Glycolipid Metabolite ß-Glucosylceramide Is a Neutrophil Extracellular Trap-Inducing Ligand of Mincle Released during Bacterial Infection and Inflammation.

Neutrophil extracellular traps (NETs) are implicated in host defense and inflammatory pathologies alike. A wide range of pathogen- and host-derived factors are known to induce NETs, yet the knowledge about specific receptor-ligand interactions in this response is limited. We previously reported that macrophage-inducible C-type lectin (Mincle) regulates NET formation. In this article, we identify glycosphingolipid ß-glucosylceramide (ß-GlcCer) as a specific NET-inducing ligand of Mincle. We found that purified ß-GlcCer induced NETs in mouse primary neutrophils in vitro and in vivo, and this effect was abrogated in Mincle deficiency. Cell-free ß-GlcCer accumulated in the lungs of pneumonic mice, which correlated with pulmonary NET formation in wild-type, but not in Mincle-/-, mice infected intranasally with Klebsiella pneumoniae Although leukocyte infiltration by ß-GlcCer administration in vivo did not require Mincle, NETs induced by this sphingolipid were important for bacterial clearance during Klebsiella infection. Mechanistically, ß-GlcCer did not activate reactive oxygen species formation in neutrophils but required autophagy and glycolysis for NET formation, because ATG4 inhibitor NSC185058, as well as glycolysis inhibitor 2-deoxy-d-glucose, abrogated ß-GlcCer-induced NETs. Forced autophagy activation by tamoxifen could overcome the inhibitory effect of glycolysis blockage on ß-GlcCer-mediated NET formation, suggesting that autophagy activation is sufficient to induce NETs in response to this metabolite in the absence of glycolysis. Finally, ß-GlcCer accumulated in the plasma of patients with systemic inflammatory response syndrome, and its levels correlated with the extent of systemic NET formation in these patients. Overall, our results posit ß-GlcCer as a potent NET-inducing ligand of Mincle with diagnostic and therapeutic potential in inflammatory disease settings.

M1 Macrophage Polarization Is Dependent on TRPC1-Mediated Calcium Entry.

Macrophage plasticity is essential for innate immunity, but in-depth signaling mechanism(s) regulating their functional phenotypes are ill-defined. Here we report that interferon (IFN) γ priming of naive macrophages induces store-mediated Ca2+ entry and inhibition of Ca2+ entry impairs polarization to M1 inflammatory phenotype. In vitro and in vivo functional analyses revealed ORAI1 to be a primary contributor to basal Ca2+ influx in macrophages, whereas IFNγ-induced Ca2+ influx was mediated by TRPC1. Deficiency of TRPC1 displayed abrogated IFNγ-induced M1 inflammatory mediators in macrophages. In a preclinical model of peritonitis by Klebsiella pneumoniae infection, macrophages showed increased Ca2+ influx, which was TRPC1 dependent. Macrophages from infected TRPC1-/- mice showed inhibited expression of M1-associated signature molecules. Furthermore, in human patients with systemic inflammatory response syndrome, the level of TRPC1 expression in circulating macrophages directly correlated with M1 inflammatory mediators. Overall, TRPC1-mediated Ca2+ influx is essential for the induction/shaping of macrophage polarization to M1 inflammatory phenotype.

Effect of alcohol on surgical dexterity after a night of moderate alcohol intake.

