Le cancer du col utérin est précédé par des lésions prénéoplasiques. Celles-ci sont associées dans plus de 95% des cas à une infection par un papillomavirus (HPV). Un phénomène fréquent durant la cancérogenèse cervicale est l'intégration du génome dun HPV oncogène dans lADN cellulaire. Celle-ci entraîne une expression sélective de gènes codant pour des oncoprotéines virales (appelées E6 et E7) capables d'inactiver les produits de certains gènes suppresseurs de tumeurs (p53, p21, pRb) ou dinteragir avec dautres protéines cellulaires impliquées dans le contrôle du cycle cellulaire. Des travaux antérieurs du laboratoire daccueil suggèrent que le développement du cancer du col utérin est associé à une faible capacité de présentation dantigènes au système immunitaire, comme le démontre la rareté et le déficit fonctionnel des cellules de Langerhans (LC, cellules dendritiques ayant une fonction professionnelle de présentation antigénique au niveau de la peau et des muqueuses) dans les lésions (pré)cancéreuses cervicales. Ces altérations pourraient empêcher une réponse immunitaire efficace et faciliter la persistance du virus ainsi que la progression tumorale. Il est actuellement bien admis que les kératinocytes (cellules cibles de linfection par HPV) sont susceptibles dinfluencer les réactions immunitaires au niveau de la peau et des muqueuses épidermoïdes par lintermédiaire de facteurs solubles, les chémokines (CCL20, contrôlant linfiltration des LC immatures au sein de lépithélium) ou de contacts membranaires (E-cadhérine). Les kératinocytes infectés par HPV pourraient se différencier des cellules normales pour la production de ces facteurs, ce qui pourrait contribuer aux altérations des cellules de Langerhans/cellules dendritiques (LC/DC) observées dans les lésions (pré)cancéreuses cervicales. Le fait que la molécule dadhésion E-cadhérine intervienne dans lattachement des LC aux kératinocytes suggère limportance de cette molécule dadhésion dans la rétention des CL au sein de lépithélium cervical. Les objectifs de ce travail ont été détudier linfluence des oncogènes viraux sur lexpression de facteurs immunitaires et dexaminer les conséquences de linhibition de E6 et de E7 sur lexpression de la E-cadhérine et de CCL20, qui jouent un rôle important dans limmunosurveillance au niveau des épithélia via leur action sur les cellules de Langerhans. En accord avec notre hypothèse, nous avons montré une diminution de lexpression de la E-cadhérine dans les lésions (pré)néoplasiques du col par rapport à lépithélium exocervical normal (Hubert et coll. 2005). Par des expériences dARN interférence (siRNA), nous avons également démontré limplication de loncoprotéine virale E7 dans linhibition de lexpression de la E-cadhérine membranaire (Caberg et coll. 2008) et limplication des oncoprotéines virales E6 et E7 dans la diminution de la sécrétion de la chémokine CCL20 dans des kératinocytes transformés par HPV16 (Caberg et coll. 2008).

Human Papillomavirus (HPV) is a key factor in the development of cervical cancer. Out of the more than 100 known HPV types 13 are considered oncogenic. In addition to presence of the virus several other factors have been proposed to influence risk of cervical cancer. This thesis focuses on viral load and HLA class II alleles as risk factors for cervical cancer. To enable quantification of the most common oncogenic HPV types, a real-time PCR-based assay was developed and evaluated in terms of technical sensitivity and specificity. This assay was then employed on archival smears from 457 cases and 552 controls to assess associations between viral load and cervical carcinoma in situ (CIS). Whereas the data indicate a pronounced dose dependent effect of HPV 16 load on the risk of CIS, other HPV types only seem to increase CIS risk at higher viral loads. These effects were observed even when cytology indicated that cells were normal. We then investigated viral load as a risk factor for invasive cervical carcinoma (ICC) in a retrospective study comprising 139 cases and 550 controls. Viral load contributed similarly to the risk of ICC as to the risk of CIS. Finally, associations between HLA class II alleles, viral load and CIS were investigated. Carriers of the DRB1*1301 allele were less prone to infections and high viral loads of HPV 31 and -18/45. Moreover, DRB1*1301 had a protective effect against CIS among women infected by HPV 31 or -18/45. In contrast, carriers of DRB1*1501 and DQB1*0602 were more susceptible to infections and high viral loads of HPV 16. These results indicate that HPV load may have HPV-type specific effects on cervical cancer risk. Furthermore, HLA class II alleles may confer either susceptibility or protection against cervical cancer by acting on the HPV infections preceding tumor development.

