Up-regulation of TRPV1 in mononuclear cells of end-stage kidney disease patients increases susceptibility to N-arachidonoyl-dopamine (NADA)-induced cell death

Abstract Transient receptor potential vanilloid (TRPV) 1 channels function as sensors for a variety of noxious and inflammatory signals, including capsaicin, heat and protons, and are up-regulated under inflammatory conditions. As end-stage kidney disease (ESKD) is associated with chronic inflammation, impaired immunity and depressed lymphocyte numbers, we sought to determine whether altered TRPV1 (and related TRPV2) expression in immune cells might be a contributing factor. TRPV1 and TRPV2 mRNA expression in peripheral blood mononuclear cells (PBMC) was similar in controls and ESKD patients by quantitative real-time RT-PCR. However, using immunocytochemistry, TRPV1-immunoreactivity was significantly higher and TRPV2-immunoreactivity was significantly lower in PBMC from ESKD patients compared to controls. The plant-derived TRPV1 agonists, capsaicin and resiniferatoxin (RTX) and the putative endovanilloid/endocannabinoids, N-arachidonoyl-dopamine (NADA) and N-oleoyl-dopamine (OLDA), induced concentration-dependent death of PBMC from healthy donors with a rank order of potency of RTX > NADA > OLDA >> capsaicin. TRPV1 (5′-iodoresiniferatoxin) and cannabinoid (CB2; AM630) receptor antagonists blocked the cytotoxic effect of NADA. In subsequent experiments, PBMC from ESKD patients exhibited significantly increased susceptibility to NADA-induced death compared to PBMC from controls. The apparent up-regulation of TRPV1 may be a response to the inflammatory milieu in which PBMC exist in ESKD and may be responsible for the increased susceptibility of these cells to NADA-induced death, providing a possible explanation as to why ESKD patients have reduced lymphocyte counts and impaired immune function. Thus, TRPV1 (and possibly CB2) antagonists may have potential for the treatment of immune dysfunction in ESKD

Rates of diagnostic transition and cognitive change at 18-month follow-up among 1,112 participants in the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing (AIBL)

Background: The Australian Imaging, Biomarkers and Lifestyle (AIBL) Flagship Study of Ageing is a prospective study of 1,112 individuals (211 with Alzheimer's disease (AD), 133 with mild cognitive impairment (MCI), and 768 healthy controls (HCs)). Here we report diagnostic and cognitive findings at the first (18-month) follow-up of the cohort. The first aim was to compute rates of transition from HC to MCI, and MCI to AD. The second aim was to characterize the cognitive profiles of individuals who transitioned to a more severe disease stage compared with those who did not. Methods: Eighteen months after baseline, participants underwent comprehensive cognitive testing and diagnostic review, provided an 80 ml blood sample, and completed health and lifestyle questionnaires. A subgroup also underwent amyloid PET and MRI neuroimaging. Results: The diagnostic status of 89.9% of the cohorts was determined (972 were reassessed, 28 had died, and 112 did not return for reassessment). The 18-month cohort comprised 692 HCs, 82 MCI cases, 197 AD patients, and one Parkinson's disease dementia case. The transition rate from HC to MCI was 2.5%, and cognitive decline in HCs who transitioned to MCI was greatest in memory and naming domains compared to HCs who remained stable. The transition rate from MCI to AD was 30.5%. Conclusion: There was a high retention rate after 18 months. Rates of transition from healthy aging to MCI, and MCI to AD, were consistent with established estimates. Follow-up of this cohort over longer periods will elucidate robust predictors of future cognitive decline.12 page(s

The burden and trend of diseases and their risk factors in Australia, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: A comprehensive understanding of temporal trends in the disease burden in Australia is lacking, and these trends are required to inform health service planning and improve population health. We explored the burden and trends of diseases and their risk factors in Australia from 1990 to 2019 through a comprehensive analysis of the Global Burden of Disease Study (GBD) 2019. Methods: In this systematic analysis for GBD 2019, we estimated all-cause mortality using the standardised GBD methodology. Data sources included primarily vital registration systems with additional data from sample registrations, censuses, surveys, surveillance, registries, and verbal autopsies. A composite measure of health loss caused by fatal and non-fatal disease burden (disability-adjusted life-years [DALYs]) was calculated as the sum of years of life lost (YLLs) and years of life lived with disability (YLDs). Comparisons between Australia and 14 other high-income countries were made. Findings: Life expectancy at birth in Australia improved from 77·0 years (95% uncertainty interval [UI] 76·9–77·1) in 1990 to 82·9 years (82·7–83·1) in 2019. Between 1990 and 2019, the age-standardised death rate decreased from 637·7 deaths (95% UI 634·1–641·3) to 389·2 deaths (381·4–397·6) per 100 000 population. In 2019, non-communicable diseases remained the major cause of mortality in Australia, accounting for 90·9% (95% UI 90·4–91·9) of total deaths, followed by injuries (5·7%, 5·3–6·1) and communicable, maternal, neonatal, and nutritional diseases (3·3%, 2·9–3·7). Ischaemic heart disease, self-harm, tracheal, bronchus, and lung cancer, stroke, and colorectal cancer were the leading causes of YLLs. The leading causes of YLDs were low back pain, depressive disorders, other musculoskeletal diseases, falls, and anxiety disorders. The leading risk factors for DALYs were high BMI, smoking, high blood pressure, high fasting plasma glucose, and drug use. Between 1990 and 2019, all-cause DALYs decreased by 24·6% (95% UI 21·5–28·1). Relative to similar countries, Australia's ranking improved for age-standardised death rates and life expectancy at birth but not for YLDs and YLLs between 1990 and 2019. Interpretation: An important challenge for Australia is to address the health needs of people with non-communicable diseases. The health systems must be prepared to address the increasing demands of non-communicable diseases and ageing. Funding: Bill &amp; Melinda Gates Foundation.</p