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.

No description available.

Impairments in both theory of mind (ToM; the ability to attribute mental states to oneself and others) and executive function (EF; a group of high-level cognitive functions which help guide and control goal-directed behaviour) have been demonstrated in individuals with autism spectrum disorders (ASDs). Both deficits have been proposed by different groups of researchers as being the single primary cognitive deficit of autism, which can subsume the other deficit as secondary or artefactual. However, few studies have examined the nature of the relationship between ToM and EF in ASDs or conducted a systematic investigation of their relative primacy. This research principally sought to establish the primacy and independence of impairments in ToM and EF in ASDs and thereby evaluate the validity of single versus multiple primary deficit models of autism. These aims were addressed in two studies, both broad in scope. The first study was an investigation of the profile, primacy, and independence of ToM and EF impairments in individuals with ASDs. The sample included 46 participants with ASDs and 48 control participants matched on age and non-verbal ability. The profile of impairments was examined by measuring ToM and a range of EF components using tasks employing, wherever possible, process-pure indices of performance. Primacy was measured by focussing on i) whether or not the deficits observed were universal among individuals with ASDs; ii) whether the deficits were able to discriminate individuals with ASDs from matched controls (i.e., predict group membership); and iii) the ability of ToM and EF deficits to explain the full range of autistic symptomatology, as measured by correlating cognitive performances with behavioural indices. The relationship between ToM and EF impairments was investigated by conducting correlations between ToM and EF variables as well as analysing the incidence of dissociations between impairments in the two domains. The ASD group was found to demonstrate significant impairments in ToM and several components of EF including planning, verbal inhibition, working memory (in a context where inhibitory control was required), and both verbal and non-verbal generativity. However, neither ToM nor EF impairments were able to meet all of the criteria for a primary deficit in ASDs. EF deficits were found to be more primary, but could not account for ToM as a secondary deficit, as ToM and EF were found to be independent (i.e., uncorrelated and dissociable) deficits in the ASD group. This pattern of results suggested that a multiple deficits model involving at least two independent impairments appeared to best characterise ASDs, but the data were compatible with several variants of such a model (e.g., involving distinct subtypes versus a multidimensional spectrum). The second study was an investigation of ToM and EF impairments in siblings of individuals with ASDs, who have previously been found to demonstrate a subclinical “broad autism phenotype”. The main aims of this study were i) to identify whether ToM or EF deficits could meet criteria for an “endophenotype” or vulnerability marker for the autism genotype in unaffected relatives, which would have further implications about the primacy of ToM and EF in ASDs; and ii) to further investigate the validity of various multiple deficits models of ASDs by examining the pattern of ToM and EF performance in those showing the broad phenotype. Participants were 108 siblings of individuals with ASDs and 67 siblings of controls, tested on the same ToM and EF tasks used in the first study. Confirming the superior primacy of EF deficits found in Study One, there was no significant difference in ToM performance between ASD and control siblings, but ASD siblings showed weaknesses on two measures of EF. Furthermore, there appeared to be different subgroups of siblings demonstrating different cognitive profiles, consistent with the heterogeneity evident in the first study. This research indicated that ASDs cannot be explained by a single primary cognitive deficit. These findings hold important theoretical and empirical implications and highlight further questions about which type of multiple deficits model might best explain ASDs.

[Truncated abstract] Increased incidence of hypertension, insulin resistance, obesity and dyslipidemia, collectively referred to as the metabolic syndrome, has been linked to low birth weight, an indicator of a poor fetal environment. This association reflects developmental programming, a process by which organ systems are affected during early development such that disease states are more likely to emerge in adult life. Fetal glucocorticoid overexposure is thought to be a key factor that mediates developmental programming. Accordingly, maternal treatment with the synthetic glucocorticoid dexamethasone retards fetal growth and leads to delayed puberty, hypertension, hyperinsulinemia, and hyperleptinemia, either with or without increased adiposity, in adult offspring. Importantly, the postnatal environment can either amplify or attenuate the long-term outcome of developmental programming. The focus of this thesis was whether adverse developmental programming outcomes can be attenuated by the postnatal environment and thus provide therapeutic potential. Specifically, the effects of a postnatal diet rich in omega-3 fatty acids on glucocorticoid-induced developmental programming outcomes was investigated. ... The adipocyte phenotype was examined in Study 6, with hyperleptinaemia evident in offspring at 6 and 12 months of age in dexamethasone-exposed animals on a standard omega-3 diet, but this effect was prevented by a high omega-3 diet. The pattern of plasma leptin was paralleled by changes in leptin mRNA in retroperitoneal fat. Similarly, plasma levels of the inflammatory markers IL-6 and IL-1β were upregulated by prenatal glucocorticoid exposure and these were attenuated by postnatal dietary omega-3 fatty acids. Overall, omega-3 ingestion reduced adiposity, as indicated by measures of body composition. In conclusion, the studies presented in this thesis demonstrate for the first time that many of the detrimental effects of excess glucocorticoid exposure in utero on the adult phenotype can be attenuated by a postnatal diet rich in omega-3 fatty acids. This beneficial effect of omega-3 fatty acids was associated with a reversal of some (e.g. adiposal leptin) but not all (e.g. renal GR) 'programmed' changes in gene expression. These findings raise the possibility that dietary supplementation with omega-3 fatty acids may provide a viable therapeutic option for preventing and/or reducing adverse programming outcomes in humans.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2002. / Härtill 5 uppsatser.

Diss. (sammanfattning) Uppsala : Univ., 2004. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol inst., 2002. / Härtill 6 uppsatser.