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Anesth Analg ; 127(2): 520-528, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29596095


BACKGROUND: Caudal block is commonly used to provide postoperative analgesia after pediatric surgery in the lower abdomen. Typically administered as a single-shot technique, 1 limitation of this block is the short duration of analgesia. To overcome this, dexamethasone has been used as an adjuvant to prolong block duration. However, there are concerns about steroid-related morbidity and the optimal route of dexamethasone administration (eg, caudal or intravenous) is unknown. METHODS: We conducted a systematic review and random-effects meta-analysis of randomized controlled trials recruiting pediatric surgical patients receiving a caudal block for surgical anesthesia or postoperative analgesia. Included studies compared dexamethasone (caudal, intravenous, or both) to control. Duration of analgesia was the primary outcome. Database sources were Medline, Embase, the Cochrane Library, and Google Scholar searched up to August 18, 2017, without language restriction. Screening of studies, data extraction, and risk of bias assessment were performed independently and in duplicate by 2 authors. Risk of bias was assessed using Cochrane methodology and the strength of evidence was scored using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. RESULTS: The initial search retrieved 93 articles. Fourteen randomized controlled trials that comprised 1315 pediatric patients met the inclusion criteria. All but 1 study involved lower abdominal operations (orchidopexy, inguinal hernia repair, and hypospadias repair). The caudal and intravenous dose of dexamethasone ranged from 0.1 to 0.2 mg/kg and 0.5 to 1.5 mg/kg, respectively, and all studies were pooled in the main analysis. Dexamethasone prolonged the duration of analgesia by both the caudal route (5.43 hours, 95% confidence interval [CI], 3.52-7.35; P < .001; I = 99.3%; N = 9; n = 620; GRADE quality = moderate) and intravenous route (5.51 hours; 95% CI, 3.56-7.46; P < .001; I = 98.9%; N = 5; n = 364; GRADE quality = moderate) versus control. Secondary benefits of dexamethasone included reduced narcotic rescue analgesia requirement in the postanesthetic care unit (relative risk [RR], 0.30; 95% CI, 0.18-0.51; P < .001; I = 0.0%; N = 5; number needed to treat for benefit [NNTB] = 5; 95% CI, 4-7), less subsequent postoperative rescue analgesia requirement (RR, 0.46; 95% CI, 0.23-0.92; P = .03; I = 96.0%; N = 9; n = 629; NNTB = 3; 95% CI, 2-20; n = 310), and lower rates of postoperative nausea and vomiting (RR, 0.47; 95% CI, 0.30-0.73; P = .001; I = 0.0%; NNTB = 11; 95% CI, 8-21; N = 9; n = 628). Adverse events linked to the dexamethasone were rare. CONCLUSIONS: Caudal and intravenous dexamethasone are similarly effective for prolonging the duration of analgesia from caudal blockade, resulting in a doubled to tripled duration. Given the off-label status of caudal dexamethasone, intravenous administration is recommended-although only high intravenous doses (0.5 mg/kg up to 10 mg) have been studied.

Analgesia/métodos , Dexametasona/uso terapêutico , Cirurgia Geral/métodos , Bloqueio Nervoso/métodos , Dor Pós-Operatória/tratamento farmacológico , Pediatria/métodos , Administração Intravenosa , Adolescente , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Dexametasona/efeitos adversos , Hérnia Inguinal , Humanos , Lactente , Infusões Intravenosas , Náusea e Vômito Pós-Operatórios/induzido quimicamente , Ensaios Clínicos Controlados Aleatórios como Assunto , Esteroides/efeitos adversos
Eur J Anaesthesiol ; 35(7): 469-483, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29369117


