A case of myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA)-associated glomerulonephritis and concurrent membranous nephropathy

BACKGROUND: Myeloperoxidase anti-neutrophil cytoplasmic antibody-associated glomerulonephritis (MPO-ANCA-GN) and concurrent membranous nephropathy (MN) are very rare combination. Their causal relationship has been suggested, but not determined. CASE PRESENTATION: A 73-years-old male with 5-year history of proteinuria underwent an operation for his sigmoid colon cancer. Seven months later, he was referred to a nephrology division due to an exacerbating renal function and hypoalbuminemia. Laboratory examination revealed positive MPO-ANCA in the serum. A renal biopsy revealed a necrotizing extracapillary proliferative glomerulonephritis with crescents, demonstrating MPO-ANCA-GN. Whereas, immunofluorescent staining documented granular deposition of immumoglobulin (Ig) G and C3 along the capillary wall and electron microscopy showed subepithelial deposits in the glomerular basement membrane demonstrating MN. Immunofluorescent staining of IgG subclass showed positive IgG1, IgG2, negative IgG3 and weak positive IgG4 suggested the possibility of malignancy-associated MN. CONCLUSION: Combination of MPO-ANCA-GN and MN are rare. Although the causal relationship has been suggested in some cases, we should consider all the possibilities including idiopathic MN and secondary MN associated with malignancy, drug use or infection

Czochralski-growth of germanium crystals containing high concentrations of oxygen impurities

Oxygen-containing germanium (Ge) single crystals with low density of grown-in dislocations were grown by the Czochralski (CZ) technique from a Ge melt, both with and without a covering by boron oxide (B(2)O(3)) liquid. Interstitially dissolved oxygen concentrations in the crystals were determined by the absorption peak at 855 cm(-1) in the infrared absorption spectra at room temperature. It was found that oxygen concentration in a Ge crystal grown from melt partially or fully covered with B(2)O(3) liquid was about 10(16) cm(-3) and was almost the same as that in a Ge crystal grown without B(2)O(3). Oxygen concentration in a Ge crystal was enhanced to be greater than 10(17) cm(-3) by growing a crystal from a melt fully covered with B(2)O(3); with the addition of germanium oxide powder, the maximum oxygen concentration achieved was 5.5 x 10(17) cm(-3). The effective segregation coefficients of oxygen in the present Ge crystal growth were roughly estimated to be between 1.0 and 1.4.ArticleJOURNAL OF CRYSTAL GROWTH. 312(19):2783-2787 (2010)journal articl

Effects of Tridocosahexaenoyl-Glycerol Emulsion on Proteinuria in Rats with Nephrotoxic Serum Nephritis

Background: Docosahexaenoic acid (DHA) is one of the n–3 polyunsaturated fatty acids and an important component of cell membrane phospholipids (PL). Nephrotoxic serum (NTS) nephritis was a worldwide model of the Goodpasture syndrome. We investigated the effects of tridocosahexaenoyl-glycerol (DHA-TG) emulsion on proteinuria in rats with NTS nephritis. Methods: Sixteen male Wistar rats weighing approximately 200 g were used. Twelve rats were treated with NTS via the tail vein and divided into 3 groups (groups A, B, and C). Another 4 rats treated with saline served as controls (group D). DHA-TG and soybean oil emulsions were intraperitoneally administered to the rats in groups A and B, respectively, 24 h prior to NTS injection, and 0, 1, 2, 3, 4, and 5 days after the injection. Saline was administered to the rats in groups C and D in the same manner. All rats were sacrificed on day 6 to obtain plasma and kidney samples. Analyses of urinary protein levels and fatty acid composition of plasma and kidney as well as histological examination of the kidneys were performed. Results: Urinary protein levels in group A were significantly lower than those in group C (35.0 ± 13.3 vs. 79.2 ± 11.8 mg/day on day 5, means ± SE, p Conclusions: These results suggest that the DHA-TG emulsion may have beneficial effects on NTS nephritis in the rat

