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The nonrecurring-items delayed nonmatching-to-sample (DNMS) task is an integral part of contemporary monkey models of brain-damage-produced amnesia. This thesis began the development of a comparable rat model of brain-damage-produced amnesia. First, a DNMS task for rats was designed by adapting key features of the monkey task. Then, the rat DNMS task was studied in three experiments; each assessed the comparability of the rat DNMS task to the monkey DNMS task. Experiment 1 determined the rate at which the rat DNMS task is learned and the asymptotic level at which it is performed, Experiment 2 assessed the memory abilities that it taps, and Experiment 3 investigated the brain structures that are involved i n its performance. In Experiment 1, rats were trained on the DNMS task and their performance was assessed at retention delays of 4, 15, 60, 120, and 600 s. All of the rats learned the DNMS task, and their performance was comparable to that commonly reported for monkeys in terms of both the rate at which they acquired the nonmatching rule at a brief retention delay and their asymptotic accuracy at delays of up to 120 s. These results establish that rats can perform a DNMS task that closely resembles the monkey DNMS task and that they can approximate the level of performance that is achieved by monkeys. Experiment 2 examined the effects of distraction during the retention delay on the DNMS performance of rats. Rats were tested at retention delays of 60 s. On half of the trials, the rats performed a distraction task during the retention delay; on the other half, they did not. Consistent with findings from monkeys and humans, distraction during the retention delay disrupted the DNMS performance of rats. This suggests that similar memory abilities are involved in the DNMS performance of rats, monkeys, and humans. Experiment 3 investigated the effects of separate and combined bilateral lesions of the hippocampus and the amygdala on DNMS performance in pretrained rats. Rats were tested both before and after surgery at retention delays of 4, 15, 60, 120, and 600 s. Each experimental rat received bilateral lesions of the hippocampus, amygdala, or both. There were no significant differences among the three experimental groups, and the rats in each of the three experimental groups were significantly impaired, in comparison to no-surgery control rats, only at the 600-s delay. In contrast, rats that had sustained inadvertent entorhinal and perirhinal cortex damage during surgery displayed profound D N M S deficits. These results parallel the results of recent studies of the neural basis of DNMS in monkeys. They suggest that, in contrast to one previously popular view, neither the hippocampus nor the amygdala play a critical role in the DNMS of pretrained animals and that the entorhinal and perirhinal cortex are critically involved. On the basis of these findings, it appears that the rat DNMS task may prove to be a useful component of rat models of brain-damage-produced amnesia. This conclusion is supported by the preliminary results of several experiments that are currently employing the task.

The possible involvement of spinal metabotropic glutamate receptors (mGluRs) were examined in animal models of persistent and chronic pain. In Study 1, it was shown that spinal administration of relatively selective group I mGluR antagonists, or a selective group III mGluR agonist, but not a non-selective mGluR antagonist, slightly, but significantly reduced nociceptive scores in the rat formalin test Also, spinal administration of a non-selective mGluR agonist, or a selective group I mGluR agonist, but not a relatively selective group II agonist, enhanced formalin-induced nociception. The pro-nociceptive effects of these agents were reversed by a non-selective mGluR antagonist or by an N-methyl-D-aspartate receptor (NMDAR) antagonist. In Study 2, it was shown that intrathecal administration of two non-selective mGluR agonists or a selective group I mGluR agonist, but not a selective group II or group III mGluR agonist, produced spontaneous nociceptive behaviours, (SNBs) in rats. Also, the SNBs induced by these agents were reduced by a non-selective mGluR antagonist or by an NMDAR antagonist. In Study 3, it was shown that intrathecal administration of a selective group I mGluR agonist produced persistent mechanical allodynia, mechanical hyperalgesia and heat hyperalgesia in rats. In Study 4, it was shown that early, but not late intrathecal administration of a relatively selective group I mGluR antagonist reduced nociceptive behaviours, in a model of neuropathic pain. In Study 5, it was shown that intrathecal administration of a selective group I mGluR antagonist reduced mechanical allodynia and cold hyperalgesia, while a selective group II mGluR agonist and a selective group III mGluR agonist only reduced mechanical allodynia and cold hyperalgesia, respectively, in the neuropathic pain model. Results from these studies first suggest that spinal group I mGluRs may be more critically involved in the development of chronic nociceptive behaviours, compared to persis