BACKGROUND: Much uncertainty exists as to whether peri-operative goal-directed therapy is of benefit. OBJECTIVES: To discover if peri-operative goal-directed therapy decreases mortality and morbidity in adult surgical patients. DESIGN: An updated systematic review and random effects meta-analysis of randomised controlled trials. DATA SOURCES: Medline, Embase and the Cochrane Library were searched up to 31 December 2016. ELIGIBILITY CRITERIA: Randomised controlled trials enrolling adult surgical patients allocated to receive goal-directed therapy or standard care were eligible for inclusion. Trauma patients and parturients were excluded. Goal-directed therapy was defined as fluid and/or vasopressor therapy titrated to haemodynamic goals [e.g. cardiac output (CO)]. Outcomes included mortality, morbidity and hospital length of stay. Risk of bias was assessed using Cochrane methodology. RESULTS: Ninety-five randomised trials (11 659 patients) were included. Only four studies were at low risk of bias. Modern goal-directed therapy reduced mortality compared with standard care [odds ratio (OR) 0.66; 95% confidence interval (CI) 0.50 to 0.87; number needed to treat = 59; N = 52; I = 0.0%]. In subgroup analysis, there was no mortality benefit for fluid-only goal-directed therapy, cardiac surgery patients or nonelective surgery. Contemporary goal-directed therapy also reduced pneumonia (OR 0.69; 95% CI, 0.51 to 0. 92; number needed to treat = 38), acute kidney injury (OR 0. 73; 95% CI, 0.58 to 0.92; number needed to treat = 29), wound infection (OR 0.48; 95% CI, 0.37 to 0.63; number needed to treat = 19) and hospital length of stay (days) (-0.90; 95% CI, -1.32 to -0.48; I = 81. 2%). No important differences in outcomes were found for the pulmonary artery catheter studies, after accounting for advances in the standard of care. CONCLUSION: Peri-operative modern goal-directed therapy reduces morbidity and mortality. Importantly, the quality of evidence was low to very low (e.g. Grading of Recommendations, Assessment, Development and Evaluation scoring), and there was much clinical heterogeneity among the goal-directed therapy devices and protocols. Additional well designed and adequately powered trials on peri-operative goal-directed therapy are necessary.

Procedimentos Cirúrgicos Cardíacos/métodos , Hidratação/métodos , Procedimentos Cirúrgicos Operatórios/métodos , Adulto , Débito Cardíaco/fisiologia , Metas , Hemodinâmica/fisiologia , Humanos , Tempo de Internação , Complicações Pós-Operatórias/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto
BMC Cardiovasc Disord ; 16(1): 246, 2016 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-27905877


BACKGROUND: Mineralocorticoid receptor antagonists (MRAs) have been associated with improved patient outcomes in patients with heart failure with reduced ejection fraction (HFrEF) but not preserved ejection fraction (HFpEF). We conducted a systematic review and meta-analysis of selective and nonselective MRAs in HFrEF and HFpEF. METHODS: We searched Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE. We included randomized controlled trials (RCT) of MRAs in adults with HFpEF or HFrEF if they reported data on major adverse cardiac events or drug safety. RESULTS: We identified 15 studies representing 16321 patients. MRAs were associated with a reduced risk of cardiovascular death (RR 0.81 [0.75-0.87], I2 0%), all-cause mortality (RR 0.83 [0.77-0.88], I2 0%), and cardiac hospitalizations (RR 0.80 [0.70-0.92], I2 58.4%). However, an a-priori specified subgroup analysis demonstrated that these benefits were limited to HFrEF (cardiovascular death RR 0.79 [0.73-0.86], I2 0%; all-cause mortality RR 0.81 [0.75-0.87], I2 0%; cardiac hospitalizations RR 0.76 [0.64-0.90], I2 68%), but not HFpEF (all-cause mortality RR 0.92 [0.79-1.08], I2 0%; cardiac hospitalizations RR 0.91 [0.67-1.24], I2 17%). MRAs increased the risk of hyperkalemia (RR 2.03 [1.78-2.31], I2 0%). Nonselective MRAs, but not selective MRAs increased the risk of gynecomastia (RR 7.37 [4.42-12.30], I2 0% vs. RR 0.74 [0.43-1.27], I2 0%). Evidence was of moderate quality for cardiovascular death, all-cause mortality and cardiovascular hospitalizations; and high-quality for hyperkalemia and gynecomastia. CONCLUSIONS: MRAs reduce the risk of adverse cardiac events in HFrEF but not HFpEF. MRA use in HFpEF increases the risk of harm from hyperkalemia and gynecomastia. Selective MRAs are equally effective as nonselective MRAs, without a risk of gynecomastia.

