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1.
Sci Rep ; 11(1): 16039, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34362979

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) induces lung injury of varying severity, potentially causing severe acute respiratory distress syndrome (ARDS). Pulmonary injury patterns in COVID-19 patients differ from those in patients with other causes of ARDS. We aimed to explore the frequency and pathogenesis of cavitary lung lesions in critically ill patients with COVID-19. Retrospective study in 39 critically ill adult patients hospitalized with severe acute respiratory syndrome coronavirus 2 including lung injury of varying severity in a tertiary care referral center during March and May 2020, Berlin/Germany. We observed lung cavitations in an unusually large proportion of 22/39 (56%) COVID-19 patients treated on intensive care units (ICU), including 3/5 patients without mechanical ventilation. Median interquartile range (IQR) time between onset of symptoms and ICU admission was 11.5 (6.25-17.75) days. In 15 patients, lung cavitations were already present on the first CT scan, performed after ICU admission; in seven patients they developed during a subsequent median (IQR) observation period of 48 (35-58) days. In seven patients we found at least one cavitation with a diameter > 2 cm (maximum 10 cm). Patients who developed cavitations were older and had a higher body mass index. Autopsy findings in three patients revealed that the cavitations reflected lung infarcts undergoing liquefaction, secondary to thrombotic pulmonary artery branch occlusions. Lung cavitations appear to be a frequent complication of severely ill COVID-19 patients, probably related to the prothrombotic state associated with COVID-19.


Assuntos
COVID-19/patologia , Pulmão/patologia , Embolia Pulmonar/patologia , Idoso , COVID-19/complicações , Estado Terminal , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Embolia Pulmonar/etiologia , Estudos Retrospectivos , SARS-CoV-2/isolamento & purificação
2.
J Clin Invest ; 131(20)2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34464358

RESUMO

BACKGROUNDCOVID-19 convalescent plasma (CCP) has been considered a treatment option for COVID-19. This trial assessed the efficacy of a neutralizing antibody containing high-dose CCP in hospitalized adults with COVID-19 requiring respiratory support or intensive care treatment.METHODSPatients (n = 105) were randomized 1:1 to either receive standard treatment and 3 units of CCP or standard treatment alone. Control group patients with progress on day 14 could cross over to the CCP group. The primary outcome was a dichotomous composite outcome of survival and no longer fulfilling criteria for severe COVID-19 on day 21.ResultsThe primary outcome occurred in 43.4% of patients in the CCP group and 32.7% in the control group (P = 0.32). The median time to clinical improvement was 26 days in the CCP group and 66 days in the control group (P = 0.27). The median time to discharge from the hospital was 31 days in the CCP group and 51 days in the control group (P = 0.24). In the subgroup that received a higher cumulative amount of neutralizing antibodies, the primary outcome occurred in 56.0% of the patients (vs. 32.1%), with significantly shorter intervals to clinical improvement (20 vs. 66 days, P < 0.05) and to hospital discharge (21 vs. 51 days, P = 0.03) and better survival (day-60 probability of survival 91.6% vs. 68.1%, P = 0.02) in comparison with the control group.ConclusionCCP added to standard treatment was not associated with a significant improvement in the primary and secondary outcomes. A predefined subgroup analysis showed a significant benefit of CCP among patients who received a larger amount of neutralizing antibodies.Trial registrationClinicalTrials.gov NCT04433910.FundingBundesministerium für Gesundheit (German Federal Ministry of Health): ZMVI1-2520COR802.

3.
Cell Syst ; 12(8): 780-794.e7, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34139154

RESUMO

COVID-19 is highly variable in its clinical presentation, ranging from asymptomatic infection to severe organ damage and death. We characterized the time-dependent progression of the disease in 139 COVID-19 inpatients by measuring 86 accredited diagnostic parameters, such as blood cell counts and enzyme activities, as well as untargeted plasma proteomes at 687 sampling points. We report an initial spike in a systemic inflammatory response, which is gradually alleviated and followed by a protein signature indicative of tissue repair, metabolic reconstitution, and immunomodulation. We identify prognostic marker signatures for devising risk-adapted treatment strategies and use machine learning to classify therapeutic needs. We show that the machine learning models based on the proteome are transferable to an independent cohort. Our study presents a map linking routinely used clinical diagnostic parameters to plasma proteomes and their dynamics in an infectious disease.


