During 2007 the UK experienced outbreaks of three notifiable exotic livestock diseases; Foot and Mouth Disease (FMD), Highly Pathogenic Avian Influenza (HPAI) and bluetongue. Large epidemics of any of these diseases would have a serious impact on animal welfare, farming, food production and the economy. In light of this, understanding holdings which are most likely to acquire and spread infection and being able to identify areas at higher risk of an epidemic is valuable when preparing for and managing an epidemic. This thesis uses a spatial epidemiological framework and the detailed disease and demographic data from the 2001 Great Britain (GB) FMD epidemic to develop static models of the risk of FMD susceptibility and transmission. These models are used to develop maps of FMD risk. These methods are then applied to the outbreak of FMD in 2007. The inputs for this analysis comprised a set of data relating to the farms diagnosed with FMD and farms culled as part of the disease control measures. The cleaning of these data is described and data which were estimated relating to dates of infection and putative sources of infection are evaluated. The distribution of farm holdings and animals is taken from the June 2000 GB agricultural census, off-fields of farms in the agricultural census are recorded in other datasets and these have been identified and linked to census holdings. A model of holding level susceptibility is developed using both farm level variables and measures of animal numbers in the locality of the holding as well as the distance to the nearest farm infected before the ban on animal movements (seeds). The overall fit of the model was very good with an area under the Receiver Operator Characteristic (ROC) curve of 0.91. A further model was developed to describe the risk of FMD transmission. However, due to incompleteness of transmission data, this was a model of the risk of finding a subsequent Infected Premises (IP) within 3km of an IP. Risk factors were a combination of holding level variables and locality measures as well as data relevant to the infection, such as infectious period and the species initially infected. The area under the ROC curve for this model was 0.71, which is regarded as an acceptable fit. Geographical barriers to FMD transmission were investigated using a case-control methodology, linear barriers comprising rivers and railways had a significant protective effect with respect to disease transmission (odds ratio = 0.54, 95% CIs = 0.30,0.96, p=0.038). Modelled values for the transmission and susceptibility models were transformed to a raster surface in ESRI ArcMap for both the disease as it was seeded in the 2001 epidemic and a non-specific background risk surface independent of the distribution of seeds. A risk map generated for the outbreak of FMD in Surrey in August 2007 suggested that there was little risk of a large outbreak in Surrey. Potential disease introductions through livestock movements from Surrey into Scotland were identified and these suggested that if the disease were introduced into Scotland there was great danger of substantial local spread. These methods described in this thesis have been used to map risk of FMD and subsequently applied to inform the risk presented by a different outbreak of FMD. The study underlines the value of detailed data both disease and demographic, for epidemic management. Similar methods could and should be applied to other infectious diseases threats of livestock such as HPAI and bluetongue.

Transmissible spongiform encephalopathies (TSEs) are a group of fatal neurodegenerative diseases that are characterised by long incubation periods, protein aggregation and vacuolation. During TSE pathogenesis the normal, cellular prion protein, (PrPC), which is encoded by the gene PRNP, misfolds and accumulates as abnormal disease associated prion protein, (PrPSc) within the central nervous system. Variants of the Prion protein gene are associated with susceptibility to TSE disease. For example sheep scrapie disease is modulated by several PRNP alleles, with certain alleles carried by susceptible animals being different from those carried by resistant animals. The mechanisms linking PRNP genetics and disease is poorly understood but may involve protein sequence, PrPC expression levels, and possibly differences in protein