Knee osteoarthritis (OA) is the commonest form of lower limb OA with a lifetime risk of over 40%. It is a disease characterised by symptoms such as pain and loss of function. In addition there are typical structural features on both radiographs and MRI. Knee OA represents a spectrum of disease, ranging from early preclinical cartilage change to established full thickness disease. Anteromedial knee OA is a particular phenotype of knee OA where disease is confined to the medial compartment. Whilst end stage arthritis is treated reliably with joint arthroplasty, those with early stage disease are treated with a variety of non- surgical interventions with varying success. This thesis is concerned with understanding the disease of patients that have early radiographic changes but symptoms not controlled by conservative measures. Up to 150 of these patients a year present to the Nuffield Orthopaedic Centre, Oxford. They have been described as being in the “Treatment Gap”. A series of validation studies were performed to determine the optimal method for diagnosing cartilage defects within the knee. The three commonest diagnostic methods were examined for their validity. Arthroscopic assessments of cartilage lesions demonstrated a moderate level of intra and inter observer reliability. In contrast, radiographs and MRI demonstrated high levels of reliability. When using MRI as a criterion standard, both radiographs and arthroscopic assessment were found to have poor accuracy. Based on the work in this thesis a formal definition of the cartilage changes exhibited in early knee OA was proposed. A cross sectional cohort of 100 patients with the symptoms and radiological features of early knee OA were identified. Their pain and function profile was compared to two comparison groups of patients at the end stage of knee OA (defined by the need for partial or total arthroplasty). In up to 78% of individual cases those with early OA had pain and function profiles as bad as those with end stage disease. The cross sectional symptoms of early knee OA demonstrate a marked discordance with their mild radiographic changes. The same cohort was extended to 125 patients. They were followed over one year with monthly PROM assessments to determine how symptoms change over time. 43% of patients experience a clinical improvement over 12 months, 31% experience a clinical deterioration and 26% remain unchanged. The range in OKS variation over 12 months was on average 12 points, with clinically relevant variation occurring on 45% of monthly measurements. Patients with early knee OA can expect to experience considerable variation in their symptoms over 12 months and this must be considered when planning interventions. A number of patients with early knee OA were noticed to demonstrate medial meniscal extrusion. Using data from the Osteo Arthritis Initiative (OAI) a nested case control study was designed to determine how the presence of meniscal extrusion in an otherwise normal knee affects the risk of developing knee OA over the next 48 months. This demonstrated an Odds Ratio of 3.5, suggesting that meniscal extrusion is a considerable risk factor for the development of OA. The presence of a knee injury or operative intervention to the index meniscus was shown to increase this risk. Many phenotypes of OA are known to demonstrate familial aggregation. In an attempt to determine where the earliest structural changes occur in medial compartment knee OA, a cohort of patients selected only for their family history of the disease were developed. This cohort was compared to spouse controls for the presence of knee OA, as well as meniscal extrusion and long leg alignment. In addition, a functional analysis of their cartilage was performed. This cohort was not shown to be at increased risk of disease compared to controls. Discussion of the possible reasons for this finding is presented. Early knee osteoarthritis is a considerable clinical problem. This thesis has aided the understanding of the condition by firstly defining the radiological description of these patients. Secondly, their cross sectional and longitudinal symptom profile have been described for the first time. In addition, the presence of an extruded meniscus has been demonstrated as a substantial risk factor for the disease. Finally, family history has not been demonstrated as a risk factor for the disease within the limits of the study described here. Future work has been proposed.

