Subject(s)
Carotid-Cavernous Sinus Fistula , Postoperative Complications , Humans , Carotid-Cavernous Sinus Fistula/surgery , Carotid-Cavernous Sinus Fistula/diagnostic imaging , Carotid-Cavernous Sinus Fistula/etiology , Postoperative Complications/etiology , Postoperative Complications/diagnostic imaging , Sphenoid Bone/surgery , Neurosurgical Procedures/adverse effectsABSTRACT
BACKGROUND: Minimizing the use of blood component can reduce known and unknown blood transfusion risks, preserve blood bank resources, and decrease healthcare costs. Red Blood Cell (RBC) transfusion is common after cardiac surgery and associated with adverse perioperative outcomes, including mortality. Acute normovolemic hemodilution (ANH) may reduce bleeding and the need for blood product transfusion after cardiac surgery. However, its blood-saving effect and impact on major outcomes remain uncertain. METHODS: This is a single-blinded, multinational, pragmatic, randomized controlled trial with a 1:1 allocation ratio conducted in Tertiary and University hospitals. The study is designed to enroll patients scheduled for elective cardiac surgery with planned cardiopulmonary bypass (CPB). Patients are randomized to receive ANH before CPB or the best available treatment without ANH. We identified an ANH volume of at least 650 ml as the critical threshold for clinically relevant benefits. Larger ANH volumes, however, are allowed and tailored to the patient's characteristics and clinical conditions. RESULTS: The primary outcome is the percentage of patients receiving RBCs transfusion from randomization until hospital discharge, which we hypothesize will be reduced from 35% to 28% with ANH. Secondary outcomes are all-cause 30-day mortality, acute kidney injury, bleeding complications, and ischemic complications. CONCLUSION: The trial is designed to determine whether ANH can safely reduce RBC transfusion after elective cardiac surgery with CPB. STUDY REGISTRATION: This trial was registered on ClinicalTrials.gov in April 2019 with the trial identification number NCT03913481.
Subject(s)
Cardiac Surgical Procedures , Cardiopulmonary Bypass , Hemodilution , Humans , Hemodilution/methods , Cardiac Surgical Procedures/methods , Single-Blind Method , Cardiopulmonary Bypass/methods , Erythrocyte Transfusion/methods , Male , Blood Loss, Surgical/prevention & control , FemaleABSTRACT
BACKGROUND: Acute kidney injury (AKI) is a serious and common complication of cardiac surgery, for which reduced kidney perfusion is a key contributing factor. Intravenous amino acids increase kidney perfusion and recruit renal functional reserve. However, the efficacy of amino acids in reducing the occurrence of AKI after cardiac surgery is uncertain. METHODS: In a multinational, double-blind trial, we randomly assigned adult patients who were scheduled to undergo cardiac surgery with cardiopulmonary bypass to receive an intravenous infusion of either a balanced mixture of amino acids, at a dose of 2 g per kilogram of ideal body weight per day, or placebo (Ringer's solution) for up to 3 days. The primary outcome was the occurrence of AKI, defined according to the Kidney Disease: Improving Global Outcomes creatinine criteria. Secondary outcomes included the severity of AKI, the use and duration of kidney-replacement therapy, and all-cause 30-day mortality. RESULTS: We recruited 3511 patients at 22 centers in three countries and assigned 1759 patients to the amino acid group and 1752 to the placebo group. AKI occurred in 474 patients (26.9%) in the amino acid group and in 555 (31.7%) in the placebo group (relative risk, 0.85; 95% confidence interval [CI], 0.77 to 0.94; P = 0.002). Stage 3 AKI occurred in 29 patients (1.6%) and 52 patients (3.0%), respectively (relative risk, 0.56; 95% CI, 0.35 to 0.87). Kidney-replacement therapy was used in 24 patients (1.4%) in the amino acid group and in 33 patients (1.9%) in the placebo group. There were no substantial differences between the two groups in other secondary outcomes or in adverse events. CONCLUSIONS: Among adult patients undergoing cardiac surgery, infusion of amino acids reduced the occurrence of AKI. (Funded by the Italian Ministry of Health; PROTECTION ClinicalTrials.gov number, NCT03709264.).