Assuntos
Biomarcadores/análise , COVID-19/patologia , Progressão da Doença , Proteoma/fisiologia , Fatores Etários , Contagem de Células Sanguíneas , Gasometria , Ativação Enzimática , Humanos , Inflamação/patologia , Aprendizado de Máquina , Prognóstico , Proteômica , SARS-CoV-2/imunologia
4.
Sci Rep ; 11(1): 13325, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34172793

RESUMO

COVID 19 is associated with a hypercoagulable state and frequent thromboembolic complications. For how long this acquired abnormality lasts potentially requiring preventive measures, such as anticoagulation remains to be delineated. We used viscoelastic rotational thrombelastometry (ROTEM) in a single center cohort of 13 critical ill patients and performed follow up examinations three months after discharge from ICU. We found clear signs of a hypercoagulable state due to severe hypofibrinolysis and a high rate of thromboembolic complications during the phase of acute illness. Three month follow up revealed normalization of the initial coagulation abnormality and no evidence of venous thrombosis in all thirteen patients. In our cohort the coagulation profile was completely normalized three months after COVID-19. Based on these findings, discontinuation of anticoagulation can be discussed in patients with complete venous reperfusion.


Assuntos
Anticoagulantes/uso terapêutico , Transtornos da Coagulação Sanguínea , COVID-19 , Tromboelastografia , Tromboembolia , Trombose Venosa , Idoso , Coagulação Sanguínea , Transtornos da Coagulação Sanguínea/tratamento farmacológico , Transtornos da Coagulação Sanguínea/patologia , COVID-19/sangue , COVID-19/tratamento farmacológico , COVID-19/patologia , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Tromboembolia/tratamento farmacológico , Tromboembolia/patologia , Trombose Venosa/tratamento farmacológico , Trombose Venosa/patologia
5.
Sci Rep ; 11(1): 10678, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-34021219

RESUMO

With an urgent need for bedside imaging of coronavirus disease 2019 (COVID-19), this study's main goal was to assess inter- and intraobserver agreement in lung ultrasound (LUS) of COVID-19 patients. In this single-center study we prospectively acquired and evaluated 100 recorded ten-second cine-loops in confirmed COVID-19 intensive care unit (ICU) patients. All loops were rated by ten observers with different subspeciality backgrounds for four times by each observer (400 loops overall) in a random sequence using a web-based rating tool. We analyzed inter- and intraobserver variability for specific pathologies and a semiquantitative LUS score. Interobserver agreement for both, identification of specific pathologies and assignment of LUS scores was fair to moderate (e.g., LUS score 1 Fleiss' κ = 0.27; subpleural consolidations Fleiss' κ = 0.59). Intraobserver agreement was mostly moderate to substantial with generally higher agreement for more distinct findings (e.g., lowest LUS score 0 vs. highest LUS score 3 (median Fleiss' κ = 0.71 vs. 0.79) or air bronchograms (median Fleiss' κ = 0.72)). Intraobserver consistency was relatively low for intermediate LUS scores (e.g. LUS Score 1 median Fleiss' κ = 0.52). We therefore conclude that more distinct LUS findings (e.g., air bronchograms, subpleural consolidations) may be more suitable for disease monitoring, especially with more than one investigator and that training material used for LUS in point-of-care ultrasound (POCUS) should pay refined attention to areas such as B-line quantification and differentiation of intermediate LUS scores.


Assuntos
COVID-19/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Sistemas Automatizados de Assistência Junto ao Leito , SARS-CoV-2 , COVID-19/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica , Variações Dependentes do Observador , Estudos Prospectivos , Ultrassonografia
6.
Cells ; 10(4)2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33920990

RESUMO

Thrombin, the ligand of the protease-activated receptor 1 (PAR1), is a well-known stimulator of proangiogenic responses in vascular endothelial cells (ECs), which are mediated through the induction of vascular endothelial growth factor (VEGF). However, the transcriptional events underlying this thrombin-induced VEGF induction and angiogenic response are less well understood at present. As reported here, we conducted detailed promotor activation and signal transduction pathway studies in human microvascular ECs, to decipher the transcription factors and the intracellular signaling events underlying the thrombin and PAR-1-induced endothelial VEGF induction. We found that c-FOS is a key transcription factor controlling thrombin-induced EC VEGF synthesis and angiogenesis. Upon the binding and internalization of its G-protein-coupled PAR-1 receptor, thrombin triggers ERK1/2 signaling and activation of the nuclear AP-1/c-FOS transcription factor complex, which then leads to VEGF transcription, extracellular secretion, and concomitant proangiogenic responses of ECs. In conclusion, exposure of human microvascular ECs to thrombin triggers signaling through the PAR-1-ERK1/2-AP-1/c-FOS axis to control VEGF gene transcription and VEGF-induced angiogenesis. These observations offer a greater understanding of endothelial responses to thromboinflammation, which may help to interpret the results of clinical trials tackling the conditions associated with endothelial injury and thrombosis.

