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41.
Willem Staels Yannick Verdonck Yves Heremans Gunter Leuckx Sofie De Groef Carlo Heirman Eelco de Koning Conny Gysemans Kris Thielemans Luc Baeyens Harry Heimberg Nico De Leu 《Diabetologia》2018,61(8):1804-1810
Aims/hypothesis
The initial avascular period following islet transplantation seriously compromises graft function and survival. Enhancing graft revascularisation to improve engraftment has been attempted through virus-based delivery of angiogenic triggers, but risks associated with viral vectors have hampered clinical translation. In vitro transcribed mRNA transfection circumvents these risks and may be used for improving islet engraftment.Methods
Mouse and human pancreatic islet cells were transfected with mRNA encoding the angiogenic growth factor vascular endothelial growth factor A (VEGF-A) before transplantation under the kidney capsule in mice.Results
At day 7 post transplantation, revascularisation of grafts transfected with Vegf-A (also known as Vegfa) mRNA was significantly higher compared with non-transfected or Gfp mRNA-transfected controls in mouse islet grafts (2.11- and 1.87-fold, respectively) (vessel area/graft area, mean?±?SEM: 0.118?±?0.01 [n?=?3] in Vegf-A mRNA transfected group (VEGF) vs 0.056?±?0.01 [n?=?3] in no RNA [p?<?0.05] vs 0.063?±?0.02 [n?=?4] in Gfp mRNA transfected group (GFP) [p?<?0.05]); EndoC-bH3 grafts (2.85- and 2.48-fold. respectively) (0.085?±?0.02 [n?=?4] in VEGF vs 0.030?±?0.004 [n?=?4] in no RNA [p?<?0.05] vs 0.034?±?0.01 [n?=?5] in GFP [p?<?0.05]); and human islet grafts (3.17- and 3.80-fold, respectively) (0.048?±?0.013 [n?=?3] in VEGF vs 0.015?±?0.0051 [n?=?4] in no RNA [p?<?0.01] vs 0.013?±?0.0046 [n?=?4] in GFP [p?<?0.01]). At day 30 post transplantation, human islet grafts maintained a vascularisation benefit (1.70- and 1.82-fold, respectively) (0.049?±?0.0042 [n?=?8] in VEGF vs 0.029?±?0.0052 [n?=?5] in no RNA [p?<?0.05] vs 0.027?±?0.0056 [n?=?4] in GFP [p?<?0.05]) and a higher beta cell volume (1.64- and 2.26-fold, respectively) (0.0292?±?0.0032 μl [n?=?7] in VEGF vs 0.0178?±?0.0021 μl [n?=?5] in no RNA [p?<?0.01] vs 0.0129?±?0.0012 μl [n?=?4] in GFP [p?<?0.001]).Conclusions/interpretation
Vegf-A mRNA transfection before transplantation provides a promising and safe strategy to improve engraftment of islets and other cell-based implants.42.
María Rubini Giménez Karin Wildi Desiree Wussler Luca Koechlin Jasper Boeddinghaus Thomas Nestelberger Patrick Badertscher Raphael Sedlmayer Christian Puelacher Tobias Zimmermann Jeanne du Fay de Lavallaz Pedro Lopez-Ayala Kathrin Leu Katharina Rentsch Òscar Miró Beatriz López F. Javier Martín-Sánchez José Bustamante Christian Mueller 《Revista espa?ola de cardiología》2021,74(6):502-509
Introduction and objectivesRelease kinetics of high-sensitivity cardiac troponin (hs-cTn) T and I in patients with acute myocardial infarction (AMI) are incompletely understood. We aimed to assess whether hs-cTnT/I release in early AMI is near linear.MethodsIn a prospective diagnostic multicenter study the acute release of hs-cTnT and hs-cTnI within 1 and 2 hours from presentation to the emergency department was quantified using 3 hs-cTnT/I assays in patients with suspected AMI. The primary endpoint was correlation between hs-cTn changes from presentation to 1 hour vs changes from presentation to 2 hours, among all AMI patients and different prespecified subgroups. The final diagnosis was adjudicated by 2 independent cardiologists, based on serial hs-cTnT from the serial study blood samples and additional locally measured hs-cTn values.ResultsAmong 2437 patients with complete hs-cTnT data, AMI was the adjudicated diagnosis in 376 patients (15%). For hs-cTnT, the correlation coefficient between 0- to 1-hour change and 0- to 2 hour change was 0.931 (95%CI, 0.916-0.944), P < .001. Similar findings were obtained with hs-cTnI (Architect) with correlation coefficients between 0- to 1-hour change and 0- to 2 hour change of 0.969 and hs-cTnI (Centaur) of 0.934 (P < .001 for both). Findings were consistent among type 1 and type 2 AMI and in the subgroup of patients presenting very early after chest pain onset.ConclusionsPatients presenting with early AMI showed a near linear release of hs-cTnT and hs-cTnI. This near linearity provides the pathophysiological basis for rapid diagnostic algorithms using 0- to 1-hour changes as surrogates for 0- to 2 hour or 0- to 3 hour changes.Registered at ClinicalTrials.gov (Identifier: NCT00470587). 相似文献
43.