Role of Dok-1 and Dok-2 in Myeloid Homeostasis and Suppression of Leukemia

Dok-1 and Dok-2 are closely related rasGAP-associated docking proteins expressed preferentially in hematopoietic cells. Although they are phosphorylated upon activation of many protein tyrosine kinases (PTKs), including those coupled with cytokine receptors and oncogenic PTKs like Bcr-Abl, their physiological roles are largely unidentified. Here, we generated mice lacking Dok-1 and/or Dok-2, which included the double-deficient mice succumbed to myeloproliferative disease resembling human chronic myelogenous leukemia (CML) and chronic myelomonocytic leukemia. The double-deficient mice displayed medullary and extramedullary hyperplasia of granulocyte/macrophage progenitors with leukemic potential, and their myeloid cells showed hyperproliferation and hypo-apoptosis upon treatment and deprivation of cytokines, respectively. Consistently, the mutant myeloid cells showed enhanced Erk and Akt activation upon cytokine stimulation. Moreover, loss of Dok-1 and/or Dok-2 induced blastic transformation of chronic phase CML-like disease in mice carrying the bcr-abl gene, a cause of CML. These findings demonstrate that Dok-1 and Dok-2 are key negative regulators of cytokine responses and are essential for myeloid homeostasis and suppression of leukemia

FAIRENESS ON DECISION-MAKING PROCESS OF MANAGEMENT POLICY FOR HIGH-LEVEL RADIOACTIVE WASTE AND SITING OF REPOSITORY IN FRANCE

The purpose of our study is to estimate procedural fairness and distributive fairness of past decision-making process of the management policy for high‒level radioactive waste (HLW) and siting of repository in France. We conducted normative analysis by document review and interview survey with CLIS members and a sociologist participated in the public debate on HLW management policy in 2005 by CNDP. The results show that prior clarification when and how decision‒making of HLW management policy and siting of repository will be carried out in the step‒wise approach is important to enhance the legitimacy of the process. With regard to distributive fairness between generations, it is important to carefully consider responsibility of current generation and decision right of future generation in terms of equity and equality in the fair decision‒making process, because HLW management policy might depend on concept of distributive fairness between generations. It is necessary to carefully debate both interregional distributive fairness of negative legacy and economical distributive fairness in the fair decision‒making process, because they are inextricably linked together.本研究は文部科学省科学研究費基盤B（課題番号24402042，研究代表者 広瀬幸雄教授）の補助を受けて実施された

Paroxysmal nocturnal hemoglobinuria in systemic lupus erythematosus: a case report

<p>Abstract</p> <p>Introduction</p> <p>Paroxysmal nocturnal hemoglobinuria is an acquired disorder of hemopoiesis and is characterized by recurrent episodes of intravascular hemolysis due to an increased sensitivity to complement-mediated hemolysis. Systemic lupus erythematosus with paroxysmal nocturnal hemoglobinuria is very rare. We report a case of paroxysmal nocturnal hemoglobinuria that developed in a patient with systemic lupus erythematosus and lupus nephritis.</p> <p>Case presentation</p> <p>A 29-year-old Mongolian woman had systemic lupus erythematosus, which manifested only as skin lesions when she was 12 years old. She had leg edema and proteinuria when she was 23 years old, and a renal biopsy revealed lupus nephritis (World Health Organization type IV). She had been treated with steroids and immunosuppressant therapy. At 29, she had headaches, nausea, general fatigue, and severe pancytopenia and was admitted to our hospital. A laboratory evaluation showed hemolytic anemia. Further examination showed a neutrophil alkaline phosphatase score of 46 points, a CD55 value of 18%, and a CD59 value of 78.6%. The results of Ham test and sugar water tests were positive. The constellation of symptoms throughout the clinical course and the laboratory findings suggested paroxysmal nocturnal hemoglobinuria.</p> <p>Conclusions</p> <p>To the best of our knowledge, systemic lupus erythematosus with paroxysmal nocturnal hemoglobinuria is very rare. Clinicians should be aware of the association between autoimmune and hematological diseases.</p

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target