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OBJECTIVE: Simulation offers an important avenue for surgical and anesthesia training. This is especially important for crisis management scenarios where individuals need to act quickly and efficiently for optimal patient care. Practice based performance can be measured and real time feedback provided during debriefing scenarios. METHODS: In this paper, we highlight a dual anesthesia and otolaryngology cavernous carotid injury scenario. The trials were run three different times with inter-trial debriefing. RESULTS: The focused debriefing improved resident performance in terms of blood loss on subsequent trials. Furthermore, the learners provided important feedback regarding the utility of training and how it improved their ability to handle crisis management scenarios in the future. CONCLUSION: Debriefing for crisis management in a simulation trial improves performance and trainee confidence. Follow up studies will evaluate real world effectiveness over a longer follow up period.
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Carotid artery injuries are serious complications of endoscopic endonasal surgery. As these occur rarely, simulation training offers an avenue for technique and algorithm development in resident learners. This study develops a realistic cadaveric model for the training of crisis resource management in the setting of cavernous carotid artery injury. An expanded endonasal approach and right cavernous carotid injury is performed on a cadaveric head. The cadaver's right common carotid artery is cannulated and connected to a perfusion pump delivering pressurized simulated blood. A simulation mannequin is incorporated into the model to allow for vital sign feedback. Surgical and anesthesia resident learners are tasked with obtaining vascular control with a muscle patch technique and medical management over the course of 3 clinical scenarios with increasing complexity. Crisis management instructions for an endoscopic endonasal approach to the cavernous carotid artery and blood pressure control were provided to the learners prior to beginning the simulation. An independent reviewer evaluated the learners on communication skills, crisis management algorithms, and implementation of appropriate skill sets. After each scenario, residents were debriefed on how to improve technique based on evaluation scores in areas of situational awareness, decision-making, communications and teamwork, and leadership. After the simulation, learners provided feedback on the simulation and this data was used to improve future simulations. The benefit of this cadaveric model is ease of set-up, cost-effectiveness, and reproducibility.
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Anestesia , Otolaringología , Entrenamiento Simulado , Arterias Carótidas , Humanos , Reproducibilidad de los ResultadosRESUMEN
INTRODUCTION: Previous data examining the effect of gender on surgical trainee autonomy is lacking. We hypothesized that female general surgery residents have less autonomy than males during laparoscopic cases. METHODS: We retrospectively reviewed factors associated with level of guidance needed during laparoscopic procedures as reported on intraoperative procedure feedback forms and on FLS tasks from one institution from 2013 to 2016. Data collected included resident and attending gender, level of guidance needed, PGY level, case characteristics, resident intraoperative performance, and skills lab FLS performance. Univariate and multivariate analyses were performed using a mixed-effects regression model. RESULTS: We analyzed data from 106 PGY1-PGY5 residents (51% Female) and 104 attendings (26% Female). Female resident gender was associated with more intraoperative guidance in univariate (pâ¯=â¯0.019) and multivariate analysis (pâ¯=â¯0.034). Technical performance between genders was similar. CONCLUSIONS: This study demonstrated gender-based inequality in intraoperative autonomy even after controlling for technical performance, PGY level, and case factors.
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Competencia Clínica , Educación de Postgrado en Medicina/métodos , Cirugía General/educación , Internado y Residencia/métodos , Quirófanos/organización & administración , Autonomía Profesional , Femenino , Humanos , Laparoscopía/educación , Masculino , Estudios Retrospectivos , Distribución por Sexo , Estados UnidosRESUMEN
BACKGROUND: Identifying factors associated with resident autonomy may help improve training efficiency. This study evaluates resident and procedural factors associated with level of guidance needed in the operating room. METHODS: Intraoperative performance and yearly performance on Fundamentals of Laparoscopic Surgery (FLS) tasks from 74 general surgery residents were retrospectively reviewed. The effect of post-graduate year (PGY), procedure complexity, case difficulty, intraoperative performance, and FLS task performance were analyzed using a mixed-effects model. RESULTS: PGY level, procedure complexity, case difficulty, operative technique, and operative knowledge were significantly associated with level of intraoperative guidance. In PGY2-4 residents, ratings of medical knowledge and communication were also significantly associated with guidance. There was no significant association between FLS performance and level of guidance for any PGY level. CONCLUSIONS: The amount of intraoperative guidance is influenced by many factors, including resident performance and case characteristics. FLS tasks performance was not significantly associated with intraoperative guidance.
