Archaeologists have favored a date of 14,000-15,000 years before present (BP) for canine domestication. However, recent studies of mutations in the mitochondrial DNA sequence by molecular geneticists have implied that dogs were domesticated over 100,000 years ago, which has challenged traditional theory. Geneticists have further hypothesized that dogs originated from wolf ancestors based upon the number of substitutions observed in dog and wolf haplotypes. Although both disciplines provide substantial evidence for their theories, the origin of dog domestication remains controversial. Several areas continue to be debatable. First, both geneticists and archaeologists incorrectly use the term domestication to describe events that clearly can not be proven to under human control. Second, the evolutionary development of canines is viewed by molecular biologists as well as archaeologist to be indicators of domestication without any further exploration of other probable causes. Third, the studies in canine genetics are so complex that most archaeologists have difficulty in providing evidence that would be contradictory to molecular theory. Fourth, both fields of study continually ignore innate behavioral characteristics of wolves that would make domestication highly improbable. Fifth, geneticists rely heavily on data gathered from sequencing of mitochondrial DNA, which has been assumed to maternally inherited. However recent human studies have shown that this assumption has now been proven to be incorrect. And finally, not only are morphological traits of fossilized dogs and wolves so similar that making a taxonomic identification improbable, but also the amount of archaeological remains available are too sparse and fragmented for accurate affiliation. An alternate theory of canine domestication will be proposed utilizing data gathered from the archaeological record and molecular research. I hypothesize that dogs diverged naturally from wolves 100,000 years ago as a result of the natural course of evolution, not human intervention, and had already evolved into a dog prior to being domesticated by humans 14,000-15,000 years ago. Evidence will be presented to clearly show that this hypothesis is a more accurate scenario of canine domestication.

Inflammation has been implicated in the development of cardiovascular disease and a potential underlying mechanism in the pathogenesis of impaired vascular function. Two different but complementary approaches were utilized to determine the role of inflammation on vascular function. First, to evaluate the effect of acute inflammation, we induced muscle damage to both small and large muscle mass and measured vascular function every 24 hours for up to 5 days of recovery. Eccentric exercise-induced muscle damage, in both small and large muscle mass, resulted in a transient increase in central arterial stiffness. Next, patients with systemic lupus erythematosus (SLE) were studied as a model of chronic inflammation. Measurements of vascular function were compared in habitually-exercising and sedentary SLE patients, and age-matched healthy controls. Individuals with SLE demonstrated lower vascular function than healthy controls. When SLE patients were grouped by exercise status, habitually-exercising SLE patients exhibited similar vascular function to healthy controls, and lower overall disease activity compared with sedentary SLE patients, supporting the beneficial effect of regular exercise in this population. Inflammatory biomarkers were associated with measures of macro- and microvascular function. In conclusion, acute muscle damage and chronic disease-related inflammation have a potent effect on measures of vascular function, suggesting that inflammation plays a role in the pathogenesis of vascular dysfunction and is an important biomarker for cardiovascular risk. / text

