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Senapati S, Bertolini TB, Minnier MA, Yazicioglu MN, Markusic DM, Zhang R, Wicks J, Nahvi A, Herzog RW, Walsh MC, Cejas PJ, Armour SM. Inhibition of IFNAR-JAK signaling enhances tolerability and transgene expression of systemic non-viral DNA delivery. MOLECULAR THERAPY. NUCLEIC ACIDS 2025; 36:102502. [PMID: 40206655 PMCID: PMC11979999 DOI: 10.1016/j.omtn.2025.102502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 02/28/2025] [Indexed: 04/11/2025]
Abstract
Lipid nanoparticles (LNPs) have demonstrated significant therapeutic value for non-viral delivery of mRNA and siRNA. While there is considerable interest in utilizing LNPs for delivering DNA (DNA-LNPs) to address a broad range of genetic disorders, acute inflammatory responses pose significant safety concerns and limit transgene expression below therapeutically relevant levels. However, the mechanisms and immune signaling pathways underlying DNA-LNP-triggered inflammatory responses are not well characterized. Through the use of gene-targeted mouse models, we have identified cGAS-STING and interferon-α/β receptor (IFNAR) pathways as major mediators of acute inflammation triggered by systemic delivery of DNA-LNPs. cGAS-STING activation induces expression of numerous JAK-STAT-activating cytokines, and we show that treatment of mice with the JAK inhibitors ruxolitinib or baricitinib significantly improves tolerability to systemically delivered DNA-LNPs. Furthermore, specific inhibition of IFNAR signaling enhances both DNA-LNP tolerability and transgene expression. Utilization of JAK inhibitors or IFNAR blockade represent promising strategies for enhancing the safety and efficacy of non-viral DNA delivery for gene therapy.
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Affiliation(s)
| | - Thais B. Bertolini
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
| | | | | | - David M. Markusic
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Rui Zhang
- Discovery Group, Spark Therapeutics, Philadelphia, PA, USA
| | - Joan Wicks
- Gene Therapy Research, Spark Therapeutics, Philadelphia, PA, USA
| | - Ali Nahvi
- Discovery Group, Spark Therapeutics, Philadelphia, PA, USA
| | - Roland W. Herzog
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
| | | | - Pedro J. Cejas
- Discovery Group, Spark Therapeutics, Philadelphia, PA, USA
| | - Sean M. Armour
- Discovery Group, Spark Therapeutics, Philadelphia, PA, USA
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Ishida M, Katayama A, Shirota G, Okimoto N, Abe H, Nyunoya K, Fujimoto K, Kurokawa M, Takahashi-Mizuki M, Inui S, Orihara S, Saito K, Ushiku T, Abe O, Gonoi W. Postmortem computed tomography assessment of intracardiac and intravascular blood clots and gravitational sedimentation: clinical and laboratory associations in 114 in-hospital deaths. Jpn J Radiol 2025:10.1007/s11604-025-01797-3. [PMID: 40413690 DOI: 10.1007/s11604-025-01797-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Accepted: 04/29/2025] [Indexed: 05/27/2025]
Abstract
PURPOSE Postmortem computed tomography (PMCT) typically reveals blood clots and sedimentation in cardiac and vascular structures. We examined the associations between these postmortem findings and antemortem clinical and laboratory parameters in in-hospital death. MATERIAL AND METHODS This prospective study included 114 non-traumatic in-hospital deaths where PMCT was performed within 24 h postmortem. Two radiologists evaluated high-density areas in the right and left atria, pulmonary artery, and thoracic aorta, and classified them as blood clots or gravitational sedimentation. The clinical and laboratory data from the week before death were analyzed using univariate and multivariate logistic regression. RESULTS Interobserver agreement was excellent for all anatomical sites (κ = 0.87-0.91). Blood clot or blood sedimentation were observed in 34-53% of cases across different locations. Per univariate analysis, non-pneumonic infections, positive blood cultures, and elevated coagulation parameters (prothrombin time-international normalized ratio, activated partial thromboplastin time) were associated with gravitational sedimentation. In contrast, solid malignancies and higher values of hematologic parameters (platelet count, red blood cells, hemoglobin, neutrophil percentage) were associated with blood clot formation (all p < .05). Per multivariate analysis, non-pneumonic infections maintained strong associations with gravitational sedimentation across all sites (p < .05), while higher platelet counts independently predicted blood clot formation in the right atrium, left atrium, and thoracic aorta (p < .05). CONCLUSION Postmortem gravitational sedimentation was associated with non-pneumonic infections, whereas clot formation correlated with higher platelet counts. These findings provide objective criteria for interpreting PMCT findings and may aid in evaluating patients' antemortem clinical status, particularly when clinical information is limited.
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Affiliation(s)
- Masanori Ishida
- Department of Radiology, School of Medicine, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan.
- Department of Radiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
| | - Akira Katayama
- Department of Radiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Go Shirota
- Department of Radiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Naomasa Okimoto
- Department of Radiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Hiroyuki Abe
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Keisuke Nyunoya
- Department of Radiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Kotaro Fujimoto
- Department of Radiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Mariko Kurokawa
- Department of Radiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Masumi Takahashi-Mizuki
- Department of Radiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Shohei Inui
- Department of Radiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Shunichiro Orihara
- Department of Health Data Science, School of Medicine, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan
| | - Kazuhiro Saito
- Department of Radiology, School of Medicine, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan
| | - Tetsuo Ushiku
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Osamu Abe
- Department of Radiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Wataru Gonoi
- Department of Radiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
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Onishi T, Shimo H, Harada S, Nogami K. The effects of emicizumab on in vitro coagulation and fibrinolysis parameters in patients with disseminated intravascular coagulation with and without addition of anti-FVIII antibody. Haemophilia 2024; 30:836-844. [PMID: 38523253 DOI: 10.1111/hae.14997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 03/02/2024] [Accepted: 03/09/2024] [Indexed: 03/26/2024]
Abstract
BACKGROUND Emicizumab (Emi) is used as haemostatic prophylaxis for patients with haemophilia A (PwHA). Disseminated intravascular coagulation (DIC) is a condition characterized by persistent systemic activation of coagulation, but there is yet no information on coagulation and fibrinolysis potentials in Emi-treated PwHA with DIC. AIM To examine the effect of Emi on coagulation and fibrinolysis potentials in HA-model DIC plasmas. METHODS Plasma from a patient with sepsis-DIC (seven patients) was treated with anti-factor (F)VIII monoclonal antibody (HA-model DIC plasma) and incubated with Emi (50 µg/mL). The plasma was then assessed using clot-fibrinolysis waveform analysis (CFWA). Coagulation and fibrinolysis parameters were expressed as ratios relative to normal plasma (|min1|-ratio and |FL-min1|-ratio, respectively). PATIENTS AND RESULTS In case 1, coagulant potential was slightly high and fibrinolytic potential was extremely low, presenting a coagulant-dominant state (|min1|-ratio/|FL-min1|-ratio: 1.1/.38). In cases 2-5, fibrinolytic potential was not suppressed, but there were marked hypercoagulant potentials, indicating relative coagulant-dominant states. In case 6, coagulant and fibrinolytic potentials were increased but well balanced (|min1|-ratio/|FL-min1|-ratio: 1.38/1.28). In case 7, both potentials were severely deteriorated in not only CFWA but also the thrombin/plasmin generation assay. The addition of Emi into the HA-model DIC plasmas increased |min1|-ratio values in all cases, but the coagulant potentials did not exceed the initial ones (DIC plasma before treatment with anti-FVIII antibody). CONCLUSIONS The presence of Emi in the HA-model DIC plasma improved coagulation potentials, but did not increase coagulation potentials beyond those of DIC plasma in non-HA states.
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Affiliation(s)
- Tomoko Onishi
- Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
- Center of Postgraduate Training Nara Medical University Hospital, Kashihara, Nara, Japan
| | - Hanako Shimo
- Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
| | - Suguru Harada
- Chugai Pharmaceutical Co., Ltd, Yokohama, Kanagawa, Japan
| | - Keiji Nogami
- Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
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Wang G, Hao C, Yao S, Wang Y, Xu Z, Zhao H, An Y. Exploring the Mediating Role of Multiple Organ Dysfunction in Sepsis-Induced Disseminated Intravascular Coagulation and Its Impact on Worsening Prognosis. Clin Appl Thromb Hemost 2024; 30:10760296241271358. [PMID: 39109998 PMCID: PMC11307354 DOI: 10.1177/10760296241271358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 07/02/2024] [Accepted: 07/23/2024] [Indexed: 08/10/2024] Open
Abstract
Disseminated intravascular coagulation (DIC) poses a high mortality risk, yet its exact impact remains contentious. This study investigates DIC's association with mortality in individuals with sepsis, emphasizing multiple organ function. Using data from the Peking University People's Hospital Investigation on Sepsis-Induced Coagulopathy database, we categorized patients into DIC and non-DIC groups based on DIC scores within 24 h of ICU admission (< 5 cutoff). ICU mortality was the main outcome. Initial data comparison preceded logistic regression analysis of mortality factors post-propensity score matching (PSM). Employing mediation analysis estimated direct and indirect associations. Of 549 participants, 131 were in the DIC group, with the remaining 418 in the non-DIC group. Following baseline characteristic presentation, PSM was conducted, revealing significantly higher nonplatelet sequential organ failure assessment (nonplt-SOFA) scores (6.3 ± 2.7 vs 5.0 ± 2.5, P < 0.001) and in-hospital mortality rates (47.3% vs 29.5%, P = 0.003) in the DIC group. A significant correlation between DIC and in-hospital mortality persisted (OR 2.15, 95% CI 1.29-3.59, P = 0.003), with nonplt-SOFA scores (OR 1.16, 95% CI 1.05-1.28, P = 0.004) and hemorrhage (OR 2.33, 95% CI 1.08-5.03, P = 0.032) as predictors. The overall effect size was 0.1786 (95% CI 0.0542-0.2886), comprising a direct effect size of 0.1423 (95% CI 0.0153-0.2551) and an indirect effect size of 0.0363 (95% CI 0.0034-0.0739), with approximately 20.3% of effects mediated. These findings underscore DIC's association with increased mortality risk in patients with sepsis, urging anticoagulation focus over bleeding management, with organ dysfunction assessment recommended for anticoagulant treatment efficacy.
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Affiliation(s)
- Guangjie Wang
- Department of Critical Care Medicine, Peking University People's Hospital, Beijing 100044, China
| | - Chenxiao Hao
- Department of Critical Care Medicine, Peking University People's Hospital, Beijing 100044, China
| | - Sun Yao
- Department of Critical Care Medicine, Peking University People's Hospital, Beijing 100044, China
| | - Yiqin Wang
- Department of Gynecology and Obstetrics, Peking University People's Hospital, Beijing 100044, China
| | - Zongtao Xu
- Department Critical Care Medicine, The Second People's Hospital of Chengyang District, Qingdao 266111, China
| | - Huiying Zhao
- Department of Critical Care Medicine, Peking University People's Hospital, Beijing 100044, China
| | - Youzhong An
- Department of Critical Care Medicine, Peking University People's Hospital, Beijing 100044, China
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Liao TH, Wu HC, Liao MT, Hu WC, Tsai KW, Lin CC, Lu KC. The Perspective of Vitamin D on suPAR-Related AKI in COVID-19. Int J Mol Sci 2022; 23:10725. [PMID: 36142634 PMCID: PMC9500944 DOI: 10.3390/ijms231810725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 09/08/2022] [Accepted: 09/13/2022] [Indexed: 01/08/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic has claimed the lives of millions of people around the world. Severe vitamin D deficiency can increase the risk of death in people with COVID-19. There is growing evidence that acute kidney injury (AKI) is common in COVID-19 patients and is associated with poorer clinical outcomes. The kidney effects of SARS-CoV-2 are directly mediated by angiotensin 2-converting enzyme (ACE2) receptors. AKI is also caused by indirect causes such as the hypercoagulable state and microvascular thrombosis. The increased release of soluble urokinase-type plasminogen activator receptor (suPAR) from immature myeloid cells reduces plasminogen activation by the competitive inhibition of urokinase-type plasminogen activator, which results in low plasmin levels and a fibrinolytic state in COVID-19. Frequent hypercoagulability in critically ill patients with COVID-19 may exacerbate the severity of thrombosis. Versican expression in proximal tubular cells leads to the proliferation of interstitial fibroblasts through the C3a and suPAR pathways. Vitamin D attenuates the local expression of podocyte uPAR and decreases elevated circulating suPAR levels caused by systemic inflammation. This decrease preserves the function and structure of the glomerular barrier, thereby maintaining renal function. The attenuated hyperinflammatory state reduces complement activation, resulting in lower serum C3a levels. Vitamin D can also protect against COVID-19 by modulating innate and adaptive immunity, increasing ACE2 expression, and inhibiting the renin-angiotensin-aldosterone system. We hypothesized that by reducing suPAR levels, appropriate vitamin D supplementation could prevent the progression and reduce the severity of AKI in COVID-19 patients, although the data available require further elucidation.