processing. Post-translational modification of PrPC leads to specific cleavage (alpha cleavage) between amino acids 115/116 of ovine PrP, producing two fragments C1 and N1. Cleavage of PrP may occur as a protective mechanism, as a response to changes in the cellular environment or as a feature of an as yet unknown biological function. In the context of TSEs, alpha cleavage may inadvertently provide a protective role by reducing available PrPC protein for conversion into PrPSc, assuming that the C1 fragment would be an inefficient substrate for conversion, the opposite theory was also proposed. The former hypothesis became the focus of this present study, with the idea that total full-length PrPC, total C1 or the ratio between full-length PrPC and C1 may be linked to differences in scrapie susceptibility. To investigate these aims the C1 fragment was measured as a percentage of total PrPC in different PRNP genotypes with varying degrees of susceptibility to scrapie and in different brain regions. This study found that PrPC alpha cleavage increased during development from the new born lamb to the adult sheep, which may have consequences for the susceptibility differences related to age. There are also variations in the amount of alpha cleavage between brain regions such as cortex and medulla that may influence scrapie strain targeting. Overall the amount of the C1 fragment in the different brain areas varied as much as 10x (range 5% to 60%). There was a significant difference in the ratio of C1 to the other PrPC forms between two PRNP genotype groups carrying the VRQ and ARQ allele but there was no correlation between C1 level and scrapie susceptibility or scrapie incubation period in our scrapie models. Alpha cleavage of PrPC also occurs in various transgenic mouse models expressing different ruminant PrP sequences. In PrPC over-expressing transgenic mouse models a higher ratio of C1 was observed, this may suggest a link between PrPC expression levels and alpha cleavage. Transgenic mice are therefore important models to further investigate the link between PrPC biology and scrapie disease phenotype. In conclusion, this thesis has shown for the first time that certain ovine PRNP alleles can influence alpha cleavage of the PrPC protein; however it appears not to be a significant indicator of TSE disease susceptibility in sheep.

Strong electron correlation lies at the root of many quantum collective phenomena observed in solids, including high Tc superconductivity. Theoretically, the problem of many interacting electrons is difficult to treat, however, and a microscopic understanding of strongly correlated systems remains one of the foremost challenges in modern physics. A particularly clean realisation of this general problem is found in magnetic systems, where theory and experiment are both well developed and complementary. The role of the chemist in this endeavour is to provide model experimental systems to both inspire new developments in theory and to confirm existing predictions. This thesis aims to demonstrate aspects of both synthesis and physical characterisation of such model systems, with particular emphasis on materials which exhibit unusual quantum ground states due to a combination of reduced dimensionality, low spin, and geometric frustration. Four materials are considered: The first among these is a new material, KTi(SO4)2·(H2O), which was prepared using a hydrothermal route, and characterised by magnetic susceptibility, specific heat, and high field magnetisation measurements. Fitting exact diagonalisation and series expansion results to these data imply that KTi(SO4)2·(H2O)is a long-sought experimental realization of the S = 1/2 Heisenberg frustrated (J1 − J2) chain model in the dimerised regime of the phase diagram. The anhydrous analogue of KTi(SO4)2·(H2O), KTi(SO4)2, was also investigated, and found by magnetic neutron scattering to exemplify the S = 1/2 Heisenberg anisotropic triangular lattice model in the 1D chain limit. The final two materials discussed are the naturally occurring minerals volborthite and herbertsmithite, both thought to realise the S = 1/2 Heisenberg kagome antiferromagnet model. Diffuse and inelastic magnetic neutron scattering experiments, however, indicate that the kagome physics are partially destroyed by defects in the former and lattice distortion in the latter.

