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Abstract Background Deer mice (Peromyscus maniculatus) are the most common mammals in North America and are reservoirs for several zoonotic agents, including Sin Nombre virus (SNV), the principal etiologic agent of hantavirus cardiopulmonary syndrome (HCPS) in North America. Unlike human HCPS patients, SNV-infected deer mice show no overt pathological symptoms, despite the presence of virus in the lungs. A neutralizing IgG antibody response occurs, but the virus establishes a persistent infection. Limitations of detailed analysis of deer mouse immune responses to SNV are the lack of reagents and methods for evaluating such responses. Results We developed real-time PCR-based detection assays for several immune-related transcription factor and cytokine genes from deer mice that permit the profiling of CD4+ helper T cells, including markers of Th1 cells (T-bet, STAT4, IFNγ, TNF, LT), Th2 cells (GATA-3, STAT6, IL-4, IL-5) and regulatory T cells (Fox-p3, IL-10, TGFβ1). These assays compare the expression of in vitro antigen-stimulated and unstimulated T cells from individual deer mice. Conclusion We developed molecular methods for profiling immune gene expression in deer mice, including a multiplexed real-time PCR assay for assessing expression of several cytokine and transcription factor genes. These assays should be useful for characterizing the immune responses of experimentally- and naturally-infected deer mice.

The objective of this study was to describe and compare the fecal bacterial microbiota of horses with equine recurrent uveitis (ERU) and healthy horses using next-generation sequencing techniques. Fecal samples were collected from 15 client-owned horses previously diagnosed with ERU on complete ophthalmic examination. For each fecal sample obtained from a horse with ERU, a sample was collected from an environmentally matched healthy control with no evidence of ocular disease. The Illumina MiSeq sequencer was used for high-throughput sequencing of the V4 region of the 16S rRNA gene. The relative abundance of predominant taxa, and alpha and beta diversity indices were calculated and compared between groups. The phyla Firmicutes, Bacteroidetes, Verrucomicrobia, and Proteobacteria predominated in both ERU and control horses, accounting for greater than 60% of sequences. Based on linear discriminant analysis effect size (LEfSe), no taxa were found to be enriched in either group. No significant differences were observed in alpha and beta diversity indices between groups ( p > 0.05 for all tests). Equine recurrent uveitis is not associated with alteration of the gastrointestinal bacterial microbiota when compared with healthy controls.

Larotrectinib, a selective TRK tyrosine kinase inhibitor (TKI), has demonstrated histology-agnostic efficacy in patients with TRK fusion-positive cancers. Although responses to TRK inhibition can be dramatic and durable, duration of response may eventually be limited by acquired resistance. LOXO-195 is a selective TRK TKI designed to overcome acquired resistance mediated by recurrent kinase domain (solvent front and xDFG) mutations identified in multiple patients who have developed resistance to TRK TKIs. Activity against these acquired mutations was confirmed in enzyme and cell-based assays and in vivo tumor models. As clinical proof of concept, the first 2 patients with TRK fusion-positive cancers who developed acquired resistance mutations on larotrectinib were treated with LOXO-195 on a first-in-human basis, utilizing rapid dose titration guided by pharmacokinetic assessments. This approach led to rapid tumor responses and extended the overall duration of disease control achieved with TRK inhibition in both patients. Significance: LOXO-195 abrogated resistance in TRK fusion-positive cancers that acquired kinase domain mutations, a shared liability with all existing TRK TKIs. This establishes a role for sequential treatment by demonstrating continued TRK dependence and validates a paradigm for the accelerated development of next-generation inhibitors against validated oncogenic targets. Cancer Discov; 7(9); 963-72. ©2017 AACR. See related commentary by Parikh and Corcoran, p. 934 This article is highlighted in the In This Issue feature, p. 920 ., (©2017 American Association for Cancer Research.)

