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1.
J Cardiothorac Vasc Anesth ; 33(10): 2685-2694, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31064730

RESUMO

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.

2.
Cell Death Dis ; 10(4): 320, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30975981

RESUMO

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.

3.
J Mol Med (Berl) ; 97(5): 675-690, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30887112

RESUMO

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.

4.
J Cardiothorac Vasc Anesth ; 33(5): 1430-1439, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30600204

RESUMO

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 (n = 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.


Assuntos
Cuidados Críticos/métodos , Estado Terminal/mortalidade , Internet , Médicos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Inquéritos e Questionários , Cuidados Críticos/tendências , Estado Terminal/terapia , Humanos , Unidades de Terapia Intensiva/tendências , Internet/tendências , Mortalidade/tendências , Médicos/tendências
6.
Int J Mol Sci ; 19(11)2018 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-30428531

RESUMO

Protein ubiquitylation plays a central role in eukaryotic cell physiology. It is involved in several regulatory processes, ranging from protein folding or degradation, subcellular localization of proteins, vesicular trafficking and endocytosis to DNA repair, cell cycle, innate immunity, autophagy, and apoptosis. As such, it is reasonable that pathogens have developed a way to exploit such a crucial system to enhance their virulence against the host. Hence, bacteria have evolved a wide range of effectors capable of mimicking the main players of the eukaryotic ubiquitin system, in particular ubiquitin ligases, by interfering with host physiology. Here, we give an overview of this topic and, in particular, we detail and discuss the mechanisms developed by pathogenic bacteria to hijack the host ubiquitination system for their own benefit.

7.
J Clin Monit Comput ; 2018 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-29789999

RESUMO

The pilot balloon palpation (or 'finger-pressure') method is still widely used to assess the endotracheal tube cuff inflation, despite consistent evidence of its poor sensitivity in recognizing cuff overinflation. It was recently speculated that this may be related to the lower wall tension (due to the smaller radius) of the pilot balloon as compared with the cuff, according to Laplace's law. To verify this hypothesis and, secondarily, to assess whether the use of a 'large' pilot balloon (identical to the cuff) increases the reliability of this technique, 62 anesthetists (41 experienced anesthesiologists and 21 residents) were asked to estimate the pressure of a cuff inflated to 88 mmHg into a simulated trachea by feeling both a usual and a modified 'large' pilot balloon. A similar test was repeated at 40 mmHg. After palpation of the usual pilot balloon, only 35% of participants (49% of experienced anesthesiologists and 10% of residents) recognized considerable overinflation (88 mmHg), as compared with 87% of participants (95% of experienced anesthesiologists and 71% of residents) after palpation of the 'large' pilot balloon. Moreover, 89% of participants (85% of experienced anesthesiologists and 95% of residents) believed that pressure was higher in the 'large' balloon than in the normal one. However, only 32% of participants (51% of experienced anesthesiologists and none of residents) recognized slight overinflation (40 mmHg) after feeling the 'large' balloon. The pilot balloon size affects the sensitivity of the 'finger-pressure' technique, but it remains poorly reliable with a larger pilot balloon.