Oxidative metabolism of the human eosinophil 总被引:14,自引:1,他引:14
We have compared the oxidative metabolism of human eosinophils (80%-90% purity) to that of neutrophils. Hexose monophosphate (HMP) shunt activity of eosinophils was higher than that of neutrophils under either resting or phagocytizing conditions. Eosinophil HMP shunt activity also was stimulated by phorbol myristate acetate, a membrane- active agent. Eosinophils showed a marked incorporation of 125I into trichloroacetic acid-insoluble material under resting conditions, which increased markedly during phagocytosis. Eosinophils likewise showed a greater reduction of nitroblue tetrazolium dye during phagocytosis than did neutrophils. Measurement of other parameters of oxidative metabolism indicated that eosinophils generated superoxide anion following phagocytosis and also elicited a burst of chemiluminescence similar to that observed during phagocytosis by neutrophils. Measurement of NADPH oxidase activity demonstrated that this enzyme was 3-6 times more active in fractions isolated from eosinophils than in corresponding fractions isolated from neutrophils; this was observed over a range of substrate concentrations. The eosinophil enzyme sedimented differently than the neutrophil enzyme with differential centrifugation; neither showed sedimentation characteristics of peroxidase. These data indicate that eosinophils possess a similar, although in some ways more potent, oxidative burst than neutrophils and are consistent with a role for NADPH oxidase in the initiation of that burst. 相似文献
44.
The renin-angiotensin system is the major contributor to development of hypertension, atherosclerosis, and many other cardiovascular diseases. Angiotensin II, one of the main effectors of this system, contributes to the pathogenesis of hypertension and plays an important role in monocyte, platelet, and endothelium interactions. The effects on platelet and endothelial function, either by angiotensin converting enzyme inhibitors or angiotensin receptor antagonists, are still not well understood. A double-blind, randomized, prospective trial of either enalapril (10-20 mg daily) or eprosartan (400-800 mg daily) over a 10-week period was conducted in 42 patients (27 males, 15 females). Platelet activation was evaluated by measuring platelet factor 4 (PF-4), beta-thromboglobulin (beta-TG), the ratio of platelet factor 4 to beta-thromboglobulin, and endothelial function by measuring total plasma nitrate levels, von Willebrand factor (vWF) levels, and blood flow using venous occlusive plethysmography. After a 10-week treatment with enalapril or eprosartan, the sitting blood pressure in both the enalapril group (from 152.2 +/- 18.7 mmHg to 141.9 +/- 23.5 mmHg, P < 0.05) and eprosartan group (from 151 +/- 10.0 mmHg to 142.3 +/- 12.9 mmHg, P < 0.05) was significantly reduced. Significant diastolic blood pressure (DPB) reduction (from 94 +/- 8.7 to 84.5 +/- 9.6 mmHg, P < 0.05) and a greater DBP reduction response were found in the eprosartan group (63% in eprosartan versus 25% in enalapril). Additionally, dose-dependent reductions in the indices of platelet activation and endothelial dysfunction were observed in patients administered high dose treatments of eprosartan and enalapril, and the beneficial effects of these agents were not correlated with the reduction of blood pressure using both agents. Eprosartan is effective and well-tolerated in the treatment of mid-to-moderate hypertension, and the DBP response reduction to eprosartin was better than that to enalapril. A high dose of either eprosartan or enalapril significantly decreased the indices of platelet activation and endothelial dysfunction in hypertensive patients. The benefits of both agents cannot be explained solely by their antihypertensive effects and possibly may be mediated through their unique effect on angiotensin blockade. 相似文献
45.
