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<p>A high-fat diet can adversely affect bone mechanical properties, but it is unknown how these changes affect bone adaptation. Bone adaptation occurs in response to strain-related mechanisms, and strain in the bone is affected by the size and mechanical properties of the bone.The purpose of this study was to compare the strain during loading in femurs from rats fed a high-fat (HF) or normal control (NC) diet. At 3 weeks of age, male and female Wistar rats were randomly assigned to receive a NC (NC–17% fat; N=8 per gender) or HF diet (HF–41% fat; N=8 per gender) until termination (39 weeks of age). Right femurs were loaded <em>ex vivo</em> in 3-point bending to physiologic levels and mechanical strain was measured. The mechanical properties of the left femurs were determined by 3-point bend tests to failure. The dietary effects were limited in both genders. Femoral cross-sectional area properties (bone area, moment of inertia), determined from µCT scans, were significantly greater in HF femurs vs. NC for males and females. Elastic modulus was calculated from strain and deformation data and no dietary effects were seen in either gender. At the applied loads, despite significantly larger cross-sectional area properties in the HF femurs, there was no significant difference in strain between HF and NC femurs for either gender. It appears that adaptive modeling occurs during growth in the HF bones to target a predetermined level of strain to preserve bone structural integrity.</p> / Master of Applied Science (MASc)

<p>This PhD thesis focuses on the mechanical activation of TGFβ in the context of pulmonary fibrosis. Mechanical TGFβ activation occurs by physical force of breathing and signals to the nucleus via phospho‐Smad2. This activation occurs in presence of strong pan‐serine protease and matrix metalloproteinase inhibition. The augmented expression of latent TGFβ in lung tissue also lead to TGFβ activity following tissue stretch. Tissue biopsies from pulmonary fibrosis patients exhibited the same mechanical TGFβ activation and subsequent accumulation of phospho‐Smad2 as was seen in animal models. In rodent models and human control tissue, TGFβ was not released in detectable quantities, nor was there any significant upregulation of phospho‐Smad2. These data show that mechanical TGFβ activation is a relevant and limited to the context of a fibrotic disease process. Non‐invasive investigation of lung fibrosis was evaluated for correlation to classical assessments. We found that non‐invasive lung function parameters measured by a rodent ventilator, and small animal CT imaging correlated significantly with histomorphometic Ashcroft scoring. Exercise testing and quantification of the maximal oxygen consumption rate was a valuable indicator of overall rodent lung health but did not correlated significantly with Ashcroft scoring. Non‐invasive investigation tools evaluated here represent important advances in the quality of interpretation of preclinical lung fibrosis trials. Finally, collagen turnover was investigated by measurement of pyridinolines and serum collagen metabolic peptides. A novel method was developed and tested to detect pyridinolines in facile procedure. We found that deoxypyridinolines, but not pyridinolines, were significantly increased in the serum of lung fibrosis patients with respect to healthy controls. Furthermore, collagen type 1 telopeptide, a collagen breakdown product, was significantly increased in lung fibrosis patient serum. These data intriguingly indicate that under stable lung fibrosis conditions, more collagen appears to be breaking down into the serum then is synthesized.</p> / Doctor of Philosophy (PhD)

Traumatic brain injury (TBI) is a prominent healthcare concern in the U.S. as millions of TBI-related emergency department visits occur annually. Recent reports estimate more than 5 million Americans currently suffer from life-long disabilities and psychiatric complications associated with TBI. While the risk of TBI has conventionally been considered to be male dominated, analyses of sex-comparable sports indicate that rates of concussions are higher and recovery time is longer following brain injury in females. Following anxiety and depression, substance use disorder (SUD) is the third most common de-novo neuropsychiatric condition diagnosed in both male and female TBI patients. Importantly, during adolescence the primary neuronal networks that regulate reward behaviors and perception of drug-induced euphoria are not fully developed, corroborating epidemiological studies identifying TBI sustained during adolescence as a risk factor for problematic drug use. Yet, to date, little is known about how TBI-induced molecular changes affect brain structures essential for the perception of reward