The first visible outcome of the fertility process is the birth of the first child. The first birth marks a woman's transition into motherhood. It plays a significant role in the future life of each individual woman and has a direct relationship with fertility. The age at which child bearing begins influences the number of children a woman bears throughout her reproductive period in the absence of any active fertility control. For countries in sub-Saharan Africa, where contraceptive use is relatively low, younger ages at first birth tend to boost the number of children a woman will have. However, even when family planning is widespread, the timing of first births can affect completed family size if contraception is used for spacing but not for limiting fertility. The birth of a child is an event of great social and individual significance and its importance is recognised in all human societies. It signifies the transition of a couple into a new social status, i.e. parenthood with its related expectations and responsibilities. It marks the sexual and social maturity of the mother and the visible consummation of sexual intercourse . The relationship between age at first birth and overall fertility in developing countries is generally an underdeveloped area as far as demographic research is concerned. Fertility analysts generally assume that child bearing only occurs within marriage. Then they treat age at first marriage to be a major proximate determinant of fertility. This assumption might have been true in most traditional societies, where births out of wedlock were not accepted and virginity was a prerequisite for marriage. This assumption, however, does not hold true in modern times, where a large number of children is born outside marriage. These facts have been the major motive of conducting the current research. This study examines the reproductive behaviour of Tanzanian women. The study found the average age at first sexual intercourse to be 16 years; age at first marriage to be 17 years, while average age at first child bearing was estimated to be 18 years. By age 15, almost 10 percent of juvenile women have given birth. This study furthermore found that 41 percent of all first live births resulted from premarital conceptions. Out-of-wedlock births account for 24 percent of all first births in Tanzania according to the 1996 TDHS. The education of a woman, place of residence, and religion play the greatest roles in influencing age at first birth in Tanzania. The striking results were place of residence as it was found that rural residents have a higher mean age at first birth than women living in Dar es Salaam. Dar es Salaam women has the lowest mean age at first birth. Moslems have lower age at first birth than Catholics. There is also a strong relationship between age at first birth and age at first intercourse also with infant and child mortality. The results indicate that the younger the age of the mother at the birth of the first child, the higher the chances that the child dies. The study of current levels and trends of fertility showed that, on the average, a Tanzanian woman bears 6 children. Between the 1960s and early 1980s, an average of 7 births per woman prevailed in Tanzania. The declining fertility in Tanzania was confirmed by the analysis of the decomposition of the change of the total fertility rate (TFR) between two TDHSs. It found that natural fertility control is being gradually replaced by contraceptive use although the percentage of women using contraception is still very low. The reduction in infant and child mortality, rising numbers of women attending schools, and a rise in age at first birth are among the factors responsible for the decline in fertility in Tanzania. Education on the other hand has played a major role in raising age at first birth. Education either delays first intercourse and subsequently birth as pregnant schoolgirls are prohibited to attend formal schools or it effects the acceptance of contraception to delay first conception. Specifically, this study establish that there is an inverse relationship between age at first birth and fertility. Marriage is a weak factor in explaining fertility in Tanzania. Women in polygamous unions had fewer number of children ever born than those in monogamous unions in Tanzania. Moslems have a lower fertility than Catholics. Women residing in urban areas have fewer children than those in the rural areas. Women's education is the strongest predictor of the use of contraceptives in Tanzania. Catholic women are less likely to use contraceptives than Moslems. Tanzanian women residing in rural areas are less likely to use contraception than their counterparts residing in urban areas. Although age at first birth did not show any significance, age at first intercourse, age at first marriage and current age are highly related to contraceptive use. Variation in age at first sexual intercourse; marriage; and birth, and the extent of practising contraception are found to depend mainly on religion, place of residence, and the age of a woman. It is important therefore to design separate programmes to raise age at first birth and to lower fertility according to the findings related to religion, place of residence, and target juvenile women separately.

