SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion

Abstract: The B.1.617.2 (Delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha)1. In vitro, B.1.617.2 is sixfold less sensitive to serum neutralizing antibodies from recovered individuals, and eightfold less sensitive to vaccine-elicited antibodies, compared with wild-type Wuhan-1 bearing D614G. Serum neutralizing titres against B.1.617.2 were lower in ChAdOx1 vaccinees than in BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies to the receptor-binding domain and the amino-terminal domain. B.1.617.2 demonstrated higher replication efficiency than B.1.1.7 in both airway organoid and human airway epithelial systems, associated with B.1.617.2 spike being in a predominantly cleaved state compared with B.1.1.7 spike. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralizing antibody, compared with that of wild-type spike. We also observed that B.1.617.2 had higher replication and spike-mediated entry than B.1.617.1, potentially explaining the B.1.617.2 dominance. In an analysis of more than 130 SARS-CoV-2-infected health care workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune-evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era

ドキシサイクリン ワ タメンテキ コウカ ニ ヨリ シスプラチン ユウハツセイ キュウセイ ジン ショウガイ オ ヨクセイ スル

熊本大

Identifying Predictors of Response to Suplatast Tosilate among Patients with Moderate to Severe Bronchial Asthma Receiving Inhaled Steroid Therapy

ABSTRACTBackgroundThe aim of this study was to identify the predictive factors, among laboratory test data and patient background variables, of an efficient response to the anti-allergic agent suplatast tosilate in patients with moderate to severe bronchial asthma.MethodsThe subjects were 44 patients with moderate to severe bronchial asthma on inhaled steroid therapy who were enrolled in a phase II clinical trial of suplatast (300 and 600 mg/day). Improvements in respiratory function parameters and symptom scores during the first 4 weeks of administration of suplatast were assessed to evaluate the response to the drug. Logistic regression analysis was used to relate the response to the independent variables. Secondly, to test whether these results were applicable to clinical practice, we examined the data from a phase III clinical trial of suplatast.ResultsTwenty-two patients were assessed as responders according to our criteria. The percentage of blood eosinophil (%EOS, P = 0.015) and basophil (%BASO, P = 0.019) counts were identified as significant variables to predict responders. When cut-off levels for %EOS and %BASO were set at 7.5 and 1.2, respectively, the sensitivity for prediction of responders with lower %EOS and %BASO was 81.8% (18/22). Furthermore, when we applied the same cut-off levels to subjects of a phase III clinical trial of suplatast, the sensitivity of prediction was found to be as high as 75.0% (6/8).ConclusionsThese results indicate that %EOS and %BASO are good candidates to predict the response to suplatast among patients with moderate to severe bronchial asthma on inhaled steroid therapy. These predictors may contribute, in combination with genomic information, to stratified medical treatment tailored to the individual needs of patients

LOX-1 deficient mice show resistance to zymosan-induced arthritis

Recent data suggest that the lectin-like oxidized low-density lipoprotein (ox-LDL) receptor-1 (LOX-1)/ox-LDL system may be involved in the pathogenesis of arthritis. We aimed to demonstrate the roles of the LOX-1/ox-LDL system in arthritis development by using LOX-1 knockout (KO) mice. Arthritis was induced in the right knees of C57Bl/6 wild-type (WT) and LOX-1 KO mice via zymosan injection. Saline was injected in the left knees. Arthritis development was evaluated using inflammatory cell infiltration, synovial hyperplasia, and cartilage degeneration scores at 1, 3, and 7 days after administration. LOX-1, ox-LDL, and matrix metalloproteinase-3 (MMP-3) expression in the synovial cells and chondrocytes was evaluated by immunohistochemistry. The LOX-1, ox-LDL, and MMP-3 expression levels in synovial cells were scored on a grading scale. The positive cell rate of LOX-1, ox-LDL, and MMP-3 in chondrocytes was measured. The correlation between the positive cell rate of LOX-1 or ox-LDL and the cartilage degeneration score was also examined. Inflammatory cell infiltration, synovial hyperplasia, and cartilage degeneration were significantly reduced in the LOX-1 KOmice with zymosan-induced arthritis (ZIA) compared to WT mice with ZIA. In the saline-injected knees, no apparent arthritic changes were observed. LOX-1 and ox-LDL expression in synovial cells and chondrocytes were detected in the knees of WT mice with ZIA. No LOX-1 and ox-LDL expression was detected in the knees of LOX-1 KOmice with ZIA or the saline-injected knees of both mice. MMP-3 expression in the synovial cells and chondrocytes was also detected in knees of both mice with ZIA, and was significantly less in the LOX-1 KO mice than in WT mice. The positive cell rate of LOX-1 or ox-LDL and the cartilage degeneration score showed a positive correlation. Our data show the involvement of the LOX-1/ox-LDL system in murine ZIA development. LOX-1-positive synovial cells and chondrocytes are potential therapeutic targets for arthritis prevention