Cervical cancer is a multifactorial disease. Infection by oncogenic types of the human papillomavirus (HPV) is the major environmental risk factor and host genetic susceptibility also influences disease development. The aim of this thesis is to identify and analyse risk genes involved in the genetic predisposition to cervical carcinoma. A unique and extensive population-based affected sib-pair (ASP) material and a large case-control sample were used in the investigations. In paper I the human leukocyte antigen (HLA) class II DQB1 and DRB1 loci are confirmed, for the first time in a family-based material, as genetic susceptibility factors for cervical cancer. It is also proposed that the HLA class II DPB1 locus independently contributes to risk of developing disease. In addition, no evidence is found for an involvement of the class I HLA-B and HLA-A loci in the genetic predisposition. Paper II conclude that the Fas receptor –670 single nucleotide polymorphism (SNP) do not have a major impact on the susceptibility to cervical carcinoma in situ in the Swedish population. In paper III we show that interactions between the HPV16 E6 gene subtype and host HLA class II genotype potentially occur during infection and disease progression. Paper IV suggests that three chromosomal regions, 9q32, 12q24 and 16q24, contain risk factors of low to moderate effects on cervical cancer development. In paper V linkage signals are further identified between a 9q32 gene encoding the thymic stromal co-transporter (TSCOT) and the disease in ASPs with mean age over 30.5 years at diagnosis within the sib-pair. These findings are important contributions towards understanding more about the aetiology of this complex cancer. The identification of new susceptibility regions opens up for further characterisation, replication and candidate gene analysis.

Women afflicted with cervical cancer who have the highest morbidity and mortality rates have been the least likely to be screened. The overall aim of this research project was to investigate non-attendance in a cervical cancer screening (CCS) program among women with no registered cervical smear during the previous five years. Both quantitative (I,III) and qualitative methods (II) as well as costeffectiveness analysis (IV) were used in this research project. In Kalmar County women (aged 23-65 years) are invited to CCS every third year. All cervical smears taken both in opportunistic and organised CCS are coordinated in a register called Sympathy. The coverage is 88.4 %. From Sympathy, a random sample of 400 women served as a study group and another 400 women as a control group (III,IV). From the study group, 133 women participated in study I and 14 women in study II. Data was collected by telephone interviews based on a questionnaire (I), qualitative face-to-face interviews (II), questionnaire, promotive efforts and outcome (III), costs and effectiveness (IV). Quantitative data was analysed by descriptive and analytic statistics (I,III), qualitative data was analysed by content analysis. In study IV, cost-effectiveness analysis was used. The women believed that CCS was a good idea for all other women, but tended to refer to various circumstances resulting in their own non-attendance. One of the most common reasons for non-attendance was the feeling of being healthy. The women prioritized family and work commitments, and the invitation to attend CCS was sometimes experienced as a stressful disturbance. The feeling of discomfort was related to the gynaecologic examination, or to health care visits in general (I,II). Of 133 women, 120 could consider having a cervical smear taken and their two most common requirements for doing so were to be assured they would be treated in a friendly way (19%) and to find a suitable time (18%) for having the cervical smear. Fifty women wanted to be helped to have a cervical smear taken. Promotive efforts ranged from making a simple telephone call to arranging an appointment time to a combination of promotive efforts including repeated encounters in order to create a trusting relationship with respect to taking the smear. In the study group, 29.5% (n=118) had a registered cervical smear at follow-up compared to 18.5% (n=74) in the control group, (p<0.001) (III). In the study group, the cost per cervical smear taken was 66.87 €, and in the control group it was 16.62 €. The incremental cost per additional cervical smear taken was 151.36 € (IV). In conclusion, women’s reasons for not attending CCS are complex and are influenced by both present and earlier circumstances. In settings with high coverage, further contact in order to promote women’s attendance at CCS seems to be associated with high costs in relation to the number of additional cervical smears taken. / On the day of the defence data the status of article I was: In press; article II: Submitted; article II: Accepted and artile IV: In press.

