RESUMO
BACKGROUND: Using echocardiography to assess right ventricular (RV) function after cardioplegic arrest is challenging. Cardiac magnetic resonance (CMR) imaging is a superior alternative, with the feature tracking technique enabling quantitative assessment of myocardial deformation. METHODS: This single-center, prospective study from 2020 to 2022 assessed RV function in 42 patients who underwent open heart surgery with cardioplegic arrest. CMR data were collected preoperatively, one week postoperatively, and at follow-up (6-12 months after surgery), and assessed using the CMR feature tracking technique. RESULTS: Postoperatively, there was no significant change in RV end-diastolic volume, but RV end-systolic volume significantly decreased, leading to a notable increase in RV ejection fraction. By follow-up, both RV end-diastolic and end-systolic volumes had significantly reduced compared with the preoperative values. Right ventricular longitudinal contractility decreased after surgery but recovered to the preoperative values by follow-up, while RV circumferential contractility improved postoperatively and remained superior to the preoperative levels at follow-up. CONCLUSION: On CMR imaging, significant changes in RV systolic motion were observed after cardioplegic arrest, with decreased longitudinal but increased circumferential contractility. At follow up, these changes had reverted to the preoperative patterns by the mid-term (6-12 months).
RESUMO
PURPOSE: Neurologic adverse events (NAEs) are a major complication after pulmonary endarterectomy (PEA) performed under periods of deep hypothermic circulatory arrest (HCA) for chronic thromboembolic pulmonary hypertension. We modified the PEA strategy to prevent NAEs and evaluated the effectiveness of these modifications. METHODS: We reviewed the surgical outcomes of 87 patients divided into the following three groups based on the surgical strategy used: group S (n = 49), periods of deep HCA with alpha-stat strategy; group M1 (n = 19), deep HCA with modifications of slower cooling and rewarming rates and the pH-stat strategy for cooling: and group M2 (n = 13), multiple short periods of moderate HCA. RESULTS: PEA provided significant improvement of pulmonary hemodynamics in each group. Sixteen (29%) of the 49 group S patients suffered NAEs, associated with total circulatory arrest time (cutoff, 57 min) and Jamieson type I disease. The Group M1 and M2 patients did not suffer NAEs, although the group M1 patients had prolonged cardiopulmonary bypass (CPB) and more frequent respiratory failure. CONCLUSIONS: NAEs were common after PEA performed under periods of deep HCA. The modified surgical strategy could decrease the risk of NAEs but increase the risk of respiratory failure. Multiple short periods of moderate HCA may be useful for patients at risk of NAEs.
Assuntos
Hipotermia Induzida , Insuficiência Respiratória , Humanos , Ponte Cardiopulmonar , Endarterectomia , Hipotermia Induzida/efeitos adversos , Pulmão , Insuficiência Respiratória/etiologiaRESUMO
OBJECTIVES: This study aimed to quantify nailfold capillary (NFC) abnormalities in anti-melanoma differentiation-associated gene 5 (MDA5) -positive DM patients and to evaluate the association with clinical parameters, including serum biomarkers. In addition, we aimed to clarify the period leading to remission of NFC abnormalities during immunosuppressive treatment in patients with DM. METHODS: A prospective observational study was conducted including patients (n = 10) who first visited Hiroshima University Hospital and were diagnosed with DM or clinically amyopathic DM with anti-MDA5 antibodies. We compared the NFC abnormalities detected by nailfold-video capillaroscopy (NVC), physical findings, blood tests, respiratory function tests, and vascular-related growth factors measured using a LEGENDplexTM Multi-Analyte Flow Assay Kit. RESULTS: NFC abnormalities improved in all patients from 2 to 17 weeks after the initiation of immunosuppressive treatment. The NVC scores were inversely correlated with anti-MDA5 antibody titres at baseline. NVC scores and forced vital capacity were positively correlated. Baseline values of M-CSF and stem cell factor were correlated with anti-MDA-5 titres. CONCLUSION: Our study suggested that NVC scores and disease activity were inversely correlated before treatment. Vascular-related growth factors, such as M-CSF and stem cell factor, may be associated with the disease mechanism in patients with anti-MDA5 antibody-positive DM.