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Affiliation(s)
- Tzu-Hsien Liao
- Department of Chinese Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan
| | - Hsien-Chang Wu
- Department of Chinese Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan
- School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien 970, Taiwan
| | - Min-Tser Liao
- Department of Pediatrics, Taoyuan Armed Forces General Hospital Hsinchu Branch, Hsinchu City 300, Taiwan
- Department of Pediatrics, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
| | - Wan-Chung Hu
- Department of Clinical Pathology and Medical Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan
| | - Kuo-Wang Tsai
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan
| | - Ching-Chieh Lin
- Department of Chest Medicine, Taoyuan Armed Forces General Hospital Hsinchu Branch, Hsinchu City 300, Taiwan
| | - Kuo-Cheng Lu
- Division of Nephrology, Department of Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan
- Division of Nephrology, Department of Medicine, Fu-Jen Catholic University Hospital, School of Medicine, Fu-Jen Catholic University, New Taipei City 242, Taiwan
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Tandayam A, Syed MHN, Kumar G. Pathophysiology and Management of Hypercoagulation in Infectious Diseases. JOURNAL OF CARDIAC CRITICAL CARE TSS 2022. [DOI: 10.1055/s-0042-1757370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
AbstractNumerous systemic infections may have hypercoagulation as one of the complications, which may range from asymptomatic presentation of elevation of biochemical markers of coagulation such as that of fibrin and thrombin generation, to a much severe, symptomatic, life-threatening, disseminated intravascular coagulation (DIC), which results in the formation of thrombi in the microvasculature of various organs. This phenomenon contributes to increase in morbidity and mortality in various infectious diseases. The current review discusses various mechanisms of hypercoagulation during infections such as tissue factor activation, endothelial cell activation, inhibition of physiological anticoagulant pathways, and fibrinolysis inhibition. The review also discusses pathophysiological changes in the coagulation system and its management in the recent pandemic of COVID-19. The article also discusses role of various parenteral and oral anticoagulants in the management of infectious diseases. The review provides clinical data on various anticoagulants used during hospitalization and extended prophylaxis for the management of venous thromboembolism in various infections.
Methodology Because this is a review of published literature and no humans or animals were involved, ethical committee approval was not required and patient consent was not required.
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Affiliation(s)
- Abhishek Tandayam
- Medical Affairs Department, Dr Reddy's Laboratories, Hyderabad, India
| | | | - Gaurav Kumar
- Medical Affairs Department, Dr Reddy's Laboratories, Hyderabad, India
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7
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Nguyen PH, Le AH, Pek JSQ, Pham TT, Jayasinghe MK, Do DV, Phung CD, Le MT. Extracellular vesicles and lipoproteins - Smart messengers of blood cells in the circulation. JOURNAL OF EXTRACELLULAR BIOLOGY 2022; 1:e49. [PMID: 38938581 PMCID: PMC11080875 DOI: 10.1002/jex2.49] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 06/12/2022] [Accepted: 06/19/2022] [Indexed: 06/29/2024]
Abstract
Blood cell-derived extracellular vesicles (BCEVs) and lipoproteins are the major circulating nanoparticles in blood that play an important role in intercellular communication. They have attracted significant interest for clinical applications, given their endogenous characteristics which make them stable, biocompatible, well tolerated, and capable of permeating biological barriers efficiently. In this review, we describe the basic characteristics of BCEVs and lipoproteins and summarize their implications in both physiological and pathological processes. We also outline well accepted workflows for the isolation and characterization of these circulating nanoparticles. Importantly, we highlight the latest progress and challenges associated with the use of circulating nanoparticles as diagnostic biomarkers and therapeutic interventions in multiple diseases. We spotlight novel engineering approaches and designs to facilitate the development of these nanoparticles by enhancing their stability, targeting capability, and delivery efficiency. Therefore, the present work provides a comprehensive overview of composition, biogenesis, functions, and clinical translation of circulating nanoparticles from the bench to the bedside.
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Affiliation(s)
- Phuong H.D. Nguyen
- Department of Pharmacology and Institute for Digital MedicineYong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
| | - Anh Hong Le
- Department of Pharmacology and Institute for Digital MedicineYong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
| | - Jonetta Shi Qi Pek
- Department of Pharmacology and Institute for Digital MedicineYong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
| | - Thach Tuan Pham
- Department of Pharmacology and Institute for Digital MedicineYong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
| | - Migara Kavishka Jayasinghe
- Department of Pharmacology and Institute for Digital MedicineYong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
- Immunology ProgrammeCancer Programme and Nanomedicine Translational ProgrammeYong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
- Department of SurgeryYong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
| | - Dang Vinh Do
- Department of Pharmacology and Institute for Digital MedicineYong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
| | - Cao Dai Phung
- Department of Pharmacology and Institute for Digital MedicineYong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
| | - Minh T.N. Le
- Department of Pharmacology and Institute for Digital MedicineYong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
- Immunology ProgrammeCancer Programme and Nanomedicine Translational ProgrammeYong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
- Department of SurgeryYong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
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Nishiyama A, Ogiwara K, Nakajima Y, Furukawa S, Matsumoto T, Takeda H, Nogami K. A case of a young boy with hyper-fibrinolysis associated with natural fibrin precipitates suspected to have occurred through a novel coagulation and fibrinolysis mechanism. Int J Hematol 2022; 116:276-287. [PMID: 35416587 DOI: 10.1007/s12185-022-03339-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 03/25/2022] [Accepted: 03/27/2022] [Indexed: 10/18/2022]
Abstract
An 8-year-old Japanese boy with no underlying disease presented with severe intramuscular hematoma of the hip, and was admitted for a disseminated intravascular coagulation-like state with fibrinolytic dominance. Laboratory examinations revealed severe hyper-fibrinolysis with elevated markers, markedly shortened euglobulin clot lysis time, mildly decreased prothrombin, and severely decreased fibrinogen and factor XIII. Natural fibrin precipitates rapidly appeared in citrate-treated, ethylene-diamine-tetra-acetic-treated, and heparin-treated samples, but not in argatroban-treated samples, indicating that the mechanism of thrombin and fibrin formation was Ca2+-independent. The precipitates were physically similar to thrombin-triggered plasma fibrin. A global coagulation assay revealed that thrombin generation potentials were normal throughout the clinical course, whereas plasmin generation was already detected before initiation of fibrin formation in the acute phase. This phenomenon disappeared with time. Changes in coagulation abnormalities and nature of fibrinolysis paralleled those seen in specific markers for streptococcal infections. Streptokinase was possibly involved in this disease, as SDS-polyacrylamide gel electrophoresis revealed that plasmin derived from streptokinase-plasminogen complex proteolyzed the prothrombin to approximately 35-kDa α-thrombin consisting of the A-B single chain, which was identified by NH2-terminal sequence analysis. The involvement of streptokinase-plasminogen-prothrombin caused by streptococcal infection may be one mechanism that produces marked hyper-fibrinolysis associated with natural fibrin precipitates.
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Affiliation(s)
- Atsuko Nishiyama
- Department of Pediatrics, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Kenichi Ogiwara
- Department of Pediatrics, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan.
| | - Yuto Nakajima
- Department of Pediatrics, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan.,Advanced Medical Science of Thrombosis and Hemostasis, Nara Medical University, Kashihara, Japan
| | - Shoko Furukawa
- Department of Pediatrics, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Tomoko Matsumoto
- Department of Pediatrics, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan.,Clinical Laboratory, Tenri Health Care University, Tenri, Japan
| | - Hiroki Takeda
- Division of Pediatric Critical Care, Hyogo Prefectural Kobe Children's Hospital, Kobe, Japan
| | - Keiji Nogami
- Department of Pediatrics, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
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Wang SC, Wang XY, Liu CT, Chou RH, Chen ZB, Huang PH, Lin SJ. The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Ameliorates Endothelial Inflammation and Microvascular Thrombosis in a Sepsis Mouse Model. Int J Mol Sci 2022; 23:ijms23063065. [PMID: 35328486 PMCID: PMC8949150 DOI: 10.3390/ijms23063065] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 03/01/2022] [Accepted: 03/10/2022] [Indexed: 02/07/2023] Open
Abstract
The pathophysiology of sepsis involves inflammation and hypercoagulability, which lead to microvascular thrombosis and compromised organ perfusion. Dipeptidyl peptidase (DPP)-4 inhibitors, e.g., linagliptin, are commonly used anti-diabetic drugs known to exert anti-inflammatory effects. However, whether these drugs confer an anti-thrombotic effect that preserves organ perfusion in sepsis remains to be investigated. In the present study, human umbilical vein endothelial cells (HUVECs) were treated with linagliptin to examine its anti-inflammatory and anti-thrombotic effects under tumor necrosis factor (TNF)-α treatment. To validate findings from in vitro experiments and provide in vivo evidence for the identified mechanism, a mouse model of lipopolysaccharide (LPS)-induced systemic inflammatory response syndrome was used, and pulmonary microcirculatory thrombosis was measured. In TNF-α-treated HUVECs and LPS-injected mice, linagliptin suppressed expressions of interleukin-1β (IL-1β) and intercellular adhesion molecule 1 (ICAM-1) via a nuclear factor-κB (NF-κB)–dependent pathway. Linagliptin attenuated tissue factor expression via the Akt/endothelial nitric oxide synthase pathway. In LPS-injected mice, linagliptin pretreatment significantly reduced thrombosis in the pulmonary microcirculation. These anti-inflammatory and anti-thrombotic effects were independent of blood glucose level. Together the present results suggest that linagliptin exerts protective effects against endothelial inflammation and microvascular thrombosis in a mouse model of sepsis.
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Affiliation(s)
- Shen-Chih Wang
- Cardiovascular Research Center, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan; (S.-C.W.); (R.-H.C.); (S.-J.L.)
- Department of Anesthesiology, Taipei Veterans General Hospital, Taipei 11217, Taiwan
| | - Xiang-Yu Wang
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan;
| | - Chung-Te Liu
- Division of Nephrology, Department of Internal Medicine, Wan Fang Hospital, Taipei 116, Taiwan;
- Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Ruey-Hsing Chou
- Cardiovascular Research Center, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan; (S.-C.W.); (R.-H.C.); (S.-J.L.)
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan;
- Department of Critical Care Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan
- Division of Cardiology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan
| | - Zhen Bouman Chen
- Department of Diabetes Complications and Metabolism, City of Hope, Duarte, CA 91010, USA
- Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010, USA
- Correspondence: (Z.B.C.); (P.-H.H.); Tel.: +626-256-4673 (Z.B.C.); +886-2-28757374 (P.-H.H.); Fax: +886-2-28757375 (P.-H.H.)
| | - Po-Hsun Huang
- Cardiovascular Research Center, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan; (S.-C.W.); (R.-H.C.); (S.-J.L.)
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan;
- Department of Critical Care Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan
- Division of Cardiology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan
- Correspondence: (Z.B.C.); (P.-H.H.); Tel.: +626-256-4673 (Z.B.C.); +886-2-28757374 (P.-H.H.); Fax: +886-2-28757375 (P.-H.H.)
| | - Shing-Jong Lin
- Cardiovascular Research Center, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan; (S.-C.W.); (R.-H.C.); (S.-J.L.)
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan;
- Division of Cardiology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan
- Division of Cardiology, Heart Center, Cheng-Hsin General Hospital, Taipei 11220, Taiwan
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan
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10
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Barbagallo M, Schiappa E. MOF in Pregnancy and Its Relevance to Eclampsia. POSTINJURY MULTIPLE ORGAN FAILURE 2022:205-239. [DOI: 10.1007/978-3-030-92241-2_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
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11
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Hong LZ, Shou ZX, Zheng DM, Jin X. The most important biomarker associated with coagulation and inflammation among COVID-19 patients. Mol Cell Biochem 2021; 476:2877-2885. [PMID: 33742367 PMCID: PMC7978444 DOI: 10.1007/s11010-021-04122-4] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 02/25/2021] [Indexed: 01/08/2023]
Abstract
Coronavirus disease 2019 (COVID-19) induced by SARS-Cov-2 can be related to coagulopathy. Also, the infection-induced inflammatory changes are found in patients with disseminated intravascular coagulopathy (DIC). The lack of previous immunity to COVID-19 has caused infection of a large number of patients worldwide and unpredictability regarding the management of the complications that appear in the course of this viral illness. Lungs are the most important target organ of the SARS-COV-2. In COVID-19 patients, acute lung injury leads to respiratory failure. However, multiorgan failure can also occur in these patients. The primary coagulopathy of COVID-19 is marked by a considerable elevation of D-dimer, ferritin, and fibrinogen degradation products. In comparison, abnormalities in platelet count, prothrombin time, and partial thromboplastin time are partly uncommon in initial presentations. Inflammatory biomarkers including CRP, LDH, and IL-6 are significantly elevated in the early stages of the disease. In this regard, inflammation-associated biomarkers and coagulation test screening, including the assessment of IL-6, CRP, LDH, D-dimer, platelet count, PT&PTT time, ferritin, and fibrinogen levels are suggested for detecting infection by this virus. Overall, COVID-19-associated coagulopathy should be managed like other patients with critical conditions, and supportive care and thromboembolic prophylaxis should be used for severe patients.
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Affiliation(s)
- Ling-Zhi Hong
- Emergency Department, Chun'an First People's Hospital (Zhejiang Provincial People's Hospital Chun'an Branch), Hangzhou, 311700, Zhejiang, China
| | - Zhang-Xuan Shou
- Department of Pharmacy, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, No. 158 Shangtang Road, Hangzhou, 310014, Zhejiang, China
| | - De-Ming Zheng
- Infectious Diseases Department, Chun'an First People's Hospital (Zhejiang Provincial People's Hospital Chun'an Branch), Hangzhou, 311700, Zhejiang, China
| | - Xue Jin
- Department of Pharmacy, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, No. 158 Shangtang Road, Hangzhou, 310014, Zhejiang, China.