8.
J Cardiothorac Vasc Anesth ; 32(5): 2152-2159, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29580796

RESUMO

OBJECTIVE: Acute kidney injury (AKI) occurs frequently after cardiac surgery. Levosimendan might reduce the incidence of AKI in patients undergoing cardiac surgery. The authors investigated whether levosimendan administration could reduce AKI incidence in a high-risk cardiac surgical population. DESIGN: Post hoc analysis of a multicenter randomized trial. SETTING: Cardiac surgery operating rooms and intensive care units of 14 centers in 3 countries. PARTICIPANTS: The study comprised 90 patients who underwent mitral valve surgery with an estimated glomerular filtration rate <60 mL/min/1.73 m2 and perioperative myocardial dysfunction. INTERVENTIONS: Patients were assigned randomly to receive levosimendan (0.025-0.2 µg/kg/min) or placebo in addition to standard inotropic treatment. MEASUREMENTS AND MAIN RESULTS: Forty-six patients were assigned to receive levosimendan and 44 to receive placebo. Postoperative AKI occurred in 14 (30%) patients in the levosimendan group versus 23 (52%) in the placebo group (absolute difference -21.8; 95% confidence interval -41.7 to -1.97; p = 0.035). The incidence of major complications also was lower (18 [39%]) in the levosimendan group versus that in the placebo group (29 [66%]) (absolute difference -26.8 [-46.7 to -6.90]; p = 0.011). A trend toward lower serum creatinine at intensive care unit discharge was observed in the levosimendan group (1.18 [0.99-1.49] mg/dL) versus that in the placebo group (1.39 [1.05-1.76] mg/dL) (95% confidence interval -0.23 [-0.49 to 0.01]; p = 0.07). CONCLUSIONS: Levosimendan may improve renal outcome in cardiac surgery patients with chronic kidney disease undergoing mitral valve surgery who develop perioperative myocardial dysfunction. Results of this exploratory analysis should be investigated in future properly designed randomized controlled trials.

9.
Cell Death Dis ; 9(1): 13, 2018 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-29317636

RESUMO

Chronic lymphocytic leukaemia (CLL) is the most common B-cell malignancy with a variable clinical outcome. Biomarkers of CLL progression are required for optimising prognosis and therapy. The Inhibitor of Bruton's tyrosine kinase-isoform α (IBTKα) gene encodes a substrate receptor of Cullin 3-dependent E3 ubiquitin ligase, and promotes cell survival in response to the reticulum stress. Searching for novel markers of CLL progression, we analysed the expression of IBTKα in the peripheral blood B-cells of CLL patients, before and after first line therapy causing remission. The expression of IBTKα was significantly increased in disease progression, and decreased in remission after chemotherapy. Consistently with a pro-survival action, RNA interference of IBTKα increased the spontaneous and Fludarabine-induced apoptosis of MEC-1 CLL cells, and impaired the cell cycle of DeFew B-lymphoma cells by promoting the arrest in G0/G1 phase and apoptosis. Consistently, RNA interference of IBTKα up regulated the expression of pro-apoptotic genes, including TNF, CRADD, CASP7, BNIP3 and BIRC3. Our results indicate that IBTKα is a novel marker of CLL progression promoting cell growth and resistance to apoptosis. In this view, IBTKα may represent an attractive cancer drug target for counteracting the therapy-resistance of tumour cells.

10.
J Cardiothorac Vasc Anesth ; 32(1): 225-235, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29122431

RESUMO

OBJECTIVE: A careful choice of perioperative care strategies is pivotal to improve survival in cardiac surgery. However, there is no general agreement or particular attention to which nonsurgical interventions can reduce mortality in this setting. The authors sought to address this issue with a consensus-based approach. DESIGN: A systematic review of the literature followed by a consensus-based voting process. SETTING: A web-based international consensus conference. PARTICIPANTS: More than 400 physicians from 52 countries participated in this web-based consensus conference. INTERVENTIONS: The authors identified all studies published in peer-reviewed journals that reported on interventions with a statistically significant effect on mortality in the setting of cardiac surgery through a systematic Medline/PubMed search and contacts with experts. These studies were discussed during a consensus meeting and those considered eligible for inclusion in this study were voted on by clinicians worldwide. MEASUREMENTS AND MAIN RESULTS: Eleven interventions finally were selected: 10 were shown to reduce mortality (aspirin, glycemic control, high-volume surgeons, prophylactic intra-aortic balloon pump, levosimendan, leuko-depleted red blood cells transfusion, noninvasive ventilation, tranexamic acid, vacuum-assisted closure, and volatile agents), whereas 1 (aprotinin) increased mortality. A significant difference in the percentages of agreement among different countries and a variable gap between agreement and clinical practice were found for most of the interventions. CONCLUSIONS: This updated consensus process identified 11 nonsurgical interventions with possible survival implications for patients undergoing cardiac surgery. This list of interventions may help cardiac anesthesiologists and intensivists worldwide in their daily clinical practice and can contribute to direct future research in the field.