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Competencia Clínica , Internado y Residencia , Laparoscopía/educación , Autonomía Profesional , Cirugía General/educación , Humanos , Estudios RetrospectivosRESUMEN
BACKGROUND: Several studies have demonstrated that minorities and Hispanic ethnicities have disproportionally greater burden of morbid obesity in the United States. However, the majority of bariatric procedures are performed in the non-Hispanic white population. OBJECTIVES: The objective of this study was to investigate the weight loss and remission of obesity-related co-morbidities based on race and ethnicity. SETTING: The Longitudinal Assessment of Bariatric Surgery prospective, multicenter, observational study was used to collect patients from 10 different health centers across the United States. METHODS: Retrospective analysis of a prospective, multicenter, observational study over a 5-year follow-up. RESULTS: All patients who underwent primary gastric bypass and provided racial/ethnic information were included in the study (n = 1695). Regardless of race or ethnicity, total weight loss was maintained over a 5-year follow-up, which included 87% of the original cohort. However, whites had on average 1.94% higher adjusted total weight loss compared with blacks (P < .0001). After adjusting for confounders there were no significant differences in resolution of co-morbidities, including diabetes. CONCLUSION: All patients regardless of race or ethnicity have significant and sustained total weight loss and resolution of co-morbidities after gastric bypass at 5-year follow-up.
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Comorbilidad , Etnicidad , Derivación Gástrica/métodos , Obesidad Mórbida/cirugía , Grupos Raciales/etnología , Pérdida de Peso/etnología , Adulto , Índice de Masa Corporal , Femenino , Estudios de Seguimiento , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Obesidad Mórbida/etnología , Estudios Prospectivos , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento , Estados UnidosRESUMEN
BACKGROUND: Revisional bariatric surgery is increasing in frequency, but the morbidity and efficacy have not been well defined. The primary aim of this study was to determine the clinical efficacy with respect to weight loss, and associated morbidity, of revisional bariatric surgery in an academic university hospital bariatric surgery program. METHODS: A retrospective review of all patients who underwent revisional bariatric surgery for failed primary restrictive procedures, including gastroplasty and gastric bypass, but not including gastric banding or malabsorptive procedures, during a 10-year period at a single university hospital was performed. The perioperative morbidity and long-term weight loss and clinical results were determined from the medical charts. RESULTS: A total of 41 patients met the inclusion criteria. The primary bariatric procedures included vertical banded gastroplasty in 20 and Roux-en-Y gastric bypass in 21. The indications for revisional surgery included poor weight loss, weight regain, and various technical problems, including anastomotic stenosis and ulcer. The major morbidity rate was 17%. No patients died. The weight loss results varied depending on the indication for the revisional surgery and reoperative solution applied. The resolution of technical problems was achieved in all patients. CONCLUSION: Revisional bariatric surgery can be performed with minimal mortality, albeit significant morbidity. The efficacy with respect to weight loss appeared acceptable, although the results were not as good as those after primary bariatric surgery. The analysis of patient subsets stratified by surgical history and revisional strategy provided important insights into the mechanisms of failure and efficacy of different revisional strategies.