The langasites are a class of geometrically frustrated compounds with the formula A3XY3Z2O14 where A,X,Y,Z are cationic sites and site A is occupied by a magnetic ion. The interactions of the magnetic ions form a star shaped pattern called the Kagomé lattice. The langasites have been widely studied by the solid state community because of their functional properties such as piezoelectricity, multiferroicity, ferroelectricity, dielectricity and for use in the telecommunication industry. It was also realized that some langasite materials exhibit exotic magnetic ground states at low temperatures. A thorough understanding of their ground state is limited by the difficulty in synthesizing new members belonging to this series due to the formation of competing phases such as the garnets. In this study, four new magnetic langasites A3Ga3Ge2BeO14 (A= Pr, Nd, Sm and Eu) and a non-magnetic lattice standard La3Ga3Ge2BeO14 were synthesized. These were further structurally characterized by powder X-ray diffraction, Rietveld refinement and bond valence analysis. Further characterization of the low-temperature magnetism was done by performing magnetization, magnetic susceptibility (field cooled and zero field cooled) and heat capacity measurements. The low temperature spin dynamics were probed using muon spin resonance performed at TRIUMF (Vancouver) and elastic and inelastic neutron scattering measurements performed at the DCS (NIST) and D7 (ILL). From all the above measurements it can be concluded that the new Be langasites exhibit net antiferromagnetic interactions at low-temperatures with clear signs of diffuse scattering for Nd3Ga3Ge2BeO14 using inelastic neutron scattering measurements. There was no evidence of magnetic long-range ordering down to as low as 0.025 K. Based on the obtained measurements these new Be-langasite compounds can be classified as potential spin liquid candidates. / February 2017

Die Magnetresonanztomographie stellt für die Detektion von zerebralen und spinalen Läsionen bei der Multiplen Sklerose die sensitivste bildgebende Methode dar und ist ein Instrument, die räumliche und zeitliche Dissemination der Erkrankung abbilden zu können. Die Spezifität des Verfahrens ist aber gering und die Applikation von MR-Kontrastmittel bei der Diagnostik zwingend notwendig. Bei der suszeptibilitätsgewichteten Magnetresonanzbildgebung (SWI) handelt sich um ein MR-Verfahren, das Schwankungen der magnetischen Suszeptibilität in der Gradientenechosequenz nutzt, um einen Bildkontrast zu erzeugen. Dadurch ist es möglich, hochaufgelöst und sensitiv Magnetfeldinhomogenitäten zu detektieren. In der vorliegenden prospektiven Studie wurden im Zeitraum von 2010 bis 2013 MRT-Untersuchungen unter Einschluss der suszeptibilitätsgewichteten Bildgebung in einem Kollektiv von 41 Patienten (33 weiblich, 8 männlich;; Durchschnittsalter 40 Jahre) mit gesicherter Multipler Sklerose und einem Vergleichskollektiv von 43 Patienten (28 weiblich, 15 männlich;; Durchschnittsalter 45 Jahre), bei denen weder bildgebend noch klinisch Hinweise auf eine Multiple Sklerose vorlagen, durchgeführt. Die Untersuchung wurde mit einem 1,5-Tesla-Magnetresonanz- tomographen realisiert. Das besondere wissenschaftliche Interesse galt dabei der „normal erscheinenden weißen Substanz“ (NAWM) und den zerebralen Läsionen. In der FLAIR-Sequenz wurden die MS-Läsionen und ROIs detektiert und markiert. Anschließend erfolgte die Übertragung in gleicher Schichthöhe auf die SWI-, T1w- und ADC-Sequenz. Zur Differenzierung von akuten und chronischen Läsionen erfolgte im Untersuchungsablauf die intravenöse Gabe von Gadolinium-DTPA- Kontrastmittel. Schon längere Zeit werden im wissenschaftlichen Diskurs krankheitsspezifische Veränderungen in der NAWM vor Auftreten der MS-Läsionen vermutet. Die Sensitivität der FLAIR-Sequenz ist aber scheinbar unzureichend. Mit der SWI- Bildgebung konnten statistisch signifikante SI-Unterschiede zwischen Referenz- und MS-Gruppe in der NAWM herausgearbeitet werden. Nach Kontrastmittelgabe wurden dabei keine Veränderungen der Signalintensität der NAWM in den beiden Gruppen festgestellt, was gegen die Hypothese einer primären Schrankenstörung in der Pathogenese der Erkrankung spricht. Insgesamt wurden 669 Läsionen identifiziert. Es folgte eine Differenzierung in 11 KM-aufnehmende (ACM-) Läsionen, 546 nicht KM-aufnehmende (NACM-) Läsionen und 112 „black holes“ (BLH). Eine gezielte Auswertung der Phasen- und Magnitudenbilder wurde nicht durchgeführt. Besonders in den KM-anreichernden Läsionen (ACM) sind bereits vor der KM-Gabe statistisch erhöhte Signalintensitäten in der SWI-Sequenz nachweisbar. Dies könnte theoretisch für den Nachweis akuter Läsionen, ohne dass eine KM-Gabe notwendig ist, genutzt werden. Doch ist die Anzahl dieser Läsionen in der Untersuchung zu gering, um verlässliche Aussagen diesbezüglich machen zu können. Dafür sind weitere Studien notwendig. Zusammenfassend betrachtet handelt es sich bei der SWI um ein hoch sensitives bildgebendes Verfahren, welches eine ausgezeichnete Differenzierung von ZNS- Läsionen ermöglicht und Veränderungen der NAWM bei der Enzephalomyelitis disseminata nachweisen kann. Es stellt somit eine sinnvolle Ergänzung zur konventionellen MS-Diagnostik dar und ist ein innovatives bildgebendes In-vivo- Verfahren zur weiteren Erforschung der Multiplen Sklerose.

