Intergenerational transmission of post-traumatic stress disorder in Australian Vietnam veterans' families.

OBJECTIVE: To assess the association between parental post-traumatic stress disorder (PTSD) and offspring PTSD and its specificity for other disorders in a non-clinical epidemiological cohort of Australian Vietnam veterans, their partners and their sons and daughters. METHOD: Veterans were interviewed twice, in 1992-1994 and 2005-2006; partners were interviewed in 2006-2007, and their offspring in 2012-2014. A total of 125 sons and 168 daughters were interviewed from 197 families, 137 of which also included partners who were the mothers of the children. Statistical analysis used multi-level modelling to compute odds ratios and 95% confidence intervals while controlling for clustering effects within families. Parent PTSD diagnoses were examined for associations with offspring trauma exposure, PTSD and other psychiatric diagnoses. RESULTS: Veteran PTSD increased the risk of PTSD and no other disorder in both sons and daughters; partner PTSD did not. Veteran depression was also a risk factor for sons' PTSD, and alcohol disorder was linked to alcohol dependence in sons and PTSD in daughters, but not when controlling for veteran PTSD. CONCLUSION: We conclude that PTSD in a Vietnam veteran father increases the risk specifically for PTSD in his sons and daughters.

Medicine: in need of culture change.

Compared with other health professionals and the general population, doctors and medical students reported higher rates of psychological distress, burnout, diagnosed mental illness, suicidal ideation and attempted suicide. Where possible, the problematic and unnecessarily stressful aspects of working as a doctor must be improved. Collectively, we must change the often toxic culture of medicine into a culture that promotes a nurturing and supportive approach to teaching and supervision. The goal should be to develop medical practices that facilitate well-being and quality of life, where sustainable medical careers can develop and better serve the community.

Induction of murine adenosine A(2A) receptor expression by LPS: analysis of the 5' upstream promoter.

Non-activated macrophages express low levels of A(2A)Rs and lipopolysaccharides (LPS) upregulates A(2A)R expression in an NF-κB-dependent manner. The murine A(2A)R gene is encoded by three exons, m1, m2 and m3. Exons m2 and m3 are conserved, while m1 encodes the 5' untranslated UTR. Three m1 variants have been defined, m1A, m1B and m1C, with m1C being farthest from the transcriptional start site. LPS upregulates A(2A)Rs in primary murine peritoneal and bone-marrow-derived macrophages and RAW264.7 cells by selectively splicing m1C to m2, through a promoter located upstream of m1C. We have cloned ∼1.6 kb upstream of m1C into pGL4.16(luc2CP/Hygro) promoterless vector. This construct in RAW 264.7 cells responds to LPS, and adenosine receptor agonists augmented LPS responsiveness. The NF-κB inhibitors BAY-11 and triptolide inhibited LPS-dependent induction. Deletion of a key proximal NF-κB site (402-417) abrogated LPS responsiveness, while deletion of distal NF-κB and C/EBPß sites did not. Site-directed mutagenesis of CREB (309-320), STAT1 (526-531) and AP2 (566-569) sites had little effect on LPS and adenosine receptor agonist responsiveness; however, mutation of a second STAT1 site (582-588) abrogated this responsiveness. Further analysis of this promoter should provide valuable insights into regulation of A(2A)R expression in macrophages in response to inflammatory stimuli.

Doing supplements to improve performance in club cycling: a life-course analysis.

Using qualitative life-course and pathway analysis, this article explores the beliefs that serious club cyclists have about performance improvement, and what they think are appropriate and inappropriate ways of achieving it. We interviewed 11 cyclists from suburban clubs in Melbourne, Australia, and invited them to discuss their approach to training, racing, and supplementation. We found that each of the 11 cyclists were not only committed to the sport, but also paid a keen interest in bike technology and training regimes. In addition, they believed that supplement use was integral to meeting the physical and mental demands of their sport, even at club level. They also understood that supplement use, like training regimes, followed a sequential pathway where the accumulation of capacity, know-know, and knowledge, allowed progression to the next level of performance. And, like similar studies of club cycling in Europe, this cohort of cyclists balked at using banned substances, but also believed that in order to effectively transition to the elite - that is, professional - level, some additional supplement and drug-use was essential.

Culturally and linguistically diverse students in health professional programs: an exploration of concerns and needs.

