The prospects for complement-targeted therapy in ANCA-associated vasculitis have been enhanced by a recent clinical trial in which C5a receptor 1 (C5aR1) inhibition safely replaced glucocorticoids in induction treatment. C5aR1 primes neutrophils for activation by anti-neutrophil cytoplasmic antibody (ANCA) and is therefore required in models of glomerulonephritis induced by anti-myeloperoxidase antibody. Although humoral and cellular autoimmunity play essential roles in ANCA-associated vasculitis, a role for C5aR1 in these responses has not been described. Here, we use murine models to dissect the role of C5aR1 in the generation of anti-myeloperoxidase autoimmunity and the effector responses resulting in renal injury. The genetic absence or pharmacological inhibition of C5aR1 results in reduced autoimmunity to myeloperoxidase with an attenuated Th1 response, increased Foxp3 regulatory T cells and reduction in generation of myeloperoxidase-ANCA. These changes are mediated by C5aR1 on dendritic cells, which promotes activation, and thus myeloperoxidase autoimmunity and glomerulonephritis. We also use renal intravital microscopy to determine the effect of C5aR1 inhibition on ANCA induced neutrophil dysfunction. We found that myeloperoxidase-ANCA induce neutrophil retention and reactive oxygen species burst within glomerular capillaries. These pathological behaviors are abrogated by C5aR1 inhibition. Thus, C5aR1 inhibition ameliorates both autoimmunity and intra-renal neutrophil activation in ANCA-associated vasculitis.

C oronavirus disease is a novel infectious disease that primarily manifests as an acute respiratory syndrome but can also cause multiorgan dysfunction. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been documented to cause vasoocclusive crisis and acute chest syndrome in patients with sickle cell anemia (1). We report another potentially major complication of infection in a patient with a common enzymatic disorder. Glucose 6-phosphate dehydrogenase (G6DP) deficiency is an X-linked enzymatic disorder that affects 400 million persons worldwide and has a high prevalence (5%-20%) in African and Asian populations (2). G6DP catalyzes the formation of nicotinamide adenine dinucleotide phosphate (NADPH) (3). NADPH maintains hemoglobin in the ferrous state by forming reduced glutathione, which prevents oxidative damage (3). G6DP deficiency increases the risk for intravascular hemolysis upon exposure to oxidative agents, such as fava beans, sulfonamides, and hydroxychloroquine, the subject of clinical trials for persons with SARS-CoV-2 infection. G6PD deficiency can induce methemoglobinemia by inhibiting NADPH-flavine reductase, which prevents the reduction of methemoglobin. Methemoglobin is unable to bind to oxygen, and the remaining oxyhemoglobin develops heightened oxygen affinity and diminished delivery, leading to tissue hypoxia (4). Viral infections, including HIV, hepatitis viruses (A, B, and E), and cytomegalovirus, can precipitate intravascular hemolysis in patients with G6PD deficiency (5,6). Concurrent methemoglobinemia has also been reported in the context of viral-induced hemolysis (5). RESEARCH LETTERS During the coronavirus disease pandemic in Spain, from April 10-24, 2020, a total of 5,869 persons were screened for severe acute respiratory syndrome coronavirus 2 at nursing homes. Among residents, 768 (23.9%) tested positive; among staff, 403 (15.2%). Of those testing positive, 69.7% of residents and 55.8% of staff were asymptomatic.

We demonstrate the challenges and illustrate the heavy workload involved in receiving widespread ethics and governance approval across Australia. We highlight the need to simplify, homogenise, and nationalise human ethics for non-clinical trial studies. Reducing unnecessary administration will enable investigators to achieve research aims more efficiently.

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Myeloperoxidase (MPO) anti-neutrophil cytoplasmic Ab (ANCA)-associated vasculitis results from autoimmunity to MPO. IL-17A plays a critical role in generating this form of autoimmune injury but its cell of origin is uncertain. We addressed the hypothesis that IL-17A-producing γδ T cells are a nonredundant requisite in the development of MPO autoimmunity and glomerulonephritis (GN). We studied MPO-ANCA GN in wild type, αβ, or γδ T cell-deficient (C57BL/6, , and respectively) mice. Both T cell populations played important roles in the generation of autoimmunity to MPO and GN. Humoral autoimmunity was dependent on intact αβ T cells but was unaffected by γδ T cell deletion. Following MPO immunization, activated γδ T cells migrate to draining lymph nodes. Studies in and transfer of γδ T cells to mice show that γδ T cells facilitate the generation of anti-MPO autoimmunity and GN. mice that received γδ T cells demonstrate that the development of anti-MPO autoimmunity and GN are dependent on γδ T cell IL-17A production. Finally, transfer of anti-MPO CD4 T cell clones to naive and wild type mice with planted glomerular MPO shows that γδ T cells are also necessary for recruitment of anti-MPO αβ CD4 effector T cells. This study demonstrates that IL-17A produced by γδ T cells plays a critical role in the pathogenesis of MPO-ANCA GN by promoting the development of MPO-specific αβ T cells.

