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1.
Anesth Analg ; 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33555691

RESUMO

BACKGROUND: Adolescent idiopathic scoliosis (AIS) surgery is associated with significant postoperative pain. Remifentanil is a short-acting opioid that is often used as a component of total intravenous anesthesia. Remifentanil has been implicated in acute opioid tolerance and opioid-induced hyperalgesia, resulting in increased postoperative pain and opioid consumption. This retrospective study sought to investigate the relationship between the dose of intraoperative remifentanil and cumulative postoperative opioid consumption through 72 hours following surgery for pediatric AIS patients. METHODS: We performed a retrospective chart review of adolescent patients undergoing posterior spine instrumentation under total intravenous general anesthesia at a single major pediatric center between January 2015 and October 2017. The relationship between intraoperative cumulative weight-adjusted remifentanil dose and logarithmic transformation of cumulative weight-adjusted opioid consumption through 72 hours following surgery was examined by regression analysis. A priori determined potential confounding variables were collected, including demographic data, perioperative analgesic agents (ie, ketamine, dexmedetomidine, and acetaminophen), surgical duration, vertebrae instrumented, and blood transfusion. Multivariable linear regression analysis was used to adjust for these possible confounding variables. RESULTS: Eighty-nine patients met inclusion criteria, of which 78 had complete data for analysis. Univariable linear regression analysis revealed no association between remifentanil dose and opioid consumption through 72 hours following surgery (slope = 0.79 [95% confidence interval [CI], 0.61-0.98; R2 = 0.0039; P = .588]). After adjustment for possible confounding factors, no relationship between remifentanil dose (regression coefficient (coeff.) -0.08; 95% CI, -1.59 to 1.43; P = .912) and opioid consumption through 72 hours was found (slope =0.90 [95% CI, -0.65 to 2.46]; R2 = 0.1634). Similar results were obtained when the model was repeated for opioid consumption in postanesthesia care unit (PACU). CONCLUSIONS: In this study examining adolescent patients undergoing surgery for idiopathic scoliosis, no association was found between the dose of intraoperative remifentanil and postoperative opioid consumption in the context of a propofol-based total intravenous anesthetic and multimodal analgesia. These results provide direction for future prospective controlled studies to further evaluate this relationship.

2.
PLoS One ; 16(2): e0246427, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33529266

RESUMO

BACKGROUND: The COVID-19 pandemic has yielded an unprecedented quantity of new publications, contributing to an overwhelming quantity of information and leading to the rapid dissemination of less stringently validated information. Yet, a formal analysis of how the medical literature has changed during the pandemic is lacking. In this analysis, we aimed to quantify how scientific publications changed at the outset of the COVID-19 pandemic. METHODS: We performed a cross-sectional bibliometric study of published studies in four high-impact medical journals to identify differences in the characteristics of COVID-19 related publications compared to non-pandemic studies. Original investigations related to SARS-CoV-2 and COVID-19 published in March and April 2020 were identified and compared to non-COVID-19 research publications over the same two-month period in 2019 and 2020. Extracted data included publication characteristics, study characteristics, author characteristics, and impact metrics. Our primary measure was principal component analysis (PCA) of publication characteristics and impact metrics across groups. RESULTS: We identified 402 publications that met inclusion criteria: 76 were related to COVID-19; 154 and 172 were non-COVID publications over the same period in 2020 and 2019, respectively. PCA utilizing the collected bibliometric data revealed segregation of the COVID-19 literature subset from both groups of non-COVID literature (2019 and 2020). COVID-19 publications were more likely to describe prospective observational (31.6%) or case series (41.8%) studies without industry funding as compared with non-COVID articles, which were represented primarily by randomized controlled trials (32.5% and 36.6% in the non-COVID literature from 2020 and 2019, respectively). CONCLUSIONS: In this cross-sectional study of publications in four general medical journals, COVID-related articles were significantly different from non-COVID articles based on article characteristics and impact metrics. COVID-related studies were generally shorter articles reporting observational studies with less literature cited and fewer study sites, suggestive of more limited scientific support. They nevertheless had much higher dissemination.