Subject(s)
Acute Kidney Injury , Amino Acids , Cardiac Surgical Procedures , Cardiopulmonary Bypass , Postoperative Complications , Aged , Female , Humans , Male , Middle Aged , Acute Kidney Injury/diagnosis , Acute Kidney Injury/epidemiology , Acute Kidney Injury/etiology , Acute Kidney Injury/prevention & control , Amino Acids/administration & dosage , Amino Acids/adverse effects , Cardiac Surgical Procedures/adverse effects , Cardiopulmonary Bypass/adverse effects , Creatinine/blood , Double-Blind Method , Infusions, Intravenous , Kidney/drug effects , Postoperative Complications/diagnosis , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Postoperative Complications/prevention & control , Renal Replacement TherapyABSTRACT
BACKGROUND: Minimizing the use of blood component can reduce known and unknown blood transfusion risks, preserve blood bank resources, and decrease healthcare costs. Red Blood Cell (RBC) transfusion is common after cardiac surgery and associated with adverse perioperative outcomes, including mortality. Acute normovolemic hemodilution (ANH) may reduce bleeding and the need for blood product transfusion after cardiac surgery. However, its blood-saving effect and impact on major outcomes remain uncertain. METHODS: This is a single-blinded, multinational, pragmatic, randomized controlled trial with a 1:1 allocation ratio conducted in Tertiary and University hospitals. The study is designed to enroll patients scheduled for elective cardiac surgery with planned cardiopulmonary bypass (CPB). Patients are randomized to receive ANH before CPB or the best available treatment without ANH. We identified an ANH volume of at least 650 mL as the critical threshold for clinically relevant benefits. Larger ANH volumes, however, are allowed and tailored to the patient's characteristics and clinical conditions. RESULTS: The primary outcome is the percentage of patients receiving RBCs transfusion from randomization until hospital discharge, which we hypothesize will be reduced from 35% to 28% with ANH. Secondary outcomes are all-cause 30-day mortality, acute kidney injury, bleeding complications, and ischemic complications. CONCLUSION: The trial is designed to determine whether ANH can safely reduce RBC transfusion after elective cardiac surgery with CPB. STUDY Registration: This trial was registered on ClinicalTrials.gov in April 2019 with the trial identification number NCT03913481.
Subject(s)
Cardiopulmonary Bypass , Randomized Controlled Trial , Critical CareABSTRACT
BACKGROUND: The critical role of different adjuncts in improving the neurological outcome in intrinsic brain lesions affecting eloquent areas is demonstrated by their more diffuse utilization. Neurosurgeons often rely on preoperative and intraoperative diffusion tensor imaging tractography to improve the operative strategy and prognosis. We aimed to identify and validate a diffusion tensor imaging-based classification considering the relationship between the brain lesion and the corticospinal tract to predict a >50% reduction of motor evoked potentials (MEPs) during surgical excision of lesions involving the motor pathways. METHODS: We included patients consecutively enrolled at our institution between April 2020 and September 2022 with 3 patterns of increasing complexity according to the relationship between the lesion and the corticospinal tract as identified on preoperative diffusion tensor imaging. Outcome measures were >50% reduction in intraoperative MEPs and neurological outcome defined as unchanged, improved, or worsened. RESULTS: The study included 83 patients. A statistically significant linear trend between higher rates of reduction of MEPs and higher classification grades was observed (P = 0.001), with sensitivity 0.60, specificity 0.88, accuracy 0.83, and area under the curve 0.75. Higher grades were associated with worse neurological outcomes (P = 0.02). CONCLUSIONS: The classification proved reliable in anticipating reduction in intraoperative MEPs and in predicting neurological outcome. Using this classification in patients undergoing surgery for lesions involving the motor pathways could help in counseling the patient, surgical planning, enhancing teamwork of operating room personnel, and improving the patient's prognosis.