Mutations of the WFS1 gene are responsible for most cases of Wolfram syndrome (WS), a rare, recessively inherited neurodegenerative disorder characterised by juvenile-onset non-autoimmune diabetes mellitus and optic atrophy. Variants of WFS1 are also associated with non-syndromic hearing loss and type-2 diabetes. Understanding the function of the WFS1 protein-product wolframin, would enable developments in targeted therapy for WS patients and important insights to its possible contribution to type-2 diabetes pathogenesis. This study was aimed at expanding the spectrum of WS-associated genetic mutations and clinical data, and investigating the molecular mechanisms responsible for phenotypic variation associated with WFS1-mutation. The mutational and phenotypic spectrum of WS is broadened by our report of novel WFS1 mutations and a case of WFS2-associated WS. New perspectives on the molecular mechanisms linking mutation to disease manifestation are also taken by characterisation of representative WFS1 mutations specific to phenotype, identification of potentially novel WFS1 interacting partners, and the first evidence linking WFS1 with the exocrine pancreas. Our data suggests that some WFS1-mutations may allow residual protein function and these findings lay the groundwork for future functional investigation of mutated wolframin to explore this hypothesis further.

Metabolite concentrations are fundamental biomarkers of disease. With increasing interest in personalised medicine, this work assessed the accuracy of non-invasive metabolite quantification with magnetic resonance spectroscopy (MRS) using a combination of simulations, phantom and in vivo data. No optimal echo time (TE) was found for measuring a range of key metabolites with quantification accuracy generally influenced more by data quality than TE choice. The T2 relaxation times of water and metabolites with MRS dominated by a singlet could be estimated using 2 TEs and were found to be significantly different in paediatric brain tumours compared with normal brain, varying between tumour types. The T2 relaxation times of paediatric brain tumours were significantly shorter at 3T compared with 1.5T. Metabolite concentrations for individual patients were most affected by changes in the T2 relaxation time of water which is quick to measure. A clinical JPRESS protocol was developed which aids assignment of overlapping metabolites using changes of MRS with TE. Overall, measurement of MRS with a short TE reduces inaccuracies associated with variability in metabolite T2 and does not tend to lead to worse quantification of overlapping resonances. Further improvements in concentration accuracy can be obtained by measuring case-specific water T2.

Tolerance of the semi-allogeneic fetus presents a significant challenge to the maternal immune system. The effect of pregnancy on maternal cellular immunity was established by assessing maternal effector and regulatory T-cell subsets during human pregnancy. This demonstrated that an increase in maternal peripheral regulatory T-cells or a shift from a Th1 to Th2 phenotype was not a requirement for normal pregnancy. We also determined the profound impact of maternal Cytomegalovirus seropositivity on maternal T- cell dynamics. T-cells with specificity for fetal epitopes have been detected in women with a history of pregnancy but it has been thought that such fetal specific cells were deleted during pregnancy. We identified, using MHC-peptide multimers, fetal-specific CD8 T-cells in half of all pregnancies. The fetal-specific response increased during pregnancy and persisted in the post natal period. Fetal-specific cells demonstrated an effector memory phenotype and retained functional potential. These data show that the development of a fetal-specific adaptive cellular immune response is a normal consequence of human pregnancy. Women with recurrent miscarriage were found to have abnormal T-cell function, with increased IFN\(\gamma\) and Il-17 production. Fetal specific T-cells were also detected in this cohort and progesterone attenuated their function, which may have therapeutic implications.

Birt Hogg Dubé (BHD) syndrome is an inherited cancer susceptibility syndrome characterised by the development of fibrofolliculomas on the face and upper torso, and increased risk of lung cysts, spontaneous pneumothorax and renal cancer. The findings presented in this thesis advance knowledge into how the mutations in the FLCN gene cause the phenotypes associated with BHD syndrome, and provides novel insights into the functions of folliculin within the cell. The results presented provide further evidence of the association between BHD syndrome and increased risk of colorectal cancer in a subset of BHD syndrome families, and suggest that this association appears restricted to those patients with an exon 11 mononucleotide tract mutation. Evolutionary conservation analysis across the FLCN sequence suggests that pathogenic mutations could be expected throughout the gene, and identifies a region between codons 100-230 of increased evolutionary significance. The experiments undertaken demonstrate a practical strategy for determining the pathogenicity of non-truncating folliculin variants in vitro, and indicate that loss of protein stability is the main mechanism of pathogenicity for the previously reported non-truncating mutations within FLCN. Finally, this thesis reports the first identification of p0071 as a folliculin interacting protein. Folliculin deficiency exerts a functional impact on previously reported p0071 functions inducing RhoA signalling upregulation, mitotic defects and disruption of cell junctions. These results demonstrate the potential efficacy of using inhibitors downstream of RhoA as therapeutic targets in BHD tumours with dyregulated RhoA signaling, and provide novel directions for research into BHD syndrome.

