and found in 31.7% of ferrets. Pulp exposure was confirmed in 60.0% of fractured teeth. The normal gingival sulcus depth measured < 0.5-mm in 87.8% of anesthetized ferrets. Clinical evidence of periodontal disease was present in 65.3% of anesthetized ferrets (gingivitis or probing depths > 0.5-mm), however advanced periodontal disease (i.e. periodontal pockets > 2-mm or stage 3 furcation exposure) was not found upon clinical examination. There was no evidence of tooth resorption, dental caries, stomatitis, or oral tumors in the examined group of ferrets.

Computed tomographic features of oral squamous cell carcinoma in cats: 18 cases (2002-2008).

OBJECTIVE: To describe the computed tomographic features of oral squamous cell carcinoma (SCC) in cats and identify imaging characteristics associated with survival time. DESIGN: Retrospective case series. ANIMALS: 18 cats with a diagnosis of oral SCC. PROCEDURES: Information on history; clinical, laboratory, and diagnostic imaging findings; treatment; and survival time was obtained from medical records of 18 cats with oral SCC. Computed tomography (CT) studies were examined to identify features associated with oral SCC. The association of CT features with survival time was evaluated. RESULTS: On CT images, SCC was centered at the following sites: sublingual or lingual region (n = 7), maxilla (5), buccal mucosa (4), mandible (4), pharyngeal mucosa (2), soft palate mucosa (1), and lip (1). These results were in agreement with the results of oral examination for all sites, except the soft palate (CT, 1 cat; oral examination, 4 cats). On CT images, extension of maxillary masses was most often observed to affect the orbit (5 cats). Heterogeneous contrast enhancement was most commonly identified (8/18). Osteolytic mass lesions were identified on CT images in 9 cats. None of the quantitative CT features that were identified, including mass size, attenuation, or lymph node width, were correlated with survival time. CONCLUSIONS AND CLINICAL RELEVANCE: Common CT features of oral SCC in cats included sublingual and maxillary locations, marked heterogeneous contrast enhancement, and osteolysis. Computed tomography may be used to determine mass extension and lymph node enlargement, but results did not correlate with survival time.

Mandibular periostitis ossificans in immature large breed dogs: 5 cases (1999-2006).

This case series describes clinical, radiographic, and histopathological features of mandibular swellings in 5 immature, large breed dogs. The dogs originated from different regions of the United States. In each case, intraoral dental radiography of the jaw swelling revealed a two-layered (double) ventral mandibular cortex. Biopsy was performed in 4 of the 5 puppies, revealing periosteal new bone formation. Resolution of the mandibular swelling was spontaneous in the 4 dogs available for follow-up examination. The authors postulate that the clinical, radiographic, and histopathological presentation of mandibular swelling in these 5 dogs is a distinct pathological entity consistent with an inflammatory condition of the maturing human mandible known as periostitis ossificans.

A geometric approach for computing tolerance bounds for elastic functional data.

We develop a method for constructing tolerance bounds for functional data with random warping variability. In particular, we define a generative, probabilistic model for the amplitude and phase components of such observations, which parsimoniously characterizes variability in the baseline data. Based on the proposed model, we define two different types of tolerance bounds that are able to measure both types of variability, and as a result, identify when the data has gone beyond the bounds of amplitude and/or phase. The first functional tolerance bounds are computed via a bootstrap procedure on the geometric space of amplitude and phase functions. The second functional tolerance bounds utilize functional Principal Component Analysis to construct a tolerance factor. This work is motivated by two main applications: process control and disease monitoring. The problem of statistical analysis and modeling of functional data in process control is important in determining when a production has moved beyond a baseline. Similarly, in biomedical applications, doctors use long, approximately periodic signals (such as the electrocardiogram) to diagnose and monitor diseases. In this context, it is desirable to identify abnormalities in these signals. We additionally consider a simulated example to assess our approach and compare it to two existing methods.