This Other Eden: Exploring a Sense of Place in Twentieth-Century Reconstructions of Australian Childhoods

This thesis explores the sense of place formed during childhood, as remembered by adult Australians who reconstruct their youth through various forms of life writing. While Australian writers do utilize traditional tropes of Western autobiography, such as the mythology of Eden and the Wordsworthian image of the child communing with Nature, these themes are frequently transformed to meet a uniquely Australian context. Isolation and distance from Europe, and the apparent indifference of our landscape towards white settlement, have received much critical attention in Australian studies generally and, indeed, broadly influence the formation of children’s sense of place across the continent. However, writers are also concerned with the role of place on a more local level. Through a comparison of writing from Western Australia, Queensland and Victoria, this thesis explores regional landscape preoccupations that create an awareness of local identity, variously contributing to or frustrating the child’s sense of belonging. Western Australian writing is dominated by images of isolation, the fragility of white settlement in a dry land lacking fresh water, and a pervasive beach culture. A strong sense of the littoral pervades writing from this region. Queensland’s frontier mythology is of a different flavour: warm and tropical, nature here is exuberant, constantly threatening to overwhelm culture, already perceived as transient due to the flimsy aspect of the “Queenslander” house. Writing from Victoria, to some extent, tends to more closely follow English models, juxtaposing country and city environments, although there is a distinctly local flavour to many representations of urban Melbourne and its flat, grid-like organization. As Australian society becomes more concentrated on the coastal fringe, the beach is an increasingly significant environment. Though more prominent in writing from some regions than others, coastal imagery broadly reflects the modern Australian’s sense of inhabiting a liminal zone with negotiable boundaries

Biological activity differences between TGF-β1 and TGF-β3 correlate with differences in the rigidity and arrangement of their component monomers

[Image: see text] TGF-β1, -β2, and -β3 are small, secreted signaling proteins. They share 71–80% sequence identity and signal through the same receptors, yet the isoform-specific null mice have distinctive phenotypes and are inviable. The replacement of the coding sequence of TGF-β1 with TGF-β3 and TGF-β3 with TGF-β1 led to only partial rescue of the mutant phenotypes, suggesting that intrinsic differences between them contribute to the requirement of each in vivo. Here, we investigated whether the previously reported differences in the flexibility of the interfacial helix and arrangement of monomers was responsible for the differences in activity by generating two chimeric proteins in which residues 54–75 in the homodimer interface were swapped. Structural analysis of these using NMR and functional analysis using a dermal fibroblast migration assay showed that swapping the interfacial region swapped both the conformational preferences and activity. Conformational and activity differences were also observed between TGF-β3 and a variant with four helix-stabilizing residues from TGF-β1, suggesting that the observed changes were due to increased helical stability and the altered conformation, as proposed. Surface plasmon resonance analysis showed that TGF-β1, TGF-β3, and variants bound the type II signaling receptor, TβRII, nearly identically, but had small differences in the dissociation rate constant for recruitment of the type I signaling receptor, TβRI. However, the latter did not correlate with conformational preference or activity. Hence, the difference in activity arises from differences in their conformations, not their manner of receptor binding, suggesting that a matrix protein that differentially binds them might determine their distinct activities

Severe aortic and arterial aneurysms associated with a TGFBR2 mutation.

BACKGROUND: A 24-year-old man presented with previously diagnosed Marfan\u27s syndrome. Since the age of 9 years, he had undergone eight cardiovascular procedures to treat rapidly progressive aneurysms, dissection and tortuous vascular disease involving the aortic root and arch, the thoracoabdominal aorta, and brachiocephalic, vertebral, internal thoracic and superior mesenteric arteries. Throughout this extensive series of cardiovascular surgical repairs, he recovered without stroke, paraplegia or renal impairment. INVESTIGATIONS: CT scans, arteriogram, genetic mutation screening of transforming growth factor beta receptors 1 and 2. DIAGNOSIS: Diffuse and rapidly progressing vascular disease in a patient who met the diagnostic criteria for Marfan\u27s syndrome, but was later rediagnosed with Loeys-Dietz syndrome. Genetic testing also revealed a de novo mutation in transforming growth factor beta receptor 2. MANAGEMENT: Regular cardiovascular surveillance for aneurysms and dissections, and aggressive surgical treatment of vascular disease