Assuntos
Dermatomiosite , Miosite , Autoanticorpos , Capilares/anormalidades , Dermatomiosite/complicações , Humanos , Imunossupressores/uso terapêutico , Helicase IFIH1 Induzida por Interferon , Fator Estimulador de Colônias de Macrófagos , Miosite/complicações , Fator de Células-Tronco , Malformações VascularesRESUMO
INTRODUCTION: Lipopolysaccharide (LPS) contamination of commercially available proteins has seriously impeded research on citrullinated fibrinogen (cit-Fb) in rheumatoid synovial cells (RSCs). METHODS: RSCs obtained from 4 rheumatoid arthritis patients who underwent full knee arthroplasty were cultured, stimulated with cit-Fb, and cytokine expression levels were measured. We then evaluated polymyxin-B (PMB), heat inactivation, and rough (R)-type LPS mutants for rapid detection of LPS contamination. RESULTS: cit-Fb induced expression of CXCL10 and IFNB in RSCs via the toll-like receptor. PMB inhibited cit-Fb-mediated CXCL10 gene expression but not protein expression induced by 20 µg/mL cit-Fb. Heat inactivation did not affect LPS-mediated CXCL10 or IL-6 induction; however, cit-Fb-mediated CXCL10expression was inhibited. Wild-type LPS from Escherichia coli (WT-LPS) strongly induces CXCL10 expression, but induction by Ra-LPS was weak, and induction by Rc- and Re-LPS was minimal. Re-LPS suppression of WT-LPS-mediated CXCL10 induction in RSCs and peripheral blood monocytes (PBMs) was dose dependent. Furthermore, Re-LPS completely suppressed cit-Fb-mediated CXCL10 induction in RSCs and PBMs. CONCLUSION: To easily identify LPS contamination during routine experiments, our results suggest that Re-LPS is a better tool for rapid detection of LPS contamination compared to PMB and heat treatment.
Assuntos
Artrite Reumatoide , Lipopolissacarídeos , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Técnicas de Cultura de Células , Células Cultivadas , Citocinas , Humanos , Lipopolissacarídeos/farmacologia , MonócitosRESUMO
The hemodynamic and exercise capacity performance of the Jarvik 2000 left ventricular assist device (LVAD), which is generally used in patients with small body size and relatively preserved cardiac function, is not well understood. We retrospectively examined 18 patients implanted with the Jarvik 2000 LVAD. Pump rotation speed was optimized by the hemodynamic ramp test one year after implantation based on the criteria of mean pulmonary capillary wedge pressure (PCWP) < 18 mmHg, mean right atrial pressure (RAP) < 12 mmHg, and cardiac index (CI) > 2.2 L/min/m2 as well as echocardiographic parameters. Exercise capacity was assessed by cardiopulmonary exercise test in an optimized setting. To investigate the impacts of larger body surface area (BSA) and extremely impaired pre-implantation cardiac function on hemodynamics and exercise capacity, two correlation analyses based on BSA and original CI were performed. At a pump speed of 9500 ± 707 rpm, the mean pulmonary artery pressure, PCWP, RAP, and CI were 17 ± 5 mmHg, 9 ± 5 mmHg, 6 ± 4 mmHg, and 2.82 ± 0.54 L/min/m2, respectively. Only one patient failed to achieve the hemodynamic criteria. The peak VO2 and VE/VCO2 slope were 12.9 ± 3.1 mL/min/kg and 37.7 ± 15.0, respectively. There was an inverse correlation between original CI and heart rate (r = -0.60, p = 0.01), and a weak correlation between BSA and PCWP (r = 0.43, p = 0.08). Based on this study, the overall performance of the Jarvik 2000 device was acceptable, and the patients' body size and original cardiac function had minimum effect on the performance of this device.
Assuntos
Insuficiência Cardíaca , Coração Auxiliar , Teste de Esforço , Tolerância ao Exercício , Hemodinâmica , Humanos , Estudos Retrospectivos , Função Ventricular EsquerdaRESUMO
OBJECTIVES: Cyclophosphamide (CYC) has been proposed as a standard induction regimen for interstitial lung disease (ILD) associated with systemic sclerosis (SSc). However, there remain patients with SSc-ILD who are intractable to the therapy. This study aimed to identify factors associated with inadequate response to CYC and investigate how to treat SSc-ILD, especially in the need for glucocorticoids (GCs) combined with CYC. METHODS: This retrospective study included consecutive patients diagnosed with SSc-ILD and treated with CYC between 2009 and 2020. Logistic regression models were used to determine the prognostic factors indicating significant progression of ILD (SP-ILD). The clinical findings of patients treated with vs. without GCs were compared. RESULTS: Nineteen patients were registered, with a median age of 61.0 years. Fifteen were females, and five were classified into SP-ILD. Baseline high C-reactive protein (CRP) levels and non-widespread or localized ground-glass opacities (GGOs) predicted SP-ILD in multivariable analyses, and the cut-off level of CRP was 0.41 mg/dL. In clinical courses, SSc-ILD with high inflammation temporarily responded to CYC, regardless of the combined use of GCs; however, the therapeutic effects deteriorated soon after stopping CYC. CONCLUSION: High CRP levels with non-widespread GGO predicted progressive ILD in patients with SSc treated with CYC.
