Deletion of Nedd4-2 results in progressive kidney disease in mice

NEDD4-2 (NEDD4L), a ubiquitin protein ligase of the Nedd4 family, is a key regulator of cell surface expression and activity of the amiloride-sensitive epithelial Na⁺ channel (ENaC). While hypomorphic alleles of Nedd4-2 in mice show salt-sensitive hypertension, complete knockout results in pulmonary distress and perinatal lethality due to increased cell surface levels of ENaC. We now show that Nedd4-2 deficiency in mice also results in an unexpected progressive kidney injury phenotype associated with elevated ENaC and Na⁺Cl⁻ cotransporter expression, increased Na⁺ reabsorption, hypertension and markedly reduced levels of aldosterone. The observed nephropathy is characterized by fibrosis, tubule epithelial cell apoptosis, dilated/cystic tubules, elevated expression of kidney injury markers and immune cell infiltration, characteristics reminiscent of human chronic kidney disease. Importantly, we demonstrate that the extent of kidney injury can be partially therapeutically ameliorated in mice with nephron-specific deletions of Nedd4-2 by blocking ENaC with amiloride. These results suggest that increased Na⁺ reabsorption via ENaC causes kidney injury and establish a novel role of NEDD4-2 in preventing Na⁺-induced nephropathy. Contrary to some recent reports, our data also indicate that ENaC is the primary in vivo target of NEDD4-2 and that Nedd4-2 deletion is associated with hypertension on a normal Na⁺ diet. These findings provide further insight into the critical function of NEDD4-2 in renal pathophysiology.Tanya L Henshall, Jantina A Manning, Omri S Alfassy, Pranay Goel, Natasha A Boase, Hiroshi Kawabe and Sharad Kuma

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

Conformity, Loyalty and the Jesuit Mission to England of 1580

In Elizabethan England, under the 1559 Act of Uniformity, church attendance was compulsory on Sundays and Holy Days for all those aged 14 or over. The law was enforced ‘upon payne of punishement by the Censures of the Churche, and also upon payne that every p[er]son so offending shall forfeite for every suche offence twelve pens’.2 The 1581 Act imposed a fine of £20 a month on Catholic recusants — a huge leap from the normal 12 pence.3 Obviously the authorities had become uneasy following the arrival in 1580 of the Jesuits Edmund Campion and Robert Persons, who challenged the Elizabethan regime’s legitimacy by urging Catholics not to attend the state Church.4 Reports for nonattendance may have been many, but the number of parishioners not receiving communion was even more significant. Church papistry was a major reason for non-reception. Communion had to be taken at least three times a year, usually at Whitsunday, Easter and Christmas. According to one John Earle as late as 1628, church papists always found a way to avoid receiving this sacrament, which they viewed as an aberration of the true communion: Once a moneth he presents himselfe at the Churche, to keepe off the Church-warden, and brings in his body to save his bayle. He kneels with the Congregation, but prayes by himselfe, and askes God forgivenesse for coming thither. If he be forced to stay out a Sermon, he puls his hat over his eyes, and frownes out the houre, and when hee comes home, thinkes to make amends by abusing the Preacher. His maine policy is to shift off the Communion, for which he is never unfurnish’t of a quarrel, and will be sure to be out of Charity at Easter; and indeed he lies not, for hee has a quarrel to the Sacrament.