Injuries to the head and neck are potentially the most severe injuries in humans, since they may damage the nervous system. In accidents, the cervical musculature stabilizes the neck in order to prevent injury to the spinal column and is also a potential site for acute muscle strain, resulting in neck pain. The musculature is consequently an important factor in the understanding of neck injuries. There is however a lack of data on muscle response and little is known about the dynamics of the individual muscles. In this thesis the numerical method of Finite Elements (FE) is used to examine the importance of musculature in accidental injuries. In order to study the influence of a continuum musculature, a 3D solid element muscle model with continuum mechanical material properties was developed. It was hypothesized that a 3D musculature model would improve the biofidelity of a numerical neck model by accounting for the passive compressive stiffness, mass inertia, and contact interfaces between muscles. A solid element representation would also enable the study of muscle tissue strain injuries. A solid element muscle model representing a 50th percentile male was created, based on the geometry from MRI, and incorporated into an existing FE model of the spine. The passive material response was modeled with nonlinear-elastic and viscoelastic properties derived from experimental tensile tests. The active forces were modeled with discrete Hill elements. In the first version of the model the passive solid element muscles were used together with separate active spring elements. In the second version the active elements were integrated in the solid mesh with coincident nodes. This combined element, called the Super-positioned Muscle Finite Element (SMFE), was evaluated for a single muscle model before it was incorporated in the more complex neck muscle model. The main limitation of the SMFE was that the serial connected Hill-type elements are unstable due to their individual force-length relationship. The instabilities in the SMFE were minimized by the addition of passive compressive stiffness from the solid element and by the decreased gradient of the force-length relation curve.  The solid element musculature stabilized the vertebral column and reduced the predicted ligament strains during simulated impacts. The solid element compressive stiffness added to the passive stiffness of the cervical model. This decreased the need for additional active forces to reproduce the kinematic response of volunteers during impact. The active response of the SMFE improved model biofidelity and reduced buckling of muscles in compression. The solid element model predicted forces, strains, and energies for individual muscles and showed that the muscle response is dependent on impact direction and severity. For each impact direction, the model identified a few muscles as main load carriers that corresponded to muscles generating high EMG signals in volunteers. The single largest contributing factor to neck injury prediction was the muscle active forces. Muscle activation reduced the risk of injury in ligaments in high-energy impacts. The most urgent improvements of the solid element muscle model concerns: the stability of the SMFE; the boundary conditions from surrounding tissues; and more detailed representations of the myotendinous junctions. The model should also be more extensively validated for the kinematical response and for the muscle load predictions. It was concluded that a solid muscle model with continuum mechanical material properties improves the kinematical response and injury prediction of a FE neck model compared to a spring muscle model. The solid muscle model can predict muscle loads and provide insight to how muscle dynamics affect spinal stability as well as muscle acute strain injuries. / QC 20100809

Pain from the musculoskeletal system is very common in the modern society. Chronic musculoskeletal pain syndromes causes not only individual suffering but also dysfunctions of movements and postural control, as large costs for the society. In spite of significant efforts, there is a shortage of knowledge on effective prevention, diagnoses and rehabilitation of different chronic musculoskeletal pain syndromes. The general aims of this thesis was to investigate the predictive value of physical, sociodemographic, and psychosocial-behavioural variables for pain reduction after multimodal rehabilitation in patients with chronic low back or neck pain, and to develop and evaluate tests for objective and quantitative evaluation of characteristic sensorimotor disturbances in chronic neck pain. Logistic regression models revealed that unchanged pain intensity could be predicted with good precision while reduced pain intensity after rehabilitation was poorly predicted by the baseline variables. Altered pain intensity in chronic low back pain was predicted by high pain intensity, low levels of pain severity and high affective distress, while reduced pain intensity for patients with chronic neck pain were predicted by high endurance, low age, high pain intensity, low need of being social along with optimistic attitudes on how the pain will interfere with daily life, and few vegetative symptoms. One of the conclusions was that objective measures of specific sensorimotor disturbances should improve the precision by which treatment-induced effects can be assessed and predicted. A study was designed to objectively and quantitatively evaluate a large numbers of different sensorimotor characteristics in a small group of patients with chronic neck pain of different aetiology (whiplash-related and insidious). Kinematic data was recorded during different motor tasks, involving cervical rotations, arm movements and standing. In comparison to a group of asymptomatic control subjects, patients with chronic neck pain was characterised by slower movements, poor balance, reduced cervical stability during perturbations, altered smoothness of movement (jerk index), and reduced movement precision (variable error and variability in range of motion). The sensorimotor variables velocity of arm movements and cervical stability, could correctly classified nearly 90% of the subjects as having chronic neck pain or being asymptomatic. There was a large diversity of sensorimotor disturbances among the individual patients. This was confirmed in a regression model that failed to separate the groups insidious neck pain (sensitivity 44%) and WAD (sensitivity 67%). By investigating associations between the different sensorimotor variables, close relations was found between the repositioning acuity and variability in range of motion, and between standing balance and cervical stability/ standing balance during perturbation. These two groups of variables were only weakly related to each other and to smoothness of movement and movement velocity. The results indicate that chronic neck pain is characterised by specific sensorimotor deficits, and that there are common pathophysiological mechanisms in chronic neck pain of different aetiology. However, the lack of associations between several sensorimotor disturbances indicates that different mechanisms are involved. The thesis indicates that objective sensorimotor tests should be used to improve the quality of functional assessments in chronic neck pain. Methods that objectively and quantitatively measure e.g. movement precision, balance and cervical stability are also needed in order to evaluate current treatment methods and to develop new rehabilitation programs for specific sensorimotor deficits.

