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Raban Jeger - One of the best experts on this subject based on the ideXlab platform.
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impact of clinical presentation stable angina pectoris vs unstable angina pectoris or non st elevation myocardial infarction vs st elevation myocardial infarction on long term outcomes in women undergoing percutaneous coronary intervention with drug
American Journal of Cardiology, 2015Co-Authors: Gennaro Giustino, Usman Baber, Giulio G Stefanini, Melissa Aquino, Gregg W Stone, Samantha Sartori, Philippe Gabriel Steg, William Wijns, Pieter C Smits, Raban JegerAbstract:The long-term risk associated with different coronary artery disease (CAD) presentations in women undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DES) is poorly characterized. We pooled patient-level data for women enrolled in 26 randomized clinical trials. Of 11,577 women included in the pooled database, 10,133 with known clinical presentation received a DES. Of them, 5,760 (57%) had stable angina pectoris (SAP), 3,594 (35%) had unstable angina pectoris (UAP) or non-ST-segment-elevation myocardial infarction (NSTEMI), and 779 (8%) had ST-segment-elevation myocardial infarction (STEMI) as clinical presentation. A stepwise increase in 3-year crude cumulative mortality was observed in the transition from SAP to STEMI (4.9% vs 6.1% vs 9.4%; p <0.01). Conversely, no differences in crude mortality rates were observed between 1 and 3 years across clinical presentations. After multivariable adjustment, STEMI was independently associated with greater risk of 3-year mortality (hazard ratio [HR] 3.45; 95% confidence interval [CI] 1.99 to 5.98; p <0.01), whereas no differences were observed between UAP or NSTEMI and SAP (HR 0.99; 95% CI 0.73 to 1.34; p = 0.94). In women with ACS, use of new-generation DES was associated with reduced risk of major adverse cardiac events (HR 0.58; 95% CI 0.34 to 0.98). The magnitude and direction of the effect with new-generation DES was uniform between women with or without ACS (pinteraction = 0.66). In conclusion, in women across the clinical spectrum of CAD, STEMI was associated with a greater risk of long-term mortality. Conversely, the adjusted risk of mortality between UAP or NSTEMI and SAP was similar. New-generation DESs provide improved long-term clinical outcomes irrespective of the clinical presentation in women.
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impact of clinical presentation stable angina pectoris vs unstable angina pectoris or non st elevation myocardial infarction vs st elevation myocardial infarction on long term outcomes in women undergoing percutaneous coronary intervention with drug
American Journal of Cardiology, 2015Co-Authors: Gennaro Giustino, Usman Baber, Giulio G Stefanini, Melissa Aquino, Gregg W Stone, Samantha Sartori, Philippe Gabriel Steg, William Wijns, Pieter C Smits, Raban JegerAbstract:The long-term risk associated with different coronary artery disease (CAD) presentations in women undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DES) is poorly characterized. We pooled patient-level data for women enrolled in 26 randomized clinical trials. Of 11,577 women included in the pooled database, 10,133 with known clinical presentation received a DES. Of them, 5,760 (57%) had stable angina pectoris (SAP), 3,594 (35%) had unstable angina pectoris (UAP) or non–ST-segment-elevation myocardial infarction (NSTEMI), and 779 (8%) had ST-segment-elevation myocardial infarction (STEMI) as clinical presentation. A stepwise increase in 3-year crude cumulative mortality was observed in the transition from SAP to STEMI (4.9% vs 6.1% vs 9.4%; p interaction = 0.66). In conclusion, in women across the clinical spectrum of CAD, STEMI was associated with a greater risk of long-term mortality. Conversely, the adjusted risk of mortality between UAP or NSTEMI and SAP was similar. New-generation DESs provide improved long-term clinical outcomes irrespective of the clinical presentation in women.
Steve Kisely - One of the best experts on this subject based on the ideXlab platform.