Assuntos
Bibliometria , Publicações Periódicas como Assunto , Comunicação , Estudos Transversais , Humanos , Pandemias , Revisão da Pesquisa por Pares , Publicações Periódicas como Assunto/normas , Análise de Componente Principal
3.
Arterioscler Thromb Vasc Biol ; : ATVBAHA120314557, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33054399

RESUMO

OBJECTIVE: LDL (low-density lipoprotein) transcytosis across the endothelium is performed by the SR-BI (scavenger receptor class B type 1) receptor and contributes to atherosclerosis. HMGB1 (high mobility group box 1) is a structural protein in the nucleus that is released by cells during inflammation; extracellular HMGB1 has been implicated in advanced disease. Whether intracellular HMGB1 regulates LDL transcytosis through its nuclear functions is unknown. Approach and Results: HMGB1 was depleted by siRNA in human coronary artery endothelial cells, and transcytosis of LDL was measured by total internal reflection fluorescence microscopy. Knockdown of HMGB1 attenuated LDL transcytosis without affecting albumin transcytosis. Loss of HMGB1 resulted in reduction in SR-BI levels and depletion of SREBP2 (sterol regulatory element-binding protein 2)-a transcription factor upstream of SR-BI. The effect of HMGB1 depletion on LDL transcytosis required SR-BI and SREBP2. Overexpression of HMGB1 caused an increase in LDL transcytosis that was unaffected by inhibition of extracellular HMGB1 or depletion of RAGE (receptor for advanced glycation endproducts)-a cell surface receptor for HMGB1. The effect of HMGB1 overexpression on LDL transcytosis was prevented by knockdown of SREBP2. Loss of HMGB1 caused a reduction in the half-life of SREBP2; incubation with LDL caused a significant increase in nuclear localization of HMGB1 that was dependent on SR-BI. Animals lacking endothelial HMGB1 exhibited less acute accumulation of LDL in the aorta 30 minutes after injection and when fed a high-fat diet developed fewer fatty streaks and less atherosclerosis. CONCLUSIONS: Endothelial HMGB1 regulates LDL transcytosis by prolonging the half-life of SREBP2, enhancing SR-BI expression. Translocation of HMGB1 to the nucleus in response to LDL requires SR-BI.

4.
Nat Commun ; 11(1): 4561, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917873

RESUMO

The protein high-mobility group box 1 (HMGB1) is released into the extracellular space in response to many inflammatory stimuli, where it is a potent signaling molecule. Although research has focused on downstream HMGB1 signaling, the means by which HMGB1 exits the cell is controversial. Here we demonstrate that HMGB1 is not released from bone marrow-derived macrophages (BMDM) after lipopolysaccharide (LPS) treatment. We also explore whether HMGB1 is released via the pore-forming protein gasdermin D after inflammasome activation, as is the case for IL-1ß. HMGB1 is only released under conditions that cause cell lysis (pyroptosis). When pyroptosis is prevented, HMGB1 is not released, despite inflammasome activation and IL-1ß secretion. During endotoxemia, gasdermin D knockout mice secrete HMGB1 normally, yet secretion of IL-1ß is completely blocked. Together, these data demonstrate that in vitro HMGB1 release after inflammasome activation occurs after cellular rupture, which is probably inflammasome-independent in vivo.


Assuntos
Proteína HMGB1/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Macrófagos/metabolismo , Proteínas de Ligação a Fosfato/metabolismo , Animais , Modelos Animais de Doenças , Endotoxemia/metabolismo , Feminino , Proteína HMGB1/genética , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Lipopolissacarídeos/efeitos adversos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas de Ligação a Fosfato/genética , Piroptose , Transdução de Sinais
5.
Can J Anaesth ; 67(12): 1814-1823, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32720256