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12
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Pathogenesis of hemorrhagic disease caused by elephant endotheliotropic herpesvirus (EEHV) in Asian elephants (Elephas maximus). Sci Rep 2021; 11:12998. [PMID: 34155304 PMCID: PMC8217522 DOI: 10.1038/s41598-021-92393-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 06/10/2021] [Indexed: 02/06/2023] Open
Abstract
Elephant endotheliotropic herpesvirus-hemorrhagic disease (EEHV-HD) is an acute fatal disease in elephants. Despite the fact that the underlying pathogenesis of EEHV-HD has been proposed, it remains undetermined as to what mechanisms drive these hemorrhagic and edematous lesions. In the present study, we have investigated and explained the pathogenesis of acute EEHV-HD using blood profiles of EEHV-HD and EEHV-infected cases, hematoxylin and eosin (H&E) stain, special stains, immunohistochemistry, quantitative polymerase chain reaction (PCR) and reverse transcriptase polymerase chain reaction (RT-PCR). It was found that EEHV genomes were predominantly detected in various internal organs of EEHV-HD cases. Damage to endothelial cells, vasculitis and vascular thrombosis of the small blood vessels were also predominantly observed. Increases in platelet endothelial cell adhesion molecules-1 (PECAM-1)- and von Willebrand factor (vWF)-immunolabeling positive cells were significantly noticed in injured blood vessels. The expression of pro-inflammatory cytokine mRNA was significantly up-regulated in EEHV-HD cases when compared to EEHV-negative controls. We have hypothesized that this could be attributed to the systemic inflammation and disruption of small blood vessels, followed by the disseminated intravascular coagulopathy that enhanced hemorrhagic and edematous lesions in EEHV-HD cases. Our findings have brought attention to the potential application of effective preventive and therapeutic protocols to treat EEHV infection in Asian elephants.
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13
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Çimen D, Aslıyüce S, Tanalp TD, Denizli A. Molecularly imprinted nanofilms for endotoxin detection using an surface plasmon resonance sensor. Anal Biochem 2021; 632:114221. [PMID: 33961908 DOI: 10.1016/j.ab.2021.114221] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 03/28/2021] [Accepted: 04/22/2021] [Indexed: 11/27/2022]
Abstract
In this study, a simple, fast, sensitive and selective surface plasmon resonance (SPR) sensor has been prepared using molecular imprinting method for endotoxin detection. Endotoxin imprinted and non-imprinted poly(hydroxyethyl methacrylate-N-methacryloyl-(L)-histidine methyl ester) based nanofilms were synthesized on the SPR chip surfaces using ultraviolet polymerization. Endotoxin imprinted and non-imprinted SPR sensors were characterized by using contact angle, atomic force microscopy and ellipsometry. After characterization studies, kinetic studies were carried out in the concentration range of 0.5-100 ng/mL. The limit of detection and quantification were obtained as 0.023 and 0.078 ng/mL, respectively. The response time for the equilibration, adsorption and regeneration was approximately 14 min. The selectivity studies with cholesterol and hemoglobin of endotoxin imprinted SPR sensor were examined. Validation studies were carried out via limulus amebocyte lysate (LAL) in order to demonstrate the applicability of the SPR sensor.
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Affiliation(s)
- Duygu Çimen
- Hacettepe University, Department of Chemistry, Ankara, Turkey
| | - Sevgi Aslıyüce
- Hacettepe University, Department of Chemistry, Ankara, Turkey
| | | | - Adil Denizli
- Hacettepe University, Department of Chemistry, Ankara, Turkey.
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14
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Hussain SA, Zafar A, Faisal H, Vasylyeva O, Imran F. Adenovirus-Associated Disseminated Intravascular Coagulation. Cureus 2021; 13:e14194. [PMID: 33948394 PMCID: PMC8086741 DOI: 10.7759/cureus.14194] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
A 21-year-old previously healthy Caucasian female presented to the emergency department (ED) in the pre-COVID-19 era for evaluation of thrombocytopenia after a flu-like illness. The patient reported fever, cough, headache and myalgias for one week. She was on oral contraceptive pills (OCPs) for five years but discontinued one week ago. She was found to be in disseminated intravascular coagulation (DIC) and her hospital course was complicated by intraparenchymal hemorrhage, deep vein thrombus (DVT) in the right arm veins, bilateral pulmonary embolus (PE) and multiple splenic infarcts. An extensive workup was negative but nasopharyngeal swab came back positive for adenovirus by polymerase chain reaction (PCR).
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Affiliation(s)
| | - Aneeqa Zafar
- Internal Medicine, El Camino Hospital, Mountain View, USA
| | - Hafsa Faisal
- Internal Medicine, Rochester Regional Health, Rochester, USA
| | - Olga Vasylyeva
- Infectious Diseases, Rochester Regional Health, Rochester, USA
| | - Farhan Imran
- Hematology Oncology, Rochester Regional Health, Rochester, USA
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15
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Marchandot B, Trimaille A, Curtiaud A, Matsushita K, Jesel L, Morel O. Thromboprophylaxis: balancing evidence and experience during the COVID-19 pandemic. J Thromb Thrombolysis 2020; 50:799-808. [PMID: 32696172 PMCID: PMC7372740 DOI: 10.1007/s11239-020-02231-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
A common and potent consideration has recently entered the landscape of the novel coronavirus disease of 2019 (COVID-19): venous thromboembolism (VTE). COVID-19 has been associated to a distinctive related coagulopathy that shows unique characteristics. The research community has risen to the challenges posed by this « evolving COVID-19 coagulopathy » and has made unprecedented efforts to promptly address its distinct characteristics. In such difficult time, both national and international societies of thrombosis and hemostasis released prompt and timely responses to guide recognition and management of COVID-19-related coagulopathy. However, latest guidelines released by the international Society on Thrombosis and Haemostasis (ISTH) on May 27, 2020, followed the American College of Chest Physicians (CHEST) on June 2, 2020 showed some discrepancies regarding thromboprophylaxis use. In this forum article, we would like to offer an updated focus on thromboprophylaxis with current incidence of VTE in ICU and non-ICU patients according to recent published studies; highlight the main differences regarding ISTH and CHEST guidelines; summarize and describe which are the key ongoing RCTs testing different anticoagulation strategies in patients with COVID-19; and finally set a proposal for COVID-19 coagulopathy specific risk factors and dedicated trials.
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Affiliation(s)
- Benjamin Marchandot
- Division of Cardiovascular Medicine, Nouvel Hôpital Civil, Strasbourg University Hospital, 1 place de l'Hôpital, 67000, Strasbourg, France
| | - Antonin Trimaille
- Division of Cardiovascular Medicine, Nouvel Hôpital Civil, Strasbourg University Hospital, 1 place de l'Hôpital, 67000, Strasbourg, France
| | - Anais Curtiaud
- Division of Cardiovascular Medicine, Nouvel Hôpital Civil, Strasbourg University Hospital, 1 place de l'Hôpital, 67000, Strasbourg, France
| | - Kensuke Matsushita
- Division of Cardiovascular Medicine, Nouvel Hôpital Civil, Strasbourg University Hospital, 1 place de l'Hôpital, 67000, Strasbourg, France
- INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative Nanomedicine, FMTS, 67000, Strasbourg, France
| | - Laurence Jesel
- Division of Cardiovascular Medicine, Nouvel Hôpital Civil, Strasbourg University Hospital, 1 place de l'Hôpital, 67000, Strasbourg, France
- INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative Nanomedicine, FMTS, 67000, Strasbourg, France
| | - Olivier Morel
- Division of Cardiovascular Medicine, Nouvel Hôpital Civil, Strasbourg University Hospital, 1 place de l'Hôpital, 67000, Strasbourg, France.
- INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative Nanomedicine, FMTS, 67000, Strasbourg, France.
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16
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Huang HC, Hsiao TS, Liao MH, Tsao CM, Shih CC, Wu CC. Low-dose hydralazine improves endotoxin-induced coagulopathy and multiple organ dysfunction via its anti-inflammatory and anti-oxidative/nitrosative properties. Eur J Pharmacol 2020; 882:173279. [PMID: 32561290 DOI: 10.1016/j.ejphar.2020.173279] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 06/01/2020] [Accepted: 06/10/2020] [Indexed: 11/30/2022]
Abstract
Coagulopathy is the major cause of organ injury as well as a strong predictor of mortality in septic patients. Systemic inflammatory response and redox imbalance are regarded as the major causes of sepsis-induced coagulopathy. There is growing evidence that a vasodilator hydralazine has beneficial effects on heart failure, hypertension, and ischemia/reperfusion injury via its antioxidant and anti-inflammatory properties. However, the effects of hydralazine on sepsis have not been examined. Therefore, we evaluated the effects of low-dose hydralazine on coagulopathy and multiple organ dysfunction in septic rats induced by endotoxin. Sepsis-induced coagulopathy was established by intravenous injection of rats with lipopolysaccharide (LPS). The changes of blood pressure, heart rate, blood glucose, hemostatic variables, prothrombin time, organ function indices, interleukin-6 (IL-6) concentration, and nitric oxide (NO) level were assessed during the experimental period. In addition, the aortas, lungs, livers, and kidneys were dissected to analyze superoxide levels and protein expressions. LPS induced (i) coagulopathy, multiple organ dysfunction, and circulatory failure successfully, and (ii) excessive superoxide, NO, and IL-6 production, accompanied by the overexpression of iNOS and Wnt5a in animals. Treatment of LPS-induced septic rats with low-dose hydralazine not only improved coagulopathy but also ameliorated multiple organ dysfunction. These could be due to attenuation of the overproduction of superoxide, NO, and IL-6, which were attributed to reduction of the overexpression of iNOS and Wnt5a. Thus, these findings indicate that low-dose hydralazine could be a potential therapy for sepsis-induced coagulopathy and multiple organ dysfunction via its anti-inflammatory and anti-oxidative/nitrosative properties.
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Affiliation(s)
- Hsieh-Chou Huang
- Department of Anesthesiology and Pain Medicine, Cheng-Hsin General Hospital, Taipei, Taiwan
| | - Tsan-Seng Hsiao
- Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan; Department of Pharmacy, Taichung Armed Forces General Hospital, Taichung, Taiwan
| | - Mei-Hui Liao
- Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan
| | - Cheng-Ming Tsao
- Department of Anesthesiology, Taipei Veterans General Hospital and National Yang-Ming University, Taipei, Taiwan
| | - Chih-Chin Shih
- Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan; Department of Pharmacy Practice, Tri-Service General Hospital, Taipei, Taiwan.
| | - Chin-Chen Wu
- Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan; Department of Pharmacy Practice, Tri-Service General Hospital, Taipei, Taiwan.
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17
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Assessment of aPTT-based clot waveform analysis for the detection of haemostatic changes in different types of infections. Sci Rep 2020; 10:14186. [PMID: 32843693 PMCID: PMC7447776 DOI: 10.1038/s41598-020-71063-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 08/02/2020] [Indexed: 01/23/2023] Open
Abstract
Infections cause varying degrees of haemostatic dysfunction which can be detected by clot waveform analysis (CWA), a global haemostatic marker. CWA has been shown to predict poor outcomes in severe infections with disseminated intravascular coagulopathy. The effect of less severe bacterial and viral infections on CWA has not been established. We hypothesized that different infections influence CWA distinctively. Patients admitted with bacterial infections, dengue and upper respiratory tract viral infections were recruited if they had an activated partial thromboplastin time (aPTT) measured on admission. APTT-based CWA was performed on Sysmex CS2100i automated analyser using Dade Actin FSL reagent. CWA parameters [(maximum velocity (min1), maximum acceleration (min2) and maximum deceleration (max2)] were compared against control patients. Infected patients (n = 101) had longer aPTT than controls (n = 112) (34.37 ± 7.72 s vs 27.80 ± 1.59 s, p < 0.001), with the mean (± SD) aPTT longest in dengue infection (n = 36) (37.99 ± 7.93 s), followed by bacterial infection (n = 52) (33.96 ± 7.33 s) and respiratory viral infection (n = 13) (29.98 ± 3.92 s). Compared to controls (min1; min2; max2) (5.53 ± 1.16%/s; 0.89 ± 0.19%/s2; 0.74 ± 0.16%/s2), bacterial infection has higher CWA results (6.92 ± 1.60%/s; 1.04 ± 0.28%/s2; 0.82 ± 0.24%/s2, all p < 0.05); dengue infection has significantly lower CWA values (3.93 ± 1.32%/s; 0.57 ± 0.17%/s2; 0.43 ± 0.14%/s2, all p < 0.001) whilst respiratory virus infection has similar results (6.19 ± 1.32%/s; 0.95 ± 0.21%/s2; 0.73 ± 0.18%/s2, all p > 0.05). CWA parameters demonstrated positive correlation with C-reactive protein levels (min1: r = 0.54, min2: r = 0.44, max2: r = 0.34; all p < 0.01). Different infections affect CWA distinctively. CWA could provide information on the haemostatic milieu triggered by infection and further studies are needed to better define its application in this area.