BACKGROUND: Alcohol misuse is commonplace among health professionals. The effects of alcohol on cognition and dexterity have been shown up to 14 hours after alcohol intake. The aerospace industry has restrictions on alcohol intake, and there is pressure for the health care industry to do the same. Few studies have addressed the lingering impact alcohol has on surgical performance, and none have measured surgical dexterity using well-established Fundamentals of Laparoscopic Surgery benchmarks. METHODS: Twenty-seven surgeons participated in this study: 11 attending surgeons, 2 fellows, and 14 resident surgeons. Three Fundamentals of Laparoscopic Surgery tasks measured surgical dexterity: peg transfer, pattern cutting, and intracorporeal suturing. Performance on these tasks was measured before alcohol intake and the morning after a night of social drinking. Alcohol levels were measured via breathalyzer 20 minutes after completion of drinking and the following morning before testing. Time and accuracy were compared. RESULTS: The mean blood alcohol level was .076 mg/100 mL blood. Times for peg transfer, pattern cutting, and intracorporeal suturing showed no differences. Accuracy in pattern cutting was not different, but accuracy for intracorporeal suturing was significantly worse the morning after alcohol intake. CONCLUSIONS: The morning after moderate alcohol intake, the time to complete Fundamentals of Laparoscopic Surgery tasks was unchanged, but accuracy was worse.

Are open abdominal procedures a thing of the past? An analysis of graduating general surgery residents' case logs from 2000 to 2011.

INTRODUCTION: Since the introduction of laparoscopic surgery for cholecystectomy in 1989, the growth of minimally invasive surgery (MIS) has increased significantly in the United States. There is a growing concern that the pendulum has now shifted too far toward MIS and that current general surgery residents' exposure to open abdominal procedures is lacking. OBJECTIVE: We sought to analyze trends in open vs MIS intra-abdominal procedures performed by residents graduating from US general surgery residency programs over the past twelve years. METHODS: We conducted a retrospective analysis of the data from the ACGME national resident case log reports for graduating US general surgery residents from 2000 to 2011. We analyzed the average number of cases per graduating chief resident for the following surgical procedures: appendectomy, inguinal/femoral hernia repair, gastrostomy, colectomy, antireflux procedures, and cholecystectomy. RESULTS: For all the procedures analyzed, except antireflux procedures, a statistically significant increase in the number of MIS cases was seen. The increases in MIS procedures were as follows: appendectomy, 8.5 to 46 (542%); inguinal/femoral hernia repair, 7.6 to 23.3 (265%); gastrostomy, 1.4 to 3 (114%); colectomy, 1.8 to 18.2 (1011%); and cholecystectomy, 84 to 105.7 (26%). The p value was set at <0.001 for all procedures. There has been a concomitant decrease in the number of open procedures. The numbers of open appendectomy decreased from 30.9 to 15.5 (p < 0.0001), open inguinal/femoral hernia repair from 52.1 to 48 (p = 0.0038), open gastrostomy from 7.7 to 4.9 (p = 0.0094), open colectomy from 48 to 40.7 (p < 0.0001), open cholecystectomy from 15.5 to 10.4 (p = 0.0005), and open antireflux procedures from 4.7 to 1.7 (p < 0.001). An analysis conducted over time reveals that the rates of increase in MIS procedures in 5 of the 6 categories continue to rise, whereas the rates of open appendectomy, open colectomy, and open antireflux procedures continue to decrease. However, the rates of decline of open hernia repairs and open gastrostomies seem to have plateaued. CONCLUSIONS: The performance of open procedures in general surgery residency has declined significantly in the past 12 years. The effect of the decline in open cases in surgical training and practice remains to be determined.

Is the Accreditation Council for Graduate Medical Education (ACGME) Resident/Fellow survey, a valid tool to assess general surgery residency programs compliance with work hours regulations?