7.
Z Geburtshilfe Neonatol ; 225(2): 183-187, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33873231

RESUMO

INTRODUCTION: SARS-CoV-2 is a novel coronavirus that was first isolated in Wuhan, China, and resulted in a rapidly spreading pandemic worldwide. Currently there is only limited evidence on the effect of COVID-19 on pregnant women. CASE: Here we present one of the first serious COVID-19 cases in pregnancy at term with subsequent delivery. Postpartum the mother required antibiotic and symptomatic treatment. She experienced acute worsening of symptoms and developed acute respiratory failure requiring endotracheal intubation and subsequently extracorporeal membrane oxygenation. CONCLUSION: COVID-19 affects all medical disciplines, requiring interdisciplinary approaches and development of patient care regimes. Obstetricians should be aware and be prepared for the special needs of pregnant women with potential prenatal and postnatal issues. Ideally pregnant COVID-19 patients should be cared for at a tertiary perinatal center with experienced perinatologists and neonatologists.


Assuntos
COVID-19 , Complicações Infecciosas na Gravidez , Síndrome do Desconforto Respiratório , China , Feminino , Humanos , Período Periparto , Gravidez , Complicações Infecciosas na Gravidez/diagnóstico , Complicações Infecciosas na Gravidez/terapia , Síndrome do Desconforto Respiratório/diagnóstico , Síndrome do Desconforto Respiratório/terapia , SARS-CoV-2
8.
Kidney Int Rep ; 2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33817450

RESUMO

Introduction: Acute kidney injury (AKI) is an important complication in COVID-19, but its precise etiology has not fully been elucidated. Insights into AKI mechanisms may be provided by analyzing the temporal associations of clinical parameters reflecting disease processes and AKI development. Methods: We performed an observational cohort study of 223 consecutive COVID-19 patients treated at 3 sites of a tertiary care referral center to describe the evolvement of severe AKI (Kidney Disease: Improving Global Outcomes stage 3) and identify conditions promoting its development. Descriptive statistics and explanatory multivariable Cox regression modeling with clinical parameters as time-varying covariates were used to identify risk factors of severe AKI. Results: Severe AKI developed in 70 of 223 patients (31%) with COVID-19, of which 95.7% required kidney replacement therapy. Patients with severe AKI were older, predominantly male, had more comorbidities, and displayed excess mortality. Severe AKI occurred exclusively in intensive care unit patients, and 97.3% of the patients developing severe AKI had respiratory failure. Mechanical ventilation, vasopressor therapy, and inflammatory markers (serum procalcitonin levels and leucocyte count) were independent time-varying risk factors of severe AKI. Increasing inflammatory markers displayed a close temporal association with the development of severe AKI. Sensitivity analysis on risk factors of AKI stage 2 and 3 combined confirmed these findings. Conclusion: Severe AKI in COVID-19 was tightly coupled with critical illness and systemic inflammation and was not observed in milder disease courses. These findings suggest that traditional systemic AKI mechanisms rather than kidney-specific processes contribute to severe AKI in COVID-19.

9.
ASAIO J ; 2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33587468

RESUMO

Drugs intoxications often lead to severe vasoplegia and cardiogenic shock, and VA-ECMO represents a viable therapy option. However, as cardiopulmonary support is not contributing to the removal of the causal agent from the blood, detoxification by a new hemoadsorption device (CytoSorb) could represent a potential therapeutic tool due to its highly efficient elimination capacity of endogenous but also exogenous hydrophobic substances for which otherwise no effective antidote exist. In this case series, four anecdotal cases of acute intoxications requiring VA-ECMO support used as extracorporeal cardiopulmonary resuscitation after intoxication-induced out-of-hospital cardiac arrest (OHCA) are presented, who were additionally treated with CytoSorb hemoadsorption in combination with renal replacement therapy. Combined treatment was associated with a considerable decrease in plasma levels of the overdosed drugs. Additionally, the combination of applied techniques was safe, practical, and technically feasible with no adverse or any device-related side effects documented during or after the treatment sessions. Based on the reported dramatic decline in drug levels during treatment, that fits in the device's characteristics, we strongly suggest to further investigate the potentially lifesaving role of CytoSorb therapy in patients with acute intoxications requiring multiple organ support techniques.

