LPS-induced Pellino3 degradation is mediated by p62-dependent autophagy

Background: In macrophages Toll-like receptor 4 (TLR4) is activated in response to lipopolysaccharide (LPS) and induces proinflammatory cytokine expression. Therefore, mechanisms terminating proinflammatory gene expression are important. Autophagy plays a central role in controlling innate immune responses by lysosomal degradation of signaling proteins, thus contributing to the resolution of inflammation. Autophagic proteins like p62 directly interact with molecules involved in the TLR4-signaling pathway, but a correlation with the IRAK E3 ligase and scaffold protein Pellino3 remains obscure. Hence, we are interested in elucidating the function of Pellino3 to prove our hypothesis that it is a key regulator in the TLR4-signaling cascade. Methods: We used the cecal ligation and puncture (CLP) mouse model causing polymicrobial sepsis to analyze Pellino3 protein and mRNA expression. Furthermore, we induced endotoxemia in RAW264.7 mouse macrophages by LPS treatment to verify in vivo experiments. Lentiviral Pellino3 knockdown in RAW264.7 macrophages was used for cytokine measurements at mRNA level. To analyze potential Pellino3 binding partners in TLR4-signaling by mass spectrometry (MS), we overexpressed FLAG-tagged Pellino3 in RAW264.7 macrophages, treated cells for 3, 6 and 24 hours with LPS and immunoprecipitated Pellino3 via its FLAG-tag. To consider Pellino3 degradation as a result of p62-mediated autophagy, we transiently knocked down p62 by siRNA in RAW264.7 macrophages and also pharmacologically blocked LPS-induced autophagy by Bafilomycin A1. Results: We demonstrated Pellino3 protein degradation in primary CD11b+ splenocytes after 24 hours following CLP operation and confirmed this in RAW264.7 macrophages after 24-hour LPS stimulation. Knockdown of Pellino3 attenuates proinflammatory cytokines, for example IL-6 mRNA, after 6 hours of LPS. Furthermore, we found by MS and verifying immunoprecipitation experiments that p62 is a Pellino3 binding partner, thus targeting Pellino3 for degradation. In line, both p62 knockdown and Bafilomycin A1 treatment prevent Pellino3 degradation, supporting an autophagic mechanism. Conclusion: Our observations highlight a regulatory role of Pellino3 on TLR4 signaling. Thus, antagonism of Pellino3 in the hyperinflammatory phase of sepsis may counteract the cytokine storm. Furthermore, stabilization of Pellino3 by inhibition of autophagy in the hypoinflammatory phase of sepsis may improve immunity. In consideration of these two conflictive sepsis phases, modulation of Pellino3 may provide a new strategy for the development of a therapy approach in sepsis

To Tube or Not to Tube? The Role of Intubation during Stroke Thrombectomy.

In the 10 years since the FDA first cleared the use of endovascular devices for the treatment of acute stroke, definitive evidence that such therapy improves outcomes remains lacking. The decision to intubate patients undergoing stroke thrombectomy impacts multiple variables that may influence outcomes after stroke. Three main areas where intubation may deleteriously affect acute stroke management include the introduction of delays in revascularization, fluctuations in peri-procedural blood pressure, and hypocapnia, resulting in cerebral vasoconstriction. In this mini-review, we discuss the evidence supporting these limitations of intubation during stroke thrombectomy and encourage neurohospitalists, neurocritical care specialists, and neurointerventionalists to carefully consider the decision to intubate during thrombectomy and provide strategies to avoid potential complications associated with its use in acute stroke

Association between time to reperfusion and outcome is primarily driven by the time from imaging to reperfusion

Background and Purpose A progressive decline in the odds of favorable outcome as time to reperfusion increases is well known. However, the impact of specific workflow intervals is not clear.; Methods We studied the mechanical thrombectomy group (n=103) of the prospective, randomized REVASCAT (Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke due to Anterior Circulation Large Vessel Occlusion Presenting Within Eight Hours of Symptom Onset) trial. We defined 3 workflow metrics: time from symptom onset to reperfusion (OTR), time from symptom onset to computed tomography, and time from computed tomography (CT) to reperfusion. Clinical characteristics, core laboratory-evaluated Alberta Stroke Program Early CT Scores (ASPECTS) and 90-day outcome data were analyzed. The effect of time on favorable outcome (modified Rankin scale, 0-2) was described via adjusted odds ratios (ORs) for every 30-minute delay.; Results Median admission National Institutes of Health Stroke Scale was 17.0 (14.0-20.0), reperfusion rate was 66%, and rate of favorable outcome was 43.7%. Mean (SD) workflow times were as follows: OTR: 342 (107) minute, onset to CT: 204 (93) minute, and CT to reperfusion: 138 (56) minute. Longer OTR time was associated with a reduced likelihood of good outcome (OR for 30-minute delay, 0.74; 95% confidence interval [CI], 0.59-0.93). The onset to CT time did not show a significant association with clinical outcome (OR, 0.87; 95% CI, 0.67-1.12), whereas the CT to reperfusion interval showed a negative association with favorable outcome (OR, 0.72; 95% CI, 0.54-0.95). A similar subgroup analysis according to admission ASPECTS showed this relationship for OTR time in ASPECTS<8 patients (OR, 0.56; 95% CI, 0.35-0.9) but not in ASPECTS8 (OR, 0.99; 95% CI, 0.68-1.44).; Conclusions Time to reperfusion is negatively associated with favorable outcome, being CT to reperfusion, as opposed to onset to CT, the main determinant of this association. In addition, OTR was strongly associated to outcome in patients with low ASPECTS scores but not in patients with high ASPECTS scores.; Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01692379.Peer ReviewedPostprint (author's final draft