Doctor of Philosophy(PhD) / BCC is the commonest cancer in European-derived populations and Australia has the highest recorded incidence in the world, creating enormous individual and societal cost in management of this disease. The incidence of this cancer has been increasing internationally, with evidence of a 1 to 2% rise in incidence in Australia per year over the last two decades. The main four epidemiological risk factors for the development of BCC are ultraviolet radiation (UVR) exposure, increasing age, male sex, and inability to tan. The pattern and timing of UVR exposure is important to BCC risk, with childhood and intermittent UVR exposure both associated with an increased risk. The complex of inherited characteristics making up an individual’s ‘sun sensitivity’ is also important in determining BCC risk. Very little is known about population genetic susceptibility to BCC outside of the rare genodermatosis Gorlin syndrome. Mutations in the tumour suppressor gene patched (PTCH) are responsible for this BCC predisposition syndrome and the molecular pathway and target genes of this highly conserved pathway are well described. Derangments in this pathway occur in sporadic BCC development, and the PTCH gene is an obvious candidate to contribute to non-syndromic susceptibility to BCC. The melanocortin 1 receptor (MC1R) locus is known to be involved in pigmentary traits and the cutaneous response to UVR, and variants have been associated with skin cancer risk. Many other genes have been considered with respect to population BCC risk and include p53, HPV, GSTs, and HLAs. There is preliminary evidence for specific familial aggregation of BCC, but very little known about the causes. 56 individuals who developed BCC under the age of 40 in the year 2000 were recruited from the Skin and Cancer Foundation of Australia’s database. This represents the youngest 7 – 8% of Australians with BCC from a database that captures approximately 10% of Sydney’s BCCs. 212 of their first degree relatives were also recruited, including 89 parents and 123 siblings of these 56 probands. All subjects were interviewed with respect to their cancer history and all reports of cancer verified with histopathological reports where possible. The oldest unaffected sibling for each proband (where available) was designated as an intra-family control. All cases and control siblings filled out a questionnaire regarding their pigmentary and sun sensitivity factors and underwent a skin examination by a trained examiner. Peripheral blood was collected from these cases and controls for genotyping of PTCH. All the exons of PTCH for which mutations have been documented in Gorlin patients were amplified using PCR. PCR products were screened for mutations using dHPLC, and all detectable variants sequenced. Prevalence of BCC and SCC for the Australian population was estimated from incidence data using a novel statistical approach. Familial aggregation of BCC, SCC and MM occurred within the 56 families studied here. The majority of families with aggregation of skin cancer had a combination of SCC and BCC, however nearly one fifth of families in this study had aggregation of BCC to the exclusion of SCC or MM, suggesting that BCCspecific risk factors are also likely to be at work. Skin cancer risks for first-degree relatives of people with early onset BCC were calculated: sisters and mothers of people with early-onset BCC had a 2-fold increased risk of BCC; brothers had a 5-fold increased risk of BCC; and sisters and fathers of people with early-onset BCC had over four times the prevalence of SCC than that expected. For melanoma, the increased risk was significant for male relatives only, with a 10-fold increased risk for brothers of people with early-onset BCC and 3-fold for fathers. On skin examination of cases and controls, several phenotypic factors were significantly associated with BCC risk. These included increasing risk of BCC with having fair, easyburning skin (ie decreasing skin phototype), and with having signs of cumulative sun damage to the skin in the form of actinic keratoses. Signs reflecting the combination of pigmentary characteristics and sun exposure - in the form of arm freckling and solar lentigines - also gave subjects a significantly increased risk BCC. Constitutive red-green reflectance of the skin was associated with decreased risk of BCC, as measured by spectrophotometery. Other non-significant trends were seen that may become significant in larger studies including associations of BCC with propensity to burn, moderate tanning ability and an inability to tan. No convincing trend for risk of BCC was seen with the pigmentary variables of hair or eye colour, and a non-significant reduced risk of BCC was associated with increasing numbers of seborrhoeic keratoses. Twenty PTCH exons (exons 2, 3, 5 to 18, and 20 to 23) were screened, accounting for 97% of the coding regions with published mutations in PTCH. Nine of these 20 exons were found to harbour single nucleotide polymorphisms (SNPs), seen on dHPLC as variant melting curves and confirmed on direct sequencing. SNPs frequencies were not significantly different to published population frequencies, or to Australian general population frequencies where SNP database population data was unavailable. Assuming a Poisson distribution, and having observed no mutations in a sample of 56, we can be 97.5% confident that if there are any PTCH mutations contributing to early-onset BCC in the Australian population, then their prevalence is less than 5.1%. Overall, this study provides evidence that familial aggregation of BCC is occurring, that first-degree relatives are at increased risk of all three types of skin cancer, and that a combination of environmental and genetic risk factors are likely to be responsible. The PTCH gene is excluded as a major cause of this increased susceptibility to BCC in particular and skin cancer in general. The weaknesses of the study design are explored, the possible clinical relevance of the data is examined, and future directions for research into the genetics of basal cell carcinoma are discussed.