Assuntos
Procedimentos Cirúrgicos Cardíacos/mortalidade , Procedimentos Cirúrgicos Cardíacos/tendências , Conferências de Consenso como Assunto , Assistência Perioperatória/métodos , Complicações Pós-Operatórias/mortalidade , Complicações Pós-Operatórias/prevenção & controle , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Congressos como Assunto/tendências , Consenso , Humanos , Internet/tendências , Mortalidade/tendências , Assistência Perioperatória/tendências , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos
11.
J Cardiothorac Vasc Anesth ; 32(1): 225-235, 2018.
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: ses-37196

RESUMO

OBJECTIVE:A careful choice of perioperative care strategies is pivotal to improve survival in cardiac surgery. However, there is no general agreement or particular attention to which nonsurgical interventions can reduce mortality in this setting. The authors sought to address this issue with a consensus-based approach.DESIGN:A systematic review of the literature followed by a consensus-based voting process.SETTING:A web-based international consensus conference.PARTICIPANTS:More than 400 physicians from 52 countries participated in this web-based consensus conference.INTERVENTIONS:The authors identified all studies published in peer-reviewed journals that reported on interventions with a statistically significant effect on mortality in the setting of cardiac surgery through a systematic Medline/PubMed search and contacts with experts. These studies were discussed during a consensus meeting and those considered eligible for inclusion in this study were voted on by clinicians worldwide.MEASUREMENTS AND MAIN RESULTS:Eleven interventions finally were selected: 10 were shown to reduce mortality (aspirin, glycemic control, high-volume surgeons, prophylactic intra-aortic balloon pump, levosimendan, leuko-depleted red blood cells transfusion, noninvasive ventilation, tranexamic acid, vacuum-assisted closure, and volatile agents), whereas 1 (aprotinin) increased mortality. A significant difference in the percentages of agreement among different countries and a variable gap between agreement and clinical practice were found for most of the interventions.CONCLUSIONS:This updated consensus process identified 11 nonsurgical interventions with possible survival implications for patients undergoing cardiac surgery. This list of interventions may help cardiac anesthesiologists and intensivists worldwide in their daily clinical practice and can contribute to direct future research in the field.(AU)


Assuntos
Período Perioperatório/mortalidade , Período Perioperatório/métodos
12.
Mol Cancer ; 16(1): 159, 2017 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-29029605

RESUMO

Tumor-derived exosomes (TDEs) play a pivotal role in tumor establishment and progression, and are emerging biomarkers for tumor diagnosis in personalized medicine. To date, there is a lack of efficient technology platforms for exosome isolation and characterization. Multiple myeloma (MM) is an incurable B-cell malignancy due to the rapid development of drug-resistance. MM-released exosomes express the immunoglobulin B-cell receptor (Ig-BCR) of the tumor B-cells, which can be targeted by Idiotype-binding peptides (Id-peptides). In this study, we analyzed the production of MM-released exosomes in the murine 5T33MM multiple myeloma model as biomarkers of tumor growth. To this end, we selected Id-peptides by screening a phage display library using as bait the Ig-BCR expressed by 5T33MM cells. By FACS, the FITC-conjugated Id-peptides detected the MM-released exosomes in the serum of 5T33MM-engrafted mice, levels of which are correlated with tumor progression at an earlier time point compared to serum paraprotein. These results indicate that Id-peptide-based recognition of MM-released exosomes may represent a very sensitive diagnostic approach for clinical evaluation of disease progression.