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avoidable emergency department presentations for dental comorbidities of psychiatric disorders a population based record linkage analysis
Journal of Psychosomatic Research, 2021Co-Authors: Steve Kisely, James Murray Ogilvie, Ratilal LallooAbstract:Abstract Background Indigenous peoples and those from non-Caucasian, poorer or rural backgrounds are at greater risk of emergency department (ED) presentations for non-traumatic or avoidable dental conditions. There is no information on people with mental illness. Objective To compare avoidable dental ED admissions in psychiatric patients with those of the general population over 2 years. Methods A population-based record-linkage analysis across state-based facilities in Queensland, Australia. Avoidable dental ED presentations were defined using ICD10 codes K02.9, K04.7, K05.0, K08.8 and K12. Results There were 1,381,428 individuals in the linked database, of whom 657,933 (47.6%) were male. Of the sample, 177,157 (13%) had a history of contact for mental health problems and 22,046 (1.5%) had at least one avoidable dental presentation. The most two common were unspecified disorders of teeth or supportive structures (n = 10,184) and periapical abscesses (n = 7970). After adjusting for confounders, those who had ever needed psychiatric treatment were 72% more likely to experience an avoidable dental presentation (95% = 1.65–1.79; p Conclusions In common with other marginalised groups, psychiatric patients have increased avoidable presentations. Possible clinical interventions could include an increased emphasis on oral health assessment in primary health care and early dental referral. Dental education and service planning should consider this population's needs including easier navigation of services, availability outside normal office hours, and free outreach dental clinics.
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avoidable emergency department presentations for dental comorbidities of psychiatric disorders a population based record linkage analysis
Journal of Psychosomatic Research, 2021Co-Authors: Steve Kisely, James Murray Ogilvie, Ratilal LallooAbstract:Background: Indigenous peoples and those from non-Caucasian, poorer or rural backgrounds are at greater risk of emergency department (ED) presentations for non-traumatic or avoidable dental conditions. There is no information on people with mental illness. Objective: To compare avoidable dental ED admissions in psychiatric patients with those of the general population over 2 years. Methods: A population-based record-linkage analysis across state-based facilities in Queensland, Australia. Avoidable dental ED presentations were defined using ICD10 codes K02.9, K04.7, K05.0, K08.8 and K12. Results: There were 1,381,428 individuals in the linked database, of whom 657,933 (47.6%) were male. Of the sample, 177,157 (13%) had a history of contact for mental health problems and 22,046 (1.5%) had at least one avoidable dental presentation. The most two common were unspecified disorders of teeth or supportive structures (n = 10,184) and periapical abscesses (n = 7970). After adjusting for confounders, those who had ever needed psychiatric treatment were 72% more likely to experience an avoidable dental presentation (95% = 1.65–1.79; p < 0.0001). Other significant independent risk factors were lower income, rurality and Indigenous status. Within the inpatient psychiatric group, those with substance use or personality disorders had the highest risk of avoidable presentations. Conclusions: In common with other marginalised groups, psychiatric patients have increased avoidable presentations. Possible clinical interventions could include an increased emphasis on oral health assessment in primary health care and early dental referral. Dental education and service planning should consider this population's needs including easier navigation of services, availability outside normal office hours, and free outreach dental clinics.
Ratilal Lalloo - One of the best experts on this subject based on the ideXlab platform.
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avoidable emergency department presentations for dental comorbidities of psychiatric disorders a population based record linkage analysis
Journal of Psychosomatic Research, 2021Co-Authors: Steve Kisely, James Murray Ogilvie, Ratilal LallooAbstract:Abstract Background Indigenous peoples and those from non-Caucasian, poorer or rural backgrounds are at greater risk of emergency department (ED) presentations for non-traumatic or avoidable dental conditions. There is no information on people with mental illness. Objective To compare avoidable dental ED admissions in psychiatric patients with those of the general population over 2 years. Methods A population-based record-linkage analysis across state-based facilities in Queensland, Australia. Avoidable dental ED presentations were defined using ICD10 codes K02.9, K04.7, K05.0, K08.8 and K12. Results There were 1,381,428 individuals in the linked database, of whom 657,933 (47.6%) were male. Of the sample, 177,157 (13%) had a history of contact for mental health problems and 22,046 (1.5%) had at least one avoidable dental presentation. The most two common were unspecified disorders of teeth or supportive structures (n = 10,184) and periapical abscesses (n = 7970). After adjusting for confounders, those who had ever needed psychiatric treatment were 72% more likely to experience an avoidable dental presentation (95% = 1.65–1.79; p Conclusions In common with other marginalised groups, psychiatric patients have increased avoidable presentations. Possible clinical interventions could include an increased emphasis on oral health assessment in primary health care and early dental referral. Dental education and service planning should consider this population's needs including easier navigation of services, availability outside normal office hours, and free outreach dental clinics.