Assuntos
Doenças Pulmonares Intersticiais , Escleroderma Sistêmico , Proteína C-Reativa , Ciclofosfamida/uso terapêutico , Feminino , Glucocorticoides/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Pulmão , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/tratamento farmacológicoRESUMO
Endoplasmic reticulum (ER) stress responses have been demonstrated to play important roles in maintaining various cellular functions and to underlie many tissue dysfunctions. In this study, we identified Sec16B as an ER stress-inducible gene by microarray analysis of brefeldin A (BFA)-inducible genes in a mouse neuroblastoma cell-line, Neuro2a. Sec16B mRNA was induced by treatment with the ER stress-inducing reagents thapsigargin (Tg) and brefeldin A in a time-dependent manner. In the genomic sequence of the mouse Sec16B gene, we found an unfolded protein response element (UPRE), which is well conserved between humans and mice. Using luciferase reporter analyses, we showed that the UPRE in the mouse Sec16B gene was functional and responded well to ER stress-inducing stimuli and spliced XBP1 (sXBP1)-overexpression. In addition, a unique ATF4-responsive sequence within the first intron of the mouse Sec16B gene was characterized. Our study may help to elucidate the regulation of trafficking through the ER-Golgi apparatus and the biogenesis of ER-derived intracellular organelles.
Assuntos
Proteínas de Ligação a DNA/genética , Estresse do Retículo Endoplasmático , Neuroblastoma/metabolismo , Transcrição Gênica , Animais , Brefeldina A/farmacologia , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , Retículo Endoplasmático/metabolismo , Regulação da Expressão Gênica , Genes Reporter , Complexo de Golgi/metabolismo , Humanos , Íntrons , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos , Regiões Promotoras Genéticas , Desnaturação Proteica , Fatores de Transcrição/genética , Resposta a Proteínas não Dobradas , Proteína 1 de Ligação a X-Box/genética , Proteína 1 de Ligação a X-Box/metabolismoRESUMO
Aortic insufficiency (AI) is known to associate with a persistently closed aortic valve during continuous-flow ventricular assist device support. Some devices carry an intermittent low-speed (ILS) function, which facilitates aortic valve opening, but whether this function prevents AI is unknown. In this study, the Jarvik 2000 device, which is programmed to reduce the pump speed each minute for 8 s, was chosen to examine this potential effect. Prospectively collected data of 85 heart transplant-eligible Jarvik 2000 recipients who met the study criteria (no pre-existing AI and aortic valve surgery) were retrospectively analyzed for the incidence, correlating factors, and clinical outcomes of de novo AI. All data were provided by the Japanese Registry for Mechanically Assisted Circulatory Support. De novo AI occurred in 58 patients, 23 of whom developed at least moderate AI during a median support duration of 23.5 months. Freedom from moderate or greater AI was 84.4%, 66.1% and 60.2% at 1, 2 and 3 years, respectively. Multivariate analyses revealed that progressive AI was correlated with decreased pulse pressure after implantation (hazard ratio 1.060, 95% confidence interval 1.001-1.127, p = 0.045). No correlation was found for mortality or other adverse events, including stroke, bleeding, infection, pump failure, hemolysis, and readmission. The benefit of the Jarvik 2000's current ILS mode against AI appears to be minimal. However, in this limited cohort where all recipients underwent implantation as a bridge to transplantation, the impact of de novo progressive AI on other clinical adversities was also minimal.
