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This thesis develops a conceptual framework for a GIS-based integrated spatial environmental impact assessment for mining projects. In recent years, GIS has become wide spread and many specified programs and applications have been developed. While spatial overlay is the most popular GIS analysis in EIA, a range of additional functions is available, which have not been fully utilised, including. environmental modelling and web-enabled and mobile GIS. In current EIA theory, strategic and holistic assessment strategies have gained in importance. GIS can contribute towards such strategies through integrated spatial analysis and linked database management. Also, visualisation techniques in GIS can improve communication between all stakeholders and become an essential part of the EIA process. The open cut iron-ore mine at Savage River was chosen as an example to demonstrate the benefits of GIS in EIA. In the hypothetical GIS-based EIA process, illustrative examples are given for analysis of different environmental and socioeconomic impacts. Implications for the existing planning system in Tasmania are discussed.

Variants in RAC3, encoding a small GTPase RAC3 which is critical for the regulation of actin cytoskeleton and intracellular signal transduction, are associated with a rare neurodevelopmental disorder with structural brain anomalies and facial dysmorphism. We investigated a cohort of 10 unrelated participants presenting with global psychomotor delay, hypotonia, behavioural disturbances, stereotyped movements, dysmorphic features, seizures and musculoskeletal abnormalities. MRI of brain revealed a complex pattern of variable brain malformations, including callosal abnormalities, white matter thinning, grey matter heterotopia, polymicrogyria/dysgyria, brainstem anomalies and cerebellar dysplasia. These patients harboured eight distinct de novo RAC3 variants, including six novel variants (NM_005052.3): c.34G > C p.G12R, c.179G > A p.G60D, c.186_188delGGA p.E62del, c.187G > A p.D63N, c.191A > G p.Y64C and c.348G > C p.K116N. We then examined the pathophysiological significance of these novel and previously reported pathogenic variants p.P29L, p.P34R, p.A59G, p.Q61L and p.E62K. In vitro analyses revealed that all tested RAC3 variants were biochemically and biologically active to variable extent, and exhibited a spectrum of different affinities to downstream effectors including p21-activated kinase 1. We then focused on the four variants p.Q61L, p.E62del, p.D63N and p.Y64C in the Switch II region, which is essential for the biochemical activity of small GTPases and also a variation hot spot common to other Rho family genes, RAC1 and CDC42. Acute expression of the four variants in embryonic mouse brain using in utero electroporation caused defects in cortical neuron morphology and migration ending up with cluster formation during corticogenesis. Notably, defective migration by p.E62del, p.D63N and p.Y64C were rescued by a dominant negative version of p21-activated kinase 1. Our results indicate that RAC3 variants result in morphological and functional defects in cortical neurons during brain development through variant-specific mechanisms, eventually leading to heterogeneous neurodevelopmental phenotypes. Scala et al. identify six de novo variants in RAC3, which encodes a small GTPase, in 10 unrelated subjects with neurodevelopmental phenotypes. In vivo and in vitro analyses in mice reveal that RAC3 variants cause morpho-functional defects in cortical neurons through variant-specific mechanisms, disrupting corticogenesis.

Gerade weil das Mammakarzinom beim Mann eine so seltene Erkrankung ist, besteht gelegentlich Unsicherheit bzgl. der Art und Agressivität der Abklärung beim Tastbefund in der männlichen Brust. Generell sollte jeder solide Herdbefund einer bildgebenden Diagnostik zugeführt werden mit einer geringen Schwelle zur weiteren zytologischen oder histologischen Abklärung. Eine sorgfältige Anamneseerhebung ist entscheidend für die Eruierung eines potentiellen metastatischen Befalls, was wiederum anstelle eines operativ-kurativen Therapieansatz lediglich eine Palliation zur Folge hätte.

Background Alopecia areata (AA) is a common hair loss disorder with a complex mode of inheritance. Autoimmune mechanisms are presumed to be crucial aetiologically. It is plausible that a number of autoimmune disorders may share a common genetic background. This phenomenon has been demonstrated in previous studies, which have shown an overlap of susceptibility alleles between AA and other autoimmune disorders. Recent studies have shown that genetic variants on the TRAF1/C5 (tumor necrosis factor receptor-associated factor 1, complement component 5) locus confer susceptibility to rheumatoid arthritis (RA). Objectives To examine the role of the TRAF1/C5 locus in the development of AA using a large sample of 1195 patients with AA and 1280 controls. Methods We genotyped the two most significant single nucleotide polymorphisms (SNPs) (rs10818488, rs2416808) from a former RA candidate gene study. After having obtained evidence for association, we performed a fine-mapping study and genotyped the locus with an additional 27 SNPs. Results While no significant result was obtained for the overall sample, rs2416808 showed significant associations in the analysis of the subgroups with severe AA and with a positive family history. The most significant P-value for rs2416808 was in familial cases (P = 0·004, Pcorr = 0·026). The fine mapping revealed significant associations for four additional SNPs in the analysis of subgroups, with rs2416808 remaining the most significant marker. Conclusions Our results point to the involvement of the TRAF1/C5 locus in the aetiology of familial and severe AA, and provide further support for a shared aetiology between AA and other autoimmune disorders.