The protective variant rs7173049 at LOXL1 locus impacts on retinoic acid signaling pathway in pseudoexfoliation syndrome.

LOXL1 (lysyl oxidase-like 1) has been identified as the major effect locus in pseudoexfoliation (PEX) syndrome, a fibrotic disorder of the extracellular matrix and frequent cause of chronic open-angle glaucoma. However, all known PEX-associated common variants show allele effect reversal in populations of different ancestry, casting doubt on their biological significance. Based on extensive LOXL1 deep sequencing, we report here the identification of a common non-coding sequence variant, rs7173049A>G, located downstream of LOXL1, consistently associated with a decrease in PEX risk (odds ratio, OR = 0.63; P = 6.33 × 10-31) in nine different ethnic populations. We provide experimental evidence for a functional enhancer-like regulatory activity of the genomic region surrounding rs7173049 influencing expression levels of ISLR2 (immunoglobulin superfamily containing leucine-rich repeat protein 2) and STRA6 [stimulated by retinoic acid (RA) receptor 6], apparently mediated by allele-specific binding of the transcription factor thyroid hormone receptor beta. We further show that the protective rs7173049-G allele correlates with increased tissue expression levels of ISLR2 and STRA6 and that both genes are significantly downregulated in tissues of PEX patients together with other key components of the STRA6 receptor-driven RA signaling pathway. siRNA-mediated downregulation of RA signaling induces upregulation of LOXL1 and PEX-associated matrix genes in PEX-relevant cell types. These data indicate that dysregulation of STRA6 and impaired retinoid metabolism are involved in the pathophysiology of PEX syndrome and that the variant rs7173049-G, which represents the first common variant at the broad LOXL1 locus without allele effect reversal, mediates a protective effect through upregulation of STRA6 in ocular tissues.

Intensive community treatment and support "Youth Wraparound" service in Western Australia: A case and feasibility study.

BACKGROUND: Multiple services are often needed to address the needs of young people with complex emotional or behavioural needs. The Youth Wraparound model of service aims to provide all health and supportive services from one coordinating agency. While this has been researched overseas, there are currently few examples of this described in the Australian psychiatric context. AIM: To document the implementation and evaluation of a Youth Wraparound service which was provided to a young person with exceptionally complex and challenging needs for 6 months. A single-case study design is presented with an evaluation of the clinical outcome and economic costs. METHODS: We present a description of the service context, principles of the model of care, implementation process, and an evaluation of service utilization data from health and child protection services and mental health records. A single-case longitudinal design compared service utilization data obtained up to 3 years prior to treatment with data collected one and a half years since treatment commenced. RESULTS: There were significant reductions in the number of admissions to emergency departments, mental health wards and secure units, and improvements in mental health and well-being. Yearly average time in institutional settings reduced from 69% to 7%. Cost savings in health utilization were estimated at $2 326 790. CONCLUSIONS: The Youth Wraparound model has the potential to offer improved clinical outcomes, significant cost savings over time, improved coordination between care providers, and an alternative to detention or incarceration.

Methods to Investigate the Molecular Basis of Progranulin Action on Neurons In Vivo Using Caenorhabditis elegans.

The C. elegans nematode is a powerful genetic tool for the study of aging, developmental biology, and neurodegenerative diseases. They are a small and simple model, but its well-known genome and presence of many human orthologs has made it an ideal model to study the effects of PGRN in vivo. Here, we will describe the protocols used by our laboratory to study how PGRN affects C. elegans neuronal morphology and locomotion behavior through the use of a loss-of-function model of the nematode otholog of the GRN gene, pgrn-1. Although these protocols have been used by us to specifically study the pgrn-1 gene, the experiments are applicable to any of the animal's genes.

Cowden syndrome. Managing multiple skeletal metastases of different origin: a case report.

BACKGROUND: Cowden Syndrome is a rare autosomal dominant multiple hamartomatous condition, characterised by both benign and malignant tumours affecting multiple systems. CASE PRESENTATION: We present a 47-year-old female patient with thigh pain that was diagnosed with Cowden syndrome 20 years ago and developed multiple and different skeletal metastases which became resistant to radio-chemotherapy. A percutaneous plate fixation of the distal femur with an intralesional excision and cementoplasty of the metastasis was performed initially. This was combined with a cemented total hip arthroplasty using an Exeter long revision stem and a cementoplasty of the femoral canal for the proximal lesions. CONCLUSION: A meticulous approach to her complex metastatic disease resulted in successful palliative prophylactic reconstructive surgery that improved her quality of life, allowing her independent pain free walking for 12 months.