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Treatment for neurological diseases has been limited by the presence of the protective blood-brain barrier. Recent studies from our laboratory have shown that direct intraventricular implantation of microcapsules containing genetically modified cells can effectively deliver the transgene product to the mouse brain, thereby circumventing the blood-brain barrier. In this thesis, the experiments were aimed at scaling up the murine experiments to determine if direct implantation of alginate-poly-L-lysine-alginate microcapsules to the central nervous system of dogs was a feasible means of treating the large animal brain. In the first two experiments reported here, microcapsules containing cells genetically modified to secrete human growth hormone were injected into the central nervous system of dogs. Two routes of delivery were examined, intraventricular brain surgery and injection into the spinal intrathecal space (cisterna magna). While empty capsules within the central nervous system were benign, microcapsules containing cells induced an acute inflammatory response in the brain and spinal cord tissue, irrespective of the route of delivery. Human growth hormone was detected transiently in four of six dogs, but the data were interpreted with caution due to extraneous variables such as compromised microcapsules in two of the dogs and previous systemic treatment in six of the other dogs. In the last experiment, microcapsules containing cells genetically modified to secrete the lysosomal enzyme a-L-iduronidase were implanted into the lateral ventricles of a dog with Mucopolysaccharidosis type I in an attempt to correct the characteristic neuronal pathology. An immune response ensued and appeared to abolish any possible effect of the microcapsule treatment. The experiments presented here demonstrate the challenges and obstacles that need to be overcome to effectively scale up therapies from rodent experiments to large animals. The data also shed light on the immunological complications that may arise with invasive and repeated treatment in the central nervous system of large animals. / Thesis / Master of Science (MS)

Leishmania infantum, an etiologic agent of zoonotic visceral leishmaniasis, has recently emerged in the foxhound population in the United States and parts of Canada. Leishmania infections are usually spread to mammals by infected sand flies, however epidemiological data do not support a role for sand fly transmission in North America. The purpose of this work was to isolate and characterize L. infantum from a naturally infected foxhound from Virginia (LIVT-1 isolate). A mouse model of North American leishmaniasis was developed using immunocompetent and genetically immunodeficient mouse strains infected with LIVT-1 promastigotes by different inoculation routes. The intravenous route of infection was superior to the subcutaneous route for inducing consistent experimental infections and mice lacking interferon gamma, inducible nitric oxide synthase, or B-cells were resistant to clinical disease. Experimental infections in dogs were performed to examine the infectivity, immune responses, and pathogenicity of LIVT-1. Experimentally infected dogs developed parasitologically proven infections and a range of clinical manifestations that were similar to those observed in naturally occurring disease. Diagnostic tests including culture and cytologic evaluation of bone marrow and lymph node aspirates, polymerase chain reaction, and serology by indirect fluorescent antibody test, and recombinant K39 (rK39) immunoassay were evaluated. Kappa statistics revealed that PCR had the highest level of agreement with culture and cytology results although the rK39 dipstick assay consistently identified more experimentally infected dogs. Flow cytometry revealed no significant differences (p>0.05) in CD4+ or CD8+ expression on peripheral blood lymphocytes. Alternate transmission mechanisms in experimentally inoculated mice and dogs were investigated. PCR revealed a low level of vertical and direct transmission of LIVT-1 in inoculated BALB/c mice. Leishmania DNA was detectable by PCR in tissues from puppies from a LIVT-1 infected beagle. Although the strain of L. infantum infecting foxhounds in North America appears to predominantly use a non-vector transmission mode, the disease it produces is similar to canine leishmaniasis in other parts of the world. Non-sand fly transmission may be responsible for maintaining infections in the foxhound population. Results from this work will lead to improvement in diagnosis, clinical management, and control of canine leishmaniasis in North America. / Ph. D.

Associations between the built environment and walking are well understood among the general population, but far less is known about how features of the built environment influence walking in older adults. As compared to other age groups, older adults, defined as those 65 years of age and older, are more likely to experience declines in physical activity, social interaction, and loss of community connectivity. Animal companionship can provide older adults the motivation to stay physically active and help them mitigate the feelings of isolation. Built environments that align with the needs and abilities of older adults and their animal companions, like dogs, can encourage and help sustain walking habits. The aim of this study was to identify and prioritize features within the built environment pertinent to older adult dog walkers. Existing literature served as the basis for identifying neighborhood design features associated with general walking and dog walking. Through the use of a three round Delphi study, 25 experts from urban planning and design, management of outdoor spaces, public health, gerontology, and human-animal relationships modified and rated the importance of the identified features as it pertains to older adult dog walkers. Following the Delphi study, 12 older adult dog owners from the Warm Hearth Village participated in a guided walk and interview using the Photovoice technique. The goal was to gather their perceptions of the outdoor walking environment. Among expert panelists, safety from motorized traffic, crime, unleashed dogs, and personal injury was paramount (mean (M)= 93.20, standard deviation (SD) = 11.54). Experts also saw the value and agreed upon the importance of dog supportive features within the built environment, like dog waste stations dog waste stations (desirable; M = 87.95, SD = 11.37), and dog policy signage (desirable; M = 79.91, SD = 11.22). Older adults also believed safety was important. They saw their dog as a protective safety factor against walking deterrents like aggressive or unleashed dogs. However, the feature that resonated most with older adult dog walkers in this study was their interaction with nature. They described the pleasure of observing seasons change and the connection with nature that came from the tree canopy cocooning the walking path. Path design is also a necessary consideration. Older adults emphasized the importance of having options between paved and unpaved walking paths. The panelists stressed the need for creating lines of sight (desirable; M = 66.46, SD = 20.71) and lighting (desirable; M = 77.92, SD =19.77). Those who plan, develop, and maintain spaces that support older adults can prioritize the features I identified in my research. Incorporating these features into the design of spaces for older adults has the potential to translate into increased walking and opportunities to socialize, contributing to mental and physical health. / Doctor of Philosophy / Associations between the built environment and walking are well understood among the general population, but less is known about how features in the built environment influence older adults. As compared to other age groups, older adults are more likely to experience declines in physical activity and social interaction. Animal companionship can provide motivation to stay physically active and help them mitigate feelings of isolation. Built environments that align with the needs of older adults and their animal companions, like dogs, can encourage and help sustain walking habits. My research identified and prioritized features within the built environment pertinent to older adult dog walkers. I implemented an iterative three round study to gain consensus among expert panelists and guided walks and interviews with older adult dog walkers. Among expert panelists, safety from motorized traffic, crime, unleashed dogs, and personal injury was paramount. Experts also saw the value of dog supportive features within the built environment, like dog waste stations. Older adults also believed safety was important. They saw their dog as a protective safety factor against walking deterrents like aggressive dogs. The feature that resonated most with older adult in this study was nature. They described the pleasure of observing seasons change and the connection with nature that came from the tree canopy cocooning the walking path. Path design is also a necessary consideration. Older adults emphasized the importance of having options between paved and unpaved walking paths. Those who plan, develop, and maintain spaces that support older adults can prioritize the features I identified in my research. Incorporating these features into outdoor spaces has the potential to translate into increased walking and opportunities to socialize, contributing to mental and physical health.