Altered neuromuscular processing and motor output as both a risk and perpetuating factor for chronic neck pain is a relative new area of study. The cervical flexion relaxation response (FRR) is a reproducible and reliable marker of differences in neuromuscular function between neck pain patients and controls. Change in joint position sense (JPS) of upper limb joints has also been linked to chronic neck pain. Studies in this thesis sought to develop an experimental model in humans to investigate whether the FRR and JPS can be altered by fatigue and/or postural stress. Additionally a pilot study on the effect of three months of chiropractic treatment on the FRR was conducted. The studies revealed that muscular fatigue is a modulator of the FRR and may play a large role in spine stabilization. Minor postural alterations in the neck can impact joint position error at the elbow and 12 weeks of chiropractic care is a useful therapy to improve chronic and recurrent neck pain as well as improving the cervical FRR. / UOIT

Measuring HPV exposure relies on detection of HPV type-specific antibodies, but methods are not standardized. Additionally, there is little information on the best sample type for HPV antibody detection. This study validated pseudovirion neutralization (PVN) assay for HPV antibody detection and compared it to IgG ELISA. Both assays were applied to paired serum and cervical mucus samples. Additionally, PVN assay was utilized to evaluate the feasibility of oral mucosal transudate (OMT) samples to monitor the HPV immune response. Serum was more likely to be positive on PVN assay than on IgG ELISA (p= 0.025). Both assays correlated with HPV-16 DNA status. HPV-18 PVN assay results correlated with HPV-18 DNA status. Few cervical mucus samples had detectable antibodies; no correlation with HPV DNA status was seen. OMT results were unsatisfactory. PVN assay was more sensitive than IgG ELISA; serum was a more reliable indicator of HPV-16/18 antibody status than cervical mucus.

Background: In Canada, the prevalence of cervical cancer in Aboriginal women continues to increase with a significantly higher mortality rate than women of non-Aboriginal ancestry. Despite that invasive cervical cancer is highly preventable with regular cervical cancer screening, participation in screening remains lower among Aboriginal women. Since limited information exists on the way cervical cancer screening is perceived and experienced, the purpose of this study was to gain an understanding of Saskatchewan Aboriginal womens perceptions related to and experiences with cervical cancer screening.<p> Methodology: This qualitative exploratory study used an interpretive descriptive approach. Perceptions related to and experiences with cervical cancer screening were elicited through individual interviews with eleven Dakota First Nation women. Women were recruited through purposive sampling techniques. Initially direct quotes from individual transcripts were coded, and then organized with other participant quotes that reflected thematic similarities.<p> Findings: Shared insights reflected a main theme that described perceptions of, experiences with, and factors influencing cervical cancer screening participation among Saskatchewan Aboriginal women. This theme, transitioning from experiencing the negatives of cervical cancer screening participation to living healthier, consisted of the womens mind-set (attitudes and cultural beliefs), knowledge, encounters with the health care system, and sharing information across the generations, which included patterns of communication and a community oriented approach.<p> Discussion: Findings of this study suggest that improving knowledge about cervical cancer screening and cervical cancer may increase screening utilization. Emphasis on health promotion and prevention should be considered when designing education programs. Interventions designed to improve screening rates are more effective when community members are involved in each phase, ensuring cultural relevance. Improving knowledge about, experiences with, and stories shared regarding cervical cancer screening among Aboriginal women may increase screening rates.

Despite being the most preventable cancer, cervical cancer remains the third leading cause of cancer death worldwide. Over 85% of cervical cancer incidence and mortality occurs in low-resource countries where screening programs for early detection are either inadequate or unavailable. In the developed world, where screening programs are well organized, incidence and mortality rates are greatly reduced. Recent advances in optical imaging have the potential to enable cervical cancer screening at the point-of-care, even in the hands of less experienced providers. High performance optical imaging systems can be constructed at relatively low cost, and image analysis can be automated; thus, these technologies may provide a way to bridge the gap to cervical cancer screening for developing countries. This work focuses on the design, construction, and clinical testing of a novel multimodal optical imaging (combination of wide-field imaging and high-resolution) for early detection of cervical neoplasia. The Multimodal Digital Imager (MDI) acquires in vivo images of cervical tissue in fluorescence, narrow band reflectance, and orthogonal polarized reflectance modes using multiple illumination wavelengths. The High Resolution Microendoscope (HRME) was used to interrogate clinically suspicious areas with subcellular spatial resolution, revealing changes in nuclear to cytoplasmic area ratio. In vivo image data from the wide-field system was combined with image data from a high- resolution microendoscope (HRME) in order to test the effectiveness of the multimodal optical imaging in discriminating between cervical neoplasia and non-neoplastic. Multimodal optical imaging coupled with computer aided diagnostic achieved a sensitivity of 82% and specificity of 85% for discriminating cervical neoplastic from non-neoplastic This work has demonstrated that multimodal optical imaging; combination of wide-field and high-resolution optical imaging of the cervix can assist in the detection of cervical neoplasia and can be implemented effectively in a low-resource setting.