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avoidable emergency department presentations for dental comorbidities of psychiatric disorders a population based record linkage analysis
Journal of Psychosomatic Research, 2021Co-Authors: Steve Kisely, James Murray Ogilvie, Ratilal LallooAbstract:Background: Indigenous peoples and those from non-Caucasian, poorer or rural backgrounds are at greater risk of emergency department (ED) presentations for non-traumatic or avoidable dental conditions. There is no information on people with mental illness. Objective: To compare avoidable dental ED admissions in psychiatric patients with those of the general population over 2 years. Methods: A population-based record-linkage analysis across state-based facilities in Queensland, Australia. Avoidable dental ED presentations were defined using ICD10 codes K02.9, K04.7, K05.0, K08.8 and K12. Results: There were 1,381,428 individuals in the linked database, of whom 657,933 (47.6%) were male. Of the sample, 177,157 (13%) had a history of contact for mental health problems and 22,046 (1.5%) had at least one avoidable dental presentation. The most two common were unspecified disorders of teeth or supportive structures (n = 10,184) and periapical abscesses (n = 7970). After adjusting for confounders, those who had ever needed psychiatric treatment were 72% more likely to experience an avoidable dental presentation (95% = 1.65–1.79; p < 0.0001). Other significant independent risk factors were lower income, rurality and Indigenous status. Within the inpatient psychiatric group, those with substance use or personality disorders had the highest risk of avoidable presentations. Conclusions: In common with other marginalised groups, psychiatric patients have increased avoidable presentations. Possible clinical interventions could include an increased emphasis on oral health assessment in primary health care and early dental referral. Dental education and service planning should consider this population's needs including easier navigation of services, availability outside normal office hours, and free outreach dental clinics.
Gennaro Giustino - One of the best experts on this subject based on the ideXlab platform.
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impact of clinical presentation stable angina pectoris vs unstable angina pectoris or non st elevation myocardial infarction vs st elevation myocardial infarction on long term outcomes in women undergoing percutaneous coronary intervention with drug
American Journal of Cardiology, 2015Co-Authors: Gennaro Giustino, Usman Baber, Giulio G Stefanini, Melissa Aquino, Gregg W Stone, Samantha Sartori, Philippe Gabriel Steg, William Wijns, Pieter C Smits, Raban JegerAbstract:The long-term risk associated with different coronary artery disease (CAD) presentations in women undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DES) is poorly characterized. We pooled patient-level data for women enrolled in 26 randomized clinical trials. Of 11,577 women included in the pooled database, 10,133 with known clinical presentation received a DES. Of them, 5,760 (57%) had stable angina pectoris (SAP), 3,594 (35%) had unstable angina pectoris (UAP) or non-ST-segment-elevation myocardial infarction (NSTEMI), and 779 (8%) had ST-segment-elevation myocardial infarction (STEMI) as clinical presentation. A stepwise increase in 3-year crude cumulative mortality was observed in the transition from SAP to STEMI (4.9% vs 6.1% vs 9.4%; p <0.01). Conversely, no differences in crude mortality rates were observed between 1 and 3 years across clinical presentations. After multivariable adjustment, STEMI was independently associated with greater risk of 3-year mortality (hazard ratio [HR] 3.45; 95% confidence interval [CI] 1.99 to 5.98; p <0.01), whereas no differences were observed between UAP or NSTEMI and SAP (HR 0.99; 95% CI 0.73 to 1.34; p = 0.94). In women with ACS, use of new-generation DES was associated with reduced risk of major adverse cardiac events (HR 0.58; 95% CI 0.34 to 0.98). The magnitude and direction of the effect with new-generation DES was uniform between women with or without ACS (pinteraction = 0.66). In conclusion, in women across the clinical spectrum of CAD, STEMI was associated with a greater risk of long-term mortality. Conversely, the adjusted risk of mortality between UAP or NSTEMI and SAP was similar. New-generation DESs provide improved long-term clinical outcomes irrespective of the clinical presentation in women.
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impact of clinical presentation stable angina pectoris vs unstable angina pectoris or non st elevation myocardial infarction vs st elevation myocardial infarction on long term outcomes in women undergoing percutaneous coronary intervention with drug
American Journal of Cardiology, 2015Co-Authors: Gennaro Giustino, Usman Baber, Giulio G Stefanini, Melissa Aquino, Gregg W Stone, Samantha Sartori, Philippe Gabriel Steg, William Wijns, Pieter C Smits, Raban JegerAbstract:The long-term risk associated with different coronary artery disease (CAD) presentations in women undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DES) is poorly characterized. We pooled patient-level data for women enrolled in 26 randomized clinical trials. Of 11,577 women included in the pooled database, 10,133 with known clinical presentation received a DES. Of them, 5,760 (57%) had stable angina pectoris (SAP), 3,594 (35%) had unstable angina pectoris (UAP) or non–ST-segment-elevation myocardial infarction (NSTEMI), and 779 (8%) had ST-segment-elevation myocardial infarction (STEMI) as clinical presentation. A stepwise increase in 3-year crude cumulative mortality was observed in the transition from SAP to STEMI (4.9% vs 6.1% vs 9.4%; p interaction = 0.66). In conclusion, in women across the clinical spectrum of CAD, STEMI was associated with a greater risk of long-term mortality. Conversely, the adjusted risk of mortality between UAP or NSTEMI and SAP was similar. New-generation DESs provide improved long-term clinical outcomes irrespective of the clinical presentation in women.
