Deficiency of Vasodilator-Stimulated Phosphoprotein (VASP) Increases Blood-Brain-Barrier Damage and Edema Formation after Ischemic Stroke in Mice

Background: Stroke-induced brain edema formation is a frequent cause of secondary infarct growth and deterioration of neurological function. The molecular mechanisms underlying edema formation after stroke are largely unknown. Vasodilator-stimulated phosphoprotein (VASP) is an important regulator of actin dynamics and stabilizes endothelial barriers through interaction with cell-cell contacts and focal adhesion sites. Hypoxia has been shown to foster vascular leakage by downregulation of VASP in vitro but the significance of VASP for regulating vascular permeability in the hypoxic brain in vivo awaits clarification. Methodology/Principal Findings: Focal cerebral ischemia was induced in Vasp2/2 mice and wild-type (WT) littermates by transient middle cerebral artery occlusion (tMCAO). Evan’s Blue tracer was applied to visualize the extent of blood-brainbarrier (BBB) damage. Brain edema formation and infarct volumes were calculated from 2,3,5-triphenyltetrazolium chloride (TTC)-stained brain slices. Both mouse groups were carefully controlled for anatomical and physiological parameters relevant for edema formation and stroke outcome. BBB damage (p,0.05) and edema volumes (1.7 mm360.5 mm3 versus 0.8 mm360.4 mm3; p,0.0001) were significantly enhanced in Vasp2/2 mice compared to controls on day 1 after tMCAO. This was accompanied by a significant increase in infarct size (56.1 mm3617.3 mm3 versus 39.3 mm3610.7 mm3, respectively; p,0.01) and a non significant trend (p.0.05) towards worse neurological outcomes. Conclusion: Our study identifies VASP as critical regulator of BBB maintenance during acute ischemic stroke. Therapeutic modulation of VASP or VASP-dependent signalling pathways could become a novel strategy to combat excessive edema formation in ischemic brain damage

Anwendbarkeit von QUIKS bei stationär konservativ behandelten Tumorpatienten

Background!#!Quality improvement in conservative pain management (QUIKS), a module for nonoperative patients in the QUIPS project was tested on a cohort of tumor patients regarding its applicability.!##!Material and methods!#!Conservatively treated inpatients at the University Hospital of Würzburg (UKW) were prospectively surveyed on the quality of pain management using the QUIKS outcome questionnaire (AZ 129/17, Ethics Committee at UKW). Information on therapy and demographics was taken from the hospital's internal documentation system.!##!Results!#!During the data collection period 100 conservatively treated inhouse tumor patients from different hospitals were included. Of the patients 74% required assistance in answering the questionnaire. Functional limitations or pain treatment-related side effects were present in 77% of the patients; the average pain level was 6 on the numerical rating scale. The most commonly reported type of pain was back pain and headache. Of the patients 18% received pain therapy with opioids and 26% with nonopioids, adjustment was made in 5% with opioids and in 44% with nonopioids and pain medicine specialists were consulted in 9% of cases.!##!Conclusion!#!The application of the questionnaire was well accepted by the patients but required a high level of assistance in completing it. A high level of pain was observed during the hospital stay and the adjustment of pain therapy or the involvement of pain medicine specialists was rare. The interpretation of statements regarding the quality of tumor pain may be limited as other (pre-existing) pain entities, such as nontumor-associated pain or chronic tumor pain could not be clearly delineated

<i>Vasp</i> deficiency does not alter anatomical and physiological parameters relevant for stroke outcome.

<p>(<b>A</b>) (left) A complete Circle of Willis (arrows) was present in wild-type (WT) and <i>Vasp^−/−</i> mice and the trunk and branches of the middle cerebral artery (MCA) were similar in both groups as depicted by ink perfusion. (right) The formation of the posterior communicating arteries (PComAs) was quantitatively assessed under a microscope in both mouse groups. The PComAs score did not differ between <i>Vasp^−/−</i> mice and WT controls (n = 5/group), p>0.05; unpaired, two-tailed Student's t-test compared with WT mice. (<b>B</b>) rCBF in the MCA territory was measured by Laser Doppler flowmetry before (baseline) and immediately after MCAO (ischemia), and again 10 min after removal of the occluding filament (reperfusion). No significant differences in rCBF were observed at any time point between WT and <i>Vasp^−/−</i> mice (n = 5/group); p>0.05. Bonferroni-corrected 2-way ANOVA compared to baseline rCBF. (<b>C</b>) Systolic and diastolic blood pressure (RR) (left) as well as heart rates (right) are similar in <i>Vasp^−/−</i> mice and WT controls, p>0.05; unpaired, two-tailed Student's t-test compared with WT mice. ns: not significant.</p

Gastrointestinal Complications After Pancreatoduodenectomy With Epidural vs Patient-Controlled Intravenous Analgesia: A Randomized Clinical Trial

IMPORTANCE Morbidity is still high in pancreatic surgery, driven mainly by gastrointestinal complications such as pancreatic fistula. Perioperative thoracic epidural analgesia (EDA) and patient-controlled intravenous analgesia (PCIA) are frequently used for pain control after pancreatic surgery. Evidence from a post hoc analysis suggests that PCIA is associated with fewer gastrointestinal complications.OBJECTIVE To determine whether postoperative PCIA decreases the occurrence of gastrointestinal complications after pancreatic surgery compared with EDA.DESIGN, SETTING, AND PARTICIPANTS In this adaptive, pragmatic, international, multicenter, superiority randomized clinical trial conducted from June 30, 2015, to October 1, 2017, 371 patients at 9 European pancreatic surgery centers who were scheduled for elective pancreatoduodenectomy were randomized to receive PCIA (n = 185) or EDA (n = 186); 248 patients (124 in each group) were analyzed. Data were analyzed from February 22 to April 25, 2019, using modified intention to treat and per protocol.INTERVENTIONS Patients in the PCIA group received general anesthesia and postoperative PCIA with intravenous opioids with the help of a patient-controlled analgesia device. In the EDA group, patients received general anesthesia and intraoperative and postoperative EDA.MAIN OUTCOMES AND MEASURES The primary end point was a composite of pancreatic fistula, bile leakage, delayed gastric emptying, gastrointestinal bleeding, or postoperative ileus within 30 days after surgery. Secondary end points included 30-day mortality, other complications, postoperative pain levels, intraoperative or postoperative use of vasopressor therapy, and fluid substitution.RESULTS Among the 248 patients analyzed (147 men; mean [SD] age, 64.9 [10.7] years), the primary composite end point did not differ between the PCIA group (61 [49.2%]) and EDA group (57 [46.0%]) (odds ratio, 1.17; 95% CI, 0.71-1.95 P = .54). Neither individual components of the primary end point nor 30-day mortality, postoperative pain levels, or intraoperative and postoperative substitution of fluids differed significantly between groups. Patients receiving EDA gained more weight by postoperative day 4 than patients receiving PCIA (mean [SD], 4.6 [3.8] vs 3.4 [3.6] kg; P = .03) and received more vasopressors (46 [37.1%] vs 31[25.0%1 P = .04). Failure of EDA occurred in 23 patients (18.5%).CONCLUSIONS AND RELEVANCE This study found that the choice between PCIA and EDA for pain control after pancreatic surgery should not be based on concerns regarding gastrointestinal complications because the 2 procedures are comparable with regard to effectiveness and safety. However, EDA was associated with several shortcomings