10.
Sci Rep ; 11(1): 1144, 2021 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-33441772

RESUMO

Mortality of patients with end-stage renal disease tremendously exceeds that of the general population due to excess cardiovascular morbidity. Large middle-sized molecules (LMM) including pro-inflammatory cytokines are major drivers of uremic cardiovascular toxicity and cannot be removed sufficiently by conventional high-flux (HFL) hemodialysis. We tested the ability of plasma from 19 hemodialysis patients participating in a trial comparing HFL with high cut-off (HCO) membranes facilitating removal of LMM to induce calcification in mesenchymal stromal cells (MSC) functioning as vascular progenitors. HCO dialysis favorably changed plasma composition resulting in reduced pro-calcific activity. LMM were removed more effectively by HCO dialysis including FGF23, a typical LMM we found to promote osteoblastic differentiation of MSC. Protein-bound uremic retention solutes with known cardiovascular toxicity but not LMM inhibited proliferation of MSC without direct toxicity in screening experiments. We could not attribute the effect of HCO dialysis on MSC calcification to distinct mediators. However, we found evidence of sustained reduced inflammation that might parallel other anti-calcifying mechanisms such as altered generation of extracellular vesicles. Our findings imply protection of MSC from dysfunctional differentiation by novel dialysis techniques targeted at removal of LMM. HCO dialysis might preserve their physiologic role in vascular regeneration and improve outcomes in dialysis patients.


Assuntos
Células-Tronco Mesenquimais/patologia , Osteoblastos/patologia , Diálise Renal/efeitos adversos , Calcificação Vascular/etiologia , Idoso , Idoso de 80 Anos ou mais , Diferenciação Celular , Feminino , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/patologia , Falência Renal Crônica/terapia , Masculino , Células-Tronco Mesenquimais/citologia , Pessoa de Meia-Idade , Osteoblastos/citologia , Diálise Renal/instrumentação , Diálise Renal/métodos , Calcificação Vascular/sangue , Calcificação Vascular/patologia
11.
Cardiovasc Res ; 117(3): 930-941, 2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-32243494

RESUMO

AIMS: Uromodulin is produced exclusively in the kidney and secreted into both urine and blood. Serum levels of uromodulin are correlated with kidney function and reduced in chronic kidney disease (CKD) patients, but physiological functions of serum uromodulin are still elusive. This study investigated the role of uromodulin in medial vascular calcification, a key factor associated with cardiovascular events and mortality in CKD patients. METHODS AND RESULTS : Experiments were performed in primary human (HAoSMCs) and mouse (MOVAS) aortic smooth muscle cells, cholecalciferol overload and subtotal nephrectomy mouse models and serum from CKD patients. In three independent cohorts of CKD patients, serum uromodulin concentrations were inversely correlated with serum calcification propensity. Uromodulin supplementation reduced phosphate-induced osteo-/chondrogenic transdifferentiation and calcification of HAoSMCs. In human serum, pro-inflammatory cytokines tumour necrosis factor α (TNFα) and interleukin-1ß (IL-1ß) co-immunoprecipitated with uromodulin. Uromodulin inhibited TNFα and IL-1ß-induced osteo-/chondrogenic signalling and activation of the transcription factor nuclear factor kappa-light-chain-enhancer of activated ß cells (NF-kB) as well as phosphate-induced NF-kB-dependent transcriptional activity in HAoSMCs. In vivo, adeno-associated virus (AAV)-mediated overexpression of uromodulin ameliorated vascular calcification in mice with cholecalciferol overload. Conversely, cholecalciferol overload-induced vascular calcification was aggravated in uromodulin-deficient mice. In contrast, uromodulin overexpression failed to reduce vascular calcification during renal failure in mice. Carbamylated uromodulin was detected in serum of CKD patients and uromodulin carbamylation inhibited its anti-calcific properties in vitro. CONCLUSIONS : Uromodulin counteracts vascular osteo-/chondrogenic transdifferentiation and calcification, at least in part, through interference with cytokine-dependent pro-calcific signalling. In CKD, reduction and carbamylation of uromodulin may contribute to vascular pathology.