Assuntos
Exossomos/metabolismo , Imunoglobulina G/metabolismo , Mieloma Múltiplo/metabolismo , Células Dendríticas/metabolismo , Citometria de Fluxo , Humanos , Idiotipos de Imunoglobulinas/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais/fisiologia , Células Tumorais Cultivadas
13.
Contemp Clin Trials ; 59: 38-43, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28533194

RESUMO

OBJECTIVE: There is initial evidence that the use of volatile anesthetics can reduce the postoperative release of cardiac troponin I, the need for inotropic support, and the number of patients requiring prolonged hospitalization following coronary artery bypass graft (CABG) surgery. Nevertheless, small randomized controlled trials have failed to demonstrate a survival advantage. Thus, whether volatile anesthetics improve the postoperative outcome of cardiac surgical patients remains uncertain. An adequately powered randomized controlled trial appears desirable. DESIGN: Single blinded, international, multicenter randomized controlled trial with 1:1 allocation ratio. SETTING: Tertiary and University hospitals. INTERVENTIONS: Patients (n=10,600) undergoing coronary artery bypass graft will be randomized to receive either volatile anesthetic as part of the anesthetic plan, or total intravenous anesthesia. MEASUREMENTS AND MAIN RESULTS: The primary end point of the study will be one-year mortality (any cause). Secondary endpoints will be 30-day mortality; 30-day death or non-fatal myocardial infarction (composite endpoint); cardiac mortality at 30day and at one year; incidence of hospital re-admission during the one year follow-up period and duration of intensive care unit, and hospital stay. The sample size is based on the hypothesis that volatile anesthetics will reduce 1-year unadjusted mortality from 3% to 2%, using a two-sided alpha error of 0.05, and a power of 0.9. CONCLUSIONS: The trial will determine whether the simple intervention of adding a volatile anesthetic, an intervention that can be implemented by all anesthesiologists, can improve one-year survival in patients undergoing coronary artery bypass graft surgery.


Assuntos
Anestesia em Procedimentos Cardíacos , Anestésicos Inalatórios , Ponte de Artéria Coronária , Doença da Artéria Coronariana/cirurgia , Complicações Pós-Operatórias , Adulto , Anestesia em Procedimentos Cardíacos/efeitos adversos , Anestesia em Procedimentos Cardíacos/métodos , Anestésicos Inalatórios/administração & dosagem , Anestésicos Inalatórios/química , Ponte de Artéria Coronária/efeitos adversos , Ponte de Artéria Coronária/métodos , Ponte de Artéria Coronária/mortalidade , Doença da Artéria Coronariana/mortalidade , Feminino , Humanos , Masculino , Avaliação de Processos e Resultados (Cuidados de Saúde) , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Análise de Sobrevida , Volatilização
14.
N Engl J Med ; 376(21): 2021-2031, 2017 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-28320259

RESUMO

BACKGROUND: Acute left ventricular dysfunction is a major complication of cardiac surgery and is associated with increased mortality. Meta-analyses of small trials suggest that levosimendan may result in a higher rate of survival among patients undergoing cardiac surgery. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled trial involving patients in whom perioperative hemodynamic support was indicated after cardiac surgery, according to prespecified criteria. Patients were randomly assigned to receive levosimendan (in a continuous infusion at a dose of 0.025 to 0.2 µg per kilogram of body weight per minute) or placebo, for up to 48 hours or until discharge from the intensive care unit (ICU), in addition to standard care. The primary outcome was 30-day mortality. RESULTS: The trial was stopped for futility after 506 patients were enrolled. A total of 248 patients were assigned to receive levosimendan and 258 to receive placebo. There was no significant difference in 30-day mortality between the levosimendan group and the placebo group (32 patients [12.9%] and 33 patients [12.8%], respectively; absolute risk difference, 0.1 percentage points; 95% confidence interval [CI], -5.7 to 5.9; P=0.97). There were no significant differences between the levosimendan group and the placebo group in the durations of mechanical ventilation (median, 19 hours and 21 hours, respectively; median difference, -2 hours; 95% CI, -5 to 1; P=0.48), ICU stay (median, 72 hours and 84 hours, respectively; median difference, -12 hours; 95% CI, -21 to 2; P=0.09), and hospital stay (median, 14 days and 14 days, respectively; median difference, 0 days; 95% CI, -1 to 2; P=0.39). There was no significant difference between the levosimendan group and the placebo group in rates of hypotension or cardiac arrhythmias. CONCLUSIONS: In patients who required perioperative hemodynamic support after cardiac surgery, low-dose levosimendan in addition to standard care did not result in lower 30-day mortality than placebo. (Funded by the Italian Ministry of Health; CHEETAH ClinicalTrials.gov number, NCT00994825 .).