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by production of a wide range of autoantibodies, multiple organ involvement and by local formation or tissue deposition of immune complexes (ICs) in the inflamed organs. In contrast to most systemic inflammatory conditions, and despite raised levels of pro-inflammatory cytokines, SLE flares are rarely reflected by elevated C-reactive protein (CRP), an important acute-phase reactant in man with homologs in vertebrates and several invertebrates. As a part of the innate immune system, CRP binds certain molecules exposed on the surface of dying cells/apoptotic bodies and on the surface of pathogens and mediates their elimination by uptake in the reticuloendothelial system. CRP also interacts with IgG-containing immune complexes, binds Fc receptors and activates the complement system via C1q. The aims of this thesis were to investigate the complement activation properties of CRP; to elucidate if anti-CRP antibodies occur in SLE and, if so, whether anti-CRP antibody levels correlate with disease activity in SLE; to test the hypothesis that autoantibodies to pro-inflammatory cytokines prevent rise of CRP; and to survey if autoantibodies to certain nuclear antigens or to CRP correlate with cytokine-inducing properties of ICs from SLE sera. We have demonstrated that CRP bound to phosphorylcholine is a powerful activator of the classical complement pathway already in the CRP concentration range 4 to 10 mg/L, but with a marked inhibition at CRP levels above 150 mg/L. Autoantibodies to the monomeric form of CRP were found in approximately 40 percent of SLE patients and in a few sera from patients with primary Sjögren’s syndrome, but not in rheumatoid arthritis or in inflammatory bowel disease. The anti-CRP antibody levels showed significant correlations to several laboratory and clinical measurements, and anti-CRP positivity was associated with renal involvement in SLE. Native CRP levels were not correlated with anti-CRP or anti-cytokine antibody levels. Hence, the presence of antibodies to monomeric CRP or to CRP-inducing cytokines is an unlikely explanation to the relative failure of CRP response in patients with active lupus. However, antibodies to TNFα were found in subnormal levels at disease flares, whereas antibodies to TGFβ were found in supranormal levels as compared to healthy subjects. In contrast to antibodies against CRP and DNA, anti-SSA and anti-SSB antibodies may regulate the inflammatory process in SLE by enhancing IC formation and subsequent production of cytokines such as IL-6, IL-10 and IL-12p40. Hypothetically, anti-CRP autoantibodies may be of pathogenic importance, for instance by binding to monomeric CRP on cell and tissue surfaces and thereby increasing the risk of extrahepatic deposition of apoptotic material and in situ formation of ICs. / On the day of the defence data the status of article I was Submitted and the tile was "C-reactive protein activates or inhibits the classical complement pathway in a concentration dependent manner" and the status of article V was: Submitted.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

No description available.

The type I interferon (IFN) system plays a central role in the etiopathogenesis of many autoimmune diseases, e.g. systemic lupus erythematosus (SLE). Activation of the type I IFN system in SLE is promoted by endogenous nucleic acid-containing immune complexes (ICs) which stimulate plasmacytoid dendritic cells (pDCs). This thesis focuses on the regulation of IFN-α production in pDCs, by interactions with B cells and natural killer (NK) cells, and by genetic factors. In Study I, RNA-IC-stimulated CD56dim NK cells were found to be activated via FcγRIIIa and enhanced the IFN-α production by pDCs. The enhancing effect of the NK cells was mediated via both soluble factors, such as the cytokine MIP-1β, and in a cell-cell contact mediated manner via the adhesion molecule LFA-1. In Study II, B cells enhanced the IFN-α production by pDCs via cell-cell contact or soluble factors, depending on the stimuli. The cell-cell contact-mediated enhancement, when the cells were stimulated with RNA-IC, was abolished by blocking the cell adhesion molecule CD31. B cells stimulated with the oligonucleotide ODN2216 enhanced the IFN-α production via soluble factors. In Study III, gene variants related to autoimmune or inflammatory diseases were analyzed for the association to the IFN-α production by pDCs, alone or in coculture with NK or B cells. Depending on cell combination, 18-86 SNPs (p < 0.001) were associated with the IFN-α production. Several of the SNPs showed novel associations to the type I IFN system, while some loci have been described earlier for their association with SLE, e.g. IL10 and PXK. In Study IV, several B cell populations were affected by cocultivation with pDCs and stimulation with RNA-IC. The frequency of CD24hiCD38hi B cells of regulatory character was increased in the pDC-B cell cocultures. However, RNA-IC-stimulation only induced modest levels of IL-10. A remarkably increased frequency of double negative CD27-IgD- B cells was found in the RNA-IC-stimulated cocultures of pDCs and B cells. In conclusion, the findings in the present thesis reveal novel mechanisms behind the regulation of the type I IFN system which could be important targets in autoimmune diseases with constantly activated pDCs.

