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1.
Hilde Tobi Paul B. van den Berg Lolkje TW de Jong‐van den Berg 《Pharmacoepidemiology and drug safety》2006,15(3):211-211
The original article to which this Erratum refers was published in Pharmacoepidemiology and Drug Safety 2005; 14: 239–247. 相似文献
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3.
Periosteal Ewing sarcoma 总被引:3,自引:0,他引:3
4.
Michelle N. Vu Kumari G. Lokugamage Jessica A. Plante Dionna Scharton Aaron O. Bailey Stephanea Sotcheff Daniele M. Swetnam Bryan A. Johnson Craig Schindewolf R. Elias Alvarado Patricia A. Crocquet-Valdes Kari Debbink Scott C. Weaver David H. Walker William K. Russell Andrew L. Routh Kenneth S. Plante Vineet D. Menachery 《Proceedings of the National Academy of Sciences of the United States of America》2022,119(32)
The furin cleavage site (FCS), an unusual feature in the SARS-CoV-2 spike protein, has been spotlighted as a factor key to facilitating infection and pathogenesis by increasing spike processing. Similarly, the QTQTN motif directly upstream of the FCS is also an unusual feature for group 2B coronaviruses (CoVs). The QTQTN deletion has consistently been observed in in vitro cultured virus stocks and some clinical isolates. To determine whether the QTQTN motif is critical to SARS-CoV-2 replication and pathogenesis, we generated a mutant deleting the QTQTN motif (ΔQTQTN). Here, we report that the QTQTN deletion attenuates viral replication in respiratory cells in vitro and attenuates disease in vivo. The deletion results in a shortened, more rigid peptide loop that contains the FCS and is less accessible to host proteases, such as TMPRSS2. Thus, the deletion reduced the efficiency of spike processing and attenuates SARS-CoV-2 infection. Importantly, the QTQTN motif also contains residues that are glycosylated, and disruption of its glycosylation also attenuates virus replication in a TMPRSS2-dependent manner. Together, our results reveal that three aspects of the S1/S2 cleavage site—the FCS, loop length, and glycosylation—are required for efficient SARS-CoV-2 replication and pathogenesis.SARS-CoV-2 emerged in late 2019 and has caused the largest pandemic since the 1918 influenza outbreak (1). An unusual feature of SARS-CoV-2 is the presence of a furin cleavage site (FCS) in its spike protein (2). The CoV spike is a trimer of spike proteins composed of the S1 and S2 subunits, responsible for receptor binding and membrane fusion, respectively (1). After receptor binding, the spike protein is proteolytically cleaved at the S1/S2 and S2′ sites to activate the fusion machinery. For SARS-CoV-2, the spike protein contains a novel cleavage motif recognized by the host cell furin protease (PRRAR) directly upstream of the S1/S2 cleavage site that facilitates cleavage prior to virion release from the producer cell. This FCS, not found in other group 2B CoVs, plays a key role in spike processing, infectivity, and pathogenesis as shown by our group and others (3, 4).Importantly, another novel amino acid motif, QTQTN, is found directly upstream of the FCS. This QTQTN motif, also absent in other group 2B CoVs, is often deleted and has been pervasive in cultured virus stocks of the alpha, beta, and delta variants (5–8). In addition, the QTQTN deletion has been observed in a small subset of patient samples as well (9–11). Because this deletion has been frequently identified, we set out to characterize it and determine whether it has consequences for viral replication and virulence. Using our infectious clone (12, 13), we demonstrated that the loss of this motif attenuates SARS-CoV-2 replication in respiratory cells in vitro and pathogenesis in hamsters. The QTQTN deletion results in reduced spike cleavage and diminished capacity to use serine proteases on the cell surface for entry. Importantly, mutations of glycosylation-enabling residues in the QTQTN motif results in similar replication attenuation despite intact spike processing. Together, our results highlight elements in the SARS-CoV-2 spike in addition to the FCS that contribute to increased replication and pathogenesis. 相似文献
5.