Sven Burgdorf - One of the best experts on this subject based on the ideXlab platform.
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Sec61 in antigen Cross-Presentation.
Oncotarget, 2015Co-Authors: Matthias Zehner, Sven BurgdorfAbstract:Upon recognition of antigens in the peripheral tissue, dendritic cells (DCs) migrate toward the draining lymph node to present internalized and processed antigens on major histocompatibility complex (MHC) molecules to T cells. In a process termed Cross-Presentation, antigen-derived peptides are presented on MHC I molecules to cytotoxic T cells. Cross-Presentation has been shown to be of crucial importance in a variety of processes e.g. for the induction of a cytotoxic T cell response against tumors of non-hematopoietic origin or against viruses that do not infect DCs. Despite intensive investigations, the molecular mechanisms regulating Cross-Presentation are not fully resolved yet. In general, there are two major pathways for antigen Cross-Presentation: the vacuolar and the endosome-to-cytosol pathway. In the vacuolar pathway, internalized antigens are degraded and loaded onto MHC I within endosomal compartments. In the endosome-to-cytosol pathway, which is considered to be the more important one, antigens need to be transported out of the endosomes for proteasomal degradation. The molecular mechanisms facilitating such intracellular transport remained unknown for a long time and were discussed controversially [1]. In a recent study, we could demonstrate that antigen transport into the cytosol for Cross-Presentation is mediated by Sec61 [2]. The trimeric translocon Sec61 is a member of the ER-degredation (ERAD) machinery that enables protein transport into the ER during translation and the export of misfolded proteins from the ER into the cytosol for proteasomal degradation. We could demonstrate that upon DC activation with endotoxins, Sec61 was recruited in a TRIF-dependent manner toward antigen-containing endosomes. Down-regulation of both essential subunits Sec61α1 and Sec61γ resulted in impaired antigen export into the cytosol and hence in reduced Cross-Presentation [2], pointing out that Sec61 might indeed be involved in the regulation of such intracellular antigen transport. Of crucial importance to demonstrate a decisive role of Sec61 in antigen translocation was an approach to trap Sec61 in the ER and to prevent its recruitment toward antigen-containing endosomes by the generation of a Sec61-specific ER-retained antibody (intrabody). To this end, we isolated a single chain variable fragment (scFv) antibody against the first luminal loop of Sec61α and expressed it provided with an ER targeting signal peptide and a KDEL ER retention signal in DCs. Due to its specific binding to Sec61 and its ER retention signal, it prevented Sec61 recruitment towards antigen-containing endosomes without affecting its functionality in the ER or without influencing the transport of other ER proteins toward endosomes. Such specific exclusion of Sec61 from endosomes resulted in impaired antigen translocation into the cytosol and hence Cross-Presentation, which was shown for a variety of antigens (including soluble and particular ovalbumin, Δ-lactamase, cytochrome C and BSA) and which unequivocally proved that endosomal Sec61 mediates antigen translocation into the cytosol for Cross-Presentation. In a recent study, it was reported that Cross-Presentation of synthetic long peptides by human DCs was independent of Sec61, since down-regulation of Sec61α1 resulted in a moderate but non-significant reduction in Cross-Presentation [3]. Efficient down-regulation was analyzed by western blot, showing a reduced expression of a protein about 95 kDa. However, since Sec61α migrates slightly above 40 kDa, and the protein depicted on the western blot was also reduced after downregulation of p97 and Derlin-1, the effect on Cross-Presentation in this study remains unclear. Nevertheless, it is not unreasonable to think that Sec61 might not be the only translocon enabling antigen translocation into the cytosol, a notion that might be further supported by observations demonstrating that dislocation at the ER can also be mediated by Hrd1, independent of Sec61 [4]. Although Hrd1 does not seem to play a specific role in Cross-Presentation [2][5], it is thinkable that in addition to Sec61, other channel proteins might mediate antigen translocation from endosomes into the cytosol [5]. Future experiments will have to reveal whether such alternative translocons exist and might enhance our understanding of the exact recruitment of Sec61 from the ER toward antigen-containing endosomes.
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Regulation of antigen transport into the cytosol for Cross-Presentation by ubiquitination of the mannose receptor.