Assuntos
Insuficiência da Valva Aórtica/prevenção & controle , Insuficiência Cardíaca/cirurgia , Coração Auxiliar , Adulto , Valva Aórtica/fisiopatologia , Valva Aórtica/cirurgia , Insuficiência da Valva Aórtica/epidemiologia , Insuficiência da Valva Aórtica/etiologia , Feminino , Seguimentos , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/fisiopatologia , Coração Auxiliar/efeitos adversos , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Estudos Retrospectivos , Fatores de TempoRESUMO
OBJECTIVE: To retrospectively evaluate whether oral glucocorticoid (GC) administration can be tapered or discontinued over a 2-year observation period in patients with rheumatoid arthritis (RA) undergoing a stable oral GC treatment, without deterioration in the disease status. METHODS: Methotrexate (MTX) and prednisolone (PSL) dosages were increased and decreased, respectively, to the maximum extent possible. Concomitant biological or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) were used as required. Changes in PSL and MTX use and disease status were evaluated at baseline (BL), year-1, and year-2. RESULTS: Thirty-six patients were enrolled (median age, 65.4 years; disease duration, 7.1 years). The proportion of patients using PSL decreased over 2 years (100-13.9%, p < .0001). While no change was observed in the proportion of patients using MTX, the average administered dose increased at year-1 (p = .06). Moreover, b/tsDMARDs were administered in nine patients (two in year-1, seven in year-2). The Clinical Disease Activity Index remission rate increased from 25.0% to 38.9%. Serious adverse events were identified in two patients. CONCLUSIONS: Oral GC administration was discontinued without deterioration in the rheumatoid arthritis disease control.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Glucocorticoides/uso terapêutico , Metotrexato/uso terapêutico , Prednisolona/uso terapêutico , Idoso , Quimioterapia Combinada , Feminino , Glucocorticoides/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Prednisolona/administração & dosagem , Estudos Retrospectivos , Suspensão de TratamentoRESUMO
OBJECTIVES: Lupus enteritis (LE) is a rare but well-known gastrointestinal manifestation of systemic lupus erythematosus (SLE). This study was conducted to identify prognostic factors associated with poor responses in patients with LE. METHODS: We consecutively registered patients diagnosed with LE between January 2009 and October 2019, and retrospectively compared their clinical characteristics based on whether they had good or poor responses to treatment. RESULTS: A total of 13 patients (17 episodes) were included. The median age was 41 years, and 12 patients were female. A comparison of clinical characteristics between groups revealed similar computed tomography (CT) findings. However, serum CH50 levels were significantly lower in the poor response group (median [interquartile ranges (IQR)]; 29.2 [25.3-46.9] U/mL vs 19.3 [7.8-24.0] U/mL, p = .0095). More patients in the poor response group had higher titers of anti-cardiolipin ß2-glycoprotein I antibody (anti-CL ß2GPI Ab) and were started on glucocorticoids (GCs) at moderate doses. In multivariable analysis, serum CH50 level was independently associated with poor response to induction therapy. CONCLUSION: Lower levels of CH50 at the time of initial treatment predicted inadequate treatment response in patients with LE.
Assuntos
Ensaio de Atividade Hemolítica de Complemento/normas , Enterite/tratamento farmacológico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Adulto , Autoanticorpos/imunologia , Enterite/sangue , Enterite/diagnóstico por imagem , Feminino , Glucocorticoides/administração & dosagem , Glucocorticoides/uso terapêutico , Humanos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , beta 2-Glicoproteína I/imunologiaRESUMO
IRE1 is the most conserved endoplasmic reticulum (ER)-resident stress sensor. Its activation not only splices XBP1 but also participates in a variety of cell signaling. We elucidated the role of IRE1α in Neuro2a cells by establishing IRE1α-deficient cells and applying four IRE1 inhibitors. IRE1α deficiency prevented almost all spliced XBP1 (sXBP1) protein expression by treatment with thapsigargin (Tg) and tunicamycin (Tm); these phenomena paralleled the values measured by our two Nanoluciferase-based IRE1 assays. However, cell viability and protein expression of other ER stress-responsive factors in the IRE1α-deficient cells were comparable to those in the parental wild-type cells with or without Tm treatment. Next, we elucidated the IRE1 inhibitory actions and cytotoxicity of four compounds: STF083010, KIRA6, 4µ8C, and toyocamycin. KIRA6 attenuated IRE1 activity in a dose-dependent manner, but it showed severe cytotoxicity even in the IRE1α-deficient cells at a low concentration. The IRE1α-deficient cells were slightly resistant to KIRA6 at 0.1 µM in both the presence and absence of ER stress; however, resistance was not observed at 0.02 µM. Treatment with only KIRA6 at 0.1 µM for 12 h remarkably induced LC3 II, an autophagic marker, in both parental and IRE1α-deficient cells. Co-treatment with KIRA6 and Tm induced LC3 II, cleaved caspase-9, and cleaved caspase-3; however, IRE1α-deficiency did not abolish the expression of these two cleaved caspases. On the other hand, KIRA6 prohibited Tm-induced ATF4 induction in an IRE1-independent manner; however, co-treatment with KIRA6 and Tm also induced LC3 II and two cleaved caspases in the ATF4-deficient Neuro2a cells. Thus, we demonstrate that IRE1α deficiency has little impact on cell viability and expression of ER stress-responsive factors in Neuro2a cells, and the pharmacological actions of KIRA6 include IRE1-independent ways.