12.
Brain Behav Immun ; 93: 415-419, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33359380

RESUMO

BACKGROUND: COVID-19 intensive care patients can present with neurological syndromes, usually in the absence of SARS-CoV-2 in cerebrospinal fluid (CSF). The recent finding of some virus-neutralizing antibodies cross-reacting with brain tissue suggests the possible involvement of specific autoimmunity. DESIGN: Blood and CSF samples from eleven critically ill COVID-19 patients presenting with unexplained neurological symptoms including myoclonus, oculomotor disturbance, delirium, dystonia and epileptic seizures, were analyzed for anti-neuronal and anti-glial autoantibodies. RESULTS: Using cell-based assays and indirect immunofluorescence on unfixed murine brain sections, all patients showed anti-neuronal autoantibodies in serum or CSF. Antigens included intracellular and neuronal surface proteins, such as Yo or NMDA receptor, but also various specific undetermined epitopes, reminiscent of the brain tissue binding observed with certain human monoclonal SARS-CoV-2 antibodies. These included vessel endothelium, astrocytic proteins and neuropil of basal ganglia, hippocampus or olfactory bulb. CONCLUSION: The high frequency of autoantibodies targeting the brain in the absence of other explanations suggests a causal relationship to clinical symptoms, in particular to hyperexcitability (myoclonus, seizures). Several underlying autoantigens and their potential molecular mimicry with SARS-CoV-2 still await identification. However, autoantibodies may already now explain some aspects of multi-organ disease in COVID-19 and can guide immunotherapy in selected cases.


Assuntos
Autoanticorpos/líquido cefalorraquidiano , COVID-19/líquido cefalorraquidiano , Doenças do Sistema Nervoso Central/virologia , Idoso , Autoantígenos , Autoimunidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
13.
Crit Care ; 24(1): 676, 2020 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-33287877

RESUMO

BACKGROUND: There is emerging evidence for enhanced blood coagulation in coronavirus 2019 (COVID-19) patients, with thromboembolic complications contributing to morbidity and mortality. The mechanisms underlying this prothrombotic state remain enigmatic. Further data to guide anticoagulation strategies are urgently required. METHODS: We used viscoelastic rotational thromboelastometry (ROTEM) in a single-center cohort of 40 critically ill COVID-19 patients. RESULTS: Clear signs of a hypercoagulable state due to severe hypofibrinolysis were found. Maximum lysis, especially following stimulation of the extrinsic coagulation system, was inversely associated with an enhanced risk of thromboembolic complications. Combining values for maximum lysis with D-dimer concentrations revealed high sensitivity and specificity of thromboembolic risk prediction. CONCLUSIONS: The study identifies a reduction in fibrinolysis as an important mechanism in COVID-19-associated coagulopathy. The combination of ROTEM and D-dimer concentrations may prove valuable in identifying patients requiring higher intensity anticoagulation.


Assuntos
COVID-19/complicações , Fibrinólise/fisiologia , Tromboelastografia/métodos , Tromboembolia/diagnóstico , Coagulação Sanguínea/fisiologia , Testes de Coagulação Sanguínea/métodos , Testes de Coagulação Sanguínea/normas , COVID-19/diagnóstico por imagem , COVID-19/fisiopatologia , Estudos de Coortes , Estado Terminal/epidemiologia , Estado Terminal/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistemas Automatizados de Assistência Junto ao Leito/normas , Sistemas Automatizados de Assistência Junto ao Leito/estatística & dados numéricos , Tromboembolia/diagnóstico por imagem , Substâncias Viscoelásticas/análise , Substâncias Viscoelásticas/uso terapêutico
14.
Scand J Trauma Resusc Emerg Med ; 28(1): 96, 2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32972428

RESUMO

OBJECTIVE: Optimal management of out of hospital circulatory arrest (OHCA) remains challenging, in particular in patients who do not develop rapid return of spontaneous circulation (ROSC). Extracorporeal cardiopulmonary resuscitation (eCPR) can be a life-saving bridging procedure. However its requirements and feasibility of implementation in patients with OHCA, appropriate inclusion criteria and achievable outcomes remain poorly defined. DESIGN: Prospective cohort study. SETTING: Tertiary referral university hospital center. PATIENTS: Here we report on characteristics, course and outcomes on the first consecutive 254 patients admitted between August 2014 and December 2017. INTERVENTION: eCPR program for OHCA. MESUREMENTS AND MAIN RESULTS: A structured clinical pathway was designed and implemented as 24/7 eCPR service at the Charité in Berlin. In total, 254 patients were transferred with ongoing CPR, including automated chest compression, of which 30 showed or developed ROSC after admission. Following hospital admission predefined in- and exclusion criteria for eCPR were checked; in the remaining 224, 126 were considered as eligible for eCPR. State of the art postresuscitation therapy was applied and prognostication of neurological outcome was performed according to a standardized protocol. Eighteen patients survived, with a good neurological outcome (cerebral performance category (CPC) 1 or 2) in 15 patients. Compared to non-survivors survivors had significantly shorter time between collaps and start of eCPR (58 min (IQR 12-85) vs. 90 min (IQR 74-114), p = 0.01), lower lactate levels on admission (95 mg/dL (IQR 44-130) vs. 143 mg/dL (IQR 111-178), p <  0.05), and less severe acidosis on admission (pH 7.2 (IQR 7.15-7.4) vs. 7.0 (IQR6.9-7.2), p <  0.05). Binary logistic regression analysis identified latency to eCPR and low pH as independent predictors for mortality. CONCLUSION: An eCPR program can be life-saving for a subset of individuals with refractory circulatory arrest, with time to initiation of eCPR being a main determinant of survival.


