Chronic activation of Toll-like receptor 2 induces an ichthyotic skin phenotype

BACKGROUND: Ichthyosis defines a group of chronic conditions that manifest phenotypically as a thick layer of scales and often affects the entire skin. While the gene mutations that lead to ichthyosis are well documented, the actual signalling mechanisms that lead to scaling are poorly characterised, however recent publications suggest that there are common mechanisms active in ichthyotic tissue, and in analogous models of ichthyosis. OBJECTIVE: To determine common mechanisms of hyperkeratosis that may be easily targeted with small molecule inhibitors. METHODS: We combined gene expression analysis of gene-specific shRNA knockdowns in rat epidermal keratinocytes of two genes mutated in autosomal recessive congenital ichthyosis (ARCI), Transglutaminase 1 (TGM1) and arachidonate 12-lipoxygenase, 12R type (ALOX12B), and proteomic analysis of skin scale from ARCI patients.as well as RNAseq data from rat epidermal keratinocytes treated with the Toll-like receptor-2 agonist PAM3CSK. RESULTS: we identified a common activation of the Toll-like receptor (TLR) 2 pathway. Exogenous TLR2 activation led to increased expression of important cornified envelope genes and in organotypic culture caused hyperkeratosis. Conversely, blockade of TLR2 signalling in ichthyosis patient keratinocytes and our shRNA models reduced the expression of keratin 1, a structural protein over-expressed in ichthyosis scale. A time-course of Tlr2 activation in rat epidermal keratinocytes revealed that although there was rapid initial activation of innate immune pathways, this was rapidly superseded by widespread up-regulation of epidermal differentiation related proteins. Both NFκβ phosphorylation and Gata3 up-regulation was associated with this switch and Gata3 overexpression was sufficient to increase Keratin 1 expression. CONCLUSION: Taken together, these data define a dual role for Toll-like receptor 2 activation during epidermal barrier repair, that may be a useful therapeutic modality in treating diseases of epidermal barrier dysfunction

Peripheral hearing loss and its association with cognition among ethnic Chinese older adults

INTRODUCTION : Many studies on hearing loss (HL) and cognition are limited by subjective hearing assessments and verbally administered cognition tests, the majority of the document findings in Western populations. This study aimed to assess the association of HL with cognitive impairment among ethnic Chinese Singaporean older adults using visually presented cognitive tests. METHODS : The hearing of community- dwelling older adults was assessed using pure tone audiometry. Cognitive function was assessed using the Computerized Cambridge Cognitive Test Battery (CANTAB). Multiple regression analyses examined the association between hearing and cognitive function, adjusted for age, education, and gender. RESULTS : HL (pure-tone average [PTA] of thresholds at 0.5, 1, 2, and 4 kHz in the better ear, BE4PTA) was associated with reduced performance in delayed matching and multitasking tasks (β = −0.25, p = 0.019, and β = 0.02, p = 0.023, respectively). Moderate to severe HL was associated with reduced performance in delayed matching and verbal recall memory tasks (β = −10.6, p = 0.019, and β = −0.28, p = 0.042). High-frequency HL was associated with reduced performance in the spatial working memory task (β = 0.004, p = 0.022). All-frequency HL was associated with reduced performance in spatial working memory and multitasking (β = 0.01, p = 0.040, and β = 0.02, p = 0.048). CONCLUSION : Similar to Western populations, HL among tonal language- speaking ethnic Chinese was associated with worse performance in tasks requiring working memory and executive function.Jurong Health Research and Development Fundhttps://www.karger.com/DEMam2022Speech-Language Pathology and Audiolog

Risk of herpes zoster prior to and following cancer diagnosis and treatment: a population-based prospective cohort study

Information on the risks of herpes zoster (zoster) preceding a cancer diagnosis and the role of cancer treatment on risk is limited.This project was supported by the Australian National Health and Medical Research Council (NHMRC) (grant number 1048180). J. Q. is supported by a Commonwealth Australian Government Research Training Program Scholarship. B. L. and E. B. are supported by NHMRC fellowships

Additional file 2: of An optimised method for the proteomic profiling of full thickness human skin

Table detailing the proteins identified in the final method (Fig. 2). (XLSX 120 kb

Additional file 1: of An optimised method for the proteomic profiling of full thickness human skin

Table detailing the proteins identifed in the original method (Fig. 1). (XLSX 19 kb

Healthcare resource utilisation associated with herpes zoster in a prospective cohort of older Australian adults

Background Herpes zoster (HZ) is a common condition that increases in incidence with older age but vaccines are available to prevent the disease. However, there are limited data estimating the health system burden attributable to herpes zoster by age. Methods In this study, we quantified excess healthcare resource usage associated with HZ during the acute/sub-acute period of disease (21days before to 90 days after onset) in 5952 cases and an equal number of controls matched on age, sex, and prior healthcare resource usage. Estimates were adjusted for potential confounders in multivariable regression models. Using population-based estimates of HZ incidence, we calculated the age-specific excess number of health service usage events attributable to HZ in the population. Results Per HZ case, there was an average of 0.06 (95% CI 0.04–0.08) excess hospitalisations, 1.61 (95% CI 1.51–1.69) excess general practitioner visits, 1.96 (95% CI 1.86–2.15) excess prescriptions filled and 0.11 (95% CI 0.09–0.13) excess emergency department visits. The average number of healthcare resource use events, and the estimated excess per 100,000 population increased with increasing age but were similar for men and women, except for higher rates of hospitalisation in men. The excess annual HZ associated burden of hospitalisations was highest in adults ≥80 years (N = 2244, 95%CI 1719–2767); GP visits was highest in those 60–69 years (N = 50567, 95%CI 39958–61105), prescriptions and ED visits were highest in 70–79 years (N = 50524, 95%CI 40634–60471 and N = 2891, 95%CI 2319–3449 respectively). Conclusions This study provides important data to establish the healthcare utilisation associated with HZ against which detailed cost-effectiveness analyses of HZ immunisation in older adults can be conducted

Peripheral Hearing Loss and Its Association with Cognition among Ethnic Chinese Older Adults

10.1159/000519291Dementia and Geriatric Cognitive Disorders504394–40