Abstract Introduction: Physiotherapy in the human intensive care setting is in common use and supported by Level 1 evidence. In the canine intensive care setting, however, physiotherapy is novel, despite many studies published to support aspects of human physiotherapy being conducted on experimental dogs and there being 83 canine intensive care beds in Sydney alone. As veterinary care progresses and people place more importance on their pet’s health care, an opportunity arises to examine the potential for physiotherapy to augment the veterinary care of client-owned dogs in a veterinary referral hospital setting. The first objective of this thesis was therefore to determine which common conditions cause dogs to present recumbent to veterinary referral hospitals, and then to conduct a literature review on these conditions and ways in which physiotherapy has the potential to add to the treatment of them. The next objective was to describe the short-term effects of recumbency on a number of key body systems in clinically unwell dogs, as concern was that recumbency itself may contribute to pathogenesis and/or poorer recovery, however this could not be investigated before preliminary studies like this were performed. The next objective was to conduct clinical trials of the use of two well-proven techniques in human physiotherapy on dogs with conditions commonly reported in the earlier studies of this thesis. The chosen techniques were continuous positive airway pressure (CPAP) to assist in the recovery of dogs with brachycephalic airway obstructive syndrome (BAOS) from general anaesthetic, and the use of manual chest physiotherapy in dogs with aspiration pneumonia following tick (Ixodes holocyclus) poisoning. Design: Retrospective epidemiological study; Literature review; Cross-sectional descriptive study; Randomised controlled trial; Clinical trial. Results: Dogs admitted recumbent represented 3.18% of total admissions, however had a confirmed survival rate of only 43.5%. Sydney canine intensive care units have a combined capacity of 83 beds, so many other dogs experience recumbency as part of their veterinary management, despite being admitted ambulant, and therefore also have the potential to benefit from physiotherapy. Diagnoses were split into categories, with suspected intervertebral disc disease the most common neurological diagnosis, hit by car the most common orthopaedic diagnosis, collapse the most common diagnosis in the ‘otherwise unwell’ category and tick (Ixodes holocyclus) poisoning and poison (e.g. metaldehyde) ingestion the most common toxicology diagnosis, all of which have the potential to be just as amenable to physiotherapy in dogs as they are in people. However, interspecies comparisons revealed that although the dogs studied had broadly comparable diagnoses to humans, they had a higher mortality rate and received much less physiotherapy than humans. Key body systems were therefore measured in recumbent dogs, with the finding that the dogs included under the strict definition of recumbency in this study maintained a fairly consistent clinical state in the short-term of their period of recumbency (median days 3 to 5 of hospitalization). This finding supported the investigation of physiotherapy as a potential to not only reduce the mortality rate but to speed return to function, which has the potential to also lower the economic burden of prolonged hospitalization on owners. Continuous positive airway pressure was therefore investigated for its potential to improve the safety of recovery from general anaesthetic in dogs with BAOS. Tolerance and effect of CPAP were investigated with positive results demonstrated to improve time to recovery, with no additional distress, in dogs with BAOS recovering from a general anaesthetic. An evidence-based protocol of manual chest physiotherapy was then tested on dogs with aspiration pneumonia following tick (Ixodes holocyclus) poisoning. Demeanour, saturation of peripheral oxygen and auscultation all improved following the first manual chest physiotherapy session, demonstrating tolerance and effect. Conclusions: Primary recumbency is an uncommon but serious condition in dogs that warrants attention by physiotherapy researchers, as dogs admitted ambulant but who spend part of their hospitalization recumbent also have the potential to benefit. This thesis determined the common causes of recumbency in dogs and determined that key body systems of recumbent dogs are clinically stable without the assistance of physiotherapy to improve their short-term rate of recovery. Positive short-term results were yielded from the use of CPAP and manual chest physiotherapy that may benefit other clinically unwell dogs with similar respiratory conditions. Further research should be conducted into other ways in which physiotherapy can augment the care of recumbent dogs, as well as lower the mortality rate and speed the return to function in dogs in the intensive care setting, as it is possible that not all positive findings in human research were replicated in these studies due to Type II error resulting from small sample sizes due to abnormal weather patterns that reduced the number of presentations of dogs with BAOS or tick poisoning during the study period.

