Reproducibility of myocardial thallium-201 washout in studies applying a standardized dipyridamole stress protocol

Thallium-201 (²⁰¹T1) washout analysis was proposed as an adjunctive tool to improve the detection of coronary artery disease (CAD). Since reproducibility of ²⁰¹T1 washout in dipyridamole (DPM) stress studies is unknown, this item was evaluated in 32 patients (24 with CAD, 8 without CAD), who were scintigraphed twice within 1–2 weeks. At 2 minutes following DPM infusion (0.5 mg/kg/5 min), 2 mCi ²⁰¹T1 were injected. Global and segmental washout were calculated by comparing circumferential profiles of respective background-corrected stress (left anterior oblique (LAO) 45°: 8 min postinfusion (p.i.), 35 min p.i.; anterior (ANT): 17 min p.i.; LAO 70°: 26 min p.i.) and redistribution (4 h p.i.) images. Whereas visual findings were comparable for study I and II, reproducibility of ²⁰¹T1 washout was low, indicated by comparing variances among patients with variance between studies, which were 28.8 and 71.2% of total variance, respectively. Mean differences of segmental washout between the studies ranged from 9.75 to 19.24% with only minor differences with regard to the different views and segments evaluated. Variability was lower using the intermediate instead of the initial scintigram as reference for the redistribution image (12.87±11.64% vs. 18.59±14.43%, n = 85; p<0.01). Variability was higher for nonstenosed compared to stenosed segments (14.54 ± 11.41%, n=32 vs. 9.89±8.03%, n=28, p<0.05). Correspondent with results of visual interpretation, variance of relative differences of washout values between neighboring segments was lower than variance statistically expected from variability of washout values between study I and II (12.79%, n=216 vs. 21.55%, n=270; F=2.76, p<0.01). It is suggested, that considerable washout variability might explain the controversially discussed diagnostic value of ²⁰¹T1 washout analysis in DPM stress studies.     

Diabetes enhances lipopolysaccharide-induced cardiac toxicity in the mouse model

Diabetic patients have a higher rate of mortality from sepsis than do their nondiabetic septic counterparts. The hypothesis in this study is that chronic diabetes may make cardiovascular systems more sensitive to septicemia. To test this hypothesis, the authors investigated the effect of diabetes on endotoxin-induced cardiac toxicity. Diabetes was induced in FVB mice by injecting a single dose (150 mg/kg) of streptozotocin. Two months after streptozotocin treatment, the diabetic mice were treated with lipopolysaccharide by intraperitoneal injection at 2 mg/kg. Cardiac toxicity was evaluated by measuring levels of serum cardiac enzymes and cardiac morphology at 1 h, 4.5 h, and 24 h after lipopolysaccharide treatment. Serum and cardiac tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were detected by enzyme-linked immunosorbent assay methods at 1 h and 4.5 h after lipopolysaccharide treatment. Lipopolysaccharide treatment did not significantly affect the diabetic manifestations, including decreased body weight gain and increased glycated hemoglobin and serum triglyceride levels. However, diabetes significantly enhanced lipopolysaccharide-induced cardiac toxicity, which was demonstrated by significant increases in the levels of cardiac enzymes such as creatine phosphokinase and troponin T, abnormal morphological changes examined under light microscope with hematoxylin and eosin staining, and oxidative damage to proteins detected by 3-nitrotyrosine staining. Lipopolysaccharide treatment significantly increased serum and cardiac TNF-α and IL-6 concentrations. Diabetes did not alter the effect of lipopolysaccharide on serum and cardiac TNF-α elevation, but it significantly enhanced lipopolysaccharide-induced cardiac IL-6 production. These results suggest that diabetes significantly enhances endotoxin-induced cardiac toxicity, possibly through mechanisms that involve inflammatory/acute-phase cytokines.     