<p>Wegener´s granulomatosis (WG) is an unusual, serious, systemic vasculitis with specific clinical findings. The studies in this thesis aim at broadening our understanding of the aetiology and outcome of WG.</p><p>Patients with WG were identified in the In-patient Register 1975-2001. During this time the incidence increased three-fold, and neither ANCA-related increased awareness, nor diagnostic drift, seem to fully explain this trend, but it is still unclear if a true rise in incidence exists. </p><p>Anti- neutrophil cytoplasmic antibodies (ANCA) have been presented as highly specific for vasculitis. In a series of consecutive cANCA/PR3-ANCA positive patients, we investigated the positive predictive value for ANCA, and the outcome of patients with a positive cANCA/PR3-ANCA but not vasculitis. These patients have a low future risk of developing vasculitis, possibly indicating that ANCA, in this setting, reflects neutrophil activating properties not specific to vasculitis.</p><p>By linkage of the WG-cohort, and randomly selected population controls, to the Multi-generation register, we identified all first-degree relatives and spouses of patients and controls, totally encompassing some 2,000 patients and 70,000 relatives. Familial aggregation of WG was the exception, with absolute risks of < 1 per 1000.However, relative risks in first-grade relatives amounted to 1.56 (95% CI 0.35-6.90) such that a moderate familial aggregation cannot be excluded.</p><p>In the WG-cohort, cancer occurrence and risk was compared to that of the general population. Patients with WG have an overall doubled risk of cancer, with particularly increased risks of bladder-cancer, haematopoietic cancers including lymphomas and squamous skin-cancer. In a case-control study nested within the WG-cohort, treatment with cyclophosphamide was compared among bladder-cancer patients and matched cancer-free controls. Absolute risk of bladder cancer as high as 10% some years after diagnosis were found, and this risk can partly be attributed to cyclophosphamide-treatment, with a dose-response relationship.</p>

Wegener´s granulomatosis (WG) is an unusual, serious, systemic vasculitis with specific clinical findings. The studies in this thesis aim at broadening our understanding of the aetiology and outcome of WG. Patients with WG were identified in the In-patient Register 1975-2001. During this time the incidence increased three-fold, and neither ANCA-related increased awareness, nor diagnostic drift, seem to fully explain this trend, but it is still unclear if a true rise in incidence exists. Anti- neutrophil cytoplasmic antibodies (ANCA) have been presented as highly specific for vasculitis. In a series of consecutive cANCA/PR3-ANCA positive patients, we investigated the positive predictive value for ANCA, and the outcome of patients with a positive cANCA/PR3-ANCA but not vasculitis. These patients have a low future risk of developing vasculitis, possibly indicating that ANCA, in this setting, reflects neutrophil activating properties not specific to vasculitis. By linkage of the WG-cohort, and randomly selected population controls, to the Multi-generation register, we identified all first-degree relatives and spouses of patients and controls, totally encompassing some 2,000 patients and 70,000 relatives. Familial aggregation of WG was the exception, with absolute risks of &lt; 1 per 1000.However, relative risks in first-grade relatives amounted to 1.56 (95% CI 0.35-6.90) such that a moderate familial aggregation cannot be excluded. In the WG-cohort, cancer occurrence and risk was compared to that of the general population. Patients with WG have an overall doubled risk of cancer, with particularly increased risks of bladder-cancer, haematopoietic cancers including lymphomas and squamous skin-cancer. In a case-control study nested within the WG-cohort, treatment with cyclophosphamide was compared among bladder-cancer patients and matched cancer-free controls. Absolute risk of bladder cancer as high as 10% some years after diagnosis were found, and this risk can partly be attributed to cyclophosphamide-treatment, with a dose-response relationship.