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Derivación Gástrica/métodos , Gastroplastia/métodos , Obesidad/cirugía , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Laparoscopía/métodos , Masculino , Persona de Mediana Edad , Morbilidad/tendencias , Complicaciones Posoperatorias/epidemiología , Reoperación , Estudios Retrospectivos , Insuficiencia del TratamientoRESUMEN
PURPOSE: Vertical sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) are currently the most common bariatric procedures. Although the safety of these operations has markedly improved, there continues to be a certain rate of complications. Such adverse events can have a significant deleterious effect on the outcome of these procedures and represent a costly burden on patients and society at large. A better understanding of these complications and their predictive factors may help ameliorate and optimize outcomes. METHODS: Seven hundred seventy-two consecutive patients who underwent SG or RYGB for morbid obesity between January 2011 and October 2015, in the Division of Bariatric Surgery at a tertiary institution, were included through retrospective review of the medical database. The complications were categorized and evaluated according to severity using the Clavien-Dindo classification system. Significant risk factors were evaluated by binary logistic regression to identify independent predictors and analyzed to identify their relationship with the type of complication. RESULTS: Independent predictors of severe complication after these procedures included male gender, open and revisional surgery, hypertension, and hypoalbuminemia. Hypoalbuminemia had significant associations with occurrence of deep surgical site infection and leak. Open surgery had significant associations with occurrence of superficial and deep surgical site infection and respiratory complications. Independent predictors of severe complication after laparoscopic primary RYGB included previous abdominal surgery. Previous abdominal surgery had significant associations with deep surgical site infection and leak. CONCLUSION: Recognition and optimization of these risk factors would be valuable in operative risk prediction before bariatric surgery.
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Simulation training is emerging as a cost-effective way to train residents on the skill sets necessary to excel as fully functioning physicians. Until recently, the simulated resident training environments have primarily focused on handling a medical crisis with learners from the same specialty. A dual otolaryngology and anesthesiology simulation was established to improve teamwork and communication skills between specialties. One otolaryngology resident was paired with one anesthesia resident per trial in our study. The multispecialty team addressed three clinical simulation scenarios to manage a cavernous carotid artery-bleeding crisis with an endoscopic endonasal approach. An independent reviewer evaluated each individual based on situation awareness, decision-making, communications and teamwork, as well as leadership. Residents improved on blood loss, pre and post anatomical exam scores, and communication measures through the course of the scenarios. Residents from both specialties rated the simulation highly and wanted further simulation training in the future. Multidisciplinary simulation training is a novel approach for improving communication skills between specialties prior to entering the wards, clinic, or operative arena. The lessons learned from this multidisciplinary simulation transcend the individual experience by allowing trainees to develop algorithms for crisis management and to improve on aspects of teamwork, leadership, and communication skills that can be applied throughout their careers.
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BACKGROUND: Although expert proficiency times for Fundamentals of Laparoscopic Surgery (FLS) tasks exist, these times are not always attainable for junior residents. We hypothesize that post-graduate year (PGY)-specific benchmarks will improve resident performance of FLS tasks. METHODS: In 2014, PGY-specific benchmarks were developed for FLS tasks for PGY1-PGY4 general surgery residents by averaging completion times for each task from 2007 to 2013. Resident performance on each FLS task and overall performance was compared for PGY1-PGY4 residents in the 2007-2013 group and the 2014-2016 group, before and after implementation of PGY-specific benchmarks. RESULTS: There was a significant improvement in FLS performance in the 2014-2016 group at the PGY1 (pâ¯=â¯0.01), PGY2 (pâ¯<â¯0.01), and PGY3 (pâ¯=â¯0.01) levels, but no difference at the PGY4 level (pâ¯=â¯0.71). CONCLUSIONS: PGY-specific benchmarks may improve efficacy of laparoscopic skills training for junior residents, increasing the efficiency of skill development.