Development of cataracts is a relatively frequent ocular disease of the dog and cataract extraction via phacoemulsification (PE) is commonly performed by veterinary ophthalmologists. Postoperative ocular hypertension (POH) describes the elevation of pressures within the eye during the acute postoperative period and can result in vision loss and poor surgical outcome. Relatively little is known about risk factors or efficacy of prophylactic treatment for POH, and current clinical practice with regard to pressure monitoring and medication administration are highly variable. The literature on POH prophylaxis in humans indicates that improved efficacy may be achieved with a multi-dose approach and that dorzolamide hydrochloride/timolol maleate (DHTM) may be more efficacious than other pressure lowering medications. The canine literature on POH prophylaxis is limited and DHTM has not yet been evaluated despite common use in the clinical setting. Our objectives, therefore, were to investigate risk factors for POH and to test the hypothesis that perioperative topical ophthalmic dorzolamide hydrochloride 2%/timolol maleate 0.5% (DHTM) reduces the prevalence and/or severity of postoperative ocular hypertension (POH) in dogs undergoing cataract extraction by phacoemulsification (PE). We employed a randomized double-masked placebo-controlled study and enrolled 103 dogs (180 eyes) presenting for unilateral or bilateral PE. Select historical, signalment, ophthalmic examination, and surgical data was collected. Dogs were treated with DHTM or Blink Contacts (BC) placebo at 14- and 2-h preoperatively and at conclusion of surgical closure. Intraocular pressures were assessed by rebound tonometry at 2, 4, 6, and 8 hours after surgery and at 8 am the following morning. POH was defined as IOP>25 mmHg and intervention consisted of latanoprost 0.005% if IOP rose to 26 mmHg - 45 mmHg or surgeon treatment of choice if >45 mmHg. Our investigation of risk factors yielded a statistically significant association only with surgeon and surgical time, which were also associated with one another. DHTM significantly reduced the prevalence of POH in comparison with BC (26% versus 49% of eyes, OR=0.36; 34% versus 62% of dogs, OR=0.32). There was also a trend toward reduction of POH severity in DHTM-treated eyes (POH value 37.17±10.47 mmHg with BC, 32.67±6.39 mmHg with DHTM). DHTM-treated eyes that developed POH were significantly more likely to respond favorably (1 hour post-treatment IOP <25 mmHg) to treatment with latanoprost than those in the BC group (76% versus 51%, OR=3.87). We conclude that multi-dose perioperative administration of DHTM may be recommended in dogs undergoing PE to reduce the risk of POH and improve responsiveness of POH to treatment with latanoprost. / Master of Science

Background: Urinary catecholamines and metanephrines have been proposed as a diagnostic tool for identifying canine pheochromocytomas, but the effects of critical illness on urine concentrations of catecholamines and metanephrines is currently unknown. Objectives: To examine the effects of illness on urine concentrations of catecholamines and metanephrines in dogs. Animals: Twenty-five critically ill dogs and twenty-five healthy age- and gender-matched control dogs. Methods: Prospective observational study. Urine was collected from healthy and critically ill dogs and urine concentrations of epinephrine, norepinephrine, metanephrine, and normetanephrine were measured by high-performance liquid chromatography (HPLC) with electrochemical detection. Urinary catecholamine and metanephrine:creatinine ratios were calculated and compared between groups. Results: Urinary epinephrine, norepinephrine, metanephrine, and normetanephrine:creatinine ratios were higher in critically ill dogs when compared to a healthy control population (P = 0.0009, P < 0.0001, P < 0.0001, and P < 0.0001 respectively). Conclusions and Clinical Relevance: Illness has a significant impact on urinary catecholamines and their metabolites in dogs. Further investigation of catecholamine and metanephrine concentrations in dogs with pheochromocytomas is warranted to fully evaluate this test as a diagnostic tool, however the findings of this study suggest that the results may be difficult to interpret in dogs with concurrent illness. / Master of Science