In this thesis I report three related studies that utilise state-of-the-art technologies to investigate germline and somatic chromosomal rearrangements in humans. Firstly, 16 patients with cytogenetically detectable deletions of 3p25-p26 were analysed with high density single nucleotide polymorphism (SNP) microarrays; Affymetrix 250K SNP microarrays (n=14) and Affymetrix SNP6.0 (n=2). Assuming complete penetrance, a critical region for congenitalheart disease (CHD) susceptibility gene was refined to approximately 200 kb and a candidate critical region for mental retardation was mapped to ~1 Mb interval containing SRGAP3. Secondly, I used SNP microarray and molecular cytogenetic studies to characterize chromosome 11p15 in 8 patients with the imprinting disorder Beckwith-Wiedemann syndrome (BWS). In addition to characterising 11p duplications in three patients, the breakpoints in two patients with balanced rearrangements were mapped to two distinct regions. Thirdly, I used high resolution SNP arrays (Affymetrix 250K Sty1 and 6.0 arrays) to identify copy number changes in renal cell carcinoma (RCC) primary tumours (n=81) and cell lines (n=23). Copy number changes most frequently involved large segments (>10Mb) and loss of 3p and gain of 5q were the most common copy number changes. A comparison of copy number changes in RCC cell lines and inherited and sporadic primary tumours was made.

Myeloid and lymphoid malignancies are potentially curable through a graft versus leukaemia (GvL) effect following allogeneic haematopoietic stem cell transplantation. Whilst donor T cell are thought to be the main mediators of GvL, the effect of donor NK cells within HLA matched T cell depleted transplant setting is more unclear. Patient blood samples were analysed during the first month post-transplant, with higher reconstitution of NK cells at two weeks conferring a relapse protection association. Donor stem cell graft samples, from which NK cells within the patient at two weeks are thought to be derived, similarly displayed a strong association between high NK cell dose and protection from disease relapse. CD56dimDNAM+ NK cells were found to be the population with the most significant association. The ability of NK cells to kill AML blasts in a DNAM dependent manner was shown indicating that direct killing of residual tumour cells may be a valid mechanism of GvL. These findings suggest that optimising the number of NK cells within stem cell grafts should be considered as a means to prevent disease relapse.

The potential for nitric oxide (NO) metabolites (e.g. inorganic nitrite) to act as stable stores of “Transported Nitric Oxide” has excited huge interest due to the substantial potential therapeutic avenues. The prospect developing of a “silver bullet” that could target areas most in need of vasodilatation, by releasing NO in areas of hypoxia and ischaemia, could prove a massive advance in the treatment of vascular disease. In this thesis I examine the effects of nitrite infusion in both hypoxia and normoxia. I examine the effects both in health and heart failure, and investigate the potential roles of Nitric Oxide Synthase (NOS) and Xanthine Oxidase (XO) in mediating the reduction of nitrite. We found, and were the first to report in man, that intra-arterial infusions of nitrite had little effect upon the vasculature in high oxygen tension environments but led to significant vasodilatation during hypoxaemia. We found that patients suffering with Chronic Heart Failure responded differently to nitrite infusion to healthy controls, possibly as a result of differences in redox-stress. In healthy volunteers, at rest, neither NOS nor XO appeared to play a significant role in nitrite induced vasodilatation in normoxia and mild hypoxia. We found that vascular myoglobin contributes to the reduction of nitrite to nitric oxide and may play a role in prolonging the vasodilatation induced by nitrite infusion.