Assuntos
Sistemas CRISPR-Cas , Citotoxinas/farmacologia , Endorribonucleases/deficiência , Deleção de Genes , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos , Proteínas Serina-Treonina Quinases/deficiência , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/genética , CamundongosRESUMO
OBJECTIVES: This study aimed to identify therapeutic predictors of abatacept (ABT) treatment in rheumatoid arthritis (RA) in vitro and in patients. METHODS: T cell cytokine, monokine, and chemokine levels in culture supernatants or serum were determined using flow cytometry bead-based immunoassays. CXCL10 mRNA and protein expressions were also assessed using qPCR and ELISA analyses, respectively. In the patient study, 25 ABT-treated patients were analysed retrospectively. The patients were divided into low disease activity (LDA) or non-low disease activity (non-LDA) groups at 24 weeks of ABT treatment. Seven T cell cytokines and CXCL10 levels were compared in these two groups. RESULTS: Peripheral blood mononuclear cells (PBMC) from healthy donors were stimulated by immobilised anti-CD3 with or without ABT for three days, and the levels of 13 T cell cytokines in culture supernatants were determined. ABT significantly inhibited anti-CD3-induced production of IFN-γ. To examine the effect of these T cell cytokines in rheumatoid synovial cells (RSC), RSCs were stimulated with 10% of culture supernatants from anti-CD3-stimulated PBMCs with or without ABT, and the levels of 23 cytokines were determined. Only CXCL10 was significantly reduced by ABT-treated supernatants. In the patient study, CXCL10 levels at baseline were not different between the LDA and non-LDA groups, whereas CXCL10 levels at 24 weeks were significantly decreased in the LDA group only. CONCLUSIONS: ABT treatment significantly affected IFN-γ and CXCL10 cytokine levels in vitro. In addition, serum CXCL10 levels were associated with better responses in ABT treatment.
Assuntos
Artrite Reumatoide , Leucócitos Mononucleares , Abatacepte/farmacologia , Artrite Reumatoide/tratamento farmacológico , Quimiocina CXCL10 , Quimiocinas , Humanos , Estudos RetrospectivosRESUMO
OBJECTIVE: Activin A is known to be highly expressed in rheumatoid synovium. In the present study, we investigated the effect of inflammatory cytokines on activin A production and its role in rheumatoid inflammation using freshly prepared rheumatoid synovial cells (fresh-RSC). METHODS: Fresh-RSC from patients with rheumatoid arthritis were obtained and stimulated with multiple cytokines for activin A production. Gene expression levels of activin A and inflammatory cytokines were determined by quantitative PCR (qPCR) analysis. An enzyme-linked immunosorbent assay (ELISA) was used to measure activin A and CXCL10 in culture supernatants. The osteoclasts generated from human peripheral monocytes by RANKL stimulation were identified by tartrate-resistant acid phosphatase staining and bone resorption assay using Osteo plate. The expression levels of NFATc1 and cathepsin K, critical intracellular proteins for osteoclastogenesis, were determined by Western blotting. RESULTS: Activin A production in fresh-RSC was markedly enhanced by the synergistic effect of TGF-ß1 with inflammatory cytokines, including TNFα, IL-1ß, and IL-6. Activin A inhibited TNFα-induced CXCL10, an important chemoattractant for pathogen-activated T cells and monocytes of osteoclast precursors, but it did not affect the expression of inflammatory cytokines and chemokines. In addition, activin A directly inhibited the expression of NFATc1 and cathepsin K, as well as osteoclast formation in human samples. CONCLUSION: Our data indicated that TGF-ß1 is involved in the expression of activin A at inflamed joints. Activin A mainly exerts an anti-inflammatory action, which prevents joint damage via the regulation of CXCL10 and osteoclastogenesis.