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18
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A Pathological Clarification of Sepsis-Associated Disseminated Intravascular Coagulation Based on Comprehensive Coagulation and Fibrinolysis Function. Thromb Haemost 2020; 120:1257-1269. [PMID: 32679594 DOI: 10.1055/s-0040-1713890] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND The functional dynamics of coagulation and fibrinolysis in patients with disseminated intravascular coagulation (DIC) vary due to the pathology and severity of various underlying diseases. Conventional measurements of hemostasis such as thrombin-antithrombin complex, plasmin-α2-plasmin-inhibitor complex, and fibrinogen-fibrin degradation products may not always reflect critical pathophysiologic mechanisms in DIC. This article aims to clarify the pathology of sepsis-associated DIC using assessment of comprehensive coagulation and fibrinolysis. METHODS Plasma samples were obtained from 57 patients with sepsis-associated DIC at the time of initial diagnosis. Hemostasis parameters were quantified by clot-fibrinolysis waveform analysis (CFWA) and thrombin/plasmin generation assays (T/P-GA). The results were expressed as ratios relative to normal plasma. RESULTS CFWA demonstrated that the maximum coagulation velocity (|min1|) ratio modestly increased to median 1.40 (min - max: 0.10 - 2.60) but the maximum fibrinolytic velocity (|FL-min1|) ratio decreased to 0.61 (0 - 1.19). T/P-GA indicated that the peak thrombin (Th-Peak) ratio moderately decreased to 0.71 (0.22 - 1.20), whereas the peak plasmin (Plm-Peak) ratio substantially decreased to 0.35 (0.02 - 1.43). Statistical comparisons identified a correlation between |min1| and Th-Peak ratios (ρ = 0.55, p < 0.001), together with a strong correlation between |FL-min1| and Plm-Peak ratios (ρ = 0.71, p < 0.001), suggesting that CFWA reflected the balance between thrombin and plasmin generation. With |min1| and |FL-min1| ratios, DIC was classified as follows: coagulation-predominant, coagulation/fibrinolysis-balanced, fibrinolysis-predominant, and consumption-impaired coagulation. The majority of patients in our cohort (80.7%) were coagulation-predominant. CONCLUSION A pathological clarification of sepsis-associated DIC based on the assessment of coagulation and fibrinolysis dynamics may be useful for the hemostatic monitoring and management of optimal treatment in these individuals.
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19
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López-Collazo E, Avendaño-Ortiz J, Martín-Quirós A, Aguirre LA. Immune Response and COVID-19: A mirror image of Sepsis. Int J Biol Sci 2020; 16:2479-2489. [PMID: 32792851 PMCID: PMC7415424 DOI: 10.7150/ijbs.48400] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 06/22/2020] [Indexed: 01/08/2023] Open
Abstract
The emergence of SARS-CoV-2 virus and its associated disease COVID-19 have triggered significant threats to public health, in addition to political and social changes. An important number of studies have reported the onset of symptoms compatible with pneumonia accompanied by coagulopathy and lymphocytopenia during COVID-19. Increased cytokine levels, the emergence of acute phase reactants, platelet activation and immune checkpoint expression are some of the biomarkers postulated in this context. As previously observed in prolonged sepsis, T-cell exhaustion due to SARS-CoV-2 and even their reduction in numbers due to apoptosis hinder the response to the infection. In this review, we synthesized the immune changes observed during COVID-19, the role of immune molecules as severity markers for patient stratification and their associated therapeutic options.
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Affiliation(s)
- Eduardo López-Collazo
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Paseo de la Castellana 261, Madrid 28046, Spain
- Tumor Immunology Laboratory, IdiPAZ, La Paz University Hospital, Paseo de la Castellana 261, Madrid 28046, Spain
- CIBER of Respiratory Diseases (CIBERES), Madrid, Spain
| | - José Avendaño-Ortiz
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Paseo de la Castellana 261, Madrid 28046, Spain
- Tumor Immunology Laboratory, IdiPAZ, La Paz University Hospital, Paseo de la Castellana 261, Madrid 28046, Spain
| | - Alejandro Martín-Quirós
- Emergency Department and Emergent Pathology Research Group, IdiPAZ La Paz University Hospital, Paseo de la Castellana 261, Madrid 28046, Spain
| | - Luis A. Aguirre
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Paseo de la Castellana 261, Madrid 28046, Spain
- Tumor Immunology Laboratory, IdiPAZ, La Paz University Hospital, Paseo de la Castellana 261, Madrid 28046, Spain
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20
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Bouzidi S, Daiki M, Nasr AA, Nsiri K, Layouni S, Hajjej Z, Fekih-Mrissa N, Ferjani M, Nsiri B. [Disseminated intravascular coagulation: role of the International Society on Thrombosis and Haemostasis (ISTH) diagnostic scoring system]. Pan Afr Med J 2020; 36:154. [PMID: 32874418 PMCID: PMC7436632 DOI: 10.11604/pamj.2020.36.154.20368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 05/25/2020] [Indexed: 11/11/2022] Open
Abstract
La coagulation intravasculaire disséminée (CIVD) est une cause de mortalité redoutable en milieu de réanimation. L´utilisation du système de score de la société internationale sur la thrombose et l´hémostase (ISTH) permet de faciliter le diagnostic précoce de la CIVD. Nous présentons trois observations cliniques de CIVD d´étiologies différentes: un adénocarcinome prostatique, un choc septique et un hématome rétro-placentaire. Les tests d´hémostase nécessaires au calcul du score de la Société Internationale sur la Thrombose et l´Hémostase (ISTH) (numération plaquettaire, taux de prothrombine, fibrinogène et D-dimères) ont été régulièrement réalisés. D´autres tests complémentaires (recherche de complexes solubles, test de lyse des euglobulines, dosage des taux d´antithrombine, de protéine C activée et du facteur V) ont été également réalisés. L´utilisation du score ISTH permet de faciliter le diagnostic précoce de la CIVD.
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Affiliation(s)
- Sawsen Bouzidi
- Laboratoire d´Hématologie, Hôpital Militaire Principal d´Instruction de Tunis, Tunis, Tunisie
| | - Mayssa Daiki
- Service d´Anesthésie Réanimation, Hôpital Militaire Principal d´Instruction de Tunis, Tunis, Tunisie
| | - Amen Allah Nasr
- Laboratoire d´Hématologie, Hôpital Militaire Principal d´Instruction de Tunis, Tunis, Tunisie
| | - Kaouther Nsiri
- Laboratoire d´Hématologie, Hôpital Militaire Principal d´Instruction de Tunis, Tunis, Tunisie
| | - Samy Layouni
- Unité de Recherche de Biologie Moléculaire (UR17DN06), Laboratoire d´Hématologie, Hôpital Militaire Principal d´Instruction de Tunis, Tunis, Tunisie
| | - Zied Hajjej
- Service d´Anesthésie Réanimation, Hôpital Militaire Principal d´Instruction de Tunis, Tunis, Tunisie
| | - Najiba Fekih-Mrissa
- Unité de Recherche de Biologie Moléculaire (UR17DN06), Laboratoire d´Hématologie, Hôpital Militaire Principal d´Instruction de Tunis, Tunis, Tunisie
| | - Mustapha Ferjani
- Service d´Anesthésie Réanimation, Hôpital Militaire Principal d´Instruction de Tunis, Tunis, Tunisie
| | - Brahim Nsiri
- Laboratoire d´Hématologie, Hôpital Militaire Principal d´Instruction de Tunis, Tunis, Tunisie
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21
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Akintayo GO, Lateef A, Azeez MA, Asafa TB, Oladipo IC, Badmus JA, Ojo SA, Elegbede JA, Gueguim-Kana EB, Beukes LS, Yekeen TA. Synthesis, bioactivities and cytogenotoxicity of animal fur-mediated silver nanoparticles. ACTA ACUST UNITED AC 2020. [DOI: 10.1088/1757-899x/805/1/012041] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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22
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Rogers CJ, Harman RJ, Bunnell BA, Schreiber MA, Xiang C, Wang FS, Santidrian AF, Minev BR. Rationale for the clinical use of adipose-derived mesenchymal stem cells for COVID-19 patients. J Transl Med 2020; 18:203. [PMID: 32423449 PMCID: PMC7232924 DOI: 10.1186/s12967-020-02380-2] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Accepted: 05/14/2020] [Indexed: 02/08/2023] Open
Abstract
In late 2019, a novel coronavirus (SARS-CoV-2) emerged in Wuhan, capital city of Hubei province in China. Cases of SARS-CoV-2 infection quickly grew by several thousand per day. Less than 100 days later, the World Health Organization declared that the rapidly spreading viral outbreak had become a global pandemic. Coronavirus disease 2019 (COVID-19) is typically associated with fever and respiratory symptoms. It often progresses to severe respiratory distress and multi-organ failure which carry a high mortality rate. Older patients or those with medical comorbidities are at greater risk for severe disease. Inflammation, pulmonary edema and an over-reactive immune response can lead to hypoxia, respiratory distress and lung damage. Mesenchymal stromal/stem cells (MSCs) possess potent and broad-ranging immunomodulatory activities. Multiple in vivo studies in animal models and ex vivo human lung models have demonstrated the MSC's impressive capacity to inhibit lung damage, reduce inflammation, dampen immune responses and aid with alveolar fluid clearance. Additionally, MSCs produce molecules that are antimicrobial and reduce pain. Upon administration by the intravenous route, the cells travel directly to the lungs where the majority are sequestered, a great benefit for the treatment of pulmonary disease. The in vivo safety of local and intravenous administration of MSCs has been demonstrated in multiple human clinical trials, including studies of acute respiratory distress syndrome (ARDS). Recently, the application of MSCs in the context of ongoing COVID-19 disease and other viral respiratory illnesses has demonstrated reduced patient mortality and, in some cases, improved long-term pulmonary function. Adipose-derived stem cells (ASC), an abundant type of MSC, are proposed as a therapeutic option for the treatment of COVID-19 in order to reduce morbidity and mortality. Additionally, when proven to be safe and effective, ASC treatments may reduce the demand on critical hospital resources. The ongoing COVID-19 outbreak has resulted in significant healthcare and socioeconomic burdens across the globe. There is a desperate need for safe and effective treatments. Cellular based therapies hold great promise for the treatment of COVID-19. This literature summary reviews the scientific rationale and need for clinical studies of adipose-derived stem cells and other types of mesenchymal stem cells in the treatment of patients who suffer with COVID-19.
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Affiliation(s)
| | | | - Bruce A. Bunnell
- Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, New Orleans, LA USA
| | - Martin A. Schreiber
- Department of Surgery, Oregon Health and Science University, Portland, OR USA
| | - Charlie Xiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003 China
| | - Fu-Sheng Wang
- Treatment and Research Center for Infectious Diseases, The Fifth Medical Center, Beijing, 100039 China
| | | | - Boris R. Minev
- Calidi Biotherapeutics, Inc., San Diego, CA USA
- Department of Radiation Medicine and Applied Sciences, Moores UCSD Cancer Center, San Diego, CA USA
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Forsblom E, Lepäntalo A, Wartiovaara-Kautto U, Ruotsalainen E, Järvinen A. Changes in hemostasis parameters in nonfatal methicillin-sensitive Staphylococcus aureus bacteremia complicated by endocarditis or thromboembolic events: a prospective gender-age adjusted cohort study. APMIS 2019; 127:515-528. [PMID: 31009118 DOI: 10.1111/apm.12955] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 04/04/2019] [Indexed: 11/29/2022]
Abstract
The aim of this study was to examine the changes in hemostasis parameters in endocarditis and thromboembolic events in nonfatal methicillin-sensitive Staphylococcus aureus bacteremia (MS-SAB) - a topic not evaluated previously. In total, 155 patients were recruited and were categorized according to the presence of endocarditis or thromboembolic events with gender-age adjusted controls. Patients who deceased within 90 days or patients not chosen as controls were excluded. SAB management was supervised by an infectious disease specialist. Patients with endocarditis (N = 21), compared to controls (N = 21), presented lower antithrombin III at day 4 (p < 0.05), elevated antithrombin III at day 90 (p < 0.01), prolonged activated partial thromboplastin time at days 4 and 10 (p < 0.05), and enhanced thrombin-antithrombin complex at day 4 (p < 0.01). Thromboembolic events (N = 8), compared to controls (N = 34), significantly increased thrombin-antithrombin complex at day 4 (p < 0.05). In receiver operating characteristic analysis, the changes in these hemostasis parameters at day 4 predicted endocarditis and thromboembolic events (p < 0.05). No differences in hemoglobin, thrombocyte, prothrombin fragment, thrombin time, factor VIII, D-dimer or fibrinogen levels were observed between cases and controls. The results suggest that nonfatal MS-SAB patients present marginal hemostasis parameter changes that, however, may have predictability for endocarditis or thromboembolic events. Larger studies are needed to further assess the connection of hemostasis to complications in SAB.
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Affiliation(s)
- Erik Forsblom
- Division of Infectious Diseases, Inflammation Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Aino Lepäntalo
- Department of Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
| | - Ulla Wartiovaara-Kautto
- Department of Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
| | - Eeva Ruotsalainen
- Division of Infectious Diseases, Inflammation Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Asko Järvinen
- Division of Infectious Diseases, Inflammation Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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Brauckmann S, Effenberger-Neidnicht K, Nagel M, Mayer C, Peters J, Hartmann M. Lipopolysaccharide-Induced Hemolysis Is Abolished by Inhibition of Thrombin Generation but Not Inhibition of Platelet Aggregation. Inflammation 2019; 42:1767-1776. [DOI: 10.1007/s10753-019-01038-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Arora H, Wilcox SM, Johnson LA, Munro L, Eyford BA, Pfeifer CG, Welch I, Jefferies WA. The ATP-Binding Cassette Gene ABCF1 Functions as an E2 Ubiquitin-Conjugating Enzyme Controlling Macrophage Polarization to Dampen Lethal Septic Shock. Immunity 2019; 50:418-431.e6. [PMID: 30770245 DOI: 10.1016/j.immuni.2019.01.014] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2018] [Revised: 05/30/2018] [Accepted: 01/24/2019] [Indexed: 12/16/2022]
Abstract
Sepsis is a bi-phasic inflammatory disease that threatens approximately 30 million lives and claims over 14 million annually, yet little is known regarding the molecular switches and pathways that regulate this disease. Here, we have described ABCF1, an ATP-Binding Cassette (ABC) family member protein, which possesses an E2 ubiquitin enzyme activity, through which it controls the Lipopolysaccharide (LPS)- Toll-like Receptor-4 (TLR4) mediated gram-negative insult by targeting key proteins for K63-polyubiquitination. Ubiquitination by ABCF1 shifts the inflammatory profile from an early phase MyD88-dependent to a late phase TRIF-dependent signaling pathway, thereby regulating TLR4 endocytosis and modulating macrophage polarization from M1 to M2 phase. Physiologically, ABCF1 regulates the shift from the inflammatory phase of sepsis to the endotoxin tolerance phase, and modulates cytokine storm and interferon-β (IFN-β)-dependent production by the immunotherapeutic mediator, SIRT1. Consequently, ABCF1 controls sepsis induced mortality by repressing hypotension-induced renal circulatory dysfunction.