INTRODUCTION: Cultural diversity among students in tertiary institutions in Australia and globally has increased rapidly in the last decade, and is continuing to do so. METHODS: Focus groups were held at the University of Newcastle, NSW to: (1) examine the specific needs of international students in the Master of Pharmacy, Bachelor of Medicine and Bachelor of Nursing programs in relation to language and cultural considerations and (2) to understand the attitudes of domestic students to the cultural issues faced among their peers. The project explored these issues with the intention to inform curricula changes to accommodate the needs of culturally and linguistically diverse students. RESULTS: The key themes emerging from international students were: difficulties in spoken language, differences in professional roles and expectations, differences in methods of learning, inadequate social interaction outside the classroom and acceptance of differences in cultural and religious practices. The domestic student views reinforced the comments from international students both in regard to social interaction and in regard to participation in class discussions. Although local students were interested in learning from international students about their culture and religious beliefs, there were limited initiatives from both sides. DISCUSSION: There is a need for tertiary institutions that benefit economically from increasing the numbers of international students to help them to study and live in a new environment. Assistance needs to go beyond learning the English language to helping students understand its use in a professional context (health terminology and slang used by patients), the nuances of the health professional disciplines in a western society, the approach to study and problem-based learning styles and skills to assist with social interaction. The results of the present exploration have led to a series of proposed actions for the University of Newcastle. These recommendations are applicable to any "Western" teaching institution with a large number of international students from developing countries enrolled in their health programs.

The social value of genomic sequencing for disadvantaged families facing rare disease.

This study explores parental expectations and value-making processes in respect to pediatric clinical genomic sequencing for socially disadvantaged families. Drawing on interviews and ethnographic observations with parents of children with undiagnosed physical and/or intellectual differences seeking to find whether these differences have a genetic etiology, we explore expectations and parental assessments of the value of genomic sequencing within the context of an ongoing research study. We demonstrate how the value of sequencing to parents goes well beyond finding diagnostic results or receiving prescriptive guidance as to the best care and treatment of their child; instead, value is co-created by parents, clinicians, and genetic counsellors throughout the enrollment and return of results process. Parents in our study found that clinicians and genetic counsellors repeatedly reenforce that parents need to lower their expectations and be prepared to wait for genetic science to provide more definitive answers. At the same time, parents experience that clinical teams validate parents for having made a good choice in their undertaking of genomic sequencing and, no matter the result, that they are not to blame for their child's symptoms. The experience of many parents (although not all) is that genomic science reduces or removes their sense of guilt for their child's condition, providing a platform that affirms them as "good parents." Moreover, rather than being voiceless and isolated, socially disadvantaged parents who enter into diagnostic sequencing find themselves in a familial-biosocial framework wherein they are co-partners in a socially and biologically authoritative vision of the future.

Health inequities: the need for action by schools of medicine.

BACKGROUND: It is well recognised that marked inequalities in mortality and morbidity exist between populations particularly those in lower socio-economic groups, including Indigenous and some ethnic minorities. Academic medicine has not yet articulated a clear stance on reducing health inequity within communities. AIM: To develop criteria that medical schools can implement to reduce health inequity. These criteria will enable the performance of a medical school's commitment to health equity to be measured. RESULTS AND CONCLUSION: We suggest that the contribution to lessening health inequity should be seen as an integral and important role of undergraduate medical education and the academic institutions that provide such programs. Five strategies aimed at increasing the commitment of medical and other undergraduate health students to work with disadvantaged groups to improve their health are described. They include student selection to increase representativeness of students and importantly, support for retention and academic success; undergraduate curriculum, both core and elective, to address inequality and provide skills necessary to implement change in a range of areas that impact on health; academic physicians modelling the above by actively working in and for disadvantaged groups; developing centres of excellence carrying out research in health inequity, particularly intervention rather than solely descriptive research and creating high status academic appointments in key designated positions addressing inequity. Schools of Medicine could be rated on their action on these criteria so that benchmarking across institutions could occur.

Erythromyeloid lineage fidelity is conserved in erythroleukaemia.

Blast cells from eight patients with erythroleukaemia and one with erythroid blast crisis of chronic myeloid leukaemia were studied for the co-expression of cell surface myeloid and erythroid markers, and the phenotype compared with that of erythroblasts from two patients with megaloblastic anaemia. The technique of dual indirect immunofluorescence was used with a panel of seven mouse monoclonal antibodies against well-defined myeloid antigens (CD11b, 13, 14, 15, 33 and HLA-DR) and a rat antibody, YTH89.1, specific for glycophorin A. No dual fluorescence, emanating from myeloid or erythroid lineage markers, was found to occur in either the neoplastic or non-neoplastic erythroid cells studied. These data support the hypothesis that lineage fidelity is conserved in leukaemia.

The helix-loop-helix containing transcription factor USF activates the promoter of the CD2 gene.

T cell development within the thymus involves the ordered expression of a number of tissue-specific components such as the CD2 gene. Control of expression of this gene is regulated by a well characterized 3' enhancer together with a promoter and upstream elements. The CD2 promoter is typical of a group of T cell-specific promoters that lack a TATA box and use multiple sites for initiation of transcription. An "E box" motif CACGTG, located just upstream from the most 5' initiation start site, was found to contribute a major effect to the level of basal transcription of a reporter gene. Analysis of the proteins in T cell extracts that bound to this site revealed that the bHLH-LZ protein USF was the major component. A functional role for USF was established in transient transfection experiments. Thus, this protein restored full promoter activity following repression caused by cotransfection with the E box binding bHLH-LZ protein Max. Taken together, these results indicate that an E box motif is critical to expression of the CD2 gene during T cell development and that the HLH protein USF acts as a transcriptional activator of the CD2 promoter.