Assuntos
Ativinas/genética , Quimiocina CXCL10/genética , Cápsula Articular/citologia , Osteogênese , Fator de Necrose Tumoral alfa/genética , Diferenciação Celular , Células Cultivadas , Citocinas/imunologia , Regulação para Baixo , Humanos , Cápsula Articular/imunologia , Leucócitos Mononucleares/imunologia , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Left ventricular assist device (LVAD) is an established therapy for patients with severe heart failure. Because the incidence of cardiotoxicity owing to anticancer agents is low, it is difficult to predict the recovery prospects when the cause of heart failure is due to anticancer agents. In this context, cancer patients who present with severe symptoms of heart failure and who fail medical therapy for heart failure may pose a dilemma, especially in countries such as Japan where implantable LVADs are not approved for purposes other than bridging to transplant. Recently, we encountered a 32-year-old woman with chemotherapy-related cardiomyopathy that developed after anticancer treatment using trastuzumab and anthracycline. LVAD therapy was the only option to save the young woman. The patient received an extracorporeal LVAD, her cardiac function gradually recovered while on support, and the device was successfully removed.
Assuntos
Antraciclinas/efeitos adversos , Antineoplásicos/efeitos adversos , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/terapia , Coração Auxiliar , Trastuzumab/efeitos adversos , Adulto , Feminino , Humanos , Leucemia Mieloide Aguda/tratamento farmacológicoRESUMO
Osteoclasts are multinucleated giant cells responsible for bone resorption. Various mediators involved in osteoclast differentiation have been investigated as possible therapeutic targets for osteoporosis and rheumatoid arthritis (RA). Although transforming growth factor beta1 (TGFß1) has been described as one such multifunctional cytokine essential for bone remodeling, its effect on osteoclastogenesis remains controversial. Therefore, we sought to examine the effect of TGFß1 on osteoclast generation induced by receptor activator of nuclear factor (NF)-κB ligand (RANKL) in humans. Peripheral blood monocytes, isolated using magnetic bead sorting, were cultured with macrophage-colony stimulating factor (M-CSF) or RANKL with or without TGFß1. Tartrate-resistant acid phosphatase (TRAP) staining, as well as bone resorption assays, revealed that TGFß1 suppressed RANKL-mediated human osteoclast development. Real-time reverse transcription PCR and Western blotting revealed that TGFß1 reduced the gene and protein expression of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), the master regulator of osteoclast differentiation, respectively. Luciferase assays indicated that TGFß1 inhibited the NF-κB p65-stimulated promoter activity of NFATc1. Immunofluorescence analysis demonstrated that TGFß1 abrogated RANKL-induced nuclear translocation of p65. Thus, TGFß1 regulates human RANKL-induced osteoclastogenesis via downregulation of NFATc1 by blocking nuclear translocation of NF-κB, suggesting that TGFß1 may be a potential therapeutic target for RA.
Assuntos
Regulação da Expressão Gênica , Fatores de Transcrição NFATC/genética , Osteogênese , Ligante RANK/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Reabsorção Óssea/genética , Reabsorção Óssea/metabolismo , Diferenciação Celular/genética , Células Cultivadas , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Imunofenotipagem , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Osteoclastos/citologia , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Regiões Promotoras Genéticas , Transporte Proteico , Ligante RANK/farmacologia , Fator de Crescimento Transformador beta1/farmacologiaRESUMO
Liver cirrhosis is a major risk factor in patients requiring cardiac surgery. Although current evidence is limited to reports coming mostly from small case series, it is clear that the surgical risk increases with the severity of the liver disease. Hemodynamic instability caused by hyperdynamic circulation, systemic fluid retention, infection, and bleeding is frequently observed postoperatively in severely cirrhotic patients. Preoperative optimization, including correction of coagulopathy and poor nutrition, is therefore crucial for minimizing the predictive postoperative complications in those patients. Postoperative management should focus on bleeding and infection control, body fluid management, adequate nutrition, and hemodynamics, particularly hepatic circulation. Multiple studies have shown that patients who are diagnosed as Child-Pugh class B or C liver cirrhosis have a high surgical mortality rate, with most reports suggesting class C as inoperable. Recently, the model for end-stage liver disease( MELD) score has been gaining attention for its reliability in identifying patients at high risk for open heart surgery. Off-pump surgery may be beneficial in improving the surgical outcomes, but the evidence is weak and further studies are required. A thorough preoperative evaluation is thus mandatory in cirrhotic patients scheduled for cardiac surgery, with a particular attention to the risks and benefits of performing the surgery itself.