The activity of S-adenosyl-L-methionine Decarboxylase (E. C. 4.1.1.50) was measured in two different normal and five different tumorous mouse mananary tissue samples. The soluble fraction was assayed for SAM decarboxylase activity using 14COOHlabeled SAM as the substrate. The amount of 14002 evolved was measured using a liquid scintillation counter.There was a significant elevation of SAM decarboxylase activity in the tumor sample group. The activities of the tumor tissue was x = 15.62 and SD = 8.24. The activity in the normal samples was too low to measure:These results suggest an increase in not only SAM decarboxylase activity, but also in the levels of spermidine and spermine. These increases are characteristics of cancer cells and may result in changes in enzyme activities and membrane phospholipid composition.

This inquiry investigated the suitability of the jaw of domestic sheep as an animal model for dental implantology research. Initially, parameters for osseous healing of critical size defects (CSD) in the sheep mandible were established. Pilot studies were conducted using machined-surface implants and a surgical protocol established for dental implant placement in ovine mandibular sites. Subsequent experiments considered the utility of this animal model for examination of techniques designed to enhance osseointegration. Hydroxyapatite-coated implants were compared with titanium plasma-sprayed (TPS) implants, either alone or combined with autogenous bone grafts or a bone graft/collagen vehicle loaded with transforming growth factor-beta (TGF-β). Immunofluorescent bone labelling gave information on the mineral apposition rate (MAR). Implant survival and "acceptability" (likelihood of clinical success) were major output variables, along with histomorphometric analysis of percent bone-implant contact (%BIC) and percent peri-implant bone density (%density). Naturally-occurring "broken-mouth" periodontitis in sheep was identified as a potential confounder. Subsequent experiments considered implants with different surfaces. The model was also extended from a two-stage surgical protocol to include single-stage implants. The effect of pre-existing ovine peridontitis was also examined. A systematic review and meta-analysis of published animal implant experiments was conducted in order to validate the candidate sheep model. Major findings were as follows. The size of non-healing sheep mandibular unicortical CSD is >12mm. Attempts to establish a chronic non-healing CSD were unsuccessful. The sheep diastema proved unsuitable for implant placement. The model was modified to a post-extraction protocol. Implant "acceptability" rates after 3 months integration in the sheep mandible (defined as implant survival with %BIC >10%) ranged from 50% - 100% for different implant surface treatments and placement protocols. Histomorphometriic analyses revealed that %BIC ranged from 11 � 17% to 81 � 29 % for different titanium surfaces and up to 85 � 11% for hydroxyapatite surfaces. Implants with TGF-β plus autogenous bone grafts had %BIC of 36 � 30% compared with 43 � 30% for implants with grafts alone. Bone per unit area (%density) adjacent to, but outside of the implant threads, ranged from 63 � 16% to 86 � 3% and was markedly lower for titanium plasma-sprayed surfaces and for one-stage implants. Within the implant threads, %density varied from 31 � 33% to 73.4 � 8.3%, and was markedly lower for machined titanium surfaces. Sheep periodontitis had little effect on the protocols investigated. The sheep mandibular model was found to be comparable to similar models in other species and merits further development.