Objective: Expression of the 70-kDa heat-shock protein (HSP70) has been demonstrated in normal canine corneal epithelium, and inducible expression has been suggested to facilitate wound resolution through organized migration, proliferation, and adhesion of the corneal epithelial cells. Diminished expression of HSP70 may therefore contribute to prolonged healing in the pathologic cornea of other companion animal species, including the horse., Animal Studied: Normal and pathologic equine cornea was evaluated to determine whether the expression of HSP70 is correlated with appropriate corneal epithelial wound healing., Procedures: Paraffin-embedded tissue from normal equine cornea and therapeutic keratectomies of sterile keratopathies was subject to routine immunohistochemistry for HSP70., Results: Normal equine corneas exhibited the baseline expression of HSP70 in the nuclei of all epithelial cells as well as the cytoplasm of the basal epithelium. Expression of HSP70 in suspected immune-mediated keratitis was localized to the cytoplasm of basal epithelial cells and nuclei of all epithelial cells, similar to the normal equine cornea. Expression in indolent ulcers was diminished; weak, diffuse staining was noted in the cytoplasm of all epithelial cells., Conclusions: These findings suggest the expression of HSP70 is induced in the normal equine cornea during re-epithelialization and may be altered in sterile keratopathies., (© 2016 American College of Veterinary Ophthalmologists.)

The purpose of this study was to determine normal ocular surface bacterial flora, tear production, and intraocular pressure in a captive flock of Humboldt penguins, Spheniscus humboldti. Twenty-eight healthy penguins were studied and equally divided between fresh- and saltwater habitats. The population consisted of 15 female and 13 male penguins, ranging from 3-20 years of age. Following complete ophthalmic exam, 4 penguins with cataracts were removed from the study. Eight penguins from each habitat were randomly selected for ocular surface aerobic bacterial culture. Corynebacterium spp. and Staphylococcus spp. were the most common isolates. Twenty-five organisms consisting of 17 species, and 15 organisms consisting of 9 species, were identified in fresh- and saltwater groups, respectively. Tear production and intraocular pressures were evaluated on 24 penguins with normal ocular exams. The range and mean (+/- standard deviation) tear production, measured with the Schirmer tear test, was 1-12 mm/min and 6.45 mm/min +/- 2.9, respectively. The mean tear production for penguins housed in the freshwater habitat was greater (8.5 mm/min) than those in saltwater (4.8 mm/min). The range and mean (+/- standard deviation) intraocular pressure, measured by applanation tonometry using a Tono-Pen XL tonometer, was 10-27 mmHg and 20.36 mmHg +/- 4.1, respectively. This data should be utilized as a reliable resource for those involved in avian and zoo medicine.

Background: Deer mice (Peromyscus maniculatus) are the most common mammals in North America and are reservoirs for several zoonotic agents, including Sin Nombre virus (SNV), the principal etiologic agent of hantavirus cardiopulmonary syndrome (HCPS) in North America. Unlike human HCPS patients, SNV-infected deer mice show no overt pathological symptoms, despite the presence of virus in the lungs. A neutralizing IgG antibody response occurs, but the virus establishes a persistent infection. Limitations of detailed analysis of deer mouse immune responses to SNV are the lack of reagents and methods for evaluating such responses., Results: We developed real-time PCR-based detection assays for several immune-related transcription factor and cytokine genes from deer mice that permit the profiling of CD4+ helper T cells, including markers of Th1 cells (T-bet, STAT4, IFNgamma, TNF, LT), Th2 cells (GATA-3, STAT6, IL-4, IL-5) and regulatory T cells (Fox-p3, IL-10, TGFbeta1). These assays compare the expression of in vitro antigen-stimulated and unstimulated T cells from individual deer mice., Conclusion: We developed molecular methods for profiling immune gene expression in deer mice, including a multiplexed real-time PCR assay for assessing expression of several cytokine and transcription factor genes. These assays should be useful for characterizing the immune responses of experimentally- and naturally-infected deer mice.