Assuntos
Baixo Débito Cardíaco/tratamento farmacológico , Procedimentos Cirúrgicos Cardíacos , Cardiotônicos/uso terapêutico , Hemodinâmica/efeitos dos fármacos , Hidrazonas/uso terapêutico , Mortalidade , Piridazinas/uso terapêutico , Idoso , Cardiotônicos/administração & dosagem , Cardiotônicos/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Hidrazonas/administração & dosagem , Hidrazonas/efeitos adversos , Infusões Intravenosas , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Período Perioperatório , Complicações Pós-Operatórias/tratamento farmacológico , Piridazinas/administração & dosagem , Piridazinas/efeitos adversos , Respiração Artificial , Simendana , Volume Sistólico/efeitos dos fármacos , Falha de Tratamento
16.
J Cardiothorac Vasc Anesth ; 31(2): 719-730, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27693206

RESUMO

OBJECTIVE: Of the 230 million patients undergoing major surgical procedures every year, more than 1 million will die within 30 days. Thus, any nonsurgical interventions that help reduce perioperative mortality might save thousands of lives. The authors have updated a previous consensus process to identify all the nonsurgical interventions, supported by randomized evidence, that may help reduce perioperative mortality. DESIGN AND SETTING: A web-based international consensus conference. PARTICIPANTS: The study comprised 500 clinicians from 61 countries. INTERVENTIONS: A systematic literature search was performed to identify published literature about nonsurgical interventions, supported by randomized evidence, showing a statistically significant impact on mortality. A consensus conference of experts discussed eligible papers. The interventions identified by the conference then were submitted to colleagues worldwide through a web-based survey. MEASUREMENTS AND MAIN RESULTS: The authors identified 11 interventions contributing to increased survival (perioperative hemodynamic optimization, neuraxial anesthesia, noninvasive ventilation, tranexamic acid, selective decontamination of the gastrointestinal tract, insulin for tight glycemic control, preoperative intra-aortic balloon pump, leuko-depleted red blood cells transfusion, levosimendan, volatile agents, and remote ischemic preconditioning) and 2 interventions showing increased mortality (beta-blocker therapy and aprotinin). Interventions then were voted on by participating clinicians. Percentages of agreement among clinicians in different countries differed significantly for 6 interventions, and a variable gap between evidence and clinical practice was noted. CONCLUSIONS: The authors identified 13 nonsurgical interventions that may decrease or increase perioperative mortality, with variable agreement by clinicians. Such interventions may be optimal candidates for investigation in high-quality trials and discussion in international guidelines to reduce perioperative mortality.


Assuntos
Consenso , Assistência Perioperatória/mortalidade , Assistência Perioperatória/métodos , Complicações Pós-Operatórias/mortalidade , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Congressos como Assunto , Humanos , Complicações Pós-Operatórias/prevenção & controle
17.
J Cardiothorac Vasc Anesth ; 31(2): 719-730, 2017.
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: ses-34731

RESUMO

Objective: Out of the 230 million patients undergoing major surgical procedure every year, morethan 1 million will die within 30 days. Thus, any nonsurgical interventions that help reduce perioperative mortality might save thousands of lives. We decided to update a previous consensus process to identify all the nonsurgical interventions, supported by randomized evidence, that may help reduce perioperative mortality. Design and Setting: A web-based international consensus conference. Participants: 500 hundred clinicians from 61 countries. Interventions: A systematic literature search was performed to identify published literature aboutnonsurgical interventions, supported by randomized evidence showing a statistically significant impact on mortality. Eligible papers were discussed by a Consensus Conference of experts. The interventions identified by the conference were then submitted to colleagues worldwide through aweb-based survey...(AU)