Pregnancy-associated cytotoxic lymphoma: a report of 4 cases

The clinicopathological and biological significance of Hodgkin's disease and non-Hodgkin's lymphoma, which are infrequently encountered in women of childbearing age, remains to be clarified. We recently reviewed 4 cases of non-Hodgkin's lymphoma of the T/natural killer (T/NK)-cell phenotype, all of which were associated with pregnancy and characterized by the expression of the cytotoxic granule-associated proteins T-cell intracellular antigen-1 and/or granzyme B. The 4 cases selected had presented between November 1993 and May 1999. The criteria for selection were that the onset of clinical manifestations occurred during pregnancy or within 6 months after delivery. The patients comprised 1 patient with p80/anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL), 1 with p80/ALK-negative ALCL, and 2 with peripheral T/NK-cell lymphomas of unspecified type. The diseases followed aggressive clinical courses: 3 patients died within 6.5 months after diagnosis, and only 1 was still alive with the disease 17 months after diagnosis. The diseases appeared to progress rapidly after delivery. Maternal immunity and hormonal changes during pregnancy may be closely related to the biological behavior of these unusual tumors.This study is, to the best of our knowledge, the first to address pregnancy-associated cytotoxic lymphoma.     

Dobutamine stress echocardiography and cardiac troponin T for the detection of significant coronary artery disease and predicting outcome in renal transplant candidates.

AIMS: Ischaemic heart disease is the leading cause of mortality and morbidity in patients with end-stage renal disease (ESRD) and after renal transplantation. However, the optimal non-invasive test for coronary artery disease (CAD) diagnosis in this population has yet to be established. The aim of this study was to assess the diagnostic accuracy of dobutamine stress echocardiography (DSE) and baseline plasma cardiac troponin T (cTnT) for detecting significant CAD and predicting adverse cardiac events in patients referred for renal transplantation. METHODS: Coronary angiography, DSE, and baseline cTnT measurements were performed in 118 consecutive patients (mean age 52+/-12 years, 75 male) with ESRD (mean creatinine 608+/-272 micromol/L) referred for renal transplantation. The mean follow-up period was 1.32+/-0.48 years. Significant CAD was defined as a reduction in luminal diameter >70% by visual estimation in at least one major epicardial vessel. An abnormal DSE result defined as the development of a new regional wall motion abnormality in one or more normal resting segments or a deterioration of wall motion in one or more resting hypokinetic segments. A baseline cTnT>0.1 microg/L was taken as positive. RESULTS: Significant CAD in at least one vessel was present in 35 patients (30%). The number of patients with significant 3 vessel and 2 vessel disease was 6 and 7, respectively. An abnormal DSE result was present in 36 (31%) patients. Thirty-one (26%) had cTnT>0.1 microg/L. Sixty-four (54%) patients were on dialysis and 46 (39%) were diabetic. The sensitivity, specificity, positive and negative predictive values for DSE in detecting significant coronary artery disease were 88%, 94%, 86% and 95%, respectively. The same values for a raised cTnT were 54%, 62%, 40% and 74%, respectively. The combination of an abnormal DSE result and raised cTnT gave values of 61%, 91%, 76%, and 80%, respectively. Over the follow-up period, mortality was significantly higher in those with a raised baseline cTnT but not those with an abnormal DSE result or significant CAD. CONCLUSION: DSE is an accurate technique for the detection of significant CAD in renal transplant candidates. An elevated cTnT does not predict significant CAD in this population and when used in conjunction with DSE, reduces the sensitivity of the combined tests. cTnT is an important marker of prognosis in renal transplant candidates.     

Investigation of the sensitivities of distinct gastric cancer cells to parvovirus H‐1 induced cytotoxicity