One of the keys to the accurate diagnosis of ocular disease is the appropriate selection and interpretation of ocular tissue samples. Without a good understanding of which test(s) to select and how to interpret test results, the clinician may arrive at an incorrect diagnosis and prescribe improper and/or ineffective therapy. This article outlines some of the more common ocular diagnostic procedures and gives guidance in the interpretation of test results.

Objective: To evaluate, for clinically normal dogs, results of Schirmer tear tests in eyes without topical anesthetic (STT) and to detect differences associated with breed, sex, age, day, and time of day in eyes in which STT was performed after use of topical anesthetic (STTa)., Animals: 41 Beagles, 43 Labrador Retrievers, 25 Golden Retrievers, 26 English Springer Spaniels, and 22 Shetland Sheepdogs., Procedure: Beagles had STT and STTa values measured twice daily for 5 days. Client-owned dogs of 4 other breeds had STT and STTa values measured once., Results: Mean +/- SD values of Beagles for STT and STTa were 20.2 +/- 2.5 and 3.8 +/- 2.7 mm/min. Mean values for STT and STTa were as follows: Labrador Retriever, 22.9 +/- 4.1 and 9.6 +/- 3.8 mm/min; English Springer Spaniel; 20.7 +/- 3.2 and 5.4 +/- 3.4 mm/min; Golden Retriever, 21.8 + 3.7 and 8.8 +/- 3.1 mm/min; and Shetland Sheepdog, 15.8 +/- 1.8 and 3.6 +/- 2.8 mm/min. Overall mean values for STT and STTa were 20.2 +/- 3.0 and 6.2 +/- 3.1 mm/min. Differences for STT and STTa were detected among breeds, but significant differences were not associated with sex or age within each breed or in overall values for all dogs., Conclusions and Clinical Relevance: Results for the STT reported here compare favorably with reported values, except for results of Shetland Sheepdogs; however, results for the STTa differ dramatically from reported values. Clinicians should consider effects attributable to breed when evaluating results of STT and STTa in dogs.

Objective: To determine the electrodiagnostic and histologic response of short-term increases of intraocular pressure (IOP) on transient pattern electroretinograms (PERG) and flash electroretinograms (FERG) in the eyes of dogs., Animals: 8 healthy mixed-breed dogs., Procedure: Transient PERG and FERG waveforms were recorded from dogs (while anesthetized) as IOP was increased from baseline (7 to 19 mm Hg) to 90 mm Hg. One hundred mean PERG responses and a single FERG response were recorded at each step during 3 recording sessions. Globes of each dog were enucleated after euthanasia on posttreatment day 7 and evaluated by a pathologist., Results: Increases in spatial frequency resulted in decreased amplitudes of N2 (second negative PERG peak). Increases in IOP resulted in decreases in all 3 PERG waveforms and the FERG waveform. All values began to return to baseline after short-term increases in IOP on day 0, and waveforms were not significantly different on posttreatment days 3 and 7, Conclusions: Data suggest that short-term increases in IOP affect PERG and FERG waveforms, and PERG waveforms are more sensitive to increases in IOP Differences were not detected between treated and control eyes on histologic examination. Further studies are necessary to determine at what IOP permanent damage to ganglion and photoreceptor cells will develop and whether PERG is a reliable clinical diagnostic technique for use in dogs to reveal retinal damage that is secondary to increased IOP prior to changes in waveforms generated by FERG in dogs.