Atherosclerosis 'is a key pathological process underlying the development and progression of three major diseases of the vascular system- coronary artery disease, cerebro-vascular and peripheral vascular disease. Chronic vascular wall inflammation is considered as a principal cause in the initiation and progression of atherosclerosis. Intimal thickening that develops in arteries and veins as an adaptive response to an injury has many similarities with atherosclerosis, but at the same time represents a unique pathological entity. This Thesis explores the utility of applying a novel DNAzyme based approach that targets "master-regulator" transcription factors c-jun and Egr-1 to in vivo and in vitro models of acute inflammation and intimal thickening. Studies included in this Thesis reveal that transcription factor c-jun plays a, key regulatory role in controlling leucocyte movement during an acute inflammation induced by IL-1 f3 through regulation of the expression of adhesion molecules ICAM, VCAM-1, E-selectin and VE-cadherin. Similarly, by applying ED5, a DNAzyme that targets transcription factor Egr-1 to the rat model of mesenteric microcirculation I demonstrate that Egr-1 controls leucocyte movement during an acute inflammation as evidenced by almost complete inhibition of leucocyte flux, adhesion and extravasation by ED5. The rabbit model of bypass grafting shows that Dz13 (a DNAzyme targeting transcription factor c-jun) significantly reduces intimal thickening in bypassed vein grafts of chow-fed animals at 28 days in vivo and in culture-grown human saphenous veins in vitro. Taken together these findings suggest that a DNAzyme based approach of targeting transcription factor c-jun has the potential to be used as a modulator of the acute inflammatory response and of intimal thickening formation. Further work needs to be done before this technology is ready for clinical use in humans.

Diabetes can be considered to be one of the main health epidemics of the 21st century. Studies conducted by the World Health Organisation (WHO) indicate that the number of people with diabetes in the year 2000 was 171 million and this is projected to increase to 366 million by 2030 (Wild et al. 2004). The increasing incidence of both Type 1 and Type 2 diabetes is due to population growth, aging, urbanisation, obesity and physical inactivity. The current treatment by insulin injections for individuals with Type 1 diabetes fails to overcome the long term microvascular and macrovascular complications associated with the disease. A major challenge in the treatment of diabetes is to provide patients with an insulin source that is capable of regulating blood glucose levels (BGL) on a minute to minute basis. Advances in medical research have enabled the investigation of a variety of potential alternative therapies that may provide Type 1 diabetic patients with a more superior control of BGL and consequently minimise complications. The utilisation of pancreases obtained from fetal pigs offers potential therapeutic value in the treatment of Type 1 diabetes. Islet-like cell clusters (ICCs) are obtained from such tissue following partial mechanical and enzymatic digestive procedures. ICCs are primarily composed of immature duct cells which, when transplanted, will mainly differentiate into insulin producing ?? cells. Such cells are able to normalise BGL in immunodeficient diabetic recipients and in immunocompetent recipients when anti-rejection drugs are administered. This study investigates microencapsulation as an immunoprotective strategy that has the potential to remove the need for immunosuppression when such cells are transplanted. A review of the literature related to current medical research in the field of diabetes is presented in Chapter 1. In order to achieve the aims of the study, an understanding of how fetal pig ICCs behave when placed within a barium alginate microcapsule both in vitro and in vivo is essential and this data is presented in Chapter 3. This chapter demonstrates that ICCs will survive and differentiate in their typical manner when enclosed within microcapsules and transplanted. Such encapsulated cells will function to normalise BGL when transplanted into diabetic immunodeficent mice for at least 25 weeks and the animals exhibit increased bodyweight. Microcapsules retrieved at this time point were observed to be intact with no breakages or evidence of cellular overgrowth. Transplantation of encapsulated insulin-producing cells into immunocompetent mice are described in Chapter 4. Allotransplantation of a microencapsulated mouse insulin-producing cell line into these diabetic mice also exhibited graft function, resulting in normal BGL in recipients. Large animal experiments are described in Chapter 5. Allotransplantation of microencapsulated fetal pig ICCs into diabetic pig recipients displayed evidence of transient graft function in terms of lower BGL and reduced exogenous insulin requirements. The xenotransplantion of encapsulated fetal pIg ICCs into diabetic immunocompetent mice described in Chapter 4 proved to be more challenging. The transplantation of such cells in this environment did not yield particularly positive results. BGL remained elevated in these recipients and the animals lost bodyweight post transplantation. This area of research warrants further investigation as it is likely that further measures such as transient immunosuppression in combination with microencapsulation will allow fetal pig ICCs to function in a xenograft setting.

Thesis(M.S.)--Auburn University, 2006. / Abstract. Vita. Includes bibliographic references.

Thesis (M.S.)--University of Michigan, 1978.

Ph.D.