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Benchmarking , Competencia Clínica , Internado y Residencia , Laparoscopía/educación , Análisis y Desempeño de Tareas , Adulto , Educación de Postgrado en Medicina , Femenino , Objetivos , Humanos , Masculino , Tempo Operativo , Mejoramiento de la Calidad , Estudios RetrospectivosRESUMEN
BACKGROUND: Simulation training has been shown to be an effective teaching tool. Learner management of an intraoperative crisis such as a major cerebrovascular bleed requires effective teamwork, communication, and implementation of key skill sets at appropriate time points. This study establishes a first of a kind simulation experience in a neurosurgery/anesthesia resident (learners) team working together to manage an intraoperative crisis. METHODS: Using a cadaveric cavernous carotid injury perfusion model, 7 neurosurgery and 6 anesthesia learners, were trained on appropriate vascular injury management using an endonasal endoscopic technique. Learners were evaluated on communication skills, crisis management algorithms, and implementation of appropriate skill sets at the right time. A preanatomic and postanatomic examination and postsimulation survey was administered to neurosurgery learners. Anesthesia learners provided posttraining evaluation through a tailored realism and teaching survey. RESULTS: Neurosurgery learners' anatomic examination score improved from presimulation (33.89%) to postsimulation (86.11%). No significant difference between learner specialties was observed for situation awareness, decision making, communications and teamwork, or leadership evaluations. Learners reported the simulation realistic, beneficial, and highly instructive. CONCLUSIONS: Realistic, first of kind, clinical simulation scenarios were presented to a neurosurgery/anesthesia resident team who worked together to manage an intraoperative crisis. Learners were effectively trained on crisis management, the importance of communication, and how to develop algorithms for future implementation in difficult scenarios. Learners were highly satisfied with the simulation training experience and requested that it be integrated more consistently into their residency training programs.
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Anestesia , Anestesiología/educación , Intervención en la Crisis (Psiquiatría) , Neurocirugia/educación , Procedimientos Neuroquirúrgicos/métodos , Entrenamiento Simulado/métodos , Adulto , Anciano , Cadáver , Arterias Carótidas/anatomía & histología , Traumatismos de las Arterias Carótidas/cirugía , Curriculum , Retroalimentación , Femenino , Humanos , Internado y Residencia , Masculino , Persona de Mediana Edad , Quirófanos/organización & administraciónRESUMEN
Achalasia presenting in the context of morbid obesity is rare. The case is presented of a woman with achalasia and morbid obesity who was treated with simultaneous laparoscopic esophageal myotomy and gastric bypass. The sparse literature addressing these rare patients is reviewed and management considerations discussed. Simultaneous laparoscopic esophageal myotomy and gastric bypass is safe, feasible and provides good results.
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Acalasia del Esófago/cirugía , Esfínter Esofágico Inferior/cirugía , Derivación Gástrica , Laparoscopía , Obesidad Mórbida/cirugía , Acalasia del Esófago/etiología , Femenino , Humanos , Persona de Mediana Edad , Obesidad Mórbida/complicacionesRESUMEN
Adenosine is an endogenous nucleoside that regulates numerous cellular functions including inflammation. Adenosine acts via cell-surface receptors subtyped as A1, A2A, A2B, and A3. The A2A receptor (A2AR) has been linked to anti-inflammatory effects of adenosine. Furthermore, microarray analysis revealed increased A2AR mRNA in lipopolysaccharide (LPS)-stimulated monocytes. We hypothesized that endogenous adenosine inhibited LPS-mediated tumor necrosis factor (TNF) production via A2AR stimulation. Using THP-1 cells, our results demonstrated that LPS increased expression of cellular A2AR and adenosine. A2AR agonism with 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamido adenosine (CGS 21680) after LPS decreased TNF production in a dose- and time-dependent manner, whereas A2AR antagonism significantly increased TNF and blocked the inhibitory effect of CGS 21680. This inhibitory pathway involved A2AR stimulation of cyclic adenosine monophosphate (cAMP) to activate protein kinase A, resulting in phosphorylation of cAMP response element-binding protein (CREB). Phospho-CREB had been shown to inhibit nuclear factor-kappaB transcriptional activity, as was observed with CGS 21680 treatment. Thus, following immune activation with LPS, endogenous adenosine mediates a negative feedback pathway to modulate cytokine expression in THP-1 cells.