Study Objectives: To study the serial radiographic manifestations of Legionnaire's disease from the initial presentation on admission to recovery using strict criteria for the diagnosis of infection., Materials and Methods: We prospectively studied the chest radiographs of patients hospitalized with a diagnosis of community-acquired pneumonia in Summit County, Ohio between November 1990 and November 1992. Forty-three patients fulfilled strict criteria for legionellosis. The diagnosis of infection was based on the criteria of "definite" diagnosis as defined by the Ohio Community-Based Pneumonia Incidence Study Group report. The criteria included the isolation of the microorganism, the presence of a significant antibody rise, or the presence of Legionella antigen in the urine., Results: Forty of 43 patients had admission radiographs interpreted as compatible with pneumonia. In spite of appropriate antimicrobial therapy, worsening of the infiltrates was found in more than half of the patients within the first week. Twenty-seven patients were observed to have pleural effusion during the course of hospitalization: 10 effusions were found on admission, another 14 developed during the first week, and 3 new effusions were discovered after the first week. Cavitation was found in only one patient. None of the patients had apical involvement., Conclusion: This study confirms previous reports using less stringent etiologic diagnosis criteria that chest radiographic findings in Legionnaire's disease are not specific. Even with appropriate therapy, more than half of the patients will have worsening of the infiltrates during the first week. Pleural effusion is common among our patients, and it is frequently detected during the serial radiographic studies during the first week of hospitalization. Chest radiography in Legionnaire's disease is useful only for the monitoring of disease progression and not for diagnostic purposes. In addition, worsening of infiltrates and pleural effusion are seen in more than half of the patients in spite of appropriate therapy and clinical improvement.

Corneal ulcers are one of the most common ocular disease presentations in the horse. With the use of correct diagnostic techniques and selection of an appropriate treatment regimen, most cases result in a satisfactory outcome. The eye does not respond well to inflammation, and in complicated ulcers, this should be managed aggressively using systemic NSAIDs with a high priority assigned to removing the infectious agent. Care needs to be taken to avoid topical or systemic corticosteroid use for the treatment of equine ocular disease, however, unless the clinician is completely sure that the corneal disease is not caused by an infectious process. The use of combination corticosteroid-antibiotic ophthalmic preparations without an appropriate treatment rationale can result in doing more harm than good. It is important to have a treatment plan and to monitor the elected treatment regimen. The clinician should decide on some objective criteria at initiation of treatment so that any changes are made rationally. This approach should also include consideration of early referral of the eye's care to a veterinary ophthalmologist.

Objective: To develop and test a noninvasive technique for determining age in dogs and cats on the basis of changes in lens reflections and transparency., Animals: 85 dogs representing 5 breeds and 73 domestic shorthair cats., Procedure: While examining dilated eyes in a darkened room, using a penlight, 2 experienced examiners who were blinded to actual age of animals individually measured the diameter of reflections from the anterior (La) and posterior (Lb) surfaces of the lens and scored lens transparency (Ltr) from 1 (clear) to 5 (severe opacity). Models were developed to predict age on the basis of these measurements., Results: Aging models developed for dogs and cats were as follows: Age(dogs) = 2.197 - 0.070 x (La) + 1.361 x (Lb) + 1.193 x (Ltr) and Age(cats) = 1.988 + 1.024 x (La) + 2.220 x (Lb) + 1.019 x (Ltr), where age was expressed in years, and La and Lb were in millimeters. All variables, except La in dogs, contributed significantly to accuracy of the models. Correlation between predicted and actual ages, as measured by Pearson's product-moment correlation coefficient, was significant in both species (P < 0.0001). Significant differences were not found between examiners or between the first and second evaluations by the same examiner., Conclusions and Clinical Relevance: A noninvasive technique based on evaluation of lens reflections and transparency can provide clinically useful predictions of age in mature dogs and cats. This technique could be an important tool for veterinarians or humane shelters in determining differential diagnoses and assessing longevity and adoptability of mature animals of unknown age.

Objective: To evaluate clinical signs of ocular blastomycosis in dogs, to determine response of blastomycosis-infected eyes to treatment with systemically administered amphotericin B and ketoconazole, and to identify prognostic indicators of successful antifungal treatment., Design: Retrospective study., Animals: 73 dogs., Procedure: Medical records were reviewed for all dogs with confirmed blastomycosis and ocular disease seen at our hospital between 1985 and 1993., Results: 6 eyes had anterior segment disease, 24 had posterior segment disease, and 78 had endophthalmitis. 40 eyes were treated with a combination of amphotericin B and ketoconazole, and 16 of the 40 responded favorably. However, 16 of the 24 eyes that were not severely affected responded favorably, but none of the 16 eyes that were severely affected did., Clinical Implications: Dogs with blastomycosis had posterior segment disease, without complete retinal separation, had a good prognosis for retaining vision. Results of histologic examination suggested that secondary glaucoma was a manifestation of endophthalmitis and was indicative of a grave prognosis for response to antifungal and antiglaucoma treatment.