Psychological Barriers in Long Term Non-Operative Treatment of Retroperitoneal Hematoma

The retroperitoneal hematoma can have, mainly, a traumatic etiology - blunt abdominal trauma (falls from height, road accidents, aggression of any kind, etc.), or open (incised wounds, puncture, penetration or gunshot wounds). Ruptured arterial aneurysms can cause hemorrhage in the retroperitoneal space. There is also spontaneous retroperitoneal trauma in patients with chronic treatment with anticoagulant or antiaggregant drugs (1). Hemorrhage in the retroperitoneal space can be iatrogenic, after surgical, open or laparoscopic, interventions (2, 3). A particular type of retroperitoneal hematoma is the psoas muscle hematoma in patients with chronic oral anticoagulant treatment (Acenocumarol, Warfarin)

Arterial-portal fistula treated with hepatic arterial embolization and portal venous aneurysm stent-graft exclusion complicated by type 2 endoleak.

Intrahepatic arterioportal fistulas may be complicated by portal hypertension. An associated portal venous aneurysm (PVA) may impinge upon adjacent structures or rupture. We present a 65-year-old man with an intrahepatic Intrahepatic arterioportal fistula and 6.4 × 5.8 cm right portal vein aneurysm extending within 0.4 cm of the hepatic margin, associated with pain concerning for impending rupture. The PVA was refractory to transarterial embolization due to recruitment of arterial collaterals. Therefore, it was additionally excluded from the portal vein with a 12 mm × 9.5 cm venous stent graft. Although endovascular therapy thrombosed the aneurysm and improved symptoms, it was complicated by a type 2 endoleak into the PVA

Systematic review of new medics’ clinical task experience by country

OBJECTIVES: There is a need for research which informs on the overall size and significance of clinical skills deficits among new medics, globally. There is also the need for a meta-review of the similarities and differences between countries in the clinical skills deficits of new medics. DESIGN: A systematic review of published literature produced 68 articles from Google/Scholar, of which 9 met the inclusion criteria (quantitative clinical skills data about new medical doctors). PARTICIPANTS: 1329 new medical doctors (e.g., foundation year-1s, interns, PGY1s). SETTING: Ten countries/regions. MAIN OUTCOME MEASURES: 123 data points and representation of a broad range of clinical procedures. RESULTS: The average rate of inexperience with a wide range of clinical procedures was 35.92% (lower CI 30.84%, upper CI 40.99%). The preliminary meta-analysis showed that the overall deficit in experience is significantly different from 0 in all countries. Focusing on a smaller selection of clinical skills such as catheterisation, IV cannulation, nasogastric tubing and venepuncture, the average rate of inexperience was 26.75% (lower CI 18.55%, upper CI 35.54%) and also significant. England presented the lowest average deficit (9.15%), followed by New Zealand (18.33%), then South Africa (19.53%), Egypt, Kuwait, Gulf Cooperation Council countries and Ireland (21.07%), after which was Nigeria (37.99%), then USA (38.5%), and Iran (44.75%). CONCLUSION: A meta-analysis is needed to include data not yet in the public domain from more countries. These results provide some support for the UK General Medical Council’s clear, detailed curriculum, which has been heralded by other countries as good practice

Oral transmucosal fentanyl

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Hemobilia due to cystic artery pseudoaneurysm: A rare late complication of laparoscopic cholecystectomy

We discuss a patient with late presentation of hemobilia following cholecystectomy, which is unusual because pseudoaneurysm caused by vascular injury during surgery typically presents soon after surgery. Endoscopic retrograde cholangiopancreatography revealed a large blood clot arising from the biliary orifice with subsequent computed tomography angiography diagnosing a large pseudoaneurysm in the region of the cystic artery adjacent to the cholecystectomy clips. Embolization was performed via direct percutaneous puncture of the pseudoaneurysm

Heparin and air filters reduce embolic events caused by intra-arterial cerebral angiography - A prospective, randomized trial

Background-Intra-arterial cerebral angiography is associated with a low risk for neurological complications, but clinically silent ischemic events after angiography have been seen in a substantial number of patients.Methods and Results-In a prospective study, diffusion-weighted magnetic resonance imaging (DW-MRI) before and after intra-arterial cerebral angiography and transcranial Doppler sonography during angiography were used to evaluate the frequency of cerebral embolism. One hundred fifty diagnostic cerebral angiographies were randomized into 50 procedures, each using conventional angiographic technique, or systemic heparin treatment throughout the procedure, or air filters between the catheter and both the contrast medium syringe and the catheter flushing. There was no neurological complication during or after angiography. Overall, DW-MRI revealed 26 new ischemic lesions in 17 patients (11%). In the control group, 11 patients showed a total of 18 lesions. In the heparin group, 3 patients showed a total of 4 lesions. In the air filter group, 3 patients exhibited a total of 4 lesions. The reduced incidence of ischemic events in the heparin and air filter groups compared with the control group was significantly different (P=0.002). Transcranial Doppler sonography demonstrated a large number of microembolic signals that was significantly lower in the air filter group compared with the heparin and control groups (P=0.01), which did not differ from each other.Conclusions-Air filters and heparin both reduce the incidence of silent ischemic events detected by DW-MRI after intra-arterial cerebral angiography and can potentially lower clinically overt ischemic complications. This may apply to any intra-arterial angiographic procedure