Antinuclear antibodies (ANA) are used in screening and diagnosis of autoimmune connective tissue disorders including systemic lupus erythematosus (SLE). CNS related disorders are prevalent in SLE patients (–80%) and ANA binds specific sites within the brain. To investigate ANA infiltration across the blood-brain barrier (BBB), an ANA injectable Lewis rat model was created using 3 rat groups (saline, ANA, and ANA with histamine; since histamine promotes BBB permeability). ANA serum levels were tested for all three rat groups and rats injected with histamine demonstrated signs of histadelia. Brain slices were obtained and examined for the presence of ANA using immunofluorescence. ANA infiltration across the BBB was observed in ANA injected groups. Though the ANA and ANA histamine groups were significantly different from controls (p<0.034, p<0.030, respectively), no significance between ANA and ANA histamine groups was observed. This model could further be used to examine BBB permeability and potential drug therapy. / Department of Physiology and Health Science

Systemic Lupus Erythematosus (SLE) is a multi-organ autoimmune disorder that may result in death due to cardiac dysfunction. This dysfunction often occurs due to an endocarditis, known as Libman-Sacks, which presents on heart valves. The condition is hard to clinically diagnose and is often observed postmortem. Heart damage has been observed in the NP-SLE Lewis rat model positive for SLE. However, research has not been done in this model on the correlation between SLE and Libman-Sacks endocarditis. Numbers of occurrence have ranged from 3-50% in SLE patients. The presence of Libman-Sacks endocarditis should likewise occur in 3-50% of NP-SLE Lewis rats. There will be seven NP-SLE Lewis rats, five negative serum control rats, and five saline injected control rats. By performing this controlled study in rats, the correlation between SLE and Libman-Sacks will be better understood. / Department of Physiology and Health Science

Canis lupus is one of the most important but least studied species of Turkish fauna, however, livestock depredation and recently increased number of publications on attacks on humans intensifies human-wildlife conflict. In this study, wolf depredation is studied in Bozdag in the province of Konya where conflicts between wolves and livestock holders are well known. The study site holds &gt / 50,000 sheep and covers 9 villages and a small town. A total of 13 shepherds are interviewed in 2004 and 2005 to reveal husbandry methods and vulnerability of livestock to wolf attacks in Bozdag. Each flock is attended by a shepherd and several livestock guarding dogs (LGDs), and experiences 1.96 wolf attacks per year, on average, independent of flock size. The flocks attended by less LGDs experience less attacks and therefore, the quality of the LGDs &amp / #8211 / not their numbers- are more important. Confining sheep in corrals that are attended by a shepherd and good quality LGDs appears to be the most effective husbandry method to decrease depredation. Human attitude towards wolf is also assessed and the perception of wolf is generally negative / 8 out of 11 shepherds are in favour of the eradication of this carnivore. Publicized wolf attacks on humans are compiled from 21 news sources on the internet and records of wolf rabies are sought from various sources. There were five publicized cases of attacks on humans, no verified records of human death between 2000 and 2005. Rabies stands out as the primary reason of wolf attacks, but it requires further research because proper records are missing.

An abrupt interface between mountains and prairies in southwestern Alberta means wilderness areas and carnivore populations overlap cattle grazing lands. Consequently, there is concern about the effects of large carnivores, especially wolves, on livestock. I used GPS clusters and scat samples to determine year-round wolf diets in this region. Both methods indicated a significant seasonal shift in wolf diets from wild prey during the non-grazing season to cattle in the grazing season. The GPS cluster method effectively identified wolf kills but this method relies on telemetry with high accuracy and precision. In southwestern Alberta, Argos satellite radicollars have been used extensively by wildlife managers. I compare how differences in precision between GPS and Argos technologies affect the estimation of habitat-selection models. Differences in accuracy and precision can lead to erroneous conclusions about animal selection of habitat. / Ecology