Assuntos
Procedimentos Cirúrgicos Cardíacos , Criança , Humanos , Cirrose Hepática/complicações , Reprodutibilidade dos Testes , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
An 82-year-old woman presented to our hospital with a deep skin ulcer in her right lower limb. Although the skin biopsy showed necrosis and neutrophil infiltration, we could not initially detect any pathogen. Chest radiography showed multiple nodules despite the lack of respiratory symptoms or fever, and the serum latex agglutination test for cryptococcus showed an elevated titer (1:512). Considering these findings, we performed additional stains of periodic acid-Schiff reaction and Grocott to the skin-biopsy specimen and detected multiple yeast-like fungi. The cultures of the skin and lung-biopsy specimens revealed Cryptococcus neoformans. In this case, it is suggested that a large deep skin ulcer can be an initial manifestation of systemic cryptococcosis, as, in some cases, pulmonary cryptococcosis may be asymptomatic. Second, cutaneous cryptococcosis of an unexposed area such as the thigh can contribute to the diagnosis of systemic cryptococcal infection because it is attributable to bloodstream dissemination from other organs.
Assuntos
Criptococose/diagnóstico , Criptococose/patologia , Cryptococcus neoformans/isolamento & purificação , Úlcera Cutânea/etiologia , Úlcera Cutânea/patologia , Idoso de 80 Anos ou mais , Biópsia , Feminino , Histocitoquímica , Humanos , Extremidade Inferior/patologia , Pulmão/patologia , Pele/patologiaRESUMO
The purpose of this study is to compare the late outcome of aortic valve replacement with or without preoperative coronary artery disease, and with or without coronary artery bypass. Between 2014 and 2015, 291 patients underwent aortic valve replacement. Average follow-up term was 2.5 ± 2.2 years. The retrospective comparative study was performed between the patients with (n = 115) or without (n = 176) preoperative coronary artery disease (Study 1) and with (n = 93) or without (n = 198) coronary artery bypass grafting (Study 2). Study 1: male patients were more, and diabetes was more in the patients with coronary artery disease. Long-term survival rate was significantly low in the patients with coronary artery disease (p = 0.0002 by log rank test). Freedom from repeat coronary revascularization rate was lower in the patients with coronary artery disease (p = 0.02 by log rank test). Study 2: operation time (419 ± 130 vs 290 ± 101; p = 0.0001) was longer in the patients with coronary artery bypass grafting. Improvement of ejection fraction at follow-up was more in the patients with coronary artery bypass(114 ± 43 vs 104 ± 26%; p = 0.03). Long-term survival rate and freedom from major adverse cardiac event rater were not different with or without coronary artery bypass grafting (p = 0.26 and p = 0.59, respectively, by log rank test). Although prevalence of coronary artery disease inversely affected the long-term outcome of the aortic valve replacement, simultaneous coronary artery bypass did not. Aggressive simultaneous coronary revascularization would be important to improve the long-term outcome of aortic valve replacement.
Assuntos
Estenose da Valva Aórtica/cirurgia , Valva Aórtica/cirurgia , Ponte de Artéria Coronária , Doença da Artéria Coronariana/complicações , Implante de Prótese de Valva Cardíaca/métodos , Idoso , Estenose da Valva Aórtica/complicações , Estenose da Valva Aórtica/mortalidade , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/mortalidade , Feminino , Seguimentos , Humanos , Japão/epidemiologia , Masculino , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Fatores de TempoRESUMO
Treating a patient with heparin-induced thrombocytopenia can be challenging particularly when the patient requires urgent cardiac surgery that uses heparin for anticoagulation. We herein report a case of a 61-year-old man with idiopathic dilated cardiomyopathy associated with heparin-induced thrombocytopenia and who underwent plasma exchange to remove heparin-induced thrombocytopenia antibodies before undergoing left ventricular assist device implantation. The surgery was performed using cardiopulmonary bypass and unfractionated heparin.