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Affiliation(s)
- Hitesh Arora
- Michael Smith Laboratories, University of British Columbia (UBC), 2185 East Mall, Vancouver, BC, V6T 1Z4, Canada; The Vancouver Prostate Centre, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada; Department of Microbiology and Immunology, UBC, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada; Centre for Blood Research, UBC, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada; Djavad Mowafaghian Centre for Brain Health, 2215 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada
| | - Sara Morgan Wilcox
- Michael Smith Laboratories, University of British Columbia (UBC), 2185 East Mall, Vancouver, BC, V6T 1Z4, Canada; Department of Microbiology and Immunology, UBC, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada; Centre for Blood Research, UBC, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada
| | - Laura Alexandra Johnson
- Michael Smith Laboratories, University of British Columbia (UBC), 2185 East Mall, Vancouver, BC, V6T 1Z4, Canada; Centre for Blood Research, UBC, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada; Department of Zoology, UBC, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada
| | - Lonna Munro
- Michael Smith Laboratories, University of British Columbia (UBC), 2185 East Mall, Vancouver, BC, V6T 1Z4, Canada; The Vancouver Prostate Centre, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada; Centre for Blood Research, UBC, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada; Djavad Mowafaghian Centre for Brain Health, 2215 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada
| | - Brett Alexander Eyford
- Michael Smith Laboratories, University of British Columbia (UBC), 2185 East Mall, Vancouver, BC, V6T 1Z4, Canada; Centre for Blood Research, UBC, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada; Djavad Mowafaghian Centre for Brain Health, 2215 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada
| | - Cheryl Gurine Pfeifer
- Michael Smith Laboratories, University of British Columbia (UBC), 2185 East Mall, Vancouver, BC, V6T 1Z4, Canada; The Vancouver Prostate Centre, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada; Centre for Blood Research, UBC, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada; Djavad Mowafaghian Centre for Brain Health, 2215 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada
| | - Ian Welch
- Department of Pathology, UBC, 4145 Wesbrook Mall, Vancouver BC V6T 1W5, Canada
| | - Wilfred Arthur Jefferies
- Michael Smith Laboratories, University of British Columbia (UBC), 2185 East Mall, Vancouver, BC, V6T 1Z4, Canada; The Vancouver Prostate Centre, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada; Department of Microbiology and Immunology, UBC, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada; Centre for Blood Research, UBC, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada; Department of Zoology, UBC, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada; Department of Medical Genetics, UBC, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada; Djavad Mowafaghian Centre for Brain Health, 2215 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada.
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Endogenous thrombin potential as marker of procoagulant response that can be useful in early stage of sepsis. Blood Coagul Fibrinolysis 2018; 28:460-467. [PMID: 28166112 DOI: 10.1097/mbc.0000000000000622] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
: Sepsis is associated with complex procoagulant and anticoagulant changes that modify inflammatory response. Identification of coagulation markers that can differentiate useful procoagulant response from adverse alteration of clotting mechanism in patient with sepsis. In total, 150 patients who fulfilled criteria for diagnosis of sepsis were included in this study. Patients were categorized in two groups according to sepsis severity in the first 24 h from intensive care unit admission: sepsis and septic shock. In total, 28-day mortality was assessed. Platelet count, activated partial thromboplastin time, prothrombin time, D-dimer, fibrinogen, protein C, protein S, antithrombin levels, and endogenous thrombin potential were determined within first 24 h from ICU admission. Differences between groups of septic patients were assessed by Mann-Whitney U test. Categorical variables were compared using χ test. Receiver operating characteristic curves were plotted to determine predictive values of variables for sepsis severity prediction. Activated partial thromboplastin time and prothrombin time were significantly prolonged with higher D-dimer, lower fibrinogen, and natural anticoagulant levels (protein C, protein S, and antithrombin) in patients with more severe form of the disease and worse outcome (P < 0.05). Endogenous thrombin potential [area under the curve (AUC) %] was significantly decreased in patients with more severe form of sepsis (66.01 ± 41.51 vs. 83.21 ± 28.83; AUC 0.76) and in patients with worse outcome (67.66 ± 37.79 vs. 81.79 ± 32.15; AUC 0.68; P < 0.05). Evaluation of initial thrombin generation is useful to distinguish between beneficial coagulation activation and hazardous haemostatic alteration, and to predict multiorgan dysfunction development and poor outcome in septic patients.
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Varadavenkatesan T, Vinayagam R, Selvaraj R. Structural characterization of silver nanoparticles phyto-mediated by a plant waste, seed hull of Vigna mungo and their biological applications. J Mol Struct 2017. [DOI: 10.1016/j.molstruc.2017.07.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
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Wang Y, Zhang S, Luo L, Norström E, Braun OÖ, Mörgelin M, Thorlacius H. Platelet-derived microparticles regulates thrombin generation via phophatidylserine in abdominal sepsis. J Cell Physiol 2017; 233:1051-1060. [PMID: 28409836 DOI: 10.1002/jcp.25959] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Accepted: 04/13/2017] [Indexed: 12/23/2022]
Abstract
Sepsis is associated with dysfunctional coagulation. Recent data suggest that platelets play a role in sepsis by promoting neutrophil accumulation. Herein, we show that cecal ligation and puncture (CLP) triggered systemic inflammation, which is characterized by formation of IL-6 and CXC chemokines as well as neutrophil accumulation in the lung. Platelet depletion decreased neutrophil accumulation, IL-6, and CXC chemokines formation in septic lungs. Depletion of platelets increased peak thrombin formation and total thrombin generation (TG) in plasma from septic animals. CLP elevated circulating levels of platelet-derived microparticles (PMPs). In vitro generated PMPs were a potent inducer of TG. Interestingly, in vitro wild-type recombinant annexin V abolished PMP-induced thrombin formation whereas a mutant annexin V protein, which does not bind to phosphatidylserine (PS), had no effect. Administration of wild-type, but not mutant annexin V, significantly inhibited thrombin formation in septic animals. Moreover, CLP-induced formation of thrombin-antithrombin complexes were reduced in platelet-depleted mice and in animals pretreated with annexin V. PMP-induced TG attenuated in FXII- and FVII-deficient plasma. These findings suggest that sepsis-induced TG is dependent on platelets. Moreover, PMPs formed in sepsis are a potent inducer of TG via PS exposure, and activation of both the intrinsic and extrinsic pathway of coagulation. In conclusion, these observations suggest that PMPs and PS play an important role in dysfunctional coagulation in abdominal sepsis.
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Affiliation(s)
- Yongzhi Wang
- Department of Clinical Sciences, Section for Surgery, Lund University, Malmö, Sweden
| | - Su Zhang
- Department of Clinical Sciences, Section for Surgery, Lund University, Malmö, Sweden
| | - Lingtao Luo
- Department of Clinical Sciences, Section for Surgery, Lund University, Malmö, Sweden
| | - Eva Norström
- Department of Laboratory Medicine, Section of Clinical Chemistry, Lund University, Malmö, Sweden
| | - Oscar Ö Braun
- Department of Clinical Sciences, Section for Cardiology, Lund University, Lund, Sweden
| | - Matthias Mörgelin
- Department of Clinical Sciences, Section for Infection Medicine, Lund University, Lund, Sweden
| | - Henrik Thorlacius
- Department of Clinical Sciences, Section for Surgery, Lund University, Malmö, Sweden
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Abstract
Broad-spectrum antibiotics are commonly used by physicians to treat various infections. The source of infection and causative organisms are not always apparent during the initial evaluation of the patient, and antibiotics are often given empirically to patients with suspected sepsis. Fear of attempting cephalosporins and carbapenems in penicillin-allergic septic patients may result in significant decrease in the spectrum of antimicrobial coverage. Empiric antibiotic therapy should sufficiently cover all the suspected pathogens, guided by the bacteriologic susceptibilities of the medical center. It is important to understand the major pharmacokinetic properties of antibacterial agents for proper use and to minimize the development of resistance. In several septic patients, negative cultures do not exclude active infection and positive cultures may not represent the actual infection. This article will review the important differences in the spectrum of commonly used antibiotics for nosocomial bacterial infections with a particular emphasis on culture-negative sepsis and colonization.
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30
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Gjonbrataj E, Kim JN, Gjonbrataj J, Jung HI, Kim HJ, Choi WI. Risk factors associated with provoked pulmonary embolism. Korean J Intern Med 2017; 32:95-101. [PMID: 27097772 PMCID: PMC5214719 DOI: 10.3904/kjim.2015.118] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2015] [Revised: 07/17/2015] [Accepted: 08/13/2015] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND/AIMS This study aimed to investigate the risk factors associated with provoked pulmonary embolism (PE). METHODS This retrospective cohort study included 237 patients with PE. Patients that had transient risk factors at diagnosis were classified as having provoked PE, with the remaining patients being classified as having unprovoked PE. The baseline clinical characteristics and factors associated with coagulation were compared. We evaluated the risk factors associated with provoked PE. RESULTS Of the 237 PE patients, 73 (30.8%) had provoked PE. The rate of respiratory failure and infection, as well as the disseminated intravascular coagulation score and ratio of right ventricular diameter to left ventricular diameter were significantly higher in patients with provoked PE than in those with unprovoked PE. The protein and activity levels associated with coagulation, including protein C antigen, protein S antigen, protein S activity, anti-thrombin III antigen, and factor VIII, were significantly lower in patients with provoked PE than in those with unprovoked PE. Multivariate analysis showed that infection (odds ratio [OR], 3.2; 95% confidence interval [CI], 1.4 to 7.4) and protein S activity (OR, 0.97; 95% CI, 0.95 to 0.99) were significantly associated with provoked PE. CONCLUSIONS Protein S activity and presence of infection were important factors associated with provoked PE. We should pay attention to the presence of infection in patients with provoked PE.
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Affiliation(s)
- Endri Gjonbrataj
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Ji Na Kim
- Department of Internal Medicine, Daegu Fatima Hospital, Daegu, Korea
| | - Juarda Gjonbrataj
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
- Department of Internal Medicine, Mother Theresa University Hospital Centre, Tirana, Albania
| | - Hye In Jung
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Hyun Jung Kim
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Won-Il Choi
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
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Lateef A, Akande MA, Ojo SA, Folarin BI, Gueguim-Kana EB, Beukes LS. Paper wasp nest-mediated biosynthesis of silver nanoparticles for antimicrobial, catalytic, anticoagulant, and thrombolytic applications. 3 Biotech 2016; 6:140. [PMID: 28330212 PMCID: PMC4917500 DOI: 10.1007/s13205-016-0459-x] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Accepted: 06/10/2016] [Indexed: 01/15/2023] Open
Abstract
Biosynthesis of silver nanoparticles (AgNPs) using nest extract of paper wasp (Polistes sp) was investigated in this work. The AgNPs were characterized by UV–Vis spectroscopy, Fourier transform infrared spectroscopy (FTIR), and transmission electron microscopy (TEM), and evaluated for antibacterial, antifungal, dye degradation, blood anticoagulation, and blood clot dissolution (thrombolytic) activities. The crystalline polydispersed AgNPs with size range of 12.5–95.55 nm absorbed maximally at 428 nm and showed anisotropic structures of sphere, triangle, hexagon, rod, and rhombus. The FTIR data showed prominent peaks at 3426 and 1641 cm−1, which indicate the involvement of phenolics compounds and proteins in the synthesis of AgNPs. The prominence of Ag in the EDX spectra showed that indeed, AgNPs were formed. The AgNPs showed potent antibacterial activities (12–35 mm) against three multi-drug strains of Pseudomonas aeruginosa and Klebsiella granulomatis. While the growth of Aspergillus flavus and Aspergillus niger was completely suppressed, the AgNPs produced growth inhibition of 75.61 % against Aspergillus fumigatus at 100 µg/ml. Furthermore, the AgNPs degraded malachite green to the tune of 93.1 %. The AgNPs also prevented coagulation of blood, while it completely dissolved preformed blood clots within 5 min showing the potent anticoagulation and thrombolytic activities. This study, which is the first of its kind to use nest extract of paper wasp for the synthesis of nanoparticles, has shown that the biosynthesized AgNPs could be deployed for biomedical and catalytic applications.
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Affiliation(s)
- Agbaje Lateef
- Laboratory of Industrial Microbiology and Nanobiotechnology, Department of Pure and Applied Biology, Ladoke Akintola University of Technology, PMB 4000, Ogbomoso, Nigeria.