Umpleby HC, Williamson RCN. Survival in acute obstructing colorectal carcinoma. Dis Col Rect 1984; 2 7 299-304. Wolmark Net al. The prognostic significance of tumour location 14. 15. 6. 7. 8. 9. 10. 11. 12. 13. and bowel obstruction-in Dukes B and C colorectal cancer. Ann Surg 1983; 198: 743-52. Welch JP, Donaldson GA. Recent experience in the management of cancer of the colon and rectum. Am J Surg 1974; 127: 258-66. Clark J, Hall AW, Moossa AR. Treatment of obstructing cancer of the colon and rectum. Surg Gynecol Obstet 1975; 141: 5414. Dutton JW, Hreno A, Hampson LG. Mortality and prognosis of obstructing carcinoma of the large bowel. Am J Surg 1976; 131: 3640. Fraser ID, Condon RE, Schulte WJ, Decosse JJ, Cowles VE. A device to simulate the mechanical component of malignant bowel obstruction. An electromyogaphic study in dogs. Gastroenterology 1983; 85: 1301-6. Fraser ID, Condon RE, Schulte WJ, Decosse JJ, Cowles VE. Intestinal motility changes in experimental large bowel obstruction. Surgery 1980; 86: 677-82. Fraser ID, Condon RE, Schulte WJ, Decosse JJ, Cowles VE. Bowel motility after primary resection for colonic obstruction. Br J Surg 1981; 68: 113-16. Huizinga JD, Diamant NE, El-Sharkaway TY. Electrical basis of contractions in the muscle layers of the pig colon. Am J Physiol 6. 7. 8. 1983; 245: G482-91. obstruction. Arch Surg 1981; 116: 194-6. Darby CF, Hammond P, Taylor I, Moms IR. A method for the simultaneous detection of motility and myo-electrical activity in smooth muscle.Parathyroid cysts are uncommon lesions of the neck and superior mediastinum. We report the first case of symptomatic spontaneous bleeding into such a cyst. Case reportA 63-year-old draughtsman presented with carcinoma of the prostate. Examination also showed multiple lipomata and a multinodular goitre, with the trachea deviated to the left. The goitre had been present, unchanged in size, for 15 years. Routine biochemical investigation revealed a serum calcium of 3.43mmol/l (normal range 2~1Cb2~60mmol/l). Whole body bone scan showed no evidence of any secondary deposits, but revealed diffusely increased tracer uptake in keeping with metabolic bone disease. After transurethral resection of his prostate, he started a 60oOcGy course of external beam radiotherapy to his prostatic bed. During the fourth week of this treatment he complained of a painful swelling in the right side of his neck and it was found on clinical examination that the swelling of this side of the neck had increased substantially in size and was tender to palpation. After a week there was considerable subcutaneous bruising on the right side of the neck and anterior chest wall. The pain and swelling gradually resolved and it was thought that he had bled into a thyroid cyst. Investigation of his persistent hypercalcaemia continued. His serum parathormone was grossly raised at 235 pg/ml and a thallium-technetium subtraction scan showed a large area of increased uptake in the right side of his thyroid. Exploration of his neck revealed a pear-shaped cystic mass, 95 mm in...

BackgroundMyeloperoxidase ANCA-associated vasculitis is a major cause of ESKD. Efficacy of anti-CD20 mAb treatment was tested in a mouse model of the disease.MethodsMPO immunization induced anti-MPO autoimmunity, and a subnephritogenic dose of sheep anti-mouse GBM globulin triggered GN.ResultsAnti-CD20 mAb treatment increased the numbers and immunomodulatory capacity of MPO-specific T regulatory cells (Tregs) and attenuated T cell–mediated and humoral anti-MPO autoimmunity and GN. Disabling of Tregs negated the therapeutic benefit of anti-CD20 treatment. The mechanism of enhancement of Treg activity could be attributed to anti-CD20 mAb effects on inducing B cell apoptosis. Administering anti-CD20 mAb-induced apoptotic splenocytes to mice developing anti-MPO GN was as effective as anti-CD20 mAb treatment in inducing Tregs and attenuating both anti-MPO autoimmunity and GN. A nonredundant role for splenic macrophages in mediating the anti-CD20 mAb-induced immunomodulation was demonstrated by showing that administration of anti-CD20 mAb ex vivo–induced apoptotic splenocytes to unmanipulated mice attenuated autoimmunity and GN, whereas deletion of splenic marginal zone macrophages prevented anti-CD20 mAb-induced immunomodulation and treatment efficacy. Six days after administering anti-CD20 mAb to mice with murine anti-MPO GN, cell-mediated anti-MPO responses and GN were attenuated, and Tregs were enhanced, but ANCA levels were unchanged, suggesting humoral autoimmunity was redundant at this time point.ConclusionsCollectively, these data suggest that, as well as reducing humoral autoimmunity, anti-CD20 mAb more rapidly induces protective anti-MPO Treg-mediated immunomodulation by splenic processing of anti-CD20–induced apoptotic B cells.