Assuntos
Reanimação Cardiopulmonar/métodos , Oxigenação por Membrana Extracorpórea , Parada Cardíaca Extra-Hospitalar/mortalidade , Parada Cardíaca Extra-Hospitalar/terapia , Acidose/complicações , Adulto , Idoso , Berlim/epidemiologia , Estudos de Coortes , Procedimentos Clínicos , Feminino , Humanos , Ácido Láctico/sangue , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença , Tempo para o Tratamento
15.
Radiol Case Rep ; 15(10): 1764-1768, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32774577

RESUMO

A 64-year-old female patient presented with severe dyspnea shortly after apparent recovery from COVID-19 disease. Chest computed tomography revealed central pulmonary embolism and ultrasonography showed a deep vein thrombosis of her right leg. The patient was tachycardiac with evidence of right ventricular strain on echocardiography. An interdisciplinary decision for interventional therapy was made. Angiographic aspiration thrombectomy resulted in a significant reduction of thrombus material and improved flow in the pulmonary arteries and immediate marked clinical improvement and subsequent normalization of functional echocardiographic parameters. This case adds to the emerging evidence for severe thromboembolic complications following COVID-19 and suggests aspiration thrombectomy can be considered in pulmonary embolism of intermediate risk.

16.
J Pathol ; 251(2): 175-186, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32232854

RESUMO

Neutrophil infiltration is a hallmark of peritoneal inflammation, but mechanisms regulating neutrophil recruitment in patients with peritoneal dialysis (PD)-related peritonitis are not fully defined. We examined 104 samples of PD effluent collected during acute peritonitis for correspondence between a broad range of soluble parameters and neutrophil counts. We observed an association between peritoneal IL-17 and neutrophil levels. This relationship was evident in effluent samples with low but not high IFN-γ levels, suggesting a differential effect of IFN-γ concentration on neutrophil infiltration. Surprisingly, there was no association of neutrophil numbers with the level of CXCL1, a key IL-17-induced neutrophil chemoattractant. We investigated therefore the production of CXCL1 by human peritoneal mesothelial cells (HPMCs) under in vitro conditions mimicking clinical peritonitis. Stimulation of HPMCs with IL-17 increased CXCL1 production through induction of transcription factor SP1 and activation of the SP1-binding region of the CXCL1 promoter. These effects were amplified by TNFα. In contrast, IFN-γ dose-dependently suppressed IL-17-induced SP1 activation and CXCL1 production through a transcriptional mechanism involving STAT1. The SP1-mediated induction of CXCL1 was also observed in HPMCs exposed to PD effluent collected during peritonitis and containing IL-17 and TNFα, but not IFN-γ. Supplementation of the effluent with IFN-γ led to a dose-dependent activation of STAT1 and a resultant inhibition of SP1-induced CXCL1 expression. Transmesothelial migration of neutrophils in vitro increased upon stimulation of HPMCs with IL-17 and was reduced by IFN-γ. In addition, HPMCs were capable of binding CXCL1 at their apical cell surface. These observations indicate that changes in relative peritoneal concentrations of IL-17 and IFN-γ can differently engage SP1-STAT1, impacting on mesothelial cell transcription of CXCL1, whose release and binding to HPMC surface may determine optimal neutrophil recruitment and retention during peritonitis. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Assuntos
Quimiocina CXCL1/metabolismo , Interferon gama/farmacologia , Interleucina-17/farmacologia , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Peritônio/efeitos dos fármacos , Peritonite/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Cultivadas , Quimiocina CXCL1/genética , Feminino , Humanos , Interferon gama/metabolismo , Interleucina-17/metabolismo , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Neutrófilos/patologia , Peritônio/metabolismo , Peritônio/patologia , Peritonite/genética , Peritonite/patologia , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais , Fator de Transcrição Sp1/genética , Transcrição Genética
17.
Sci Rep ; 8(1): 12087, 2018 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-30108259