A clinical trial was undertaken using three different inhalant anaesthetic agents and one intravenous anaesthetic agent in dogs undergoing routine desexing surgery. Healthy adult dogs undergoing either ovariohysterectomy or castration were assessed as to their demeanour, with the more excitable dogs being placed in groups receiving premedication with acepromazine and morphine. All dogs were then randomly assigned an anaesthetic agent for induction of general anaesthesia. The agents were the inhalants halothane, isoflurane and sevoflurane, and the intravenous agent propofol. Inhalant inductions were undertaken using a tight fitting mask attached to a standard anaesthetic machine with a rebreathing circuit, with the maximum dose of inhalant available from a standard vaporiser. Propofol inductions were undertaken via intravenous catheter. Dogs induced with propofol were randomly assigned one of the three inhalant agents for maintenance. Those induced by inhalant agent were maintained using the same agent. The surgical procedure was undertaken in standard fashion, as was recovery from anaesthesia. All dogs received the non-steroidal anti-inflammatory agent meloxicam. Data collection was divided into three stages: induction, maintenance, and recovery from anaesthesia. Variables measured at induction of anaesthesia were time to intubation, number of intubation attempts, tolerance of mask, quality of induction and quality of transfer to the maintenance stage. Standard variables for monitoring of anaesthesia were recorded throughout the maintenance of anaesthesia. Variables measured at recovery were time to righting, time to standing and quality of recovery. The mean time to intubation when using the newer inhalant sevoflurane (196.2 � 14.8sec, mean � SE) was not significantly different to that for halothane (221.4 � 14.0sec) or isoflurane (172.4 � 15.0sec). Time to intubation with isoflurane was significantly faster than with halothane. Mean time to intubation with propofol (85.4 � 7.7sec) was significantly faster than that for any of the three inhalants. Choice of inhalant had no effect on quality of induction. The use of premedication significantly improved the quality of induction. The use of propofol for induction likewise significantly improved the quality of induction. Standard cardiorespiratory variables measured during the maintenance phase of anaesthesia remained within normal clinical ranges for all three inhalants, and were therefore not further analysed. Choice of inhalant agent had no significant effect on the time to righting or standing in recovery. The use of propofol for induction had no effect on these variables. Animals placed in groups receiving premedication had significantly longer times to righting and standing. The oesophageal temperature at the end of the procedure had a significant effect on times to righting and standing, with lower temperatures contributing to slower recoveries. Independent of procedure time, male dogs had shorter times to righting than female dogs.

Doctor of Philosophy / The African wild dog (Lycaon pictus) is one of Africa’s most endangered carnivores. Previous research into this species has focussed on the largest extant populations in Africa. However, there are a large number of relatively small populations (20 to 50 dogs) distributed across Africa, which represent an important component of the diversity of the species and its remaining habitat. This study investigated the status of a small population of wild dogs in the Lower Zambezi area in Zambia. Objectives focussed on assessing population dynamics and identifying causes of decline. Research was carried out over a broad range of topics in an effort to provide comprehensive information for conservation management of the population. The scope of the project was divided into five sections: 1) Demography and pack dynamics were assessed to identify the structure and status of the population, and the main causes of mortality. 2) An assessment of habitat types and related ecological factors was carried out to determine wild dog habitat utilisation in relation to vegetation type, prey densities and hunting success in each area. 3) The effects of interpredator competition on wild dog population dynamics was investigated, specifically, the effects of lions (Panthera leo) and spotted hyaenas (Crocuta crocuta). 4) Genetic analyses were carried out to assess the historic and contemporary genetic variability of the population, and to define patterns of geographic structuring and population differentiation. 5) Results were combined to assess the viability of the population and recommend conservation management strategies. Snaring was identified as the most important cause of adult mortality, and a threat to wild dog population persistence. Inbreeding avoidance led to the emigration of adult males and females from the area and appeared to be a substantial contributor to population decline. Limited mate selection corresponded with neither sex displaying philopatry and large dispersal distances effectively removed adults from the population. This result has important implications for the management of small populations, whereby lack of mate choice may increase dispersal distances and thereby increase edge effects on populations, regardless of home range sizes. Home range sizes were related to den locations in remote areas of the Zambian Escarpment, which was used as a breeding refuge area. The Zambezi River and Zambian Escarpment appeared to be effective barriers to wild dog home range movements. The study area contained a diversity of habitats on the alluvial terraces of the river valley floor. There was a high density of impala (Aeypceros melampus), which formed the main prey base for the wild dog population. Studies of other populations have found that wild dogs often avoided areas with high competing predator densities, which corresponded with high prey density areas. In contrast to those findings, the Lower Zambezi wild dog population showed a strong preference for high prey density areas. This population also showed only temporal avoidance of high lion density areas. Low lion density areas were preferred during breeding periods, while moderate to high lion density areas were preferred during non-breeding periods. Direct predation of adult wild dogs by lion and spotted hyaenas was rare. Kleptoparasitism of wild dog kills by either competing predator species was also rare. Predator competition was not considered to be an important determinant of population decline. The Lower Zambezi population suffered from a loss of heterozygosity, low allelic richness, and there was significant evidence of a recent population bottleneck. The population did not contain any new mtDNA haplotypes, nor any unique alleles on the commonly used microsatellite loci, but was differentiated from African wild dog populations in other regions. There was evidence of historical and recent gene flow between the Lower Zambezi and the neighbouring southern African populations of Hwange and Okavango. This was the first study to show a loss of genetic variability in a free-ranging African wild dog population. Although more immediate anthropogenic and demographic factors were the critical determinants of population decline, the loss of genetic variability has important implications for the conservation of the remaining small and fragmented wild dog populations in Africa. Results showed that due to its small size the population is likely to have suffered from inverse density dependence and Allee effects on dispersal and reproductive success. Management recommendations focussed on mitigating anthropogenic causes of mortality, and improving connectivity with a larger, potential source population to increase the probability of successful dispersal and to restore genetic diversity. The high density prey base, small home range sizes and low levels of interpredator competition detected in this study suggest that the area has the capacity to support a large and potentially viable population of wild dogs if appropriate management strategies are implemented.