and processing drug-induced euphoria. The following experiments were designed to test the hypothesis that adolescent TBI-induced neuroinflammation in areas such as prefrontal cortex (PFC) and nucleus accumbens (NAc) results in remodeling of neuronal reward networks and affect how the rewarding effects of cocaine shift as a consequence of TBI. Notably, the extent of sex differences in SUD susceptibility in TBI has not be investigated. Therefore, we also investigated whether the immune response stimulated by early-life TBI alters maturation of reward neurocircuits, leading to increased SUD vulnerability in a sex-dependent manner. Following the induction of TBI using the controlled cortical impact (CCI) model of brain injury, we utilized a biased, three-phased cocaine conditioned place preference (CPP) assay to assess the behavioral response to the rewarding effects of cocaine following adolescent injury in male and female C57BL6 mice. Furthermore, we characterized the effect of CCI-TBI on the stimulation of neuroinflammation within the PFC and NAc, comprising the reward pathway. Specifically, our studies revealed a sex-specific increase in 1) sensitivity to the rewarding efficacy of a subthreshold doses of cocaine interpreted from significantly higher cocaine CPP shifts, 2) the activation and phagocytosis of microglia observed by the positive expression of neuronal synaptic proteins in microglia sorted using flow cytometry, 3) increase in permeability of the blood-brain barrier indicated by discontinuous and depleted expression of tight junction proteins that line microvasculature isolated from reward nuclei, 4) decreased neuronal complexity, arborization, and spine density quantified from Golgi-cox stained NAc neurons, 5) changes in expression of genes related to the dopamine system analyzed by qRT-PCR in only male mice injured during adolescence. Additionally, our results imply that high levels of female hormones can promote neuroprotection against increased sensitivity to the rewarding properties of cocaine following injury, associated with decreased neuroinflammatory profiles after TBI in adolescent females. The studies herein aimed to elucidate underlying neuropathological outcomes following TBI in the reward circuitry that could be contributing to increased risk of addiction-like behavior observed clinically. Our findings suggest that TBI during adolescence may enhance the abuse liability of cocaine in adulthood and vulnerability to the rewarding effects of cocaine could be higher as a result of brain injury. Key pathological findings in the NAc such as activated microglial phagocytosis, BBB changes, reduced neuronal complexity, and changes in dopamine gene expression in areas of the reward pathways support the notion that neuroinflammation may contribute to how the rewarding efficacy of cocaine are affected post-TBI during adolescence. The ultimate goal of this research is to 1) advance TBI and SUD literature with the potential to increase awareness and help health care providers inform TBI patients about the increased risk for SUDs, and 2) to translate identified correlated mechanisms into novel targeted therapies that would provide a launching point for the treatment of patients with TBI-related SUD. / Biomedical Sciences

An animal model (Rattus norvegicus) was employed to study the effects of chronic prenatal alcohol exposure on pup development and on the functional efficacy of pup vocalizations on the maternal behavior of the dam. Subjects were 72 dams and their litters. Dams were matched by weight and assigned to either an Ethanol (EtOH), a Pair-fed (PF), or an Untreated Control (UC) group. Ethanol dams received 15% ethanol as their sole source of fluid throughout the experiment. Pair-fed dams were fed isocalorically to EtOH dams. Untreated Control dams received food and water ad libitum. Dam's retrieval behavior was assessed in a runway choice situation when pups were 3, 5, 7, and 9 days old. Developmental measures were taken on pups from ages 0 through 13 days. Blood ethanol concentrations were also analyzed for dams and pups. The data showed that the BEC of EtOH dams was .1% and that EtOH pups showed a negligible BEC postpartum. Prenatal alcohol exposure was shown to have a direct pharmacological and indirect nutritional effect on pup development. Ethanol dams retrieved a reliably smaller percentage of pups and retrieved reliably more slowly than did controls. Pair-fed pups showed a higher rate of calling than did other pups and tended to be chosen more often by UC and PF dams than were EtOH or UC pups. Ethanol dams tended to chose UC pups more often than other pups. These findings suggest that chronic prenatal alcohol exposure produces altered behavior and responsiveness in the dam and the pup. This altered behavior and responsiveness may have a synergistic effect on the interaction between the dam and the pup. / Master of Science