LOX-1 deficient mice show resistance to zymosan-induced arthritis

Recent data suggest that the lectin-like oxidized low-density lipoprotein (ox-LDL) receptor-1 (LOX-1)/ox-LDL system may be involved in the pathogenesis of arthritis. We aimed to demonstrate the roles of the LOX-1/ox-LDL system in arthritis development by using LOX-1 knockout (KO) mice. Arthritis was induced in the right knees of C57Bl/6 wild-type (WT) and LOX-1 KO mice via zymosan injection. Saline was injected in the left knees. Arthritis development was evaluated using inflammatory cell infiltration, synovial hyperplasia, and cartilage degeneration scores at 1, 3, and 7 days after administration. LOX-1, ox-LDL, and matrix metalloproteinase-3 (MMP-3) expression in the synovial cells and chondrocytes was evaluated by immunohistochemistry. The LOX-1, ox-LDL, and MMP-3 expression levels in synovial cells were scored on a grading scale. The positive cell rate of LOX-1, ox-LDL, and MMP-3 in chondrocytes was measured. The correlation between the positive cell rate of LOX-1 or ox-LDL and the cartilage degeneration score was also examined. Inflammatory cell infiltration, synovial hyperplasia, and cartilage degeneration were significantly reduced in the LOX-1 KOmice with zymosan-induced arthritis (ZIA) compared to WT mice with ZIA. In the saline-injected knees, no apparent arthritic changes were observed. LOX-1 and ox-LDL expression in synovial cells and chondrocytes were detected in the knees of WT mice with ZIA. No LOX-1 and ox-LDL expression was detected in the knees of LOX-1 KOmice with ZIA or the saline-injected knees of both mice. MMP-3 expression in the synovial cells and chondrocytes was also detected in knees of both mice with ZIA, and was significantly less in the LOX-1 KO mice than in WT mice. The positive cell rate of LOX-1 or ox-LDL and the cartilage degeneration score showed a positive correlation. Our data show the involvement of the LOX-1/ox-LDL system in murine ZIA development. LOX-1-positive synovial cells and chondrocytes are potential therapeutic targets for arthritis prevention

Liddle’s-like syndrome associated with nephrotic syndrome secondary to membranous nephropathy: the first case report

Abstract Background Liddle’s syndrome is a rare monogenic form of hypertension caused by truncating or missense mutations in the C termini of the epithelial sodium channel (ENaC) β or γ subunits. Patients with this syndrome present with early onset of hypertension, hypokalemia, metabolic alkalosis, hyporeninemia and hypoaldosteronism, and a potassium-sparing diuretics (triamterene or amiloride) can drastically improves the disease condition. Although elderly patients having these characteristics were considered to have Liddle’s syndrome or Liddle’s-like syndrome, no previous report has indicated that Liddle’s-like syndrome could be caused by nephrotic syndrome of primary glomerular disease, which is characterized by urinary excretion of > 3 g of protein/day plus edema and hypoalbuminemia, or has explained how the activity function of ENaC could be affected in the setting of high proteinuria. Case presentation A 65-year-old Japanese man presented with nephrotic syndrome. He had no remarkable family history, but had a medical history of hypertension and hyperlipidemia. On admission, hypertension, spironolactone-resistant hypokalemia (2.43 mEq/l), hyporeninemic hypoaldosteronism, and metabolic alkalosis, which suggested Liddle’s syndrome, were observed. Treatment with triamterene together with a steroid for nephrotic syndrome resulted in rapid and remarkable effective on improvements of hypertension, hypokalemia, and edema of the lower extremities. Renal biopsy revealed membranous nephropathy (MN) as the cause of nephrotic syndrome, and advanced gastric cancer was identified on screening examination for cancers that could be associated with the development of MN. After total gastrectomy, triamterene was not required and proteinuria decreased. A mutation in the β or γ subunits of the ENaC gene was not identified. Conclusion We reported for the first time a case of Liddle’s-like syndrome associated with nephrotic syndrome secondary to MN. Aberrant activation of ENaC was suggested transient during the period of high proteinuria, and the activation was reversible with a decrease in proteinuria

Time Trend in the Prevalence of Adult Asthma in Japan: Findings from Population-Based Surveys in Fujieda City in 1985,1999, and 2006

Background: The burden of asthma is recognized as an important public health problem worldwide. In most countries, the prevalence of asthma has been reported to increase in the last few decades. However, more recent epidemiological studies have shown that the prevalence of asthma has been flat or even decreasing after the 1990s in some developed countries. The recent time trend in the prevalence of adult asthma in Japan is unknown. Methods: Population-based surveys were conducted three times in the same region, in 1985, 1999, and 2006, at Fujieda City, Shizuoka, Japan, and the results were reported previously. We compared the results of these surveys to reveal the time trend in the prevalence of adult asthma. Although the questionnaires used in these surveys were not exactly the same, the time trend was assessed by comparing the responses to relevant questions between questionnaires. Results: The prevalences of wheeze following a common cold and dyspneal feeling at night increased significantly from 1985 to 1999 (4.2% to 7.6%, and 3.2% to 5.3%, respectively). The prevalences of lifetime asthma and current asthma also significantly increased from 1999 to 2006 (5.1% to 6.7%, and 1.5% to 3.4%, respectively). Conclusions: The prevalences of asthma among adults in Fujieda City consistently increased from 1985 to 2006. There was no evidence that the prevalences were in plateau or decreasing. These findings suggest that more efforts are required to stop the increase in the burden of this disease in Japan