Ophthalmic manifestations of dental disease may occur in dogs and cats because of the proximity between posterior maxillary teeth and the orbit. Ophthalmic disorders may be diagnosed promptly, but the initiating dental disease may be overlooked. Inappropriate diagnosis and treatment of dental disease may result in loss of teeth, irreversible vision-threatening ophthalmic disease, or, ultimately, loss of the globe. When ophthalmic examination results are suggestive of a primary dental disorder, thorough examination of the maxillary teeth is imperative to diagnose appropriately the underlying dental disease. Therapy should include treatment of the dental disease and secondary ophthalmic disorders.

Fibrin clots were induced in eyes of dogs by injection of autogenous citrated plasma into the anterior chamber. Twenty-four hours after clot formation, one 50-microliters drop of tissue plasminogen activator at a concentration of 5 mg/ml (group 1, n = 7) was administered topically 9 times at 5-minute intervals, or a collagen shield that was hydrated with tissue plasminogen activator at a concentration of 5 mg/ml (group 2, n = 7) was applied. The contralateral eye served as a nontreated control. Serial photographs were taken of the fibrin clots after topical application of tissue plasminogen activator. Computerized morphometric analysis was then used to evaluate changes in cross-sectional surface area of the fibrin clot. There was no significant mean percentage decrease in clot surface area of treated eyes of group-1 dogs or in treated eyes of group-2 dogs. In addition, there was no significant difference in mean percentage decrease in clot surface area between treated eyes of group-1 and group-2 dogs.

Eye enucleations performed on 109 dogs, 29 horses, and 23 cats involved placement of 136 silicone orbital implants and 7 mesh implants. Mean follow-up times were 2.4 years (range, 3 weeks to 9 years) in dogs, 3.4 years (range, 10 days to 10.5 years) in horses, and 1.5 years (range, 3 weeks to 7.5 years) in cats. Implants failed in 1 of 96 dogs (1.04%), 3 of 29 horses (10.3%), and 3 of 18 cats (16.7%). Implant failure was attributable to various causes in all species; however, cats appeared to be more prone to late extrusion that were dogs and horses. Implantation of an orbital prosthesis was a safe and inexpensive method for improving cosmetic appearance after enucleation in dogs, horses, and cats.

Specific details on surgical procedures, although not covered here, are available in other references. Factors enhancing the overall cosmetic appearance obtained with procedures are emphasized, providing information that should allow veterinarians to offer clients a good cosmetic appearance and effective treatment for disfiguring ocular problems in their horses. Questions regarding procedures should be addressed to your referral ophthalmologist or, in the case of a corneoscleral prosthesis, the ocularist assisting.

Twelve female patients participated in a study designed to employ computer-assisted biostereometric analysis for the detection of breast masses. All breast masses were previously documented by physical examination and followed by xeromammography, stereophotography, and histopathologic confirmation of tumor type. "Contour mammograms" were produced from the biostereometric photographs. These data were analyzed first for tumor detection and location by visual inspection. A second analysis employed a computed algorithm designed to locate and measure surface aberrations that suggest the possibility of underlying breast tumor. Visual analysis yielded the exact location of breast tumors in eight of the ten malignancies; computer analysis exactly located nine of the ten malignancies. In the computer analysis, one malignancy not exactly located by quadrant was, nevertheless, located in the correct breast. The results of the study suggest that the biostereometric process may have future use in screening or prescreening procedures for breast cancer detection. It is noninvasive, applicable to large numbers of women and with suitable refinements, and capable of being fully automated.