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Adenosina/análogos & derivados , Citocinas/biosíntesis , Regulación hacia Abajo , Monocitos/inmunología , Receptores Purinérgicos P1/fisiología , Transducción de Señal , Adenosina/biosíntesis , Adenosina/farmacología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Humanos , Cinética , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , FN-kappa B/metabolismo , Fenetilaminas/farmacología , Antagonistas de Receptores Purinérgicos P1 , ARN Mensajero/biosíntesis , Receptor de Adenosina A2A , Receptores Purinérgicos P1/genética , Células Tumorales Cultivadas , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
BACKGROUND: The Curriculum Committee of the American College of Surgeons-Accredited Educational Institutes conducted a need assessment to (1) identify gaps between ideal and actual practices in areas of surgical care, (2) explore educational solutions for addressing these gaps, and (3) shape a vision to advance the future of training in surgery. METHODS: National stakeholders were recruited from the committee members' professional network and interviewed via telephone. Interview questions targeted areas for improving surgical patient care, optimal educational solutions for training in surgery including simulation roles, and entities that should primarily bear training costs. We performed an iterative, qualitative analysis including member checking to identify key themes. RESULTS: Twenty-two interviewees included state/national board representatives, risk managers, multispecialty faculty/program directors, nurses, trainees, an industry representative, and a patient. Surgeons' communication with patients, families, and team members was raised consistently by stakeholders as a way to establish clear expectations regarding pre-, peri-, and postoperative care. Other comments highlighted the surgeon's development and demonstration and maintenance of cognitive and technical skills, including surgical judgment. Stakeholders also reiterated the critical need for surgeons to engage in on-going self-assessment and professional development to identify and remediate recognized limitations. Recommended learning modalities for meeting surgeons' needs included active learning (deliberate practice, diverse patient experiences), experiential learning (simulation), and peer and mentored learning (preceptorship). CONCLUSION: This first formal needs assessment of education for surgeons points to opportunities for educational programs in patient-centered communication, learning models that match preferences of new generations of trainees, and training in interprofessional/interdisciplinary team communication and teamwork.
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Educación de Postgrado en Medicina/tendencias , Cirugía General/educación , Procedimientos Quirúrgicos Operativos/educación , Competencia Clínica , Simulación por Computador , Instrucción por Computador , Curriculum , Educación Médica Continua/tendencias , Humanos , Modelos Educacionales , Evaluación de Necesidades , Sociedades Médicas , Estados UnidosRESUMEN
HYPOTHESIS Although the risks for operating room distractions and interruptions (ORDIs) are acknowledged, most research on this topic is unrealistic, inconclusive, or methodologically unsound. We hypothesized that realistic ORDIs induce errors in a simulated surgical procedure performed by novice surgeons. DESIGN, SETTING, AND PARTICIPANTS Eighteen second-year, third-year, and research-year surgical residents completed a within-subjects experiment on a laparoscopic virtual reality simulator. Based on 9 months of operating room observations, 4 distractions and 2 interruptions were designed and timed to occur during critical stages in simulated laparoscopic cholecystectomy. The control factor was the absence or presence of ORDIs, with order randomly counterbalanced across the subjects. MAIN OUTCOME MEASURES The primary outcome measure was surgical errors measured by the simulator as damage to arteries, bile duct, or other organs. The second outcome measure was whether the participants remembered a prospective memory task assigned prior to the procedure and important to operative conduct. RESULTS Major surgical errors were committed in 8 of 18 simulated procedures (44%) with ORDIs vs only 1 of 18 (6%) without ORDIs (P = .02). Interrupting questions caused the most errors. Sidebar conversations were the next most likely distraction to lead to errors. Ten of 18 participants (56%) forgot the prospective memory task with ORDIs, while 4 of 18 (22%) forgot the task without ORDI (P = .04). All 8 surgical errors with ORDIs occurred after 1 PM (P = .001). CONCLUSIONS Typical ORDIs have the potential to cause operative errors in surgical trainees. This performance deficit was prevalent in the afternoon.