RESUMO

Severe vascular calcification develops almost invariably in chronic kidney patients posing a substantial risk to quality of life and survival. This unmet medical need demands identification of novel therapeutic modalities. We aimed to pinpoint components of the uremic microenvironment triggering differentiation of vascular progenitors to calcifying osteoblast-like cells. In an unbiased approach, assessing the individual potency of 63 uremic retention solutes to enhance calcific phenotype conversion of vascular progenitor cells, the pro-inflammatory cytokines IL-1ß and TNF-α were identified as the strongest inducers followed by FGF-2, and PTH. Pharmacologic targeting of these molecules alone or in combination additively antagonized pro-calcifying properties of sera from uremic patients. Our findings stress the importance of pro-inflammatory cytokines above other characteristic components of the uremic microenvironment as key mediators of calcifying osteoblastic differentiation in vascular progenitors. Belonging to the group of "middle-sized molecules", they are neither effectively removed by conventional dialysis nor influenced by established supportive therapies. Specific pharmacologic interventions or novel extracorporeal approaches may help preserve regenerative capacity and control vascular calcification due to uremic environment.


Assuntos
Anti-Inflamatórios/farmacologia , Citocinas/antagonistas & inibidores , Falência Renal Crônica/terapia , Uremia/terapia , Calcificação Vascular/prevenção & controle , Adolescente , Anti-Inflamatórios/uso terapêutico , Diferenciação Celular/efeitos dos fármacos , Criança , Pré-Escolar , Citocinas/imunologia , Feminino , Voluntários Saudáveis , Humanos , Lactente , Falência Renal Crônica/sangue , Falência Renal Crônica/complicações , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/fisiologia , Monócitos , Osteoblastos/fisiologia , Cultura Primária de Células , Diálise Renal , Uremia/sangue , Uremia/imunologia , Calcificação Vascular/sangue , Calcificação Vascular/imunologia , Adulto Jovem
18.
J Clin Invest ; 128(7): 3024-3040, 2018 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-29889103

RESUMO

Medial vascular calcification, associated with enhanced mortality in chronic kidney disease (CKD), is fostered by osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs). Here, we describe that serum- and glucocorticoid-inducible kinase 1 (SGK1) was upregulated in VSMCs under calcifying conditions. In primary human aortic VSMCs, overexpression of constitutively active SGK1S422D, but not inactive SGK1K127N, upregulated osteo-/chondrogenic marker expression and activity, effects pointing to increased osteo-/chondrogenic transdifferentiation. SGK1S422D induced nuclear translocation and increased transcriptional activity of NF-κB. Silencing or pharmacological inhibition of IKK abrogated the osteoinductive effects of SGK1S422D. Genetic deficiency, silencing, and pharmacological inhibition of SGK1 dissipated phosphate-induced calcification and osteo-/chondrogenic transdifferentiation of VSMCs. Aortic calcification, stiffness, and osteo-/chondrogenic transdifferentiation in mice following cholecalciferol overload were strongly reduced by genetic knockout or pharmacological inhibition of Sgk1 by EMD638683. Similarly, Sgk1 deficiency blunted vascular calcification in apolipoprotein E-deficient mice after subtotal nephrectomy. Treatment of human aortic smooth muscle cells with serum from uremic patients induced osteo-/chondrogenic transdifferentiation, effects ameliorated by EMD638683. These observations identified SGK1 as a key regulator of vascular calcification. SGK1 promoted vascular calcification, at least partly, via NF-κB activation. Inhibition of SGK1 may, thus, reduce the burden of vascular calcification in CKD.


Assuntos
Proteínas Imediatamente Precoces/metabolismo , Miócitos de Músculo Liso/metabolismo , NF-kappa B/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Calcificação Vascular/metabolismo , Animais , Benzamidas/farmacologia , Transdiferenciação Celular/efeitos dos fármacos , Transdiferenciação Celular/genética , Transdiferenciação Celular/fisiologia , Células Cultivadas , Condrogênese/efeitos dos fármacos , Condrogênese/genética , Condrogênese/fisiologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Hidrazinas/farmacologia , Proteínas Imediatamente Precoces/deficiência , Proteínas Imediatamente Precoces/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Knockout para ApoE , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Osteogênese/fisiologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/genética , Insuficiência Renal/metabolismo , Insuficiência Renal/patologia , Transdução de Sinais , Calcificação Vascular/etiologia , Calcificação Vascular/patologia
19.
J Am Soc Nephrol ; 29(6): 1636-1648, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29654213