RESUMO

PURPOSE: Under times of supply chain stress, the availability of some medical equipment and supplies may become limited. The current pandemic involving severe acute respiratory syndrome coronavirus 2 has highlighted limitations to the ordinary provision of personal protective equipment (PPE). For perioperative healthcare workers, N95 masks provide a stark example of PPE in short supply necessitating the creation of scientifically valid protocols for their decontamination and reuse. METHODS: We performed a systematic literature search of MEDLINE, Embase, Cochrane CENTRAL databases, and ClinicalTrials.gov to identify peer-reviewed articles related to N95 mask decontamination and subsequent testing for the integrity of mask filtration and facial seal. To expand this search, we additionally surveyed the official statements from key health agencies, organizations, and societies for relevant citations. RESULTS: Our initial database search resulted in five articles that met inclusion criteria, with 26 articles added from the expanded search. Our search did not reveal any relevant randomized clinical trials or cohort studies. We found that moist mask heating (65-80°C at 50-85% relative humidity for 20-30 min) and vaporous hydrogen peroxide treatment were supported by the literature to provide consistent viral decontamination without compromising mask seal and filtration efficiency. Other investigated decontamination methods lacked comprehensive scientific evidence for all three of these key criteria. CONCLUSIONS: N95 mask reprocessing using either moist heat or vaporous hydrogen peroxide is recommended to ensure healthcare worker safety.

6.
PLoS One ; 14(5): e0215221, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31120888

RESUMO

Poor reporting quality may contribute to irreproducibility of results and failed 'bench-to-bedside' translation. Consequently, guidelines have been developed to improve the complete and transparent reporting of in vivo preclinical studies. To examine the impact of such guidelines on core methodological and analytical reporting items in the preclinical anesthesiology literature, we sampled a cohort of studies. Preclinical in vivo studies published in Anesthesiology, Anesthesia & Analgesia, Anaesthesia, and the British Journal of Anaesthesia (2008-2009, 2014-2016) were identified. Data was extracted independently and in duplicate. Reporting completeness was assessed using the National Institutes of Health Principles and Guidelines for Reporting Preclinical Research. Risk ratios were used for comparative analyses. Of 7615 screened articles, 604 met our inclusion criteria and included experiments reporting on 52 490 animals. The most common topic of investigation was pain and analgesia (30%), rodents were most frequently used (77%), and studies were most commonly conducted in the United States (36%). Use of preclinical reporting guidelines was listed in 10% of applicable articles. A minority of studies fully reported on replicates (0.3%), randomization (10%), blinding (12%), sample-size estimation (3%), and inclusion/exclusion criteria (5%). Statistics were well reported (81%). Comparative analysis demonstrated few differences in reporting rigor between journals, including those that endorsed reporting guidelines. Principal items of study design were infrequently reported, with few differences between journals. Methods to improve implementation and adherence to community-based reporting guidelines may be necessary to increase transparent and consistent reporting in the preclinical anesthesiology literature.


Assuntos
Avaliação Pré-Clínica de Medicamentos/normas , Relatório de Pesquisa/normas , Analgésicos/uso terapêutico , Animais , Bases de Dados Factuais , Guias como Assunto , Dor/tratamento farmacológico
10.
Science ; 363(6427): 639-644, 2019 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-30733420

RESUMO

Although widely studied as a neurotransmitter, T cell-derived acetylcholine (ACh) has recently been reported to play an important role in regulating immunity. However, the role of lymphocyte-derived ACh in viral infection is unknown. Here, we show that the enzyme choline acetyltransferase (ChAT), which catalyzes the rate-limiting step of ACh production, is robustly induced in both CD4+ and CD8+ T cells during lymphocytic choriomeningitis virus (LCMV) infection in an IL-21-dependent manner. Deletion of Chat within the T cell compartment in mice ablated vasodilation in response to infection, impaired the migration of antiviral T cells into infected tissues, and ultimately compromised the control of chronic LCMV clone 13 infection. Our results reveal a genetic proof of function for ChAT in T cells during viral infection and identify a pathway of T cell migration that sustains antiviral immunity.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Colina O-Acetiltransferase/imunologia , Interleucinas/imunologia , Coriomeningite Linfocítica/imunologia , Animais , Linfócitos T CD4-Positivos/enzimologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/enzimologia , Movimento Celular , Colina O-Acetiltransferase/genética , Feminino , Ativação Linfocitária , Vírus da Coriomeningite Linfocítica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Vasodilatação
11.
Bioelectron Med ; 4: 3, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-32232079