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Granulocyte-macrophage-colony-stimulating factor (GM-CSF) plays a critical role in innate immunity by stimulating the differentiation of tissue macrophages via the transcription factor PU.1. Previous studies showed that GMCSF-deficient(GM-CSF-/-) mice had susceptibility to and impaired clearance of group B streptococcal bacteria by macrophages. For these studies, we hypothesized that GM-CSF-/- mice have increased susceptibility to peritonitis caused by immune dysfunction of peritoneal macrophages. We examined the role of peritoneal macrophages in pathogen clearance, cytokine responses, and survival in a murine cecal ligation and puncture (CLP) model of peritonitis/sepsis. Surprisingly, CLP minimally affected survival in GM-CSF-/- mice while markedly reducing survival in wild-type mice. This was not explained by differences in the composition of microbial flora, rates of bacterial peritonitis, or sepsis, all of which were similar in GM-CSF-/- and wild-type mice. However, survival correlated with peritoneal and serum TNF-alpha and IL-6 levels that were significantly lower in GM-CSF-/- than in control mice. After peritoneal LPS instillation, GM-CSF-/- mice also had improved survival and reduced TNF-alpha and IL-6 responses. In vitro studies demonstrated reduced secretion of TNF-alpha and IL-6 by peritoneal macrophages isolated from sham GM-CSF-/- mice as compared with macrophages from sham control mice. Peritoneal instillation of GM-CSF-/-/PU.1+ macrophages, but not GM-CSF-/-/PU.1+ macrophages into GM-CSF-/- mice conferred susceptibility to death after CLP or peritoneal LPS exposure. These results demonstrate that GM-CSFY/PU.1-dependent peritoneal macrophage responses are a critical determinant of survival after experimentally induced peritonitis/sepsis or exposure to LPS and have implications for therapies to treat such infections.
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Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Macrófagos Peritoneales/metabolismo , Peritonitis/sangre , Sepsis/sangre , Animales , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Sistema Inmunológico , Interleucina-6/metabolismo , Lipopolisacáridos/metabolismo , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Peritonitis/metabolismo , Sepsis/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: Administrative and financial pressures on surgical education have created a need for efficient training curricula. Predictors of innate technical ability, which would guide the optimization of such a curriculum, are not well described. The goal of this study was to identify student characteristics predictive of innate pretraining skill level and response to training during the course of a four-week laparoscopic skills development program. METHODS: Laparoscopic skills in 35 first-year surgical residents were assessed with the McGill Inanimate System for Training and Evaluation of Laparoscopic Skills (MISTELS) before and after a four-week skills training program and after an interval of approximately 1 year. The correlation between trainee characteristics, including age, sex, designated surgical specialty, and laparoscopic skill level was assessed by using Pearson's correlation and paired t-test studies. RESULTS: Intake MISTELS scores showed no significant correlation to age, sex, or designated field. Interns designated for the general surgery training program had significantly higher final scores than those entering other fields (p = 0.02). There was a negative correlation between trainee age and both degree of improvement during training and final scores (p = 0.02 and 0.05). A history of video game use correlated with significantly higher initial scores and better skills retention (p = 0.03 and 0.04). CONCLUSIONS: A laparoscopic technical curriculum can achieve basic proficiency even when taught to a diverse group of trainees. Older residents beginning their surgical careers may be slower to develop technical skills. Choice of subspecialty seems to predict higher level of proficiency after completion of a skills training program among resident students.