Molecular immunology, 2012Co-Authors: Matthias Zehner, Sven BurgdorfAbstract:The molecular mechanisms governing Cross-Presentation of extracellular antigens on MHC I molecules are not fully understood. It is generally assumed that, in order to be processed for Cross-Presentation, most antigens need to be transported from the endosomal compartment into the cytosol to be processed by the cytosolic proteasome. The mechanisms regulating such intracellular transport are largely unknown. In a recent study, we demonstrated that the ubiquitination status of the mannose receptor (MR), an endocytic receptor that targets its ligands specifically toward Cross-Presentation, can regulate such antigen export into the cytosol. Poly-ubiquitination of the MR recruits p97 toward the endosomal membrane, which is essential for antigen translocation out of the endosomes. Furthermore, we identified Tumor Susceptibility Gene 101 (TSG101) as an important regulator of MR poly-ubiquitination and hence of antigen translocation and Cross-Presentation. Additionally, we describe in this article some perspectives and open questions regarding the molecular mechanisms of Cross-Presentation. In particular, we highlight the search for proteins regulating antigen translocation in the cytosol, the recruitment of ER proteins and proteasomes toward antigen-containing endosomes and the importance of antigen stability for Cross-Presentation.
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mannose receptor polyubiquitination regulates endosomal recruitment of p97 and cytosolic antigen translocation for cross presentation
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Matthias Zehner, Achmet Imam Chasan, Verena Schuette, Maria Embgenbroich, Thomas Quast, Waldemar Kolanus, Sven BurgdorfAbstract:The molecular mechanisms regulating noncanonical protein transport across cellular membranes are poorly understood. Cross-Presentation of exogenous antigens on MHC I molecules by dendritic cells (DCs) generally requires antigen translocation from the endosomal compartment into the cytosol for proteasomal degradation. In this study, we demonstrate that such translocation is controlled by the endocytic receptor and regulated by ubiquitination. Antigens internalized by the mannose receptor (MR), an endocytic receptor that targets its ligands specifically toward Cross-Presentation, were translocated into the cytosol only after attachment of a lysin48-linked polyubiquitin chain to the cytosolic region of the MR. Furthermore, we identify TSG101 as a central regulator of MR ubiquitination and antigen translocation. Importantly, we demonstrate that MR polyubiquitination mediates the recruitment of p97, a member of the ER-associated degradation machinery that provides the driving force for antigen translocation, toward the endosomal membrane, proving the central role of the endocytic receptor and its ubiquitination in antigen translocation.
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Spatial and mechanistic separation of Cross-Presentation and endogenous antigen presentation
Nature immunology, 2008Co-Authors: Sven Burgdorf, Christian Scholz, Andreas Kautz, Robert Tampé, Christian KurtsAbstract:Antiviral or antitumor immunity requires activation of cytotoxic CD8+ T cells by dendritic cells, which present viral or tumor antigens on major histocompatibility complex (MHC) class I molecules. The intracellular mechanisms facilitating MHC class I-restricted presentation of extracellular antigens ('Cross-Presentation') are unclear. Here we demonstrate that Cross-Presentation of soluble antigen occurred in an early endosomal compartment distinct from the endoplasmic reticulum where endogenous antigen is loaded onto MHC class I. Efficient Cross-Presentation required endotoxin-induced, Toll-like receptor 4- and signaling molecule MyD88-dependent relocation of the transporter associated with antigen processing, essential for loading of MHC class I, to early endosomes. Transport of cross-presented antigen from endosomes to the cell surface was inhibited by primaquine, which blocks endosomal trafficking. Thus, Cross-Presentation is spatially and mechanistically separated from endogenous MHC class I-restricted antigen presentation and is biased toward antigens containing microbial molecular patterns.
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distinct pathways of antigen uptake and intracellular routing in cd4 and cd8 t cell activation
Science, 2007Co-Authors: Sven Burgdorf, Percy A. Knolle, Andreas Kautz, Volker Bohnert, Christian KurtsAbstract:The mechanisms that allow antigen-presenting cells (APCs) to selectively present extracellular antigen to CD8+ effector T cells (Cross-Presentation) or to CD4+ T helper cells are not fully resolved. We demonstrated that APCs use distinct endocytosis mechanisms to simultaneously introduce soluble antigen into separate intracellular compartments, which were dedicated to presentation to CD8+ or CD4+ T cells. Specifically, the mannose receptor supplied an early endosomal compartment distinct from lysosomes, which was committed to Cross-Presentation. These findings imply that antigen does not require intracellular diversion to access the Cross-Presentation pathway, because it can enter the pathway already during endocytosis.