RESUMO

Background: The vagus nerve plays an important role in the regulation of organ function, including reflex pathways that regulate immunity and inflammation. Recent studies using genetically modified mice have improved our understanding of molecular mechanisms in the neural control of immunity. However, mapping neural signals transmitted in the vagus nerve in mice has been limited by technical challenges. Here, we have standardized an experimental protocol to record compound action potentials transmitted in the vagus nerve. Methods: The vagus nerve was isolated in Balb/c and B6.129S mice, and placed either on a hook or cuff electrode. The electrical signals from the vagus nerve were digitized using either a Neuralynx or Plexon data acquisition system. Changes in the vagus nerve activity in response to anesthesia, feeding and administration of bacterial endotoxin were analyzed. Results: We have developed an electrophysiological recording system to record compound action potentials from the cervical vagus nerve in mice. Cuff electrodes significantly reduce background noise and increase the signal to noise ratio as compared to hook electrodes. Baseline vagus nerve activity varies in response to anesthesia depth and food intake. Analysis of vagus neurograms in different mouse strains (Balb/c and C57BL/6) reveal no significant differences in baseline activity. Importantly, vagus neurogramactivity in wild type and TLR4 receptor knock out mice exhibits receptor dependency of endotoxin mediated signals. Conclusions: These methods for recording vagus neurogram in mice provide a useful tool to further delineate the role of vagus neural pathways in a standardized murine disease model.

12.
CMAJ Open ; 4(3): E444-E447, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27730108

RESUMO

BACKGROUND: Physicians have traditionally been at the forefront of medical research, bringing clinical questions to the laboratory and returning with ideas for treatment. However, we have anecdotally observed a decline in the popularity of basic science research among trainees. We hypothesized that fewer resident physicians have been pursuing basic science research training over time. METHODS: We examined records from residents in the Surgeon-Scientist and Clinician-Investigator programs at the University of Toronto (1987-2016). Research by residents was categorized independently by 2 raters as basic science, clinical epidemiology or education-related based on the title of the project, the name of the supervisor and Pubmed searches. The study population was divided into quintiles of time, and the proportion pursuing basic science training in each quintile was calculated. RESULTS: Agreement between the raters was 100%; the categorization of the research topic remained unclear in 9 cases. The proportion of trainees pursuing basic science training dropped by 60% from 1987 to 2016 (p = 0.005). INTERPRETATION: Significantly fewer residents in the Surgeon-Scientist and Clinician-Investigator Programs at the University of Toronto are pursuing training in the basic sciences as compared with previous years.

13.
Nat Biotechnol ; 34(10): 1066-1071, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27617738

RESUMO

Blood pressure regulation is known to be maintained by a neuro-endocrine circuit, but whether immune cells contribute to blood pressure homeostasis has not been determined. We previously showed that CD4+ T lymphocytes that express choline acetyltransferase (ChAT), which catalyzes the synthesis of the vasorelaxant acetylcholine, relay neural signals. Here we show that these CD4+CD44hiCD62Llo T helper cells by gene expression are a distinct T-cell population defined by ChAT (CD4 TChAT). Mice lacking ChAT expression in CD4+ cells have elevated arterial blood pressure, compared to littermate controls. Jurkat T cells overexpressing ChAT (JTChAT) decreased blood pressure when infused into mice. Co-incubation of JTChAT and endothelial cells increased endothelial cell levels of phosphorylated endothelial nitric oxide synthase, and of nitrates and nitrites in conditioned media, indicating increased release of the potent vasorelaxant nitric oxide. The isolation and characterization of CD4 TChAT cells will enable analysis of the role of these cells in hypotension and hypertension, and may suggest novel therapeutic strategies by targeting cell-mediated vasorelaxation.