Subject(s)
Brain Neoplasms , Diffusion Tensor Imaging , Humans , Diffusion Tensor Imaging/methods , Prognosis , Brain/surgery , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/surgery , Brain Neoplasms/pathology , Pyramidal Tracts/diagnostic imaging , Pyramidal Tracts/surgery , Pyramidal Tracts/pathologyABSTRACT
BACKGROUND: Intraoperative ultrasonography (IOUS) in traumatic brain injury is a fast, easy, and low-cost technique that has been poorly investigated so far even though it could potentially answer many of the intraoperative needs of the surgeon. The aim of this study was to investigate the role of IOUS in patients undergoing surgery for traumatic acute subdural hematoma (aSDH), focusing on its influence on intraoperative surgical strategy, particularly regarding the management of intracerebral contusions (ICCs) associated with aSDH. METHODS: Data of patients who consecutively underwent surgical evacuation of traumatic aSDH with IOUS assistance at our institution from May 2017 to December 2020 were retrospectively analyzed. Patients were dichotomized into an ICC group (ICCs associated with aSDH on preoperative computed tomography scan) and no ICC group (no ICCs associated with aSDH on preoperative computed tomography scan). RESULTS: The study included 41 patients. Before aSDH evacuation, IOUS findings were similar to preoperative computed tomography data. After aSDH evacuation, IOUS detected a new-onset ICC in 13% of patients in the no ICC group and a volume increase of the known ICCs in 22% of patients in the ICC group. Therefore, IOUS made it possible to evacuate these new-onset or expanding hematomas in the same operation, changing our surgical strategy and avoiding a delayed reintervention. CONCLUSIONS: Our study suggests that IOUS in patients undergoing surgery for traumatic aSDH can promptly identify possible evolution of a primary head injury, leading to early and effective treatment.
Subject(s)
Hematoma, Subdural, Acute , Hematoma, Subdural, Intracranial , Humans , Hematoma, Subdural, Acute/diagnostic imaging , Hematoma, Subdural, Acute/surgery , Retrospective Studies , Hematoma, Subdural/surgery , Treatment Outcome , UltrasonographyABSTRACT
BACKGROUND: Postoperative acute kidney injury (AKI) is frequent in cardiac surgery patients. Its pathophysiology is complex and involves decreased renal perfusion. Preliminary clinical evidence in critically ill patients shows that amino acids infusion increases renal blood flow and may decrease the incidence and severity of AKI. We designed a study to evaluate the effectiveness of perioperative continuous infusion of amino acids in decreasing AKI. METHODS: This is a phase III, multi-center, randomized, double-blind, placebo-controlled trial. Adults undergoing cardiac surgery with cardiopulmonary bypass (CPB) are included. Patients are randomly assigned to receive either continuous infusion of a balanced mixture of amino acids in a dose of 2 g/kg ideal body weight/day or placebo (balanced crystalloid solution) from the operating room up to start of renal replacement therapy (RRT), or ICU discharge, or 72 h after the first dose. The primary outcome is the incidence of AKI during hospital stay defined by KDIGO (Kidney Disease: Improving Global Outcomes). Secondary outcomes include the need for, and duration of, RRT, mechanical ventilation; ICU and hospital length of stay; all-cause mortality at ICU, hospital discharge, 30, 90, and 180 days after randomization; quality of life at 180 days. Data will be analyzed in 3500 patients on an intention-to-treat basis. DISCUSSION: The trial is ongoing and currently recruiting. It will be one of the first randomized controlled studies to assess the relationship between amino acids use and kidney injury in cardiac surgery. If our hypothesis is confirmed, this practice could reduce morbidity in the studied population. STUDY REGISTRATION: This trial was registered on ClinicalTrials.gov with the trial identification NCT03709264 in October 2018.