The present thesis examines the effects of transcranial direct current stimulation and forelimb rehabilitation on motor recovery after stroke in rats. Post-stroke motor outcomes were quantified using an innovative battery of behavioural tests and high resolution, in vivo electrophysiology was employed to examine coherence of neural activity between hemispheres. It was shown that rats that received brain stimulation concurrently with forelimb rehabilitation displayed functional recovery, whereas rats that received rehabilitation alone partially regained motor function, but the improvements were not due to restitution of original movement patterns. Results from electrophysiological recordings showed that rats that received brain stimulation and rehabilitation regained pre-stroke levels of interhemispheric coherence, but rats that received rehabilitation alone did not. The present thesis suggests that transcranial direct current stimulation may be a viable adjunct therapy to increase the efficacy of physical rehabilitation with regard to post-stroke motor outcomes. Interhemishperic coherence between homotopic neuronal populations may represent a biomarker of genuine motor recovery after stroke. / ix, 75 leaves : col. ill. ; 29 cm

Thesis (MScMedSc)--Stellenbosch University, 2015. / ENGLISH ABSTRACT: Obesity has reached epidemic proportions worldwide and is currently a serious health problem. It is associated with metabolic abnormalities, oxidative stress, hypertension, insulin resistance and an increased disposition for the development of cardiovascular disease. Elucidation of the pathophysiological mechanisms underlying obesity and its relationship with metabolic and cardiovascular diseases is essential for prevention and management of these disorders. Melatonin, the pineal gland hormone, is a powerful antioxidant and has been shown to protect the myocardium against ischaemia/reperfusion (I/R) injury. Long- as well as shortterm melatonin treatment also reversed several of the harmful effects of obesity in an animal model of hyperphagia-induced obesity (DIO). However, its effects on myocardial I/R injury and intracellular signalling in obesity induced by a high fat diet (HFD) are still unknown. Aims of study: (i) To evaluate the ability of a high fat diet (HFD) to induce obesity in rats. Apart from evaluating its effects on the biometric parameters and resistance to ischaemia/reperfusion injury (as indicated by infarct size in regional ischaemia and functional recovery after global ischaemia), special attention will be given on the interplay between adiponectin, AMPK, leptin, and FFA in this model. (ii) To evaluate the effect of daily oral administration of melatonin to rats on the HFD as well as their littermate controls, on the parameters listed above as well as on the development of obesity. In this study melatonin will be administered from the onset of the feeding of the high fat diet. Methods: Male Wistar rats were divided into 4 groups: (i) control rats (receiving normal rat chow) (C); (ii) control rats receiving melatonin (CM); (iii) obese rats (receiving HFD) (HFD); (iv) obese rats receiving melatonin (HM). Animals were kept on the diet for 16 weeks and melatonin treatment (10mg/kg/day, added to the drinking water) started at the onset of the feeding. Following feeding and treatment, the animals were grouped into fasted/ non-fasted of which biometric parameters were recorded and blood collected at the time of sacrifice for metabolic and biochemical assays. Hearts were perfused in the working mode for evaluation of myocardial function and infarct size determination after exposure to 35min regional ischaemia/60min reperfusion. For study of intracellular signaling, hearts were perfused in the working mode, subjected to 20min global ischaemia/10min reperfusion and freeze-clamped for Western blotting. Plasma leptin, adiponectin, free fatty acid, triglycerides, total cholesterol, phospholipids, conjugated dienes and thiobarbituric reactive substances (TBARS) levels were determined. Several kinases were investigated including, the RISK (reperfusion injury salvage kinase) (PKB/Akt and ERK p44/42) and SAFE (survivor activating factor enhancement) (STAT-3) pathways, AMPK and JNK under baseline conditions or following 10 min reperfusion. In addition, expression of UCP-3 and PGC1-α was determined. Results: Significant increases in body weight, visceral fat, blood glucose, insulin, HOMA index and leptin and a reduction in adiponectin levels were observed in the fasted high fat diet (HFD) group when compared with controls (C). Significant increases in free fatty acid and triglyceride levels were also noted the HFD group while other serum lipid parameters, including TBARS, remained unchanged. No