Assuntos
Pressão Sanguínea/fisiologia , Linfócitos T CD4-Positivos/fisiologia , Colina O-Acetiltransferase/metabolismo , Hemostasia/fisiologia , Animais , Células Cultivadas , Retroalimentação Fisiológica/fisiologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL
14.
Anesthesiology ; 124(5): 1174-89, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26982508

RESUMO

Inflammation and immunity are regulated by neural reflexes. Recent basic science research has demonstrated that a neural reflex, termed the inflammatory reflex, modulates systemic and regional inflammation in a multiplicity of clinical conditions encountered in perioperative medicine and critical care. In this review, the authors describe the anatomic and physiologic basis of the inflammatory reflex and review the evidence implicating this pathway in the modulation of sepsis, ventilator-induced lung injury, postoperative cognitive dysfunction, myocardial ischemia-reperfusion injury, and traumatic hemorrhage. The authors conclude with a discussion of how these new insights might spawn novel therapeutic strategies for the treatment of inflammatory diseases in the context of perioperative and critical care medicine.


Assuntos
Inflamação/fisiopatologia , Sistema Nervoso/fisiopatologia , Animais , Cuidados Críticos , Humanos , Inflamação/imunologia , Sistema Nervoso/imunologia , Assistência Perioperatória , Reflexo
15.
Bioelectron Med ; 3: 7-17, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-30003120

RESUMO

The axons of the sensory, or afferent, vagus nerve transmit action potentials to the central nervous system in response to changes in the body's metabolic and physiological status. Recent advances in identifying neural circuits that regulate immune responses to infection, inflammation and injury have revealed that vagus nerve signals regulate the release of cytokines and other factors produced by macrophages. Here we record compound action potentials in the cervical vagus nerve of adult mice and reveal the specific activity that occurs following administration of the proinflammatory cytokines tumor necrosis factor (TNF) and interleukin 1ß (IL-1ß). Importantly, the afferent vagus neurograms generated by TNF exposure are abolished in double knockout mice lacking TNF receptors 1 and 2 (TNF-R1/2KO), whereas IL-1ß-specific neurograms are eliminated in knockout mice lacking IL-1ß receptor (IL-1RKO). Conversely, TNF neurograms are preserved in IL-1RKO mice, and IL-1ß neurograms are unchanged in TNF-R1/2KO mice. Analysis of the temporal dynamics and power spectral characteristics of afferent vagus neurograms for TNF and IL-1ß reveals cytokine-selective signals. The nodose ganglion contains the cell bodies of the sensory neurons whose axons run through the vagus nerve. The nodose neurons express receptors for TNF and IL-1ß, and we show that exposing them to TNF and IL-1ß significantly stimulates their calcium uptake. Together these results indicate that afferent vagus signals in response to cytokines provide a basic model of nervous system sensing of immune responses.

16.
FASEB J ; 30(2): 515-8, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26467794

RESUMO

Explosive growth in our understanding of genomics and molecular biology have fueled calls for the pursuit of personalized medicine, the notion of harnessing biologic variability to provide patient-specific care. This vision will necessitate a deep understanding of the underlying pathophysiology in each patient. Medical journals play a pivotal role in the education of trainees and clinicians, yet we suspected that the amount of basic science in the top medical journals has been in decline. We conducted an automated search strategy in PubMed to identify basic science articles and calculated the proportion of articles dealing with basic science in the highest impact journals for 8 different medical specialties from 1994 to 2013. We observed a steep decline (40-60%) in such articles over time in almost all of the journals examined. This rapid decline in basic science from medical journals is likely to affect practitioners' understanding of and interest in the basic mechanisms of disease and therapy. In this Life Sciences Forum, we discuss why this decline may be occurring and what it means for the future of science and medicine.


Assuntos
Pesquisa Biomédica/estatística & dados numéricos , Publicações Periódicas como Assunto , Editoração , Fatores de Tempo
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