In CBA/NJ mice, splenic natural killer (NK) cell activity varies with stages of estrous. Susceptibility of ICR mice to intravaginal inoculation of herpes simplex virus type 2 (HSV-2) decreases with age. Susceptibility of female ICR and CBA/NJ mice to HSV-2 inoculated intravaginally and intraperitoneally was examined during the estrous cycle. In cycling ICR mice, greatest susceptibility to intravaginal inoculation was observed during diestrous and the least during metestrous. CBA/NJ mice were most susceptible to intravaginal inoculation of HSV-2 during diestrous. ICR mice were ovariectomized to mimic diestrous and found to be highly susceptible to intravaginal inoculation at all virus doses. No difference in susceptibility among phases of the estrous cycle was seen following intraperitoneal inoculation.

Le champ magnétique terrestre présente une vaste gamme de variations temporelles, de l'année à plusieurs millions d'années. J'ai étudié au cours de ma thèse divers aspects de ces fluctuations, des variations séculaires récentes aux renversements.La première partie de ma thèse porte sur l'archéomagnétisme, discipline qui permet de retracer l'évolution temporelle du champ magnétique terrestre au cours des derniers millénaires, principalement à partir des matériaux archéologiques. J'ai étudié deux jeux d'échantillons provenant pour l'un de la Grèce (période néolithique, 6800-3200 avant J.C.) et pour l'autre du Mexique (Palenque, période Maya Classique 320-840 après J.C.), dans le but d'acquérir de nouvelles données d'archéointensité et de mieux contraindre la variation séculaire du champ magnétique terrestre. La comparaison de mes données avec celles disponibles dans la bibliographie et avec les différents modèles globaux et régionaux a mis en évidence que les variations séculaires au Néolithique en Grèce et au cours du premier millénaire en Amérique Centrale sont très mal définies. Mes données suggèrent que des composantes locales, non prisent en compte dans les modèles globaux peuvent exister au niveau ces régions. Elles renforcent l'intérêt de développer des modèles régionaux précis, qui nécessitent un développement en harmoniques sphériques à un degré plus élevé. Pour ce faire, l'acquisition de nouvelles données de haute qualité est un élément majeur.La deuxième partie traite de la description d'un renversement du champ magnétique terrestre. Cette étude a été basée sur deux points précis: étudier les directions transitionnelles afin d'apporter de nouvelles contraintes sur le possible confinement longitudinal des pôles géomagnétiques virtuels (PGV) d'une part, et d'autre part vérifier des paléointensités transitionnelles obtenues sur la séquence volcanique d'Akaroa (Nouvelle Zélande), dont l'intensité est significativement supérieure à celles des intensités avant et après le renversement. Nous avons ré-échantillonné cette séquence, et l'évolution directionnelle obtenue pour ce renversement est une succession complexe de polarités N-T-R-T-N-T-R. Les PGV obtenus semblent se regrouper sous deux bandes longitudinales sous l'Australie et l'Amérique, ce qui renforce l'hypothèse d'une interaction entre le manteau et le noyau sur plusieurs millions d'années. Suite à une étude de minéralogie magnétique, j'ai sélectionné les échantillons susceptibles de fournir une valeur de paléointensité par les méthodes de Thellier et du multispecimen. Les paléointensités obtenues sont relativement faibles (environ 20 microT) au cours du changement de polarité et forte à la fin de la séquence. Mon interprétation, basée à la fois sur les valeurs de l'intensité du champ et sur les données radiochronologiques montrant que la séquence s'est mise en place très rapidement, est de considérer que seul le renversement C4Ar.1n-C4Ar.1r a été enregistré dans cette séquence. Dans cette hypothèse, le renversement montre un cheminement complexe comparable à d'autres renversements enregistrés dans l'hémisphère nord (Steens Mountain par exemple), incluant un phénomène de rebond avant de se stabiliser. La troisième partie de ma thèse est consacrée au développement d'une nouvelle méthodologie et d'un nouvel appareillage pour déterminer des paléointensités. Le faible taux de réussite des expériences de paléointensité de l'étude précédente m'a poussé à m'intéresser au protocole multispecimen, qui peut s'appliquer aux échantillons possédant un comportement polydomaine. L'inconvénient technique majeur de cette méthode réside