differences in functional recovery during reperfusion or infarct size after exposure to 35 min regional ischaemia, as well as functional recovery during reperfusion after 20 min global ischaemia were observed between the control and HFD groups. Baseline and 10 min reperfusion data were similar for the RISK and SAFE pathway kinases for the control vs HFD groups. The HFD also had no effect on the expression and phosphorylation of myocardial AMPK and JNK, as well as on the expression of UCP-3 and PGC1-α, when compared to the controls. Treatment with melatonin significantly reduced body weight, visceral fat, blood glucose, HOMA index and serum leptin levels in HFD treated groups, while having no effect on the lipid profile. Although melatonin significantly reduced infarct size in both control [% of area at risk: 20.59 ± 2.29 (CM) vs 38.08 ± 2.77 (C)] and high-fat diet groups [% of area at risk: 11.43 ± 2.94 (HM) vs 38.06 ± 3.59 (H)], it was without effect on myocardial functional recovery during reperfusion. Melatonin had no effect on the intracellular signaling pathways studied. Conclusions: The HFD proved to be a useful model of diet-induced obesity with a more pronounced impact on biometric and metabolic changes compared to the DIO model. Long-term melatonin treatment successfully prevented the development of metabolic abnormalities associated with the high fat diet and obesity as well as significantly reduced myocardial infarct size. The mechanisms involved in melatonin-induced cardioprotection in obesity have not been fully elucidated in this study and require further investigation. However, the anti-obesogenic and cardioprotective properties of melatonin were very significant indeed and support the suggestion of this hormone as a potential tool in the treatment of obesity and associated cardiovascular complications. / AFRIKAANSE OPSOMMING: Inleiding: Vetsug (obesiteit) het wêreldwyd epidemiese afmetings aangeneem en word tans as ‘n ‘n ernstige gesondheidsprobleem beskou. Vetsug word geassosieer met metaboliese afwykings, oksidatiewe stres, hipertensie, insulienweerstandigheid en is‘n belangrike risikofaktor vir die ontwikkeling van kardiovaskulêre siekte. Ten spyte hiervan, het onlangse studies ‘n gunstige effek van vetsug op die uitkomste van miokardiale infarksie in pasiënte gerapporteer, die sg obesiteitsparadoks. Kennis van die patofisiologiese meganismes onderliggend aan vetsug en die ontstaan van metaboliese afwykinge en hartsiekte is noodsaaklik vir die voorkoming en behandeling van hierdie toestande. Melatonien, die hormoon afgeskei deur die pineaalklier, is ‘n kragtige antioksidant en vry radikaal opruimer. Dit is voorheen aangetoon dat dit die hart teen iskemie/herperfusie (I/H) besering kan beskerm en sommige van die skadelike gevolge van vetsug in diermodelle kan omkeer. Die effek van melatonien op miokardiale I/H besering en intrasellulêre seintransduksie prosesse in vetsug geïduseer deur ‘n hoë vet dieet is egter nog onbekend. Doelstellings: (i) Die ontwikkeling en karakterisering van ‘n nuwe model van vetsug en insulienweerstandigheid geïnduseer deur 'n hoë vet dieet (HVD) en die evaluering van die effek daarvan op miokardiale I/H besering en die gepaardgaande intrasellulêre seintransduksieprosesse; (ii) Bepaling van die effek van daaglikse toediening van melatonien aan rotte op die HVD sowel as aan kontroles op ‘n standard dieet, op die ontwikkeling van dieet-geïnduseerde metaboliese veranderinge, miokardiale infarktgrootte en funksionele herstel na koronêre arterie afbinding, sowel as intrasellulêre seintransduksie. Metodiek: Vier groepe van manlike Wistar rotte is bestudeer: (i) kontrole rotte (op‘n standaard dieet) (K); (ii) kontrole rotte op ‘n standard dieet plus melatonien (KM); (iii) dieetrotte (op‘n HVD); (iv) HVD rotte wat melatonien ontvang (HM). Die HVD en melatonien (10mg/kg/dag in die drinkwater) is vir 16 weke toegedien. Na die periode van behandeling, is die diere in vastende en nie-vastende groepe verdeel, die biometriese parameters genoteer en bloedmonsters vir metaboliese en biochemiese bepalings versamel, tydens verwydering van die harte. Harte is geperfuseer volgens die werkhartmodel vir bepaling van miokardiale funksie en infarktgrootte na blootstelling aan 35min streeksiskemie. Vir evaluering van intrasellulêre seintransduksie, is geperfuseerde werkende rotharte blootgestel aan 15min globale iskemie/10 min herperfusie en gevriesklamp vir latere analises volgens die Western kladtegniek.hart. Serum leptien, adiponektien, vryvetsure, trigliseried, totale cholesterol, fosfolipiede, gekonjugeerde diene en tiobarbituursuur reaktiewe stowwe (TBARS) is bepaal. Met gebruik van Western kladtegniek, is die aktivering en/of uitdrukking van die RISK (PKB/ Akt en ERK p44/42) en SAFE (STAT-3) seintransduksiepaaie, AMPK, JNK, UCP-3 en