Familial aggregation of prostate cancer has been demonstrated in studies conducted in a number of countries prior to the widespread adoption of prostate-specific antigen (PSA) testing for prostate cancer detection. PSA testing leads to over-diagnosis of asymptomatic disease that may not have become clinically significant within a man’s normal lifetime. This increase in the number of asymptomatic men diagnosed might alter the magnitude of familial risk estimates and the importance of a prostate cancer family history. (For complete abstract open document)

Doctor of Philosophy(PhD) / BCC is the commonest cancer in European-derived populations and Australia has the highest recorded incidence in the world, creating enormous individual and societal cost in management of this disease. The incidence of this cancer has been increasing internationally, with evidence of a 1 to 2% rise in incidence in Australia per year over the last two decades. The main four epidemiological risk factors for the development of BCC are ultraviolet radiation (UVR) exposure, increasing age, male sex, and inability to tan. The pattern and timing of UVR exposure is important to BCC risk, with childhood and intermittent UVR exposure both associated with an increased risk. The complex of inherited characteristics making up an individual’s ‘sun sensitivity’ is also important in determining BCC risk. Very little is known about population genetic susceptibility to BCC outside of the rare genodermatosis Gorlin syndrome. Mutations in the tumour suppressor gene patched (PTCH) are responsible for this BCC predisposition syndrome and the molecular pathway and target genes of this highly conserved pathway are well described. Derangments in this pathway occur in sporadic BCC development, and the PTCH gene is an obvious candidate to contribute to non-syndromic susceptibility to BCC. The melanocortin 1 receptor (MC1R) locus is known to be involved in pigmentary traits and the cutaneous response to UVR, and variants have been associated with skin cancer risk. Many other genes have been considered with respect to population BCC risk and include p53, HPV, GSTs, and HLAs. There is preliminary evidence for specific familial aggregation of BCC, but very little known about the causes. 56 individuals who developed BCC under the age of 40 in the year 2000 were recruited from the Skin and Cancer Foundation of Australia’s database. This represents the youngest 7 – 8% of Australians with BCC from a database that captures approximately 10% of Sydney’s BCCs. 212 of their first degree relatives were also recruited, including 89 parents and 123 siblings of these 56 probands. All subjects were interviewed with respect to their cancer history and all reports of cancer verified with histopathological reports where possible. The oldest unaffected sibling for each proband (where available) was designated as an intra-family control. All cases and control siblings filled out a questionnaire regarding their pigmentary and sun sensitivity factors and underwent a skin examination by a trained examiner. Peripheral blood was collected from these cases and controls for genotyping of PTCH. All the exons of PTCH for which mutations have been documented in Gorlin patients were amplified using PCR. PCR products were screened for mutations using dHPLC, and all detectable variants sequenced. Prevalence of BCC and SCC for the Australian population was estimated from incidence data using a novel statistical approach. Familial aggregation of BCC, SCC and MM occurred within the 56 families studied here. The majority of families with aggregation of skin cancer had a combination of SCC and BCC, however nearly one fifth of families in this study had aggregation of BCC to the exclusion of SCC or MM, suggesting that BCCspecific risk factors are also likely to be at work. Skin cancer risks for first-degree relatives of people with early onset BCC were calculated: sisters and mothers of people with early-onset BCC had a 2-fold increased risk of BCC; brothers had a 5-fold increased risk of BCC; and sisters and fathers of people with early-onset BCC had over four times the prevalence of SCC than that expected. For melanoma, the increased risk was significant for male relatives only, with a 10-fold increased risk for brothers of people with early-onset BCC and 3-fold for fathers. On skin examination of cases and controls, several phenotypic factors were significantly associated with BCC risk. These included increasing risk of BCC with having fair, easyburning skin (ie decreasing skin phototype), and with having signs of cumulative sun damage to the skin in the form of actinic keratoses. Signs reflecting the combination of pigmentary characteristics and sun exposure - in the form of arm freckling and solar lentigines - also gave subjects a significantly increased risk BCC. Constitutive red-green reflectance of the skin was associated with decreased risk of BCC, as measured by spectrophotometery. Other non-significant trends were seen that may become significant in larger studies including associations of BCC with propensity to burn, moderate tanning ability and an inability to tan. No convincing trend for risk of BCC was seen with the pigmentary variables of hair or eye colour, and a non-significant reduced risk of BCC was associated with increasing numbers of seborrhoeic keratoses. Twenty PTCH exons (exons 2, 3, 5 to 18, and 20 to 23) were screened, accounting for 97% of the coding regions with published mutations in PTCH. Nine of these 20 exons were found to harbour single nucleotide polymorphisms (SNPs), seen on dHPLC as variant melting curves and confirmed on direct sequencing. SNPs frequencies were not significantly different to published population frequencies, or to Australian general population frequencies where SNP database population data was unavailable. Assuming a Poisson distribution, and having observed no mutations in a sample of 56, we can be 97.5% confident that if there are any PTCH mutations contributing to early-onset BCC in the Australian population, then their prevalence is less than 5.1%. Overall, this study provides evidence that familial aggregation of BCC is occurring, that first-degree relatives are at increased risk of all three types of skin cancer, and that a combination of environmental and genetic risk factors are likely to be responsible. The PTCH gene is excluded as a major cause of this increased susceptibility to BCC in particular and skin cancer in general. The weaknesses of the study design are explored, the possible clinical relevance of the data is examined, and future directions for research into the genetics of basal cell carcinoma are discussed.