Repression of CD2 gene expression is mediated by an AP-2 related factor.

Tissue specific and developmental expression of the CD2 gene is tightly regulated during T cell development. DNase I hypersensitivity analysis has revealed the presence of two sites (DHS1 and 2) located 5' to the CD2 gene which have been reported to be implicated in the developmental regulation of expression of CD2. The location of DHS2 marks the position of the minimal promoter whereas DHS1 is located approximately 1800 bp upstream. We show that repressor and derepressor activities are contained within the region of DNA marked by DHS1. The repressor is capable of regulating homologous and heterologous promoters regardless of orientation. This activity is entirely dependent upon the presence of an AP-2 binding site as mutation of this site resulted in a loss of repressor activity. A nuclear factor found in Jurkat cells specifically binds this site but was shown to be serologically distinct from AP-2.

A transgenic T cell receptor restores thymocyte differentiation in interleukin-7 receptor alpha chain-deficient mice.

Interleukin-7 (IL-7) receptor alpha chain-deficient (IL-7R alpha-/-) mice have severely depleted lymphocyte populations and thymocyte development is arrested at the double-negative (DN) stage. We show that thymocyte development in these mice can be reconstituted by the introduction of a transgenic T cell receptor (TCR), implying that one function of the IL-7R alpha chain is to initiate TCR gene rearrangement. Expression of the recombinase-activating genes RAG1 and RAG2 was greatly reduced in the IL-7R alpha-/- thymuses, and in DN thymocytes from the TCR transgenic IL-7R alpha-/- mice, but was restored in double-positive thymocytes from the TCR transgenic IL-7R alpha-/- mice. These data suggest that the IL-7R alpha chain controls RAG expression and initiation of TCR beta chain VDJ rearrangement in DN cells. In contrast, once cells have progressed beyond the DN stage of development the IL-7R alpha chain becomes no longer essential for RAG expression.

Distinct roles of the interleukin-7 receptor alpha chain in fetal and adult thymocyte development revealed by analysis of interleukin-7 receptor alpha-deficient mice.

Mouse mutants lacking expression of the IL-7 receptor (IL-7R) alpha chain are defective in thymopoiesis. The adult thymus has multiple defects, including reduced cell numbers and proportions of the more mature thymocyte subsets, a complete absence of CD25+ cells and a reduced level of RAG1 and RAG2 expression. We show here that, in contrast to the profound developmental arrest observed in the adult thymus, fetal thymocytes from IL-7Ralpha-/- mice have normal proportions of all of the major thymocyte subpopulations, including CD25+ thymocytes and the most mature single-positive subsets. Moreover, normal levels of RAG1 and RAG2 were observed. Total thymocyte numbers, however, remained reduced. These data suggest that the IL-7Ralpha chain is a key regulator of both survival and proliferation during thymocyte development but that it is not essential for the production of T cells during fetal thymopoiesis.

Hedgehog signaling regulates differentiation from double-negative to double-positive thymocyte.

The hedgehog (Hh) signaling pathway is involved in the development of many tissues. Here we show that sonic hedgehog (Shh) is involved in thymocyte development. Our data suggest that termination of Hh signaling is necessary for differentiation from CD4-CD8-double-negative (DN) to CD4+CD8+ double-positive (DP) thymocyte. Shh is produced by the thymic stroma, and Patched and Smoothened (Smo), the transmembrane receptors for Shh, are expressed in DN thymocytes. A neutralizing monoclonal antibody against Shh increases differentiation of DN to DP thymocytes, and Shh protein arrests thymocyte differentiation at the CD25+ DN stage, after T cell receptor beta (TCRbeta) gene rearrangement. We show that one consequence of pre-TCR signaling is downregulation of Smo, allowing DN thymocytes to proliferate and differentiate.

Selective silencing of full-length CD80 but not IgV-CD80 leads to impaired clonal deletion of self-reactive T cells and altered regulation of immune responses.

Co-stimulation provided by the B7 family of proteins underpins the development of protective immunity. There are three identified members of this family: CD80, its splice variant IgV-CD80 and CD86. It has hitherto been difficult to analyze the expression and function of IgV-CD80 since there are no appropriate reagents capable of distinguishing it from CD80. We have generated mice, by gene targeting, the lack CD80 whilst maintaining expression of IgV-CD80. Mutant animals did not delete T cells bearing mammary tumor virus-reactive TCR as efficiently as wild-type animals. We also demonstrate the importance of IgV-CD80 in the responses of recently activated cells and reveal a role for CD80 in sustaining T cell responses. CD86, whilst critical to primary T cell activation, made only a minor contribution to re-activation of normal cells.