dans l'application du champ le long de l'aimantation naturelle, difficile à réaliser avec précision dans les fours standards. Pour ce faire, nous avons décidé de développer des porte-échantillons permettant d'orienter les échantillons dans l'espace pour le four standard et un prototype de four à chauffage ultra-rapide particulièrement bie / The Earth's magnetic field shows a large range of temporal variations from the year to several million years. I studied during my PhD thesis several aspects of these fluctuations, from recent secular variations to reversals.The first part of my manuscript deals with archeomagnetism, a discipline that allows to track the temporal variations of the Earth's magnetic field through millennia, mainly from archeological materials. I studied two sets of samples, one from Greece (Neolithic period 6800-3200 B.C.) and the other from Mexico (Palenque, Maya Classic period 320-840 A.D.), to acquire new archeointensity data in order to better constrain the secular variation of the geomagnetic field. By comparing my data with those available in the literature and with the various global and regional models, I showed that the secular variations during the Neolithic in Greece and during the first millennium in Central America are poorly defined. My data suggest that local components, not described by global models, may exist in these regions. They reinforce the importance of developing specific regional models, which require development in higher spherical harmonic degree. As a consequence, the acquisition of new high quality data is of main importance. The second part presents the description of a geomagnetic field reversal. This work was based on two points: first by studying transitional directions to provide new constraints on the possible preferred longitudinal paths of virtual geomagnetic poles (VGPs) and second by checking transitional paleointensities obtained on a volcanic sequence in Akaroa volcano (New Zealand). Indeed the transitional field intensity is significantly higher than the field intensity before and after the reversal. We re-sampled this sequence, and the directional results show a complex sequence of N-T-R-T-N-T-R polarity. The transitional VGPs obtained are clustered in two longitudinal bands through Australia and America. This observation seems to reinforce the assumption of a core-mantle interaction over several million years. Following a rock magnetic study, I selected samples that could provide a value for the Thellier and multispecimen paleointensity methods. The obtained paleointensity are relatively low (about 20 microT) during the polarity change and strong at the end of the sequence.Based both on the field strength values and on the radiochronological ages, showing that the sequence was erupted in a very short time, I suggest that only the C4Ar.1n-C4Ar.1r reversal was recorded in this sequence. In this assumption, the reversal shows a complex path comparable to other reversals recorded in the northern hemisphere (for example the Steens Mountain), including a rebound before stabilizing.Finally the last part is devoted to the development of a new methodology and a new apparatus to determine absolute paleointensity. Following the low success rate of paleointensity experiments from the previous study, I decided to test the multispecimen protocol, which can be applied to samples yielding a predominant multidomaine behavior. The main technical drawback of this method lies in the application of the laboratory field along the natural remanent magnetization, a difficult task to perform accurately in standard paleointensity ovens. Thus, we decided to adapt sample holders from our standard oven in order to allow the sample orientation in space and to develop an ultra-fast heating oven prototype particularly well-suited for this method, allowing to apply the laboratory field in the 3 dimensions. I checked the different multispecimen protocols on historical lavas from Reunion and Etna volcano, yielding very different magnetic mineralogies. For all flows, I obtained paleointensities very close from the expected values, regardless from the magnetic mineralogy, revealing the feasibility of our apparatus and the promising interest of the method. The application of various corrections on the statistical estimation o