Aneurysmal disease is associated with lower carotid intima-media thickness than occlusive arterial disease

Objective: Patients with aneurysmal and occlusive arterial disease have overlapping cardiovascular risk profiles. The question remains how atherosclerosis is related to the formation of aortic aneurysms. Common carotid artery intima-media thickness (CIMT) is an easily accessible and objective marker of early atherosclerosis. The aim of the current study was to investigate whether there is a difference in atherosclerotic burden as measured by CIMT between patients with aneurysmal and those with occlusive arterial disease. Methods: From 2004 to 2011, the CIMT was measured using B-mode ultrasound scanning in patients undergoing vascular surgery for aortic aneurysmal or occlusive arterial disease at the Erasmus University Medical Center. Cardiovascular risk factors, comorbidities, and medication were recorded. Patients treated for combined aneurysmal and occlusive arterial disease and patients diagnosed with a genetic aneurysm syndrome were excluded. Univariable and multivariable analyses wer

Into the wild, out of the woods: A systematic case study on facilitating emotional change

Cognitive and behavioral treatment programs for individuals who commit sexual offences (ISOs) have shown significant but small effect sizes. A growing body of research points towards the importance of difficulties in affect regulation (AR) as a risk factor for sexual recidivism. On this basis, it seems important to target difficulties in AR in treatment. The current systematic case study investigates the potential contribution of Emotion-Focused Therapy (EFT) to changing problematic AR in ISOs. Kevin was a high-risk offender with a traumatic history who met the diagnostic criteria of pedophilic and borderline disorders, with serious AR difficulties. Self-report outcome measures, observation measures and a biomarker were used to track changes in AR, psychological symptoms and distress during baseline (phase A), treatment as usual (phase B), treatment with an EFT component added (phase C), and follow up (phase A). Statistically significant change was found in AR, psychological symptoms and distress during treatment phase (phase B+C), however it is not possible to attribute these changes causally to EFT. An examination of the qualitative process data provides deeper insights into how the client reacted to specific EFT-interventions. Verbatim clinical vignettes are included to clarify key interventions, hindrances and mechanisms of change. This study provides preliminary support for the role of therapy to facilitate emotional change in ISOs

A mutation update for the FLNC gene in myopathies and cardiomyopathies

Filamin C (FLNC) variants are associated with cardiac and muscular phenotypes. Originally, FLNC variants were described in myofibrillar myopathy (MFM) patients. Later, high-throughput screening in cardiomyopathy cohorts determined a prominent role for FLNC in isolated hypertrophic and dilated cardiomyopathies (HCM and DCM). FLNC variants are now among the more prevalent causes of genetic DCM. FLNC-associated DCM is associated with a malignant clinical course and a high risk of sudden cardiac death. The clinical spectrum of FLNC suggests different pathomechanisms related to variant types and their location in the gene. The appropriate functioning of FLNC is crucial for structural integrity and cell signaling of the sarcomere. The secondary protein structure of FLNC is critical to ensure this function. Truncating variants with subsequent haploinsufficiency are associated with DCM and cardiac arrhythmias. Interference with the dimerization and folding of the protein leads to aggregate formation detrimental for muscle function, as found in HCM and MFM. Variants associated with HCM are predominantly missense variants, which cluster in the ROD2 domain. This domain is important for binding to the sarcomere and to ensure appropriate cell signaling. We here review FLNC genotype–phenotype correlations based on available evidence

Assessing methods for dealing with treatment switching in randomised controlled trials: a simulation study