Cheuk-Kwan Sun Yen-Yi Zhen Steve Leu Tzu-Hsien Tsai Li-Teh Chang Jiunn-Jye Sheu Yung-Lung Chen Sarah Chua Han-Tan Chai Hung-I Lu Hsueh-Wen Chang Fan-Yen Lee Hon-Kan Yip 《International journal of cardiology》2014
Background
This study tested whether adipose-derived mesenchymal stem cells (ADMSC) embedded in platelet-rich fibrin (PRF) scaffold is superior to direct ADMSC implantation in improving left ventricular (LV) performance and reducing LV remodeling in a rat acute myocardial infarction (AMI) model of left anterior descending coronary artery (LAD) ligation.Methods
Twenty-eight male adult Sprague Dawley rats equally divided into group 1 [sham control], group 2 (AMI only), group 3 (AMI + direct ADMSC implantation), and group 4 (AMI + PRF-embedded autologous ADMSC) were sacrificed on day 42 after AMI.Results
LV systolic and diastolic dimensions and volumes, and infarct/fibrotic areas were highest in group 2, lowest in group 1 and significantly higher in group 3 than in group 4, whereas LV performance and LV fractional shortening exhibited a reversed pattern (p < 0.005). Protein expressions of inflammation (oxidative stress, IL-1β, MMP-9), apoptosis (mitochondrial Bax, cleaved PARP), fibrosis (Smad3, TGF-β), and pressure-overload biomarkers (BNP, MHC-β) displayed a pattern similar to that of LV dimensions, whereas anti-inflammatory (IL-10), anti-apoptotic (Bcl-2), and anti-fibrotic (Smad1/5, BMP-2) indices showed a pattern similar to that of LV performance among the four groups (all p < 0.05). Angiogenesis biomarkers at protein (CXCR4, SDF-1α, VEGF), cellular (CD31 +, CXCR4 +, SDF-1α +), and immunohistochemical (small vessels) levels, and cardiac stem cell markers (C-kit +, Sca-1 +) in infarct myocardium were highest in group 4, lowest in group 1, and significantly higher in group 3 than in group 2 (all p < 0.005).Conclusion
PRF-embedded ADMSC is superior to direct ADMSC implantation in preserving LV function and attenuating LV remodeling. 相似文献46.
Patient perspectives on de‐simplifying their single‐tablet co‐formulated antiretroviral therapy for societal cost savings 下载免费PDF全文
Objectives
The incremental costs of expanding antiretroviral (ARV) drug treatment to all HIV‐infected patients are substantial, so cost‐saving initiatives are important. Our objectives were to determine the acceptability and financial impact of de‐simplifying (i.e. switching) more expensive single‐tablet formulations (STFs) to less expensive generic‐based multi‐tablet components. We determined physician and patient perceptions and acceptance of STF de‐simplification within the context of a publicly funded ARV budget.Methods
Programme costs were calculated for patients on ARVs followed at the Southern Alberta Clinic, Canada during 2016 (Cdn$). We focused on patients receiving Triumeq® and determined the savings if patients de‐simplified to eligible generic co‐formulations. We surveyed all prescribing physicians and a convenience sample of patients taking Triumeq® to see if, for budgetary purposes, they felt that de‐simplification would be acceptable.Results
Of 1780 patients receiving ARVs, 62% (n = 1038) were on STF; 58% (n = 607) of patients on STF were on Triumeq®. The total annual cost of ARVs was $26 222 760. The cost for Triumeq® was $8 292 600. If every patient on Triumeq® switched to generic abacavir/lamivudine and Tivicay® (dolutegravir), total costs would decrease by $4 325 040. All physicians (n = 13) felt that de‐simplifying could be safely achieved. Forty‐eight per cent of 221 patients surveyed were agreeable to de‐simplifying for altruistic reasons, 27% said no, and 25% said maybe.Conclusions
De‐simplifying Triumeq® generates large cost savings. Additional savings could be achieved by de‐simplifying other STFs. Both physicians and patients agreed that selective de‐simplification was acceptable; however, it may not be acceptable to every patient. Monitoring the medical and cost impacts of de‐simplification strategies seems warranted.47.
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50.
Ke Zheng Jordi Xiol Michael Reuter Sigrid Eckardt N. Adrian Leu K. John McLaughlin Alexander Stark Ravi Sachidanandam Ramesh S. Pillai Peijing Jeremy Wang 《Proceedings of the National Academy of Sciences of the United States of America》2010,107(26):11841-11846
Piwi-interacting RNAs (piRNAs) are essential for silencing of transposable elements in the germline, but their biogenesis is poorly understood. Here we demonstrate that MOV10L1, a germ cell–specific putative RNA helicase, is associated with Piwi proteins. Genetic disruption of the MOV10L1 RNA helicase domain in mice renders both MILI and MIWI2 devoid of piRNAs. Absence of a functional piRNA pathway in Mov10l1 mutant testes causes loss of DNA methylation and subsequent derepression of retrotransposons in germ cells. The Mov10l1 mutant males are sterile owing to complete meiotic arrest. This mouse mutant expresses Piwi proteins but lacks piRNAs, suggesting that MOV10L1 is required for piRNA biogenesis and/or loading to Piwi proteins. 相似文献