- Nanotechnology Research Group (NANO+), Ladoke Akintola University of Technology, PMB 4000, Ogbomoso, Nigeria.
| | - Monsurat A Akande
- Laboratory of Industrial Microbiology and Nanobiotechnology, Department of Pure and Applied Biology, Ladoke Akintola University of Technology, PMB 4000, Ogbomoso, Nigeria
| | - Sunday A Ojo
- Laboratory of Industrial Microbiology and Nanobiotechnology, Department of Pure and Applied Biology, Ladoke Akintola University of Technology, PMB 4000, Ogbomoso, Nigeria
| | - Bolaji I Folarin
- Laboratory of Industrial Microbiology and Nanobiotechnology, Department of Pure and Applied Biology, Ladoke Akintola University of Technology, PMB 4000, Ogbomoso, Nigeria
| | - Evariste B Gueguim-Kana
- Department of Microbiology, School of Life Sciences, University of KwaZulu-Natal, Private Bag X01, Scottsville, PieterMaritzburg, 3209, South Africa
| | - Lorika S Beukes
- Microscopy and Microanalysis Unit, School of Life Sciences, University of KwaZulu-Natal, Private Bag X01, Scottsville, PieterMaritzburg, 3209, South Africa
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Park SH. Pulmonary embolism is more prevalent than deep vein thrombosis in cases of chronic obstructive pulmonary disease and interstitial lung diseases. SPRINGERPLUS 2016; 5:1777. [PMID: 27795919 PMCID: PMC5061682 DOI: 10.1186/s40064-016-3475-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Accepted: 10/05/2016] [Indexed: 11/10/2022]
Abstract
BACKGROUND Chronic lung diseases may have an influence on pulmonary vessel walls as well as on pulmonary haemodynamics. However, there is limited data on the occurrence of pulmonary embolism (PE) and deep vein thrombosis (DVT) in patients with chronic lung diseases, which have the potential to contribute to the development of pulmonary vascular abnormalities. We aimed to explore the prevalence of PE and DVT in patients with COPD and ILD. METHODS We evaluated the venous thromboembolism prevalence associated with COPD and ILD using Korean Health Insurance Review and Assessment Service (HIRA) data from January 2011 to December 2011. This database (HIRA-NPS-2011-0001) was created using random sampling of outpatients; 1,375,842 sample cases were collected, and 670,258 (age ≥40) cases were evaluated. Patients with COPD, ILDs, or CTD were identified using the International Classification of Disease-10 diagnostic codes. RESULTS The PE prevalence rates per 100,000 persons for the study population with COPD, ILD, CTD, and the general population were 1185, 1746, 412, and 113, respectively, while the DVT prevalence for each group was 637, 582, 563, and 138, respectively. CONCLUSIONS PE prevalence was significantly higher than that of DVT in patients with COPD or ILDs, while the prevalence of PE was lower than that for DVT in the general population or in patients with CTD.
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Affiliation(s)
- Sun Hyo Park
- Department of Internal Medicine, Keimyung University Dongsan Medical Center, 56 Dalseong-ro, Jung-gu, Daegu, 41931 Republic of Korea
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Lateef A, Ojo SA, Oladejo SM. Anti-candida, anti-coagulant and thrombolytic activities of biosynthesized silver nanoparticles using cell-free extract of Bacillus safensis LAU 13. Process Biochem 2016. [DOI: 10.1016/j.procbio.2016.06.027] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Chaari A, Abdel Hakim K, Bousselmi K, Etman M, El Bahr M, El Saka A, Hamza E, Ismail M, Khalil EM, Kauts V, Casey WF. Pancreatic injury in patients with septic shock: A literature review. World J Gastrointest Oncol 2016; 8:526-531. [PMID: 27559431 PMCID: PMC4942740 DOI: 10.4251/wjgo.v8.i7.526] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Revised: 04/26/2016] [Accepted: 05/27/2016] [Indexed: 02/05/2023] Open
Abstract
Sepsis and septic shock are life threatening condition associated with high mortality rate in critically-ill patients. This high mortality is mainly related to the inadequacy between oxygen delivery and cellular demand leading to the onset of multiorgan dysfunction. Whether this multiorgan failure affect the pancreas is not fully investigated. In fact, pancreatic injury may occur because of ischemia, overwhelming inflammatory response, oxidative stress, cellular apoptosis and/or metabolic derangement. Increased serum amylase and/or lipase levels are common in patients with septic shock. However, imaging test rarely reveal significant pancreatic damage. Whether pancreatic dysfunction does affect the prognosis of patients with septic shock or not is still a matter of debate. In fact, only few studies with limited sample size assessed the clinical relevance of the pancreatic injury in this group of patients. In this review, we aimed to describe the epidemiology and the physiopathology of pancreatic injury in septic shock patients, to clarify whether it requires specific management and to assess its prognostic value. Our main finding is that pancreatic injury does not significantly affect the outcome in septic shock patients. Hence, increased serum pancreatic enzymes without clinical features of acute pancreatitis do not require further imaging investigations and specific therapeutic intervention.
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Zhao T, Alam HB, Liu B, Bronson RT, Nikolian VC, Wu E, Chong W, Li Y. Selective Inhibition of SIRT2 Improves Outcomes in a Lethal Septic Model. Curr Mol Med 2016; 15:634-41. [PMID: 26299770 PMCID: PMC4824319 DOI: 10.2174/156652401507150903185852] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND Seven isoforms of histone deacetylase Class III have been reported - Sirtuin (SIRT) 1-7. We recently demonstrated that EX-527, an inhibitor of SIRT1, reduces mortality in a mouse model of lethal-cecal-ligationand- puncture (CLP)-induced septic shock. Our present study was aimed at determining whether selective inhibition of SIRT2, with AGK2, would decrease animal death and attenuate the inflammatory response in a septic model. METHODS Experiment I: C57BL/6J mice were intraperitoneally given either AGK2 (82 mg/kg) in dimethyl sulfoxide (DMSO) or DMSO alone, and 2 h later subjected to CLP. Survival was monitored for 240 hours. Experiment II: mice treated the same way as Experiment I, were grouped into (i) DMSO vehicle, and (ii) AGK2, with sham mice (operating but without any treatment) serving as controls. Peritoneal fluid and peripheral blood were examined at 24 and 48 hours for cytokine production. Samples of blood at 48 h were also allocated to assess coagulability using Thrombelastography (TEG). Morphological changes of bone marrow were evaluated from long bones (femurs and tibias) with hematoxylin and eosin (H&E) staining. Bone marrow atrophy was quantified by a blinded pathologist. Experiment III: cytokines in supernatant of the cultured normal primary splenocytes were measured after the cells were stimulated by lipopolysaccharide and treated with or without AGK2 (10 µM) for 6 hours. RESULTS AGK2 significantly reduced mortality and decreased levels of cytokines in blood (TNF-α: 298.3±24.6 vs 26.8±2.8 pg/ml, p=0.0034; IL-6: 633.4±82.8 vs 232.6±133.0 pg/ml, p=0.0344) and peritoneal fluid (IL-6: 704.8±67.7 vs 391.4±98.5 pg/ml, p=0.033) compared to vehicle control. Also, AGK2 suppressed the TNF-α and IL-6 production in the cultured splenocytes (TNF-α: 68.1±6.4 vs 23.9±2.8 pg/ml, p=0.0009; IL-6: 73.1±4.2 vs 49.6±3.0 pg/ml; p=0.0051). The TEG data showed that the mice subjected to CLP displayed prolonged fibrin formation and fibrin cross-linkage time, slower clot formation, decreased platelet function, and clot rigidity. AGK2 treatment was associated with dramatic improvements in fibrin cross-linkage and clot formation times, without a significant impact on the clot initiation parameters or platelet function. Additionally, AGK2 significantly attenuated the bone marrow atrophy (58.3±6.5 vs 30.0±8.2%, p=0.0262). CONCLUSION Selective inhibition of SIRT2 significantly improves survival, and attenuates sepsis-associated "cytokine storm", coagulopathy, and bone marrow atrophy in a mouse model of lethal septic shock.
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Affiliation(s)
| | | | | | | | | | | | - W Chong
- Department of Emergency, The First Hospital of China Medical University, 155 North Nanjing Street, Shenyang, Liaoning 110001, China.
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Kolanut (Cola nitida) Mediated Synthesis of Silver–Gold Alloy Nanoparticles: Antifungal, Catalytic, Larvicidal and Thrombolytic Applications. J CLUST SCI 2016. [DOI: 10.1007/s10876-016-1019-6] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Ewers EC, Pratt WD, Twenhafel NA, Shamblin J, Donnelly G, Esham H, Wlazlowski C, Johnson JC, Botto M, Hensley LE, Goff AJ. Natural History of Aerosol Exposure with Marburg Virus in Rhesus Macaques. Viruses 2016; 8:87. [PMID: 27043611 PMCID: PMC4848582 DOI: 10.3390/v8040087] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Revised: 02/20/2016] [Accepted: 02/20/2016] [Indexed: 12/04/2022] Open
Abstract
Marburg virus causes severe and often lethal viral disease in humans, and there are currently no Food and Drug Administration (FDA) approved medical countermeasures. The sporadic occurrence of Marburg outbreaks does not allow for evaluation of countermeasures in humans, so therapeutic and vaccine candidates can only be approved through the FDA animal rule—a mechanism requiring well-characterized animal models in which efficacy would be evaluated. Here, we describe a natural history study where rhesus macaques were surgically implanted with telemetry devices and central venous catheters prior to aerosol exposure with Marburg-Angola virus, enabling continuous physiologic monitoring and blood sampling without anesthesia. After a three to four day incubation period, all animals developed fever, viremia, and lymphopenia before developing tachycardia, tachypnea, elevated liver enzymes, decreased liver function, azotemia, elevated D-dimer levels and elevated pro-inflammatory cytokines suggesting a systemic inflammatory response with organ failure. The final, terminal period began with the onset of sustained hypotension, dehydration progressed with signs of major organ hypoperfusion (hyperlactatemia, acute kidney injury, hypothermia), and ended with euthanasia or death. The most significant pathologic findings were marked infection of the respiratory lymphoid tissue with destruction of the tracheobronchial and mediastinal lymph nodes, and severe diffuse infection in the liver, and splenitis.
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Affiliation(s)
- Evan C Ewers
- Department of Medicine, Tripler Army Medical Center, Honolulu, HI 96859, USA.
| | - William D Pratt
- US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21702, USA.
| | - Nancy A Twenhafel
- Department of Medicine, Tripler Army Medical Center, Honolulu, HI 96859, USA.
- US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21702, USA.
| | - Joshua Shamblin
- US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21702, USA.
| | - Ginger Donnelly
- US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21702, USA.
| | - Heather Esham
- US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21702, USA.
| | - Carly Wlazlowski
- US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21702, USA.
| | - Joshua C Johnson
- Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD 21702, USA.
| | - Miriam Botto
- US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21702, USA.
| | - Lisa E Hensley
- Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD 21702, USA.
| | - Arthur J Goff
- Department of Medicine, Tripler Army Medical Center, Honolulu, HI 96859, USA.
- US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21702, USA.
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Venkatasubramanian S, Tripathi D, Tucker T, Paidipally P, Cheekatla S, Welch E, Raghunath A, Jeffers A, Tvinnereim AR, Schechter ME, Andrade BB, Mackman N, Idell S, Vankayalapati R. Tissue factor expression by myeloid cells contributes to protective immune response against Mycobacterium tuberculosis infection. Eur J Immunol 2016; 46:464-79. [PMID: 26471500 PMCID: PMC4740218 DOI: 10.1002/eji.201545817] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Revised: 09/03/2015] [Accepted: 10/12/2015] [Indexed: 12/19/2022]
Abstract
Tissue factor (TF) is a transmembrane glycoprotein that plays an essential role in hemostasis by activating coagulation. TF is also expressed by monocytes/macrophages as part of the innate immune response to infections. In the current study, we determined the role of TF expressed by myeloid cells during Mycobacterium tuberculosis (M. tb) infection by using mice lacking the TF gene in myeloid cells (TF(Δ) ) and human monocyte derived macrophages (MDMs). We found that during M. tb infection, a deficiency of TF in myeloid cells was associated with reduced inducible nitric oxide synthase (iNOS) expression, enhanced arginase 1 (Arg1) expression, enhanced IL-10 production and reduced apoptosis in infected macrophages, which augmented M. tb growth. Our results demonstrate that a deficiency of TF in myeloid cells promotes M2-like phenotype in M .tb infected macrophages. A deficiency in TF expression by myeloid cells was also associated with reduced fibrin deposition and increased matrix metalloproteases (MMP)-2 and MMP-9 mediated inflammation in M. tb infected lungs. Our studies demonstrate that TF expressed by myeloid cells has newly recognized abilities to polarize macrophages and to regulate M. tb growth.