Les séquences argileuses peu perméables telles que les argilites callovo-oxfordiennes du bassin de<br />Paris ou les siltites vraconiennes du Gard, ont été choisies pour l'implantation éventuelle d'un<br />laboratoire souterrain destiné à tester les propriétés physico-chimiques de ces formations dans<br />l'éventualité d'un stockage profond de déchets nucléaires. La connaissance et la compréhension des<br />modifications post-sédimentaires sont fondamentales dans la définition de ces propriétés. Le but du<br />présent travail visait donc à évaluer et quantifier ces changements par l'étude de ces roches, en<br />particulier des minéraux argileux.<br />Les échantillons proviennent de deux forages (HTM102 et MAR501). Les principaux minéraux<br />argileux dans le forage HTM102 sont l'illite et les interstratifiés illite/smectite. Les observations au<br />MET et au MEB couplées aux analyses isotopiques K-Ar et Rb-Sr mettent en évidence la néoformation de carbonates (calcite, dolomite) et d'argiles. Celles-ci apparaissent au MET comme des particules authigènes lattées en croissance sur des particules détritiques. La durée et l'extension de ces événements diagénétiques sont difficiles à évaluer du fait d'une contamination systématique des<br />échantillons par une contribution détritique, et ce même dans les fractions les plus fines. Cependant,<br />l'étude d'un niveau de bentonite dans la séquence permet de caler l'époque et la durée de la<br />diagenèse. En assimilant cette bentonite à un pôle authigène, il a été possible de reconstruire les<br />variations des valeurs K-Ar de chaque fraction argileuse dans la séquence. Ainsi, la corrélation<br />observée entre les variations du niveau marin relatif et la formation d'un matériel argileux riche en<br />smectite d'une part, et des chimies de fluides différentes d'autre part, sont autant d'arguments en<br />faveur de réactions diagénétiques en système sinon clos du moins restreint.<br />Les travaux sur le forage MAR501 sont comparables à ceux réalisés sur le forage HTM102, avec<br />également un mélange entre deux populations argileuses d'âge différent. Les glauconites<br />diagénétiques ont permis de caler le Vraconien au voisinage de 93,7 ± 0,3 Ma, en accord avec les<br />données stratigraphiques. L'étude d'une fracture colmatée par une matrice essentiellement argileuse<br />confirme le caractère confiné de cette séquence. Aucune migration d'éléments, et en particulier de<br />TR, n'a été mise en évidence lors de la circulation de paléofluides, indiquant que les minéraux<br />argileux ont conservé leurs propriétés géochimiques.<br />L'ensemble de ces résultats est en faveur de propriétés de confinement fiables dans le cas des deux séquences argileuses.

<p>The relationship between Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) is not entirely elucidated and a clonal relation may be present more often than previously believed. Mechanisms of tumour progression and resistance to therapy are poorly understood.</p><p>Between 1974 and 1994 all individuals in Sweden with both HL and NHL were identified. Thirty-two cases were studied using clinical, histopathological and immunohistochemical methods. The second lymphoma often appeared in an aggressive clinical form and a significant correlation between the expression of p53 and LMP-1 in the first and second lymphoma was demonstrated.</p><p>The treatment outcome for 307 patients with advanced stages of HL, in an unselected population was in accordance with the treatment results of large centres world-wide. Some patients were successfully selected for a shorter chemotherapy-regimen without inferior treatment results.</p><p>In 124 patients with relapse, the survival of those primarily treated with radiotherapy according to the National guidelines was in accordance with the survival of patients of initially advanced stages. A worse outcome was found for those who received both chemotherapy and radiotherapy initially, probably because of a higher frequency of bulky disease in this group. </p><p>Immunohistochemical analysis of the tumour suppressor protein p53 and retinoblastoma protein (Rb) of paired samples at diagnosis and at relapse in 81 patients did not reveal any specific staining pattern affecting survival.</p><p>A novel B-cell line (U-2932) was established from a patient with a diffuse large B-cell lymphoma previously treated for advanced stage and subsequent relapses of HL. An identical rearranged IgH gene was demonstrated in tumour cells from the patient and in U-2932. A p53 point mutation was detected and over-expression of the p53 protein was found. A complex karyotype with high-level amplifications of the chromosomal regions 18q21 and 3q27, i.e. the loci for <i>bcl-2</i> and <i>bcl-6</i> were demonstrated. </p>