Thesis (M.S.)--Wildlife and Fisheries Sciences Dept., South Dakota State University, 2009. / Includes bibliographical references. Also available via the World Wide Web.

Thesis (M.S.)--University of Michigan, 1975.

Thesis (Ph. D.)--University of Washington, 2002. / Vita. Includes bibliographical references (leaves 81-97).

Thesis (M. Sc.)--Carleton University, 1996. / Also available in electronic format on the Internet.

Thesis (Ph. D.)--Ohio State University, 2009. / Title from first page of PDF file. Includes vita. Includes bibliographical references (p. 113-121).

Alzheimer’s disease (AD) is characterized by cognitive decline and hallmark neuropathology, including β-amyloid (Aβ). Therapeutic strategies for AD are focusing on reducing Aβ. Canines develop Aβ neuropathology and cognitive decline with age similar to AD patients. In previous studies, immunization with Aβ1-42 (VAC) in aged canines decreased brain Aβ but did not improve cognition. Behavioral enrichment (ENR) improved cognition without reducing brain Aβ. We hypothesized that VAC combined with ENR would provide cognitive benefits and reduce Aβ neuropathology, as compared individual VAC and ENR treatments. Aged beagles were placed into groups: control, VAC with fibrillar Aβ1-42, ENR, and combination treatment (VAC+ENR) for 18 months. Learning and memory was evaluated throughout the study. Serum IgG antibody titers, cerebral spinal fluid (CSF) and brain Aβ were measured. Serum anti-Aβ1-42 IgG increased significantly in VAC animals. ENR but not VAC significantly increased CSF Aβ1-40. No cognitive improvements were observed in any group. VAC significantly reduced brain Aβ1-40 and 1-42, as well as reduced plaque load. An overall slowing of plaque accumulation was seen in the ENR group. VAC and ENR were able to modify pathology when used as separate treatments; however, the combination treatment did not succeed in further reducing Aβ or improving cognition. Previous AD clinical trials using immunotherapy yielded similar outcomes to our study showing reduced Aβ pathology but little to no cognitive improvements. In combination these results suggest that future studies should focus on prevention approaches both in the canine model and in human clinical trials.

Malignant brain tumors are diseases with poor prognosis and/or severe long-term side effects of treatment. This thesis aimed to discover novel regulators in brain tumor development, based on studying neural stem cell and progenitor cell (NSPC) differentiation and using animal models to introduce new insights to mechanisms of human brain tumors. The enzyme heparanase (HPSE) that degrades heparan sulfate (HS) is active in cell signaling and ECM remodeling. In paper I, we found an enhanced differentiation to oligodendrocytes in ES cell-derived NSPCs overexpressing HPSE. Further analysis suggested that this enhanced formation of oligodendrocytes was associated with alterations in receptor tyrosine kinase signaling, and that HPSE might also exert anti-apoptotic functions. Subsequently, in paper II we studied the involvement of HPSE in glioma development. We observed that high HPSE levels associated with poor survival in glioma patients. In experimental models, we found that HPSE promoted glioma growth, and that an inhibitor of HPSE reduced glioma progression both in vitro and in vivo. We hypothesize that regulators in NSPC differentiation could have a potential role in brain tumor development. In paper III, we explored the function of NRBP2, a pseudokinase that is up-regulated during NSPC differentiation. We found low expression of NRBP2 in brain tumors, in comparison to normal brain. In medulloblastoma, in particular, low NRBP2 expression is linked to poor prognosis. Overexpression of NRBP2 in medulloblastoma cells led to impaired cell growth and migration, concomitant with an increased cell death. In paper IV, we searched for novel glioma susceptibility genes by sequencing dog breeds from the same ancestor but with different glioma incidence. In this way we identified three new glioma-associated genes. Two of these are significantly regulated in human glioma and one of those might have a role in glioblastoma stem cell differentiation.