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Affiliation(s)
| | - Deepak Tripathi
- Department of Pulmonary Immunology, University of Texas Health Science Center at Tyler, Tyler, TX 75708, USA
| | - Torry Tucker
- Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler, Tyler, TX 75708, USA
| | - Padmaja Paidipally
- Department of Pulmonary Immunology, University of Texas Health Science Center at Tyler, Tyler, TX 75708, USA
| | - Satyanarayana Cheekatla
- Department of Pulmonary Immunology, University of Texas Health Science Center at Tyler, Tyler, TX 75708, USA
| | - Elwyn Welch
- Department of Pulmonary Immunology, University of Texas Health Science Center at Tyler, Tyler, TX 75708, USA
| | - Anjana Raghunath
- Department of Pulmonary Immunology, University of Texas Health Science Center at Tyler, Tyler, TX 75708, USA
| | - Ann Jeffers
- Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler, Tyler, TX 75708, USA
| | - Amy R. Tvinnereim
- Department of Pulmonary Immunology, University of Texas Health Science Center at Tyler, Tyler, TX 75708, USA
| | - Melissa E Schechter
- Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
| | - Bruno B Andrade
- Investigative Medicine Branch, Laboratory of Immune Regulation, Centro de Pesquisas Gonçalo Moniz (CPqGM), Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Bahia, 40296-710, Brazil
- Research Center, Brazilian Institute for Tuberculosis Research, Salvador, Bahia, 45204-040, Brazil
| | - Nizel Mackman
- Department of Medicine, The University of North Carolina at Chapel Hill School of Medicine, NC 27516, USA
| | - Steven Idell
- Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler, Tyler, TX 75708, USA
| | - Ramakrishna Vankayalapati
- Department of Pulmonary Immunology, University of Texas Health Science Center at Tyler, Tyler, TX 75708, USA
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Dahn H, Buth K, Legare JF, Mingo H, Kent B, Whynot S, Scheffler M. Endocarditis is not an Independent Predictor of Blood Transfusion in Aortic Valve Replacement Patients With Severe Aortic Regurgitation. J Cardiothorac Vasc Anesth 2016; 30:687-91. [PMID: 26750645 DOI: 10.1053/j.jvca.2015.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Indexed: 11/11/2022]
Abstract
OBJECTIVE This study sought to evaluate if the presence of endocarditis was independently associated with increased perioperative blood transfusion in patients undergoing aortic valve replacements (AVR) with aortic regurgitation. DESIGN This was a retrospective study. SETTING Large Canadian tertiary care hospital. PARTICIPANTS Six hundred sixty-two consecutive patients with aortic regurgitation score of 3 or higher undergoing AVR from 1995 to 2012. INTERVENTIONS No interventions were performed in this retrospective study. MEASUREMENTS AND MAIN RESULTS After REB approval, data were obtained from a center-specific database. Univariate analysis was performed to identify variables that may be associated with transfusion of any allogeneic blood product perioperatively. A multivariate logistic regression was generated to identify independent predictors of perioperative transfusion. Unadjusted transfusion rates in patients with no endocarditis and with endocarditis were 32% and 70% (p<0.001), respectively. Independent predictors of any transfusion were moderate-to-severe preoperative anemia, preoperative renal failure, non-isolated AVR, age>70, urgent/emergent surgery, BMI<25, and female sex. Endocarditis was not an independent predictor of transfusion (OR = 0.748; 95% CI = 0.35-1.601). CONCLUSIONS In patients undergoing AVR, unadjusted perioperative transfusion rates were higher when endocarditis was present. However, after adjustment, aortic valve endocarditis was not independently associated with blood transfusion. The authors' observation could be explained by the higher prevalence of many independent predictors of transfusion, such as comorbidities or more complex surgery, within the endocarditis group. Thus, AV endocarditis, in the absence of other risk factors, was not associated with increased perioperative transfusion risk.
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Affiliation(s)
- Hannah Dahn
- Department of Anesthesia, Pain Management, and Perioperative Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
| | - Karen Buth
- Department of Surgery, Dalhousie University, Halifax, Nova Scotia, Canada
| | | | - Heather Mingo
- Department of Anesthesia, Pain Management, and Perioperative Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Blaine Kent
- Department of Anesthesia, Pain Management, and Perioperative Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Sara Whynot
- Department of Anesthesia, Pain Management, and Perioperative Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Matthias Scheffler
- Department of Anesthesia, Pain Management, and Perioperative Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
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Tan L, Huang Y, Pan X, Quan S, Xu S, Li D, Song L, Zhang X, Chen W, Pan J. Administration of bone marrow stromal cells in sepsis attenuates sepsis-related coagulopathy. Ann Med 2016; 48:235-45. [PMID: 26969493 DOI: 10.3109/07853890.2016.1157725] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
INTRODUCTION Coagulopathy plays an important role in sepsis. The aim of this study was to determine whether bone marrow stromal cell (BMSC) administration could attenuate coagulopathy in sepsis. MATERIALS AND METHODS In vitro: endothelial cells were cultured with/without BMSCs for 6 h following LPS stimulation and were collected for thrombomodulin (TM) and endothelial protein C receptor (EPCR) measurements. In vivo: Thirty-six mice were randomized into sham, sepsis, and sepsis + BMSC groups (n = 12 each group). Sepsis was induced through cecal ligation and puncture (CLP). BMSC infusion was started at 6 h after CLP. Lung tissues and plasma samples were collected at 24 h after CLP for enzyme-linked immunosorbent assay (ELISA), quantitative real-time RT-PCR, western blot, and immunohistochemistry analysis. RESULTS In vitro: BMSCs attenuated the decrease in TM and EPCR mRNA and protein expression levels in LPS-stimulated endothelial cells. In vivo: BMSC treatment decreased lung injury and mesenteric perfusion impairment, and ameliorated coagulopathy, as suggested by the reduction in elevated TF, vWF, and TAT circulation levels. BMSC infusion decreased TF mRNA transcription and protein expression levels in lung tissues, and increased TM and EPCR mRNA transcription and expression levels. DISCUSSION BMSC administration attenuated coagulopathy, and decreased lung injury and mesenteric perfusion impairment in sepsis. Key messages BMSCs increased the expression of TM and EPCR from endothelium cells exposed to LPS in vitro. BMSC treatment attenuated lung injury and coagulopathy in the mice cecal ligation and puncture (CLP) model. BMSC administration-attenuated coagulopathy is related to the reduced expression of TF and increased expression of TM and EPCR.
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Affiliation(s)
- Lifei Tan
- a Department of the First Clinical Medical , The First Affiliated Hospital of Wenzhou Medical University , Wenzhou , Zhejiang , People's Republic of China
| | - Yueyue Huang
- b Department of Intensive Care Unit , The First Affiliated Hospital of Wenzhou Medical University , Wenzhou , Zhejiang , People's Republic of China
| | - Xiaojun Pan
- a Department of the First Clinical Medical , The First Affiliated Hospital of Wenzhou Medical University , Wenzhou , Zhejiang , People's Republic of China
| | - Shichao Quan
- c Department of General Medicine , The First Affiliated Hospital of Wenzhou Medical University , Wenzhou , Zhejiang , People's Republic of China
| | - Shunyao Xu
- a Department of the First Clinical Medical , The First Affiliated Hospital of Wenzhou Medical University , Wenzhou , Zhejiang , People's Republic of China
| | - Dequan Li
- d Department of Traumatology , The First Affiliated Hospital of Wenzhou Medical University , Wenzhou , Zhejiang , People's Republic of China
| | - Lijun Song
- a Department of the First Clinical Medical , The First Affiliated Hospital of Wenzhou Medical University , Wenzhou , Zhejiang , People's Republic of China
| | - Xiaomin Zhang
- a Department of the First Clinical Medical , The First Affiliated Hospital of Wenzhou Medical University , Wenzhou , Zhejiang , People's Republic of China
| | - Wanzhou Chen
- b Department of Intensive Care Unit , The First Affiliated Hospital of Wenzhou Medical University , Wenzhou , Zhejiang , People's Republic of China
| | - Jingye Pan
- b Department of Intensive Care Unit , The First Affiliated Hospital of Wenzhou Medical University , Wenzhou , Zhejiang , People's Republic of China
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Houston S, Taylor JS, Denchev Y, Hof R, Zuerner RL, Cameron CE. Conservation of the Host-Interacting Proteins Tp0750 and Pallilysin among Treponemes and Restriction of Proteolytic Capacity to Treponema pallidum. Infect Immun 2015; 83:4204-16. [PMID: 26283341 PMCID: PMC4598410 DOI: 10.1128/iai.00643-15] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Accepted: 08/06/2015] [Indexed: 12/13/2022] Open
Abstract
The spirochete Treponema pallidum subsp. pallidum is the causative agent of syphilis, a chronic, sexually transmitted infection characterized by multiple symptomatic and asymptomatic stages. Although several other species in the genus are able to cause or contribute to disease, T. pallidum differs in that it is able to rapidly disseminate via the bloodstream to tissue sites distant from the site of initial infection. It is also the only Treponema species able to cross both the blood-brain and placental barriers. Previously, the T. pallidum proteins, Tp0750 and Tp0751 (also called pallilysin), were shown to degrade host proteins central to blood coagulation and basement membrane integrity, suggesting a role for these proteins in T. pallidum dissemination and tissue invasion. In the present study, we characterized Tp0750 and Tp0751 sequence variation in a diversity of pathogenic and nonpathogenic treponemes. We also determined the proteolytic potential of the orthologs from the less invasive species Treponema denticola and Treponema phagedenis. These analyses showed high levels of sequence similarity among Tp0750 orthologs from pathogenic species. For pallilysin, lower levels of sequence conservation were observed between this protein and orthologs from other treponemes, except for the ortholog from the highly invasive rabbit venereal syphilis-causing Treponema paraluiscuniculi. In vitro host component binding and degradation assays demonstrated that pallilysin and Tp0750 orthologs from the less invasive treponemes tested were not capable of binding or degrading host proteins. The results show that pallilysin and Tp0750 host protein binding and degradative capability is positively correlated with treponemal invasiveness.
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Affiliation(s)
- Simon Houston
- Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada
| | - John S Taylor
- Department of Biology, University of Victoria, Victoria, British Columbia, Canada
| | - Yavor Denchev
- Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada
| | - Rebecca Hof
- Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada
| | - Richard L Zuerner
- Bacterial Diseases of Livestock Research Unit, National Animal Disease Center, Agricultural Research Service, U.S. Department of Agriculture, Ames, Iowa, USA Department of Biomedicine and Veterinary Public Health, Swedish University of Agricultural Research, Uppsala, Sweden
| | - Caroline E Cameron
- Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada
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Sepsis and ARDS: The Dark Side of Histones. Mediators Inflamm 2015; 2015:205054. [PMID: 26609197 PMCID: PMC4644547 DOI: 10.1155/2015/205054] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Accepted: 09/01/2015] [Indexed: 12/13/2022] Open
Abstract
Despite advances in management over the last several decades, sepsis and acute respiratory distress syndrome (ARDS) still remain major clinical challenges and the leading causes of death for patients in intensive care units (ICUs) due to insufficient understanding of the pathophysiological mechanisms of these diseases. However, recent studies have shown that histones, also known as chromatin-basic structure proteins, could be released into the extracellular space during severe stress and physical challenges to the body (e.g., sepsis and ARDS). Due to their cytotoxic and proinflammatory effects, extracellular histones can lead to excessive and overwhelming cell damage and death, thus contributing to the pathogenesis of both sepsis and ARDS. In addition, antihistone-based treatments (e.g., neutralizing antibodies, activated protein C, and heparin) have shown protective effects and have significantly improved the outcomes of mice suffering from sepsis and ARDS. Here, we review researches related to the pathological role of histone in context of sepsis and ARDS and evaluate the potential value of histones as biomarkers and therapeutic targets of these diseases.
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Predictive value of the complement system for sepsis-induced disseminated intravascular coagulation in septic patients in emergency department. J Crit Care 2015; 30:290-5. [DOI: 10.1016/j.jcrc.2014.11.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2014] [Revised: 10/28/2014] [Accepted: 11/13/2014] [Indexed: 11/21/2022]
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Histone deacetylase III as a potential therapeutic target for the treatment of lethal sepsis. J Trauma Acute Care Surg 2015; 77:913-9; discussion 919. [PMID: 25051385 DOI: 10.1097/ta.0000000000000347] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND We have recently demonstrated that inhibition of histone deacetylase (HDAC) Class I, II, and IV with nonspecific HDAC inhibitors improves survival in a mouse model of lethal cecal ligation and puncture (CLP). However, the consequence of HDAC Class III inhibition is unknown in this model. The aims of the present study were to explore the effect of EX-527, a selective Sirtuin 1 (SIRT1) inhibitor, on survival in the lethal model of CLP-sepsis and to assess the impact of the treatment on inflammatory cytokine production, coagulopathy, and bone marrow atrophy during severe sepsis. METHODS For Experiment I, C57BL/6J mice were subjected to CLP and, 1 hour later, intraperitoneally injected with either EX-527 dissolved in dimethyl sulfoxide (DMSO) or DMSO only. Survival was monitored for 10 days. For Experiment II, 1 hour after CLP animals were randomly treated with (1) DMSO vehicle and (2) EX-527. Peritoneal fluid and blood samples were collected for measurement of cytokines, and blood was also used to evaluate coagulation status using thrombelastography. In addition, long bones (femurs and tibias) were examined to determine morphologic changes in the marrow by hematoxylin and eosin staining. For Experiment III, normal primary splenocytes were cultured and treated with lipopolysaccharide in the presence or absence of EX-527 to assess cytokine production. RESULTS EX-527 significantly improved survival (50% vs. 0% survival as compared to vehicle, p = 0.0007) and attenuated levels of cytokines tumor necrosis factor α and interleukin 6 in the blood and the peritoneal fluid compared with the vehicle control. It also decreased tumor necrosis factor α and interleukin 6 production by splenocytes in vitro. Selective inhibition of SIRT1 was associated with significant improvements in fibrin cross-linkage, platelet function, and clot rigidity but had no significant impact on the clot initiation parameters. Moreover, inhibition of SIRT1 was associated with a significant decrease in bone marrow atrophy. CONCLUSION Selective inhibition of Class III HDAC SIRT1 significantly improves survival, attenuates cytokine levels and sepsis-associated coagulopathy, and decreases bone marrow atrophy in a lethal mouse septic model.