Hemodynamic consequences of neonatal polycythemia 总被引:2,自引:0,他引:2
The hemodynamic consequences of neonatal polycythemic hyperviscosity and the effects of partial exchange transfusion were evaluated in 13 infants. Mean (+/- SD) venous hematocrit was 72% +/- 2.5%. After partial exchange transfusion, whole blood viscosity at a shear rate of 11.5 sec-1 decreased from 16.2 to 8.4 centipoise. There were significant (P less than 0.05) increases in heart rate (127 +/- 7.5 to 139 +/- 7.8 beats/min), Doppler-derived cardiac index (200 +/- 35 to 263 +/- 48 ml/kg/min), left ventricular stroke volume index (1.56 +/- 0.23 to 1.89 +/- 0.33 ml/kg), systemic oxygen transport (51.4 +/- 8.4 to 57.9 +/- 11.9 ml/kg/min), and laser-Doppler peripheral (cutaneous) blood flow (+80%) after partial exchange transfusion. The increase in cardiac index probably resulted from reductions in pulmonary and systemic vascular resistance index, the latter decreasing from 0.26 to 0.19 mm Hg/ml/min/kg-1. The greater increase in cutaneous blood flow (+80%) versus cardiac index (+32%) after exchange transfusion suggests hemodynamic compromise and a redistribution of blood flow away from organs that use little oxygen during polycythemia. Our data provide a possible basis for the symptoms of neonatal polycythemia, and demonstrate the acute hemodynamic benefits of partial exchange transfusion. 相似文献
6.
C Rizan J Ansell TW Tilston N Warren J Torkington 《Annals of the Royal College of Surgeons of England》2015,97(8):549-555
Introduction
Self-assessment is a way of improving technical capabilities without the need for trainer feedback. It can identify areas for improvement and promote professional medical development. The aim of this review was to identify whether selfassessment is an accurate form of technical skills appraisal in general surgery.Methods
The PubMed, MEDLINE®, Embase™ and Cochrane databases were searched for studies assessing the reliability of self-assessment of technical skills in general surgery. For each study, we recorded the skills assessed and the evaluation methods used. Common endpoints between studies were compared to provide recommendations based on the levels of evidence.Results
Twelve studies met the inclusion criteria from 22,292 initial papers. There was no level 1 evidence published. All papers compared the correlation between self-appraisal versus an expert score but differed in the technical skills assessment and the evaluation tools used. The accuracy of self-assessment improved with increasing experience (level 2 recommendation), age (level 3 recommendation) and the use of video playback (level 3 recommendation). Accuracy was reduced by stressful learning environments (level 2 recommendation), lack of familiarity with assessment tools (level 3 recommendation) and in advanced surgical procedures (level 3 recommendation).Conclusions
Evidence exists to support the reliability of self-assessment of technical skills in general surgery. Several variables have been shown to affect the accuracy of self-assessment of technical skills. Future work should focus on evaluating the reliability of self-assessment during live operating procedures. 相似文献7.
A non-human primate antiserum was prepared to acute lymphoblastic leukemia of T-cell phenotype (T-ALL) and, after absorptions with normal blood elements, reacted by immunofluorescence and microcytotoxicity to all the T-ALL tested. In addition, the antiserum reacted with cells from about 70% of the common ALL studied and immunoprecipitated the common ALL antigen of 100,000 daltons. However, when the anti-T-ALL serum was absorbed with with lymphoblasts from common ALL, it failed to react with common ALL lymphoblasts, yet reacted significantly with cells from patients with T-ALL phenotype and defined a 100,000-dalton membrane component not found on common ALL lymphoblasts. In addition, sequential immunoprecipitation of 125I-labeled T-ALL membranes by anti- common-ALL serum followed by anti-T-ALL serum detected the T-ALL membrane component of 100,000 daltons that was not found on common ALL. Thus, our results demonstrate the presence of of a unique human T-ALL antigen present on all T-ALL distinct from the common ALL antigen. 相似文献
8.
SJ Smith CV Rahman PA Clarke AA Ritchie TW Gould JH Ward KM Shakesheff RG Grundy R Rahman 《Annals of the Royal College of Surgeons of England》2014,96(7):495-501
Introduction
The median survival of patients with glioblastoma multiforme (astrocytoma grade 4) remains less than 18 months despite radical surgery, radiotherapy and systemic chemotherapy. Surgical implantation of chemotherapy eluting wafers into the resection cavity has been shown to improve length of survival but the current licensed therapy has several drawbacks. This paper investigates in vivo efficacy of a novel drug eluting paste in glioblastoma.Methods
Poly(lactic-co-glycolic acid)/poly(ethylene glycol) (PLGA/PEG) self-sintering paste was loaded with the chemotherapeutic agent etoposide and delivered surgically into partially resected tumours in a flank murine glioblastoma xenograft model.Results
Surgical delivery of the paste was successful and practical, with no toxicity or surgical morbidity to the animals. The paste was retained in the tumour cavity, and preliminary results suggest a useful antitumour and antiangiogenic effect, particularly at higher doses. Bioluminescent imaging was not affected significantly by the presence of the paste in the tumour.Conclusions
Chemotherapy loaded PLGA/PEG paste seems to be a promising technology capable of delivering active drugs into partially resected tumours. The preliminary results of this study suggest efficacy with no toxicity and will lead to larger scale efficacy studies in orthotopic glioblastoma models. 相似文献9.