Master of Science / Department of Civil Engineering / Mustaque Hossain / Because of recent rises in asphalt binder prices, state agencies and contractors are now willing to use higher volumes of reclaimed asphalt pavement (RAP). In this project, the effects of increasing RAP percentage and using fractionated RAP (FRAP) in hot-mix asphalt (HMA) mixtures have been studied. Fractionation involved processing and separating of RAP materials into at least two sizes, typically a coarse fraction and a fine fraction. This study evaluated the effects of increasing the proportions of RAP and FRAP on moisture resistance, rutting, and fatigue cracking of Superpave mixtures. Furthermore, the effect of using different sources of RAP in the mix has been investigated. HMA mixtures with five varying RAP and FRAP contents (20, 30, and 40% RAP, and 30 and 40% FRAP) were studied. The Hamburg wheel-tracking device (HWTD) test (TEX-242-F), the Kansas standard test method no. 56 (KT-56), or modified Lottman test, and the dynamic modulus test (AASHTO TP: 62-03) were used to predict moisture damage, rutting potential, and fatigue cracking resistance of the mixes. HMA specimens were made based on Superpave HMA mix design criteria for 12.5-mm (1/2-inch) nominal maximum aggregate size (NMAS) and compacted using the Superpave gyratory compactor. For the first source of RAP, results of this study showed that although mixture performance declined as the percentage of RAP increased, mixtures with even 40% RAP met minimum performance requirements. The second source of RAP, however, almost failed to meet minimum requirements even at 20% RAP. Results proved the maximum percentage of RAP allowed in the mix is highly influenced by its source. Although some improvements have been observed, especially for the second source of RAP, when RAP is compared to FRAP, FRAP does not seem to considerably affect performance of the HMA mixture.

Master of Science / Department of Diagnostic Medicine/Pathobiology / Sanjeev K. Narayanan / Acute diarrhea induced by Escherichia coli is an important illness in humans, especially in children under age of two in developing countries. Citrobacter rodentium is used as murine model for E. coli infection in humans because it causes ultrastructural changes in murine colonic epithelium comparable to lesions produced by enteropathogenic E. coli (EPEC) and enterohemorrhagic E. coli (EHEC). Adult mice of many strains develop self-limiting epithelial hyperplasia when infected, whereas adult C3H and FVB mice are highly susceptible to infection and demonstrate mortality rates between 60 and 100% two weeks after infection. These susceptible strains of mice also have higher bacterial translocation to mesenteric lymph nodes. In mice, the cause of death could be hypovolemia due to dehydration that may occur due to an increase in paracellular permeability as well as dysregulation of apical and basolateral ion transporting proteins. C. rodentium virulence factors resemble those of E. coli and are believed to primarily alter tight junctions of colonic epithelial cells. Effectors delivered via the type III secretory system have been associated with actin condensation and pedestal formation. The exact mechanisms of C. rodentium infection, as well as changes that occur in vitro as well as in the intestine of various strains of mice are not completely understood. This study introduced a new in vitro Ptk6 cell line for C. rodentium infection, which can also serve as a model for EPEC in humans. Effect of C. rodentium on colonic epithelial cells of susceptible and resistant mice was determined in in vivo study. C. rodentium attached to Ptk6 colonic epithelial cells, inducing attaching and effacing (A/E) lesions and loss of monolayer integrity, which charachterizes this cell line as a relevant in vitro model of C. rodentium and EPEC infections. Murine studies revealed that C. rodentium induced more severe disease and 100% mortality in juvenile C3H mice whereas Swiss Webster (SW) mice expressed only moderate morbidity. The colonic lesions and changes in barrier function of colonic epithelium were more prominent in C3H mice. This study determined potential targets in the murine colon that play role the establishment and the outcome of the infection, indicating multifactorial nature of C. rodentium-induced diarrhea. This study identified host factors involved in the initiation of C. rodentium-associated diarrhea and the outcome of infection, which can be useful in developing of novel strategies for preventing and treatment of infectious colitis.