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Murata A, Okamoto K, Mayumi T, Muramatsu K, Matsuda S. Observational study to compare antithrombin and thrombomodulin for disseminated intravascular coagulation. Int J Clin Pharm 2015; 37:139-147. [PMID: 25515615 DOI: 10.1007/s11096-014-0052-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2014] [Accepted: 12/06/2014] [Indexed: 12/31/2022]
Abstract
BACKGROUND There have been no studies comparing the effects of antithrombin (AT-III) and recombinant human soluble thrombomodulin (rhs-TM) on outcomes in patients with disseminated intravascular coagulation (DIC) associated with infectious diseases. OBJECTIVE The aim of this observational study is to compare AT-III and rhs-TM in terms of outcomes such as mortality, length of hospitalization, and medical costs in patients with DIC associated with infectious diseases based on a Japanese administrative database. SETTING A total of 7,535 patients with DIC associated with infectious diseases in 886 hospitals from 2010 to 2012 in Japan. Methods We collected patients' data from the administrative database to compare clinical and medical economic outcomes of patients with DIC. Patients were divided into two groups according to treatment of DIC: AT-III (n = 3,601) and rhs-TM (n = 3,934). MAIN OUTCOMES MEASURE In-hospital mortality (within 14 days, within 28 days, and overall mortality), length of stay (LOS), and medical costs during hospitalization. RESULTS Multilevel logistic regression analysis showed that there were no significant differences with regard to in-hospital mortality between AT-III and rhs-TM within 14 days (odds ratio (OR) of rhs-TM 0.97, 95 % confidence interval (CI) 0.85-1.11, p = 0.744), within 28 days (OR 1.00, 95 % CI 0.89-1.13, p = 0.919), and overall (OR 0.95, 95 % CI 0.85-1.07, p = 0.470). However, multilevel linear regression analysis revealed that use of rhs-TM significantly decreased LOS and medical costs during hospitalization. The coefficient for LOS was -2.92 days (95 % CI -4.79 to -1.04 days; p = 0.002) whereas that for medical costs during hospitalization was -798.3 Euro (95 % CI -1,515.7 to -81.0 Euro; p = 0.029). CONCLUSION This study demonstrated no significant difference in in-hospital mortality between AT-III and rhs-TM. However, use of rhs-TM was significantly associated with decreased LOS and medical costs during hospitalization in patients with DIC associated with infectious diseases.
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Affiliation(s)
- Atsuhiko Murata
- Department of Preventive Medicine and Community Health, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka, 807-8555, Japan,
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Funk DJ, Kumar A. Ebola virus disease: an update for anesthesiologists and intensivists. Can J Anaesth 2014; 62:80-91. [PMID: 25373801 PMCID: PMC4286619 DOI: 10.1007/s12630-014-0257-z] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2014] [Accepted: 10/17/2014] [Indexed: 12/25/2022] Open
Abstract
Purpose Ebola virus disease (EVD) is a viral hemorrhagic fever that is highly transmissible and all too often rapidly fatal. Recent outbreaks in West Africa reveal that this infection has the potential to be transmitted worldwide. Anesthesiologists and intensivists, due to their training in the management of the critically ill, may be called upon to assist in the management of these patients. The focus of this brief review is on the epidemiology, pathogenesis, and management of patients with EVD. Source Review of the current literature. Principal findings Ebola virus disease causes severe diarrhea, electrolyte disturbances and other major end-organ dysfunction. Early aggressive resuscitation may reduce the mortality of this disease. There is presently no available vaccine nor cure, with experimental therapies having yielded limited success. Personal protective equipment (PPE) is necessary for all patient contact, and enhanced PPE is required for all aerosol-generating medical procedures. Conclusion Anesthesiologists and intensivists may be called upon to manage patients with EVD. It is important that these clinicians have an appreciation for the epidemiology and pathogenesis of this disease and for the proper utilization of PPE when treating these patients.
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Affiliation(s)
- Duane J Funk
- Departments of Anesthesiology and Medicine, Section of Critical Care, Faculty of Medicine, University of Manitoba, 2nd Floor Harry Medovy House, 671 William Avenue, Winnipeg, MB, Canada,
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Trombosis microvascular. ANGIOLOGIA 2014. [DOI: 10.1016/j.angio.2014.05.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Gopinathan U, Brusletto BS, Olstad OK, Kierulf P, Berg JP, Brandtzaeg P, Øvstebø R. IL-10 immunodepletion from meningococcal sepsis plasma induces extensive changes in gene expression and cytokine release in stimulated human monocytes. Innate Immun 2014; 21:429-49. [PMID: 25233959 DOI: 10.1177/1753425914547743] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2014] [Accepted: 07/22/2014] [Indexed: 11/15/2022] Open
Abstract
The severity of systemic meningococcal disease (SMD) correlates to plasma concentrations of LPS and IL-10, with the highest levels detected in non-survivors. Here, plasma from patients with SMD containing high and low concentrations of LPS were incubated with human monocytes before and after immunodepletion of IL-10 to study the effect of IL-10 on gene expression and cytokine release. Patient plasma containing IL-10 induced the expression of 1657 genes in human monocytes when compared with gene expression induced by low LPS plasma. After immunodepletion of IL-10, this number increased to 2260. By directly comparing the gene expression profiles induced before and after immunodepletion of IL-10, the presence of IL-10 differentially regulated 373 genes. Functional classes associated with these genes were cellular function and maintenance, cellular development, cellular growth and proliferation, cell-cell signaling and interaction and cellular movement. Immunodepletion of IL-10 resulted in down-regulation of genes of the leukocyte immunoglobulin-like receptor family, and up-regulation of genes of type I IFN signaling, TLR signaling, the inflammasomes, coagulation and fibrinolysis. Finally, immunodepletion of IL-10 increased the protein levels of IL-1β, IL-8, TNF-α, MIP-1α and MIP-1β. Data suggest that IL-10 in meningococcal sepsis plasma regulates a variety of genes and signaling pathways, likely leading to an overall inhibitory effect on the inflammatory response induced in meningococcal sepsis.
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Affiliation(s)
- Unni Gopinathan
- Blood Cell Research Group, Section for Research, Department of Medical Biochemistry, Oslo University Hospital, University of Oslo, Oslo, Norway Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Berit Sletbakk Brusletto
- Blood Cell Research Group, Section for Research, Department of Medical Biochemistry, Oslo University Hospital, University of Oslo, Oslo, Norway
| | - Ole Kristoffer Olstad
- Blood Cell Research Group, Section for Research, Department of Medical Biochemistry, Oslo University Hospital, University of Oslo, Oslo, Norway
| | - Peter Kierulf
- Blood Cell Research Group, Section for Research, Department of Medical Biochemistry, Oslo University Hospital, University of Oslo, Oslo, Norway Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Jens Petter Berg
- Blood Cell Research Group, Section for Research, Department of Medical Biochemistry, Oslo University Hospital, University of Oslo, Oslo, Norway Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Petter Brandtzaeg
- Blood Cell Research Group, Section for Research, Department of Medical Biochemistry, Oslo University Hospital, University of Oslo, Oslo, Norway Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway Department of Pediatrics, Oslo University Hospital, University of Oslo, Oslo, Norway
| | - Reidun Øvstebø
- Blood Cell Research Group, Section for Research, Department of Medical Biochemistry, Oslo University Hospital, University of Oslo, Oslo, Norway
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Zakaryan H, Karalova E, Voskanyan H, Ter-Pogossyan Z, Nersisyan N, Hakobyan A, Saroyan D, Karalyan Z. Evaluation of hemostaseological status of pigs experimentally infected with African swine fever virus. Vet Microbiol 2014; 174:223-8. [PMID: 25239678 DOI: 10.1016/j.vetmic.2014.08.029] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Revised: 08/05/2014] [Accepted: 08/26/2014] [Indexed: 10/24/2022]
Abstract
African swine fever is a highly contagious hemorrhagic disease of pigs caused by African swine fever virus (ASFV). Hemorrhages are the most frequently reported lesions in acute and subacute forms of ASF. Hemorrhagic lesions are accompanied by impaired hemostasis, which includes thrombocytopenia and changes in the coagulation system. In the present study, experimental infection was conducted to elucidate whether a highly virulent ASFV genotype II circulating in the Trans-Caucasus and Eastern Europe affects the hemostasis of infected pigs. Platelet count changes and platelet size, as well as coagulation parameters were evaluated upon experimental infection. In contrast to other ASFV strains, ASFV genotype II showed a significant decrease in the number of platelets from 3rd dpi onwards. Furthermore, a decrease in platelet size was observed throughout the entire period of experiment. A significant increase in the number of platelet aggregates was observed from the beginning of infection. Unlike other ASFV strains, ASFV genotype II induced a slight shortening of an activated partial thromboplastin time (aPTT) throughout the experiment. Thrombin time (TT) was prolonged from day 5 onwards, whereas no changes in prothrombin time (PT) were found upon infection. The level of d-dimers was permanently higher than in control with a peak on day 3 post-infection. ASFV induced a significant decrease in the level of fibrinogen from day 5 till the end of experiment. Thus, it can be concluded that ASFV genotype II isolated in Armenia affects the hemostasis of infected pigs and causes changes that differ from that of other ASFV strains described previously.
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Affiliation(s)
- Hovakim Zakaryan
- Laboratory of Cell Biology and Virology, Institute of Molecular Biology of NAS RA, P.O. Box 0014, Yerevan, Armenia
| | - Elena Karalova
- Laboratory of Cell Biology and Virology, Institute of Molecular Biology of NAS RA, P.O. Box 0014, Yerevan, Armenia
| | - Henrik Voskanyan
- Laboratory of Cell Biology and Virology, Institute of Molecular Biology of NAS RA, P.O. Box 0014, Yerevan, Armenia; Scientific Center of Stock Breading and Veterinary RA, P.O. Box 0071, Nubarashen Sarahat 2, Yerevan, Armenia
| | - Zarine Ter-Pogossyan
- Laboratory of Cell Biology and Virology, Institute of Molecular Biology of NAS RA, P.O. Box 0014, Yerevan, Armenia
| | - Narek Nersisyan
- Laboratory of Cell Biology and Virology, Institute of Molecular Biology of NAS RA, P.O. Box 0014, Yerevan, Armenia
| | - Astghik Hakobyan
- Laboratory of Cell Biology and Virology, Institute of Molecular Biology of NAS RA, P.O. Box 0014, Yerevan, Armenia
| | - David Saroyan
- Laboratory of Cell Biology and Virology, Institute of Molecular Biology of NAS RA, P.O. Box 0014, Yerevan, Armenia
| | - Zaven Karalyan
- Laboratory of Cell Biology and Virology, Institute of Molecular Biology of NAS RA, P.O. Box 0014, Yerevan, Armenia.
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Ilinskaya AN, Man S, Patri AK, Clogston JD, Crist RM, Cachau RE, McNeil SE, Dobrovolskaia MA. Inhibition of phosphoinositol 3 kinase contributes to nanoparticle-mediated exaggeration of endotoxin-induced leukocyte procoagulant activity. Nanomedicine (Lond) 2014; 9:1311-26. [PMID: 24279459 PMCID: PMC4035470 DOI: 10.2217/nnm.13.137] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2013] [Indexed: 01/17/2023] Open
Abstract
AIM Disseminated intravascular coagulation is an increasing concern for certain types of engineered nanomaterials. Recent studies have shed some light on the nanoparticle physicochemical properties contributing to this toxicity; however, the mechanisms are poorly understood. Leukocyte procoagulant activity (PCA) is a key factor contributing to the initiation of this toxicity. We have previously reported on the exaggeration of endotoxin-induced PCA by cationic dendrimers. Herein, we report an effort to discern the mechanism. MATERIALS & METHODS Poly(amidoamine) dendrimers with various sizes and surface functionalities were studied in vitro by the recalcification test, flow cytometry and other relevant assays. RESULTS & CONCLUSION Cationic dendrimers exaggerated endotoxin-induced PCA, but their anionic or neutral counterparts did not; the cationic charge prompts this phenomenon, but different cationic surface chemistries do not influence it. Cationic dendrimers and endotoxin differentially affect the PCA complex. The inhibition of phosphoinositol 3 kinase by dendrimers contributes to the exaggeration of the endotoxin-induced PCA.
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Affiliation(s)
- Anna N Ilinskaya
- Nanotechnology Characterization Laboratory, Advanced Technology Program, SAIC-Frederick Inc., NCI-Frederick, 1050 Boyles Street, Building 469, Frederick, MD 21702, USA
| | - Sonny Man
- Nanotechnology Characterization Laboratory, Advanced Technology Program, SAIC-Frederick Inc., NCI-Frederick, 1050 Boyles Street, Building 469, Frederick, MD 21702, USA
| | - Anil K Patri
- Nanotechnology Characterization Laboratory, Advanced Technology Program, SAIC-Frederick Inc., NCI-Frederick, 1050 Boyles Street, Building 469, Frederick, MD 21702, USA
| | - Jeffrey D Clogston
- Nanotechnology Characterization Laboratory, Advanced Technology Program, SAIC-Frederick Inc., NCI-Frederick, 1050 Boyles Street, Building 469, Frederick, MD 21702, USA
| | - Rachael M Crist
- Nanotechnology Characterization Laboratory, Advanced Technology Program, SAIC-Frederick Inc., NCI-Frederick, 1050 Boyles Street, Building 469, Frederick, MD 21702, USA
| | - Raul E Cachau
- Advanced Biomedical Computing Center, SAIC-Frederick Inc., NCI-Frederick, Frederick, MD 21702, USA
| | - Scott E McNeil
- Nanotechnology Characterization Laboratory, Advanced Technology Program, SAIC-Frederick Inc., NCI-Frederick, 1050 Boyles Street, Building 469, Frederick, MD 21702, USA
| | - Marina A Dobrovolskaia
- Nanotechnology Characterization Laboratory, Advanced Technology Program, SAIC-Frederick Inc., NCI-Frederick, 1050 Boyles Street, Building 469, Frederick, MD 21702, USA
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