The familial aggregation of Major Depressive Disorder (MDD) has been repeatedly demonstrated. Several studies have investigated associations between various clinical characteristics of MDD in probands and overall rates of MDD in relatives. Few studies, however, have considered the familial aggregation of clinical characteristics of MDD. The aim of the present report is to examine mother–offspring associations of a variety of clinical characteristics of MDD in a general population sample. Data were derived from baseline and 4-year-follow-up data of 933 adolescents and their biological mothers of the Early Developmental Stages of Psychopathology (EDSP) study, a prospective-longitudinal community study. MDD and its characteristics were assessed with the Munich-Composite International Diagnostic Interview. We found that children of mothers who had a lifetime history of severe MDD and high number of symptoms, high impairment and/or melancholia, revealed elevated odds of MDD regarding the same characteristics as their mothers (ORs between 5.2 and 13.9). The observed associations did not differ by the children’s sex. DSM-IV melancholia and severity as well as impairment were found to aggregate within families. This finding can be interpreted as a validation of the DSM-IV MDD severity subtypes as well as of the melancholic specifier. Severe and melancholic MDD reveal a considerable high degree of familiar aggregation making the search for mechanisms involved in the familiar transmission of these forms of MDD particularly promising.

It has been proved from several studies that the genetic influence has been the most significant factor for having preeclampsia (PE). Still there are many uncertainties about origin and magnitude of the genetic effects as no specific inheritance patterns have been established. In this study, heritage risk of PE is in both the woman’s family and her partner’s family to her risk of PE is examined, along women and men own history with same and different partners. Moreover it is also examined whether timing of onset of PE is also has any impact on familial clustering of PE. Here, we used the population based Danish birth and multi generation registers to identify a cohort of women who have given birth during 1978 to 2008; which consisted of 1,79,69,28 singleton deliveries. This information is linked with pedigree information from the Danish Family Relation Database to define both maternal and paternal relationships. Risk ratios were estimated comparing women with and without various PE histories. It is found that the recurrence risk of a woman suffering from PE is 12.4 with 95% confidence limits (11.9, 12.8). Woman's recurrence risk diminishes only slightly when she changes partner means that particularly maternal genetic factors play the largest role, compared to male partner whose recurrence risk almost diminishes if he changes his female partner. Women and men from families with PE contribute to risk of PE in pregnancies they are involved in. The woman’s family history is still more important compared to man family history of PE; except for increased rick in pregnancies fathered by men who were born to preeclamptic mothers.  The recurrence risk of a women suffering from PE, if she already has suffered from this condition before 34 weeks is found to be very high (RR=25.4 with 95% confidence limits (21.8, 29.1)) with same male partner. It is found that early-onset PE and later-onset varieties have a clear genetic component but the intensity of early onset is stronger than late onset varieties. There are both maternal and paternal genetic contributions to early-onset PE, with the maternal ones seeming to be stronger.

The familial aggregation of Major Depressive Disorder (MDD) has been repeatedly demonstrated. Several studies have investigated associations between various clinical characteristics of MDD in probands and overall rates of MDD in relatives. Few studies, however, have considered the familial aggregation of clinical characteristics of MDD. The aim of the present report is to examine mother–offspring associations of a variety of clinical characteristics of MDD in a general population sample. Data were derived from baseline and 4-year-follow-up data of 933 adolescents and their biological mothers of the Early Developmental Stages of Psychopathology (EDSP) study, a prospective-longitudinal community study. MDD and its characteristics were assessed with the Munich-Composite International Diagnostic Interview. We found that children of mothers who had a lifetime history of severe MDD and high number of symptoms, high impairment and/or melancholia, revealed elevated odds of MDD regarding the same characteristics as their mothers (ORs between 5.2 and 13.9). The observed associations did not differ by the children’s sex. DSM-IV melancholia and severity as well as impairment were found to aggregate within families. This finding can be interpreted as a validation of the DSM-IV MDD severity subtypes as well as of the melancholic specifier. Severe and melancholic MDD reveal a considerable high degree of familiar aggregation making the search for mechanisms involved in the familiar transmission of these forms of MDD particularly promising.