Insuficiência Cardíaca/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Volume Sistólico/efeitos dos fármacos , Insuficiência Cardíaca/fisiopatologia , Hospitalização/tendências , Humanos
PLoS Genet ; 6(9): e1001092, 2010 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-20824081


Eukaryotic DNA replication origins differ both in their efficiency and in the characteristic time during S phase when they become active. The biological basis for these differences remains unknown, but they could be a consequence of chromatin structure. The availability of genome-wide maps of nucleosome positions has led to an explosion of information about how nucleosomes are assembled at transcription start sites, but no similar maps exist for DNA replication origins. Here we combine high-resolution genome-wide nucleosome maps with comprehensive annotations of DNA replication origins to identify patterns of nucleosome occupancy at eukaryotic replication origins. On average, replication origins contain a nucleosome depleted region centered next to the ACS element, flanked on both sides by arrays of well-positioned nucleosomes. Our analysis identified DNA sequence properties that correlate with nucleosome occupancy at replication origins genome-wide and that are correlated with the nucleosome-depleted region. Clustering analysis of all annotated replication origins revealed a surprising diversity of nucleosome occupancy patterns. We provide evidence that the origin recognition complex, which binds to the origin, acts as a barrier element to position and phase nucleosomes on both sides of the origin. Finally, analysis of chromatin reconstituted in vitro reveals that origins are inherently nucleosome depleted. Together our data provide a comprehensive, genome-wide view of chromatin structure at replication origins and suggest a model of nucleosome positioning at replication origins in which the underlying sequence occludes nucleosomes to permit binding of the origin recognition complex, which then (likely in concert with nucleosome modifiers and remodelers) positions nucleosomes adjacent to the origin to promote replication origin function.

Cromatina/química , Replicação do DNA/genética , Células Eucarióticas/metabolismo , Variação Genética , Genoma Fúngico/genética , Origem de Replicação/genética , Saccharomyces cerevisiae/genética , Sequência de Bases , Sequência Consenso/genética , Período de Replicação do DNA/genética , Genes Fúngicos/genética , Nucleossomos/metabolismo , Complexo de Reconhecimento de Origem/metabolismo , Ligação Proteica , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Sítio de Iniciação de Transcrição
Genetics ; 182(2): 623-6, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19332878


Modulating gene dose is an effective way to alter protein levels and modify phenotypes to understand gene function. In addition, combining gene-dose alleles with chemical perturbation can provide insight into drug-gene interactions. Here, we present a strategy that combines diverse loss-of-function alleles to systematically modulate gene dose in Saccharomyces cerevisiae. The generated gene dosage allele set expands the genetic toolkit for uncovering novel phenotypes.

Alelos , Dosagem de Genes/efeitos dos fármacos , Dosagem de Genes/genética , Metotrexato/farmacologia , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Regulação Fúngica da Expressão Gênica/genética , Fenótipo , RNA Fúngico/análise , RNA Fúngico/genética , Sensibilidade e Especificidade
Nucleic Acids Res ; 36(7): 2123-35, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18187505


Lsr2 is a small, basic protein present in Mycobacterium and related actinomycetes. Recent studies suggest that Lsr2 is a regulatory protein involved in multiple cellular processes including cell wall biosynthesis and antibiotic resistance. However, the underlying molecular mechanisms remain unknown. In this article, we performed biochemical studies of Lsr2-DNA interactions and structure-function analysis of Lsr2. Analysis by atomic force microscopy revealed that Lsr2 has the ability to bridge distant DNA segments, suggesting that Lsr2 plays a role in the overall organization and compactness of the nucleoid. Mutational analysis identified critical residues and selection of dominant negative mutants demonstrated that both DNA binding and protein oligomerization are essential for the normal functions of Lsr2 in vivo. These results provide strong evidence that Lsr2 is a DNA bridging protein, which represents the first identification of such proteins in bacteria phylogenetically distant from the Enterobacteriaceae. DNA bridging by Lsr2 also provides a mechanism of transcriptional regulation by Lsr2.

Proteínas de Bactérias/metabolismo , Proteínas de Ligação a DNA/metabolismo , Mycobacterium tuberculosis/genética , Sequência Rica em At , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , DNA Bacteriano/química , DNA Bacteriano/metabolismo , DNA Bacteriano/ultraestrutura , DNA Circular/química , DNA Circular/metabolismo , DNA Circular/ultraestrutura , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Microscopia de Força Atômica , Mutação