Assuntos
Assistência Perioperatória , Mortalidade , Anestesia , Consenso , Cuidados Críticos
18.
Contemp Clin Trials ; 59: 38-43, 2017. tab
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: ses-37191

RESUMO

Objective: There is initial evidence that the use of volatile anesthetics can reduce the postoperative release of cardiac troponin I, the need for inotropic support, and the number of patients requiring prolonged hospitalization following coronary artery bypass graft (CABG) surgery. Nevertheless,small Randomized Controlled Trials have failed to demonstrate a survival advantage. Thus, whethervolatile anesthetics improve the postoperative outcome of cardiac surgical patients remains uncertain. An adequately powered randomized controlled trial appears desirable.Design: Single blinded, international, multicenter randomized controlled trial with 1:1 allocation ratio.Setting: Tertiary and University hospitals. (AU)


Assuntos
Humanos , Masculino , Feminino , Adulto , Anestesia , Mortalidade , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos
19.
J Cardiothorac Vasc Anesth ; 31(2): 719-730, 2017.
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: ses-37195

RESUMO

OBJECTIVE:Of the 230 million patients undergoing major surgical procedures every year, more than 1 million will die within 30 days. Thus, any nonsurgical interventions that help reduce perioperative mortality might save thousands of lives. The authors have updated a previous consensus process to identify all the nonsurgical interventions, supported by randomized evidence, that may help reduce perioperative mortality. (AU)


Assuntos
Humanos , Anestesia , Mortalidade
20.
Int J Mol Sci ; 17(11)2016 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-27827994

RESUMO

The IBTK gene encodes the major protein isoform IBTKα that was recently characterized as substrate receptor of Cul3-dependent E3 ligase, regulating ubiquitination coupled to proteasomal degradation of Pdcd4, an inhibitor of translation. Due to the presence of Ankyrin-BTB-RCC1 domains that mediate several protein-protein interactions, IBTKα could exert expanded regulatory roles, including interaction with transcription regulators. To verify the effects of IBTKα on gene expression, we analyzed HeLa and K562 cell transcriptomes by RNA-Sequencing before and after IBTK knock-down by shRNA transduction. In HeLa cells, 1285 (2.03%) of 63,128 mapped transcripts were differentially expressed in IBTK-shRNA-transduced cells, as compared to cells treated with control-shRNA, with 587 upregulated (45.7%) and 698 downregulated (54.3%) RNAs. In K562 cells, 1959 (3.1%) of 63128 mapped RNAs were differentially expressed in IBTK-shRNA-transduced cells, including 1053 upregulated (53.7%) and 906 downregulated (46.3%). Only 137 transcripts (0.22%) were commonly deregulated by IBTK silencing in both HeLa and K562 cells, indicating that most IBTKα effects on gene expression are cell type-specific. Based on gene ontology classification, the genes responsive to IBTK are involved in different biological processes, including in particular chromatin and nucleosomal organization, gene expression regulation, and cellular traffic and migration. In addition, IBTK RNA interference affected RNA maturation in both cell lines, as shown by the evidence of alternative 3'- and 5'-splicing, mutually exclusive exons, retained introns, and skipped exons. Altogether, these results indicate that IBTK differently modulates gene expression and RNA splicing in HeLa and K562 cells, demonstrating a novel biological role of this protein.


Assuntos
Processamento Alternativo , Proteínas de Transporte/genética , Biossíntese de Proteínas , Transcriptoma , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Transporte Biológico , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/metabolismo , Movimento Celular , Proteínas Culina/genética , Proteínas Culina/metabolismo , Células HeLa , Humanos , Células K562 , Nucleossomos/metabolismo , Nucleossomos/ultraestrutura , Especificidade de Órgãos , Complexo de Endopeptidases do Proteassoma/metabolismo , Domínios Proteicos , Proteólise , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
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