The Accreditation Council for Graduate Medical Education (ACGME) uses the resident/fellow survey to assess residency programs compliance with ACGME work hours regulations. Survey results can have significant consequences for residency programs including ACGME letters of warning, shortened program accreditation cycle, immediate full program and institutional site visits, or administrative withdrawal of a program's accreditation. Survey validity was assessed by direct query of general surgery residents who answer the survey each year. A multiple-choice survey was created to assess all US general surgery residents' interpretation and understanding of the ACGME survey. The survey was distributed to all surgery residency program directors in the US in 2009. Responses were compiled via an online survey program. Statistical analysis was performed in aggregate and between junior and senior residents. Nine hundred sixty-five (13.2%) general surgical residents responded with 961 (99.6%) completing all questions. All responding residents had taken the ACGME survey at least once with 634 (66%) having taken it more than once. Nineteen percent of residents had difficulty understanding the questions with senior residents (23%) reporting difficulty more than junior residents (14%), p < 0.001. Thirty-five percent of residents had discussed the survey with their faculty or program director prior to taking it, while 17% were instructed on how to answer the survey. One hundred thirty-three residents (14%) admitted to not answering the questions truthfully while 352 (37%) of residents felt that the survey did not provide an accurate evaluation of their work hours in residency training. An evaluation tool in which 1 in 7 residents admit to answering the questions falsely and 1 in 5 residents had difficulty interpreting the questions may not be a valid method to evaluate compliance with work hours regulations. Evaluation of work hours regulations compliance should be based on actual work hours data rather than an anonymous survey.

Motorcycle collisions involving white-tailed deer in central and northern Wisconsin: a rural trauma center experience.

BACKGROUND: Risk of deer motorcycle collisions (DMC) continues to increase in Midwestern and East Coast States and is a growing regional public health issue. METHODS: We conducted a retrospective chart review of all motorcycle collisions involving animals over a 9-year period from October 1993 to October 2002. Data collected included Injury Severity Score (ISS), injury type, outcome, use of helmets/alcohol, time of year/day. RESULTS: Fifty-five DMC were identified, 49 drivers, and 6 passengers. ISS for helmeted patients was 6.02+/-4.6 and 17.6+/-14.9 for non-helmeted patients. There were 7 human fatalities (all without helmets). Of the 55 patients, 16% of those injured were intoxicated, without helmets, and had average ISS higher than those non-intoxicated. Head, chest and orthopedic extremity trauma accounted for >70% of injuries seen within the entire population. Incidence peaked in June/July, and 55% of the collisions occurred between the hours of 1800 and 2200. CONCLUSION: DMC are a significant public health issue in mid-western states. Education about helmet and alcohol use and safety on rural roads may be the best prevention. Continued research focusing on prevention is necessary.

Incidence and propagation of infrageniculate deep venous thrombosis in trauma patients.

BACKGROUND: The incidence and propagation of thrombosis involving vessels distal to the popliteal vein has not been clearly defined in trauma patients. Our aim was to determine the incidence and rate of propagation of infrageniculate deep venous thrombosis (DVT) in a trauma population and identify potential risk factors specific to propagation. METHODS: Retrospective review of all trauma admissions between the years 2001 and 2003 was conducted. Only those 18 years or older with an isolated infrageniculate DVT who underwent a lower extremity venous duplex scan during admission were included in the study. Nature of injury, injury severity score (ISS), method of DVT prophylaxis, thrombus location, and risk factors for hypercoagulable states were recorded. RESULTS: During the study period, 698 trauma admissions were included, and 109 (15.7%) with infrageniculate DVT were identified. Thirty-nine (35.7%) had thrombus propagation (14 suprageniculate and 25 infrageniculate) with a mean ISS of 27.6. Seventy (64.3%) had infrageniculate DVT without propagation and a mean ISS of 19.6. Thirty-eight (97%) patients with propagating infrageniculate DVT had received mechanical prophylaxis, and 33 (84%) also received chemical prophylaxis. The 14 patients with suprageniculate thrombus propagation were the most severely injured (mean ISS = 35.1). Elevated ISS, operation, age < or =62 years, and intensive care unit admission were positively correlated with propagation of infrageniculate DVT. CONCLUSION: The incidence and propagation of infrageniculate DVT in an aggressively prophylaxed trauma population are greater than previously reported. The clinical significance of isolated infrageniculate DVT remains to be determined, but when associated with a multiple injury trauma, the patient may be at risk for future suprageniculate DVT formation and may benefit from therapeutic anticoagulation.