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Competencia Clínica , Educación de Postgrado en Medicina/métodos , Cirugía General/educación , Internado y Residencia , Laparoscopía , Adulto , Curriculum , Evaluación Educacional , Femenino , Humanos , Masculino , Análisis y Desempeño de TareasRESUMEN
Regulation of pulmonary inflammation involves an intricate balance of both pro- and anti-inflammatory mediators. Acute lung injury can result from direct pulmonary insults that activate alveolar macrophages to respond with increased cytokine expression. Such cytokine gene expression is mediated in part via NF-kappaB. IL-10 has been previously identified as an important endogenous anti-inflammatory cytokine in vivo on the basis of inhibiting NF-kappaB activation; however, the mechanism of this inhibition remains incompletely defined. We hypothesized that IL-10 regulated NF-kappaB activation in vivo via IkappaK inhibition. A bitransgenic mouse that allowed for externally regulated, lung-specific human IL-10 overexpression was generated. In the bitransgenic mice, introduction of doxycycline induced lung-specific, human IL-10 overexpression. Acute induction of IL-10 resulted in significant decreases in bronchoalveolar lavage fluid neutrophils (48%, P = 0.03) and TNF (62%, P < 0.01) following intratracheal LPS compared with bitransgenic negative mice. In vitro kinase assays showed this decrease to correlate to diminished lung IkappaK activity. Furthermore, we also examined the effect of chronic IL-10 overexpression in these transgenic mice. Results show that IL-10 overexpression in lungs of mature mice increased the number of intrapulmonary cells the phenotype of which was skewed toward increased B220+/CD45+ B cells and CD4+ T cells and was associated with increased CC chemokine expression. Thus regulated, lung-specific IL-10 overexpression may have a variety of complex immunologic effects depending on the timing and duration of expression.
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Sistema Inmunológico/efectos de los fármacos , Sistema Inmunológico/fisiología , Interleucina-10/metabolismo , Interleucina-10/farmacología , Pulmón/inmunología , Pulmón/metabolismo , Animales , Quimiocinas/metabolismo , Esquema de Medicación , Marcación de Gen , Humanos , Interleucina-10/administración & dosificación , Interleucina-10/genética , Lipopolisacáridos/farmacología , Pulmón/citología , Pulmón/fisiología , Ratones , Ratones Noqueados , Ratones Transgénicos , FN-kappa B/metabolismo , Infiltración Neutrófila/efectos de los fármacos , FenotipoRESUMEN
OBJECTIVE: Application of heat shock before an inflammatory stimulus often results in an attenuated response to that stimulus. As a result, it has become increasingly appreciated that heat shock may induce cross-tolerance to a variety of stimuli based on in vitro and in vivo models. Circulating peripheral blood monocytes are key mediators of cytokine release following endotoxin challenge. The mitogen-activated protein kinases play a key role in the transcriptional regulation of this response including expression of tumor necrosis factor. As such, counterregulatory phosphatases that target mitogen-activated protein kinase may play a role in this heat shock-mediated effect. We hypothesized that prior heat shock to monocytes would induce a phosphatase, MKP-1, that regulated mitogen-activated protein kinase activity and subsequently conferred cross-tolerance to lipopolysaccharide stimulation. DESIGN: Experimental. SETTING: University research foundation laboratory. SUBJECTS: THP-1 human monocyte cell line. INTERVENTIONS: THP-1 cells were exposed to either heat shock (43 degrees C, 1 hr) or normothermia (37 degrees C, 1 hr) and allowed to recover before stimulation with endotoxin (lipopolysaccharide). MEASUREMENTS AND MAIN RESULTS: Induction of a heat shock response was determined by heat shock protein-70 expression. Tumor necrosis factor and interleukin-10 were measured by enzyme-linked immunosorbent assay to assess heat shock inhibition of lipopolysaccharide-induced gene expression. The effect of heat shock on lipopolysaccharide-mediated activation of the p38 and ERK kinases was examined by measuring phospho-specific isoforms of p38 and ERK1/2 and correlated to in vitro kinase activity. Confirmatory data were generated from experiments employing either pharmacologic inhibition or genetic deletion of MKP-1. Heat shock induced the nuclear localized phosphatase, MKP-1, that attenuated p38 and ERK kinase activity resulting in significantly diminished tumor necrosis factor expression in response to lipopolysaccharide. CONCLUSIONS: The effect of heat shock on decreasing the tumor necrosis factor response to lipopolysaccharide is conferred by induction of MKP-1, which negatively regulates p38 and ERK kinases. Modulation of phosphatase activity may be a potential strategy for attenuating acute inflammatory responses.