Subject(s)
Acute Kidney Injury , Cardiac Surgical Procedures , Acute Kidney Injury/epidemiology , Acute Kidney Injury/etiology , Acute Kidney Injury/prevention & control , Adult , Amino Acids , Clinical Trials, Phase III as Topic , Crystalloid Solutions , Humans , Kidney , Multicenter Studies as Topic , Quality of Life , Randomized Controlled Trials as TopicABSTRACT
PURPOSE: The aim of this study is to compare the use of 5-aminolevulinic acid (5-ALA) and sodium fluorescein (SF) in IV ventricular ependymoma (IVEP) surgical resection. METHODS: In this retrospective study, six patients with IVEP were enrolled. Gender ratio 2:1 male to female, with mean age 38.9 years old. A 5-ALA oral dose of 20 mg/kg and a SF intravenous dose of 2 mg/kg were administered. Telo-velar approach, operative microscope, and intraoperative monitoring were used in all the operations. We retrospectively compared the two fluorescence techniques at four steps during the surgical procedure: step 1: exposure of the tumor; step 2: dissection of the lesion from the cerebellum; step 3: assessment of the tumor borders and differentiation from normal tissue at the base of implants; and step 4: evaluation of possible residual tissue in the surgical cavity. RESULTS: At the first step, the ependymomas resulted well delineated by both fluorescent agents. In this step, 5-ALA was particularly helpful in the case of recurrent ependymoma. At step 2, 5-ALA provided a better identification of the ependymoma boundaries and distinction from cerebellum hemispheres than SF. In steps 3 and 4, SF was really helpful to detect tumor tissue. CONCLUSION: According to our experience, fluorescence-guided surgery of IVEP with 5-ALA and SF is useful to maximize surgical resection with less risk of brainstem injury. Both fluorescence techniques are helpful in different steps of IVEP resection. However, further studies are needed to confirm our preliminary data.
Subject(s)
Brain Neoplasms , Ependymoma , Adult , Aminolevulinic Acid , Brain Neoplasms/pathology , Ependymoma/diagnostic imaging , Ependymoma/surgery , Female , Fluorescein , Humans , Male , Neoplasm Recurrence, Local/surgery , Neurosurgical Procedures/methods , Retrospective StudiesABSTRACT
OBJECTIVES: Healthcare systems worldwide have been overburdened by the coronavirus disease 2019 (COVID-19) outbreak. Accordingly, hospitals had to implement strategies to profoundly reshape both non-COVID-19 medical care and surgical activities. Knowledge about the impact of the COVID-19 pandemic on cardiac surgery practice is pivotal. The goal of the present study was to describe the changes in cardiac surgery practices during the health emergency at the national level. METHODS: A 26-question web-enabled survey including all adult cardiac surgery units in Italy was conducted to assess how their clinical practice changed during the national lockdown. Data were compared to data from the corresponding period in 2019. RESULTS: All but 2 centres (94.9%) adopted specific protocols to screen patients and personnel. A significant reduction in the number of dedicated cardiac intensive care unit beds (-35.4%) and operating rooms (-29.2%), along with healthcare personnel reallocation to COVID departments (nurses -15.4%, anaesthesiologists -7.7%), was noted. Overall adult cardiac surgery volumes were dramatically reduced (1734 procedures vs 3447; P < 0.001), with a significant drop in elective procedures [580 (33.4%) vs 2420 (70.2%)]. CONCLUSIONS: This national survey found major changes in cardiac surgery practice as a response to the COVID-19 pandemic. This experience should lead to the development of permanent systems-based plans to face possible future pandemics. These data may effectively help policy decision-making in prioritizing healthcare resource reallocation during the ongoing pandemic and once the healthcare emergency is over.
Subject(s)
COVID-19 , Cardiac Surgical Procedures , Communicable Disease Control , Humans , Italy , Pandemics , SARS-CoV-2ABSTRACT
Despite improvements in surgical techniques and perioperative care, cardiac surgery still is burdened by relatively high mortality and frequent major postoperative complications, including myocardial dysfunction, pulmonary complications, neurologic injury, and acute kidney injury. Although the surgeon's skills and volume and patient- and procedure-related risk factors play a major role in the success of cardiac surgery, there is growing evidence that also optimizing perioperative care may improve outcomes significantly. The present review focuses on the aspects of perioperative care that are strictly related to the anesthesia regimen, with special reference to volatile anesthetics and neuraxial anesthesia, whose effect on outcome in adult cardiac surgery has been investigated extensively.
