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Podocyte ADAM10 expression is induced in the setting of antibody-mediated injury in humans and mice. Podocyte ADAM10 deficiency attenuates the clinical course of APN and preserves the morphologic integrity of podocytes, despite subepithelial immune-deposit formation. Functionally, ADAM10-related ectodomain shedding results in cleavage of the cell-adhesion proteins N- and P-cadherin, thus decreasing their injury-related surface levels. This favors podocyte loss and the activation of downstream signaling events through the Wnt signaling pathway in an ADAM10-dependent manner.

ADAM10-mediated ectodomain shedding of injury-related cadherins drives podocyte injury.

ADAM10-mediated ectodomain shedding of injury-related cadherins drives podocyte injury.

Further investigation of the causal effects of psychologic wellbeing on kidney function is warranted.

In this Mendelian randomization (MR) study, genetic instruments for positive affect, life satisfaction, depressive symptoms, and neuroticism were introduced from a previous genome-wide association study meta-analysis of European individuals. Summary-level MR was performed using the CKDGen data of European ancestry (

=567,460), and additional allele score-based MR was performed in the individual-level data of White British UK Biobank participants (

=321,024).

In summary-level MR with the CKDGen data, depressive symptoms were a significant causative factor for kidney function impairment (CKD OR, 1.45; 95% confidence interval, 1.07 to 1.96; eGFR change [%] beta -2.18; 95% confidence interval, -3.61 to -0.72) and pleiotropy-robust sensitivity analysis results supported the causal estimates. A genetic predisposition for positive affect was significantly associated with better kidney function (CKD OR, 0.69; 95% confidence interval, 0.52 to 0.91), eGFR change [%] beta 1.50; 95% confidence interval, 0.09 to 2.93) and sensitivity MR analysis results supported the finding for CKD outcome, but was nonsignificant for eGFR. Life satisfaction and neuroticism exposures showed nonsignificant causal estimates. In the UK Biobank with covariate-adjusted allele score MR analysis, allele scores for positive affect and life satisfaction were causally associated with reduced risk of CKD and higher eGFR. In contrast, neuroticism allele score was associated with increased risk of CKD and lower eGFR, and depressive symptoms allele score was associated with lower eGFR, but showed nonsignificant association with CKD.

Health care providers in the nephrology field should be aware of the causal linkage between psychologic wellbeing and kidney function.

Health care providers in the nephrology field should be aware of the causal linkage between psychologic wellbeing and kidney function.

To determine 30-year brain atrophy rates following clinically isolated syndromes and the relationship of atrophy in the first 5 years and clinical outcomes 25 years later.

A cohort of 132 people who presented with a clinically isolated syndrome suggestive of multiple sclerosis (MS) were recruited between 1984-1987. Clinical and MRI data were collected prospectively over 30 years. Selleck GLPG0634 Widths of the third ventricle and the medulla oblongata were used as linear atrophy measures.

At 30 years, 27 participants remained classified as having had a clinically isolated syndrome, 34 converted to relapsing remitting MS, 26 to secondary progressive MS and 16 had died due to MS. The mean age at baseline was 31.7 years (SD 7.5) and the mean disease duration was 30.8 years (SD 0.9). Change in medullary and third ventricular width within the first 5 years, allowing for white matter lesion accrual and Expanded Disability Status Scale increases over the same period, predicted clinical outcome measures at 30 years. 1 mm of medullary atrophy within the first 5 years increased the risk for secondary progressive MS or MS related death by 30 years by 583% (OR 5.83, 95% CI 1.74 to 19.61, p<0.005), using logistic regression.

Our findings show that brain regional atrophy within 5 years of a clinically isolated syndrome predicts progressive MS or a related death, and disability 25 years later.

Our findings show that brain regional atrophy within 5 years of a clinically isolated syndrome predicts progressive MS or a related death, and disability 25 years later.

Intracranial arterial stenosis (ICAS) is an important cause of stroke worldwide. Separate reports in Caucasians and Asians with stroke/transient ischaemic attack (TIA) have suggested lower ICAS prevalence in Caucasians, but there has been no direct comparisons of the two ethnic groups with the same criteria to define ICAS.

Acute minor stroke or TIA patients in two cohorts respectively recruiting patients in Oxford (2011-2018, predominantly Caucasians) and Hong Kong (2011-2015, predominantly Chinese) were compared. ICAS was defined as ≥50% stenosis/occlusion in any major intracranial artery in MR/CT angiography. Prevalence, distribution and risk factors of ICAS were compared between the two cohorts. We also systematically reviewed literature on ICAS prevalence in stroke/TIA patients in different populations.

Among 1287 patients from Oxford and 691 from Hong Kong (mean age 69 vs 66), ICAS prevalence was higher in Chinese than in Caucasians (43.0% vs 20.0%; OR 3.02; 95% CI 2.47 to 3.70; p<0.001), independent of age (age-adjusted OR 3.73; 95% CI 3.00 to 4.63; p<0.001) and vascular risk factors (multivariable-adjusted OR 3.21; 95% CI 2.56 to 4.02; p<0.001). This ethnic difference was greater (p interaction=0.005) at age <70 years (OR 5.33; 95% CI 3.79 to 7.50; p<0.001) than at ≥70 years (OR 2.81; 95% CI 2.11 to 3.74; p<0.001). ICAS prevalence increased with age and with vascular risk factors in both cohorts, with equivalent prevalence in Chinese aged <60 years and Caucasians aged ≥80, and in Chinese with no vascular risk factor and Caucasians with two vascular risk factors. ICAS locations also differed between Chinese and Caucasian patients.

Chinese are more susceptible to ICAS than Caucasians, with an earlier onset age and a higher prevalence, independent of vascular risk factors.

Chinese are more susceptible to ICAS than Caucasians, with an earlier onset age and a higher prevalence, independent of vascular risk factors.