OBJECTIVE: To investigate the sensitivities of distinct gastric cancer cells to parvovirus H‐1 induced cytotoxicity and the possible mechanism(s). METHODS: There were six distinct differentiated gastric cancer cell lines: HGC27 (undifferentiated), BGC823 (undifferentiated), MKN45 (poorly differentiated), AGS (poorly differentiated), SGC7901 (moderately differentiated) and MKN28 (well differentiated). The cell cycle distributions were measured by flow cytometry and the differential sensitivities of the six distinct gastric cancer cells after H‐1 virus infection were detected by MTT assay. RT‐PCR was used to detect viral NS1 gene expression in all six gastric cancer cell lines. RESULTS: The S phase ratios of HGC27, BGC823, MKN45, AGS, SGC7901 and MKN28 were 24.72%, 30.15%, 27.10%, 29.03%, 31.82% and 33.73%, respectively. HGC27 cells were sensitive to H‐1 virus induced cytotoxicity, followed by SGC7901 cells. MKN45 and AGS cells were moderately sensitive and MKN28 cells were insensitive. However, BGC823 cells were resistant to H‐1 virus induced cytotoxicity. The expressions of viral NS1 were higher in HGC27, BGC823, MKN45 and SGC7901 cells, and lower in AGS and MKN28 cells. CONCLUSIONS: The sensitivities of the distinct gastric cancer cells to H‐1 virus induced cytotoxicity were markedly different. In general, the poorly differentiated cells showed an enhanced sensitivity to H‐1 virus attack compared with well‐differentiated ones. The enhanced sensitivity of poorly versus well‐differentiated gastric cancer cells to H‐1 virus is related in part to the enhanced capacity of the former for NS1 protein production and accumulation. The undifferentiated BGC823 cells were resistant to H‐1 virus triggered cytotoxicity. It may further verify that not all tumor cells are sensitive to H‐1 virus lytic effects.     

中国人群中类风湿性关节炎患者外周血T细胞亚群表达的Meta分析

目的：评价类风湿关节炎（RA ）患者外周血T细胞亚群的变化与RA发病机制及疾病发生、发展的关系。方法检索中国生物医学文献数据库、中国知网和万方数据库,收集和筛选符合条件的研究结果,用Meta分析方法进行相关数据统计。结果纳入12篇研究,Meta分析结果显示RA患者的外周血CD3＋、CD4＋、CD8＋T细胞含量所占的比重较对照组差异无显著性（WMD ＝－0．02,95％CI[－0．07,0．02],P＝0．27;WMD ＝0．02,95％CI [0．03,0．08],P＝0．41;WMD ＝－0．03,95％CI[－0．19,0．14],P＝0．74）,但CD4＋／CD8＋比值在类风湿关节炎外周血中较健康组有明显增高（WMD ＝0．81,95％CI[0．74,0．89],P＜0．001）。结论类风湿关节炎患者外周血中,CD4＋／CD8＋比值失衡可能是RA的发病和发展过程的重要机制。     

IL-37b gene transfer enhances the therapeutic efficacy of mesenchumal stromal cells in DSS-induced colitis mice

Aim:

To investigate whether the transfer of the IL-37b gene, a newly identified inhibitor of both innate and adaptive immunity, could improve the therapeutic efficacy of mesenchumal stromal cells (MSCs) in inflammatory bowel disease (IBD).

Methods:

The expression of IL-37 in biopsied specimens of the patients with active ulcerative colitis (UC) was detected using RT-PCR and immunohistochemistry. Mice were treated with 3% dextran sulfate sodium (DSS) for 8 days to induce colitis. Before DSS treatment, the mice were injected with MSCs, MSC-eGFP or MSC-IL37b. Their body weight was measured each day, and the colons and spleens were harvested on d 10 for pathological and biochemical analyses.

Results:

In biopsied specimens of the patients with active UC, the expression of IL-37 was dramatically elevated in inflamed mucosa, mainly in epithelial cells and infiltrating immune cells. Compared to MSC-eGFP or MSCs, MSC-IL37b administration significantly attenuated the body weight and colon length reduction, and decreased the histological score in DSS-induced colitis mice. Furthermore, MSC-IL37b administration increased the percentage of myeloid-derived suppressor cells (MDSCs) among total splenic mononuclear cells as well as the percentage of regulatory T cells (Tregs) among splenic CD4+ T cells in the mice. Moreover, MSC-IL37b administration increased the IL-2+ cells and decreased the IFN-γ+ cells among splenic CD4+ T cells.