<p>Abstract</p> <p>Background</p> <p>We investigate methods used to analyse the results of clinical trials with survival outcomes in which some patients switch from their allocated treatment to another trial treatment. These included simple methods which are commonly used in medical literature and may be subject to selection bias if patients switching are not typical of the population as a whole. Methods which attempt to adjust the estimated treatment effect, either through adjustment to the hazard ratio or via accelerated failure time models, were also considered. A simulation study was conducted to assess the performance of each method in a number of different scenarios.</p> <p>Results</p> <p>16 different scenarios were identified which differed by the proportion of patients switching, underlying prognosis of switchers and the size of true treatment effect. 1000 datasets were simulated for each of these and all methods applied. Selection bias was observed in simple methods when the difference in survival between switchers and non-switchers were large. A number of methods, particularly the AFT method of Branson and Whitehead were found to give less biased estimates of the true treatment effect in these situations.</p> <p>Conclusions</p> <p>Simple methods are often not appropriate to deal with treatment switching. Alternative approaches such as the Branson & Whitehead method to adjust for switching should be considered.</p

LRP1 Functions as an Atheroprotective Integrator of TGFβ and PDGF Signals in the Vascular Wall: Implications for Marfan Syndrome

BACKGROUND: The multifunctional receptor LRP1 controls expression, activity and trafficking of the PDGF receptor-β in vascular smooth muscle cells (VSMC). LRP1 is also a receptor for TGFβ1 and is required for TGFβ mediated inhibition of cell proliferation. METHODS AND PRINCIPAL FINDINGS: We show that loss of LRP1 in VSMC (smLRP(−)) in vivo results in a Marfan-like syndrome with nuclear accumulation of phosphorylated Smad2/3, disruption of elastic layers, tortuous aorta, and increased expression of the TGFβ target genes thrombospondin-1 (TSP1) and PDGFRβ in the vascular wall. Treatment of smLRP1(−) animals with the PPARγ agonist rosiglitazone abolished nuclear pSmad accumulation, reversed the Marfan-like phenotype, and markedly reduced smooth muscle proliferation, fibrosis and atherosclerosis independent of plasma cholesterol levels. CONCLUSIONS AND SIGNIFICANCE: Our findings are consistent with an activation of TGFβ signals in the LRP1-deficient vascular wall. LRP1 may function as an integrator of proliferative and anti-proliferative signals that control physiological mechanisms common to the pathogenesis of Marfan syndrome and atherosclerosis, and this is essential for maintaining vascular wall integrity

Loss-of-function mutations in the X-linked biglycan gene cause a severe syndromic form of thoracic aortic aneurysms and dissections.

Thoracic aortic aneurysm and dissection (TAAD) is typically inherited in an autosomal dominant manner, but rare X-linked families have been described. So far, the only known X-linked gene is FLNA, which is associated with the periventricular nodular heterotopia type of Ehlers-Danlos syndrome. However, mutations in this gene explain only a small number of X-linked TAAD families. We performed targeted resequencing of 368 candidate genes in a cohort of 11 molecularly unexplained Marfan probands. Subsequently, Sanger sequencing of BGN in 360 male and 155 female molecularly unexplained TAAD probands was performed. We found five individuals with loss-of-function mutations in BGN encoding the small leucine-rich proteoglycan biglycan. The clinical phenotype is characterized by early-onset aortic aneurysm and dissection. Other recurrent findings include hypertelorism, pectus deformity, joint hypermobility, contractures, and mild skeletal dysplasia. Fluorescent staining revealed an increase in TGF-β signaling, evidenced by an increase in nuclear pSMAD2 in the aortic wall. Our results are in line with those of prior reports demonstrating that Bgn-deficient male BALB/cA mice die from aortic rupture. In conclusion, BGN gene defects in humans cause an X-linked syndromic form of severe TAAD that is associated with preservation of elastic fibers and increased TGF-β signaling.Genet Med 19 4, 386-395