Subject(s)
Anesthesia , Anesthetics, Inhalation , Cardiac Surgical Procedures , Adult , Anesthesia/adverse effects , Cardiac Surgical Procedures/adverse effects , Humans , Perioperative Care , Postoperative Complications/etiology , Postoperative Complications/prevention & controlSubject(s)
Coronavirus Infections , Coronavirus , Pandemics , Pneumonia, Viral , Betacoronavirus , COVID-19 , Humans , Operating Rooms , SARS-CoV-2 , SingaporeABSTRACT
PURPOSE: Perioperative myocardial dysfunction occurs frequently in cardiac surgery, and is a risk factor for morbidity and mortality. Levosimendan has been suggested to reduce mortality of patients with perioperative myocardial dysfunction. However, long-term outcome data on its efficacy in cardiac surgery are lacking. MATERIALS AND METHODS: Cardiac surgery patients with perioperative myocardial dysfunction were randomized to levosimendan or placebo, in addition to standard inotropic care. One-year mortality data were collected. RESULTS: We randomized 506 patients (248 to levosimendan 258 to placebo). At 1-year follow-up, 41 patients (16.5%) died in the levosimendan group, while 47 (18.3%) died in the placebo group (absolute risk difference -1.8; 95% CI -8.4 to 4.9; Pâ¯=â¯.60). Female sex, history of chronic obstructive pulmonary disease, previous myocardial infarction, serum creatinine, hematocrit, mean arterial pressure, and duration of cardiopulmonary bypass were independently associated with 1-year mortality. CONCLUSIONS: Levosimendan administration does not improve 1-year survival in cardiac surgery patients with perioperative myocardial dysfunction. One-year mortality in these patients is 17%. Six predictive factors for long-term mortality were identified. STUDY REGISTRATION NUMBER: NCT00994825 (ClinicalTrials.gov).
Subject(s)
Cardiac Output, Low/drug therapy , Simendan/therapeutic use , Age Factors , Cardiac Output, Low/mortality , Cardiotonic Agents/administration & dosage , Cardiotonic Agents/therapeutic use , Cardiovascular Surgical Procedures/adverse effects , Double-Blind Method , Female , Humans , Male , Middle Aged , Postoperative Complications/drug therapy , Postoperative Complications/mortality , Simendan/administration & dosage , Survival Analysis , Treatment OutcomeABSTRACT
Unlike general anaesthesia, neuraxial anaesthesia (NA) reduces the burden and risk of respiratory adverse events in the post-operative period. However, both patients affected by chronic obstructive pulmonary disease (COPD) and chest wall disorders and/or neuromuscular diseases may experience the development or the worsening of respiratory failure, even during surgery performed under NA; this latter negatively affects the function of accessory respiratory muscles, resulting in a blunted central response to hypercapnia and possibly in an exacerbation of cardiac dysfunction (NA-induced relative hypovolemia). According to European Respiratory Society (ERS) and American Thoracic Society (ATS) guidelines, non-invasive ventilation (NIV) is effective in the post-operative period for the treatment of both impaired pulmonary gas exchange and ventilation, while the intra-operative use of NIV in association with NA is just anecdotally reported in the literature. Whilst NIV does not assure a protected patent airway and requires the patient's cooperation, it is a handy tool during surgery under NA: NIV is reported to be successful for treatment of acute respiratory failure; it may be delivered through the patient's home ventilator, may reverse hypoventilation induced by sedatives or inadvertent spread of anaesthetic up to cervical dermatomes, and allow the avoidance of intubation in patients affected by chronic respiratory failure, prolonging the time of non-invasiveness of respiratory support (i.e., neuromuscular patients needing surgery). All these advantages could make NIV preferable to oxygen in carefully selected patients.