PGC1-α, onder basislyn toestande of na 10 min herperfusie bestudeer. Resultate:‘n Beduidende toename in liggaamsgewig, visserale vet, die HOMA indeks, insulien en leptien vlakke is in die HVD groep waargeneem vergeleke met die kontrole (K) rotte. Adiponektien vlakke was laer in die HVD groep. Die HVD groep is ook gekenmerk deur ‘n beduidende styging in serum vryvetsuur en trigliseried vlakke, terwyl die ander lipied parameters, insluitende die TBARS vlakke, onveranderd was. Infarktgrootte en funksionele herstel tydens herperfusie na blootstelling aan 35 min streeksiskemie, asook funksionele herstel tydens herperfusie na 20 min globale iskemie het nie verskil tussen harte van die kontrole en HVD rotte nie. Aktivering van PKB/Akt, ERK p44/p42, STAT3, AMPK en JNK by basislyn en na 10 min herperfusie was soortgelyk in die kontrole en HFD groepe. Die HVD het ook geen effek op die uitdrukking van UCP-3 en PGC1-α in vergelyking met die kontrole gehad nie. Behandeling met melatonien het die liggaamsgewig, visserale vet, bloedglukose, HOMA indeks en serum leptien vlakke in die HVD groepe statisties beduidend verlaag, terwyl dit geen invloed op die lipiedprofiel gehad het nie. Melatonien behandeling het die miokardiale infarktgrootte beduidend en tot dieselfde mate verminder in beide kontrole [20.59 ± 2.29 (KM) vs 38.08 ± 2.77% (K)] en HVD groepe [11.43 ± 2.94 (HM) vs 38.06 ± 3.59% (HVD)]. Geen verskille is egter tussen die funksionele herstel gedurende herperfusie van die behandelde en onbehandelde kontrole en HVD groepe waargeneem nie. Melatonien het ook geen uitwerking op die intrasellulêre seintransduksiepaaie gehad nie. Gevolgtrekkings: Die resultate het getoon dat die HFD 'n goeie model van dieetgeïnduseerde vetsug en insulien weerstandigheid ontlok, met 'n meer uitgesproke impak op biometriese en metaboliese veranderinge as die voorheen gebruikte hoë-sukrose dieet. Langtermyn melatonien- behandeling het die ontwikkeling van metaboliese abnormaliteite geassosieer met die HVD, voorkom, asook miokardiale infarktgrootte na koronêre afbinding beduidend verminder. Die meganismes betrokke in melatonien-geïnduseerde miokardiale beskerming moet egter in meer detail ondersoek word. Die resultate verkry steun die voorstel dat melatonientoediening voordelig sal wees in die behandeling van vetsug en sy kardiovaskulêre komplikasies.

Background: The main aim of the studies in this thesis is to provide insights into the neonatal phencyclidine (PCP) induced deficits in male and female rats as a neurodevelopmental animal model of schizophrenia. Methods: Both male and female rats were treated with neonatal PCP on postnatal days (PNDs) 7,9 and 11 or vehicle, followed by weaning on PND 21-22. The rats were then tested in behavioural paradigms such as novel object recognition, spatial memory and social interaction in their adolescent and adult stages and were also tested with acute treatment of typical and atypical antipsychotic agents. Results: Neonatal PCP treatment (10 &amp; 20 mg/kg in males and 10 mg/kg in females; once a day for 3 days on PND 7,9 and 11) caused novel object recognition and spatial memory impairment in male and female rats both in the adolescent (PND35-56) and in the adult stages (PND&gt;56) (chapter 2) and robust deficits in social interaction behaviours in the adolescent stage. The SI deficits were observed in adulthood in female but not in male rats thereby establishing a sex-specific social behavioural deficit (chapter 3). The object memory and social interaction deficits induced by neonatal PCP treatment were reversed following acute risperidone but not haloperidol. Finally, the temporal profile of this treatment regime was investigated and the male and female animals were tested on PND 190 and PND 365. The animals did not have any challenge dose of PCP during their testing stage. The result showed that there was significant deficit in object and spatial recognition memory in both male and female animals at both time points, thereby establishing enduring deficits. Conclusion: Given the heterogeneity of the schizophrenic disorder and its complex aetiology, it is understandably difficult to find animal models that completely mimic most or all of the symptoms associated with the disorder. However, data from the studies in this thesis support the use of neonatal PCP as a valid animal model of cognitive and negative symptoms, and explores the effect of antipsychotics in understanding the model. Also, in light of the efficacy of neonatal PCP to produce robust object, spatial memory and social interaction deficits in rats, it appears that this model may be a useful tool to investigate the potential of novel therapeutic candidates that may help improve therapy and understand the illness.

published_or_final_version / abstract / Chinese Medicine / Master / Master of Philosophy