Conclusion:

IL-37 is involved in the pathophysiology of UC. IL-37b gene transfer enhances the therapeutic efficacy of MSCs in DSS-induced colitis mice by inducing Tregs and MDSCs and regulating cytokine production.     

Pathogénie des vascularites associées aux ANCA en 2021 : mise au point

Anticytoplasmic neutrophil antibodies (ANCA)-associated vasculitis (AAV) are rare systemic immune-mediated diseases characterized by small vessel necrotizing vasculitis and/or respiratory tract inflammation. Over the last 2 decades, anti-MPO vasculitis mouse model has enlightened the role of ANCA, neutrophils, complement activation, T helper cells (Th1, Th17) and microbial agents. In humans, CD4T cells have been extensively studied, while the dramatic efficacy of rituximab demonstrated the key role of B cells. Many areas of uncertainty remain, such as the driving force of GPA extra-vascular granulomatous inflammation and the relapse risk of anti-PR3 AAV pathogenesis. Animal models eventually led to identify complement activation as a promising therapeutic target. New investigation tools, which permit in depth immune profiling of human blood and tissues, may open a new era for the studying of AAV pathogenesis.     

In vitro immunotoxicology of quantum dots and comparison with dissolved cadmium and tellurium

The increasing use of products derived from nanotechnology has raised concerns about their potential toxicity, especially at the immunocompetence level in organisms. This study compared the immunotoxicity of cadmium sulfate/cadmium telluride (CdS/Cd‐Te) mixture quantum dots (QDs) and their dissolved components, cadmium chloride (CdCl₂)/sodium telluride (NaTeO₃) salts, and a CdCl₂/NaTeO₃ mixture on four animal models commonly used in risk assessment studies: one bivalve (Mytilus edulis), one fish (Oncorhynchus mykiss), and two mammals (mice and humans). Our results of viability and phagocytosis biomarkers revealed that QDs were more toxic than dissolved metals for blue mussels. For other species, dissolved metals (Cd, Te, and Cd‐Te mixture) were more toxic than the nanoparticles (NPs). The most sensitive species toward QDs, according to innate immune cells, was humans (inhibitory concentration [IC₅₀] = 217 μg/mL). However, for adaptative immunity, lymphoblastic transformation in mice was decreased for small QD concentrations (EC₅₀ = 4 μg/mL), and was more sensitive than other model species tested. Discriminant function analysis revealed that blue mussel hemocytes were able to discriminate the toxicity of QDs, Cd, Te, and Cd‐Te mixture (Partial Wilk's λ = 0.021 and p < 0.0001). For rainbow trout and human cells, the immunotoxic effects of QDs were similar to those obtained with the dissolved fraction of Cd and Te mixture. For mice, the toxicity of QDs markedly differed from those observed with Cd, Te, and dissolved Cd‐Te mixture. The results also suggest that aquatic species responded more differently than vertebrates to these compounds. The results lead to the recommendation that mussels and mice were most able to discriminate the effects of Cd‐based NPs from the effects of dissolved Cd and Te at the immunocompetence level. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 9–25, 2015.     

Differential effects of route of T‐2 toxin exposure on hepatic oxidative damage in mice

T‐2 toxin is the most toxic among mycotoxins and poses a potential health hazard for both humans and animals. At high doses, T‐2 toxin can cause shock‐like syndrome that can result in death. We evaluated the effect of time course and route of exposure on hepatic oxidative damage in mice and it is only such study so far to compare the effects of dermal and subcutaneous exposure of T‐2 toxin. Mice were exposed to 1 LD50 of T‐2 toxin either by percutaneous (5.94 mg/kg body weight) or subcutaneous (1.54 mg/kg body weight) route and sacrificed at 0, 1, 3, and 7 days postexposure. Analysis of a number of serum biochemical variables, antioxidant enzymes activity, gene and protein expression by immunoblot assay showed time and route dependent effects of T‐2 induced hepatic oxidative damage. Time dependent increase in protein carbonyl content and protein oxidation was seen in serum and liver. Results of our study may provide possible mechanism for developing medical countermeasures against T‐2 toxin. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 64–73, 2015.