Subject(s)
Anesthesia, Epidural/methods , Anesthesia, Spinal/methods , Noninvasive Ventilation/methods , Humans , Neuromuscular Diseases/complications , Neuromuscular Diseases/physiopathology , Patient Selection , Pulmonary Disease, Chronic Obstructive/complications , Pulmonary Disease, Chronic Obstructive/physiopathology , Respiratory Insufficiency/etiology , Respiratory Insufficiency/prevention & control , Thoracic Diseases/complications , Thoracic Diseases/physiopathologyABSTRACT
OBJECTIVE: Reducing mortality is a key target in critical care and perioperative medicine. The authors aimed to identify all nonsurgical interventions (drugs, techniques, strategies) shown by randomized trials to increase mortality in these clinical settings. DESIGN: A systematic review of the literature followed by a consensus-based voting process. SETTING: A web-based international consensus conference. PARTICIPANTS: Two hundred fifty-one physicians from 46 countries. INTERVENTIONS: The authors performed a systematic literature search and identified all randomized controlled trials (RCTs) showing a significant increase in unadjusted landmark mortality among surgical or critically ill patients. The authors reviewed such studies during a meeting by a core group of experts. Studies selected after such review advanced to web-based voting by clinicians in relation to agreement, clinical practice, and willingness to include each intervention in international guidelines. MEASUREMENTS AND MAIN RESULTS: The authors selected 12 RCTs dealing with 12 interventions increasing mortality: diaspirin-crosslinked hemoglobin (92% of agreement among web voters), overfeeding, nitric oxide synthase inhibitor in septic shock, human growth hormone, thyroxin in acute kidney injury, intravenous salbutamol in acute respiratory distress syndrome, plasma-derived protein C concentrate, aprotinin in high-risk cardiac surgery, cysteine prodrug, hypothermia in meningitis, methylprednisolone in traumatic brain injury, and albumin in traumatic brain injury (72% of agreement). Overall, a high consistency (ranging from 80% to 90%) between agreement and clinical practice was observed. CONCLUSION: The authors identified 12 clinical interventions showing increased mortality supported by randomized controlled trials with nonconflicting evidence, and wide agreement upon clinicians on a global scale.
Subject(s)
Critical Care/methods , Critical Illness/mortality , Perioperative Care/methods , Physicians , Randomized Controlled Trials as Topic/methods , Surveys and Questionnaires , Cardiac Surgical Procedures/adverse effects , Cardiac Surgical Procedures/mortality , Critical Illness/therapy , Humans , Internet , Mortality/trendsABSTRACT
Increasing evidence supports the involvement of IBTK in cell survival and tumor growth. Previously, we have shown that IBTK RNA interference affects the wide genome expression and RNA splicing in cell-type specific manner. Further, the expression of IBTK gene progressively increases from indolent to aggressive stage of chronic lymphocytic leukemia and decreases in disease remission after therapy. However, the role of IBTK in tumorigenesis has not been elucidated. Here, we report that loss of the murine Ibtk gene raises survival and delays tumor onset in Eµ-myc transgenic mice, a preclinical model of Myc-driven lymphoma. In particular, we found that the number of pre-cancerous B cells of bone marrow and spleen is reduced in Ibtk-/-Eµ-myc mice owing to impaired viability and increased apoptosis, as measured by Annexin V binding, Caspase 3/7 cleavage assays and cell cycle profile analysis. Instead, the proliferation rate of pre-cancerous B cells is unaffected by the loss of Ibtk. We observed a direct correlation between Ibtk and myc expression and demonstrated a Myc-dependent regulation of Ibtk expression in murine B cells, human hematopoietic and nonhematopoietic cell lines by analysis of ChIP-seq data. By tet-repressible Myc system, we confirmed a Myc-dependent expression of IBTK in human B cells. Further, we showed that Ibtk loss affected the main apoptotic pathways dependent on Myc overexpression in pre-cancerous Eµ-myc mice, in particular, MCL-1 and p53. Of note, we found that loss of IBTK impaired cell cycle and increased apoptosis also in a human epithelial cell line, HeLa cells, in Myc-independent manner. Taken together, these results suggest that Ibtk sustains the oncogenic activity of Myc by inhibiting apoptosis of murine pre-cancerous B cells, as a cell-specific mechanism. Our findings could be relevant for the development of IBTK inhibitors sensitizing tumor cells to apoptosis.
Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Apoptosis/genetics , B-Lymphocytes/metabolism , Lymphoma, B-Cell/metabolism , Adaptor Proteins, Signal Transducing/metabolism , Animals , B-Lymphocytes/cytology , Bone Marrow Cells/cytology , Bone Marrow Cells/metabolism , Cell Cycle Checkpoints/genetics , Cell Proliferation/genetics , Cell Survival/genetics , HEK293 Cells , HeLa Cells , Humans , Lymphoma, B-Cell/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolism , Spleen/cytology , Spleen/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolismABSTRACT
The antigen-mediated triggering of B cell receptor (BCR) activates the transcription factor NF-κB that regulates the expression of genes involved in B cell differentiation, proliferation, and survival. The tyrosine kinase Btk is essentially required for the activation of NF-κB in BCR signaling through the canonical pathway of IKK-dependent phosphorylation and proteasomal degradation of IκB-α, the main repressor of NF-κB. Here, we provide the evidence of an additional mechanism of NF-κB activation in BCR signaling that is Btk-dependent and IKK-independent. In DeFew B lymphoma cells, the anti-IgM stimulation of BCR activated Btk and NF-κB p50/p65 within 0.5 min in absence of IKK activation and IκB-α degradation. IKK silencing did not affect the rapid activation of NF-κB. Within this short time, Btk associated and phosphorylated IκB-α at Y289 and Y305, and, concomitantly, p65 translocated from cytosol to nucleus. The mutant IκB-α Y289/305A inhibited the NF-κB activation after BCR triggering, suggesting that the phosphorylation of IκB-α at tyrosines 289 and 305 was required for NF-κB activation. In primary chronic lymphocytic leukemia cells, Btk was constitutively active and associated with IκB-α, which correlated with Y305-phosphorylation of IκB-α and increased NF-κB activity compared with healthy B cells. Altogether, these results describe a novel mechanism of NF-κB activation in BCR signaling that could be relevant for Btk-targeted therapy in B-lymphoproliferative disorders. KEY MESSAGES: Anti-IgM stimulation of BCR activates NF-κB p50/p65 within 30 s by a Btk-dependent and IKK-independent mechanism. Btk associates and phosphorylates IκB-α at Y289 and Y305, promoting NF-κB activation. In primary CLLs, the binding of Btk to IκB-α correlates with tyrosine phosphorylation of IκB-α and increased NF-κB activity.
Subject(s)
Agammaglobulinaemia Tyrosine Kinase/immunology , NF-KappaB Inhibitor alpha/immunology , NF-kappa B/immunology , Receptors, Antigen, B-Cell/immunology , Cell Line, Tumor , HEK293 Cells , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Phosphorylation , Signal TransductionABSTRACT
The authors aimed to identify interventions documented by randomized controlled trials (RCTs) that reduce mortality in adult critically ill and perioperative patients, followed by a survey of clinicians' opinions and routine practices to understand the clinicians' response to such evidence. The authors performed a comprehensive literature review to identify all topics reported to reduce mortality in perioperative and critical care settings according to at least 2 RCTs or to a multicenter RCT or to a single-center RCT plus guidelines. The authors generated position statements that were voted on online by physicians worldwide for agreement, use, and willingness to include in international guidelines. From 262 RCT manuscripts reporting mortality differences in the perioperative and critically ill settings, the authors selected 27 drugs, techniques, and strategies (66 RCTs, most frequently published by the New England Journal of Medicine [13 papers], Lancet [7], and Journal of the American Medical Association [5]) with an agreement ≥67% from over 250 physicians (46 countries). Noninvasive ventilation was the intervention supported by the largest number of RCTs (nâ¯=â¯13). The concordance between agreement and use (a positive answer both to "do you agree" and "do you use") showed differences between Western and other countries and between anesthesiologists and intensive care unit physicians. The authors identified 27 clinical interventions with randomized evidence of survival benefit and strong clinician support in support of their potential life-saving properties in perioperative and critically ill patients with noninvasive ventilation having the highest level of support. However, clinician views appear affected by specialty and geographical location.