A number of polymorphisms in the human VDR gene (located on chromosome 12q12-14) have previously been associated with TB susceptibility, of which most commonly, FokI, BsmI, ApaI and TaqI. The active metabolite of vitamin D, 1,25 dihydroxyvitamin D3, is an important immunoregulatory hormone. Its effects are exerted via the VDR, which is present on human monocytes and activated T and B-lymphocytes. Considering the role of the VDR and it specific immunological functions, including activation of monocytes, stimulation of cell-mediated immunity, suppression of lymphocyte proliferation, immunoglobulin production and cytokine synthesis, variation in the VDR genes may contribute to disease susceptibility. Hypothesis and objectives: In this study it was hypothesized that polymorphisms in the vitamin D receptor (VDR) gene influence TB susceptibility in the Venda population of South Africa. The role of VDR polymorphisms in TB susceptibility was investigated by setting the following objectives: 1. Typing of VDR gene polymorphisms (FokI, BsmI, ApaI and TaqI) in controls and TB cases as well as family samples from a Venda population of the Northern Province of South Africa. Comparing VDR allele and genotype frequencies between the Venda population and other populations as reported in the literature. 2. Analysis of possible associations in the case-control and family-based study 3. Studying Linkage disequilibrium (LD) in the case-control and the family samples. 4. Screening VDR haplotypes in the case-control and family-based study for possible association with TB. Patient and laboratory methods: VDR polymorphisms were studied in controls (n=110), TB cases (n=113) and 25 families in the Venda population inhabiting the Northern Province of South Africa. Case-control studies are vulnerable to false positive results caused by inadequate matching of the two groups. For this reason, a withinfamily association test was also implemented (the transmission disequilibrium test, TDT), as this is robust to this possible source of error. ARMS-PCR was used to type the VDR allele polymorphisms. The Statistical Package for Social Sciences (SPSSv10) was used to analyze possible association in case-controls, while TRANSMIT was used to analyze transmission of VDR alleles to affected offspring. LD between the single nucleotide polymorphisms (SNPs) of the VDR gene was investigated using the software “Graphical Overview of Linkage Disequilibrium” (GOLD) in both case-control and family studies. Possible association of TB with haplotypes comprising the VDR SNPs, ApaI and TaqI, were determined using SPSSv10 and TRANSMIT respectively for case-controls and the family based study. Results: 1. The comparative analysis indicated that the allele frequencies of the VDR SNPs related to the African American population. Genotype frequencies for FokI, BsmI and TaqI were similar to the West African population, whereas ApaI did not relate to any of the populations investigated. 2. No significant differences existed concerning the allele frequencies or genotype distribution between controls and TB cases with regard the VDR SNPs; FokI, BsmI and TaqI. The ApaI allele ‘A’ differed between cases and controls (p=0.041) but, no significant differences were obtained for genotype distribution between cases and controls for this SNP. All SNPs were in Hardy-Weinburg equilibrium except for ApaI. No differences between controls and cases were observed concerning allele presence or absence. In the family-based study, no significant difference was observed between observed and expected numbers of transmission for neither alleles nor genotypes, although, a borderline association was observed between TaqI ‘T’ allele and TB susceptibility (p=0.084). 3. LD in the case-control study was found between the VDR SNPs: BsmI and ApaI (p=0.051, D’=0.478), BsmI and TaqI (p=0.007, D’=0.222) and ApaI and TaqI (p=0.003, D’=0.479). In the family-based study, LD was only observed between ApaI and TaqI (p=0.049, D’=0.001) 4. Haplotype analysis in the case-control study indicated that no significant difference between controls and TB cases was observed. The family-based study indicated that transmission of the VDR haplotype ‘AT’ and ‘at’ differed from the expected transmission, but was of borderline significance. ‘AT’ was transmitted more than expected (P=0.090) and ‘at’ was transmitted less than expected (P=0.075), indicating that ‘AT’ may play a role in TB susceptibility and ‘at’ may play a protective role. Conclusion: The current study supports a possible role for VDR polymorphisms, ApaI (‘A’, p=0.041), or nearby yet unidentified markers in TB susceptibility in African populations (FokI-ApaI-BsmI-TaqI) (p=0.049). A larger sample size may clarify associations found to be of borderline significance. Results obtained may contribute to an improved understanding of genetic susceptibility factors in Africans. / Prof. L. Bornman