RESUMO

Background The high cardiovascular morbidity and mortality of patients with CKD may result in large part from medial vascular calcification, a process promoted by hyperphosphatemia and involving osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs). Reduced serum zinc levels have frequently been observed in patients with CKD, but the functional relevance of this remains unclear.Methods We performed experiments in primary human aortic VSMCs; klotho-hypomorphic (kl/kl), subtotal nephrectomy, and cholecalciferol-overload mouse calcification models; and serum samples from patients with CKD.Results In cultured VSMCs, treatment with zinc sulfate (ZnSO4) blunted phosphate-induced calcification, osteo-/chondrogenic signaling, and NF-κB activation. ZnSO4 increased the abundance of zinc-finger protein TNF-α-induced protein 3 (TNFAIP3, also known as A20), a suppressor of the NF-κB pathway, by zinc-sensing receptor ZnR/GPR39-dependent upregulation of TNFAIP3 gene expression. Silencing of TNFAIP3 in VSMCs blunted the anticalcific effects of ZnSO4 under high phosphate conditions. kl/kl mice showed reduced plasma zinc levels, and ZnSO4 supplementation strongly blunted vascular calcification and aortic osteoinduction and upregulated aortic Tnfaip3 expression. ZnSO4 ameliorated vascular calcification in mice with chronic renal failure and mice with cholecalciferol overload. In patients with CKD, serum zinc concentrations inversely correlated with serum calcification propensity. Finally, ZnSO4 ameliorated the osteoinductive effects of uremic serum in VSMCs.Conclusions Zinc supplementation ameliorates phosphate-induced osteo-/chondrogenic transdifferentiation of VSMCs and vascular calcification through an active cellular mechanism resulting from GPR39-dependent induction of TNFAIP3 and subsequent suppression of the NF-κB pathway. Zinc supplementation may be a simple treatment to reduce the burden of vascular calcification in CKD.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Falência Renal Crônica/sangue , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/fisiologia , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/metabolismo , Calcificação Vascular/prevenção & controle , Sulfato de Zinco/farmacologia , Animais , Aorta , Transdiferenciação Celular , Células Cultivadas , Suplementos Nutricionais , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Glucuronidase/genética , Humanos , Hidroxietilrutosídeo , Hiperfosfatemia/sangue , Hiperfosfatemia/complicações , Camundongos , NF-kappa B/antagonistas & inibidores , Nefrectomia , Nefrocalcinose/prevenção & controle , Fosfatos , Transdução de Sinais , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Calcificação Vascular/sangue , Calcificação Vascular/etiologia , Zinco/sangue
20.
Blood Purif ; 45(1-3): 131-138, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29402827

RESUMO

BACKGROUND: Vascular calcification is a common phenomenon in patients with chronic kidney disease and strongly associated with increased cardiovascular mortality. Vascular calcification is an active process mediated in part by inflammatory processes in vascular smooth muscle cells (VSMC). These could be modified by the insufficient removal of proinflammatory cytokines through conventional high-flux (HF) membranes. Recent trials demonstrated a reduction of inflammation in VSMC by use of dialysis membranes with a higher and steeper cut-off. These membranes caused significant albumin loss. Therefore, the effect of high retention Onset (HRO) dialysis membranes on vascular calcification and its implications in vitro was evaluated. METHODS: In the PERCI II trial, 48 chronic dialysis patients were dialyzed using HF and HRO dialyzers and serum samples were collected. Calcifying VSMC were incubated with the serum samples. Calcification was determined using alizarin red staining (AZR) and determination of alkaline phosphatase (ALP) activity. Furthermore, apoptosis was evaluated, and release of matrix Gla protein (MGP), osteopontin (OPN) and growth differentiation factor 15 (GDF-15) were measured in cell supernatants. RESULTS: Vascular calcification in vitro was significantly reduced by 24% (ALP) and 36% (AZR) after 4 weeks of HRO dialysis and by 33% (ALP) and 48% (AZR) after 12 weeks of dialysis using HRO membranes compared to HF dialysis. Apoptosis was significantly lower in the HRO group. The concentrations of MGP and OPN were significantly elevated after incubation with HF serum compared to HRO serum and healthy controls. Similarly, GDF-15 release in the supernatant was elevated after incubation with HF serum, an effect significantly ameliorated after treatment with HRO medium. CONCLUSIONS: Expanded haemodialysis therapy reduces the pro-calcific potential of serum from dialysis patients in vitro. With a markedly reduced albumin filtration compared to high cut-off dialysis, use of the HRO dialyzers may possibly provide a treatment option for chronic dialysis patients to reduce the progression of vascular calcification.


Assuntos
Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Diálise Renal , Calcificação Vascular/metabolismo , Calcificação Vascular/prevenção & controle , Biomarcadores/metabolismo , Feminino , Humanos , Masculino , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Calcificação Vascular/patologia
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