α-Synuclein (αSN) aggregation is central to the etiology of Parkinson's disease (PD). Large-scale screening of compounds to identify aggregation inhibitors is challenged by stochastic αSN aggregation and difficulties in detecting early-stage oligomers (αSOs). We developed a high-throughput screening assay combining SDS-stimulated αSN aggregation with FRET to reproducibly detect initial stages in αSN aggregation. We screened 746,000 compounds, leading to 58 hits that markedly inhibit αSN aggregation and reduce αSOs' membrane permeabilization activity. The most effective aggregation inhibitors were derivatives of (4-hydroxynaphthalen-1-yl)sulfonamide. They interacted strongly with the N-terminal part of monomeric αSN and reduced αSO-membrane interactions, possibly by affecting electrostatic interactions. Several compounds reduced αSO toxicity toward neuronal cell lines. The inhibitors introduced chemical modifications of αSN that were, however, not a prerequisite for inhibitory activity. We also identified several phenyl-benzoxazol compounds that promoted αSN aggregation (proaggregators). These compounds may be useful tools to modulate αSN aggregation in cellula.
Postoperative pain after laparoscopic cholecystectomy can be severe. Despite multimodal analgesia regimes, administration of high doses of opioids is often necessary. This can further lead to several adverse effects such as drowsiness and respiratory impairment as well as postoperative nausea and vomiting. This will hinder early mobilization and discharge of the patient from the day surgery setting and is suboptimal in an Early Recovery after Surgery setting. The ultrasound-guided Erector Spinae Plane (ESP) block is a novel truncal interfascial block technique providing analgesia of the thoracic or abdominal segmental innervation depending on the level of administration. Local anesthetic penetrates anteriorly presumably through the costotransverse foramina to the paravertebral space. We demonstrate the analgesic efficacy of the ESP block in a case series of three patients scheduled for ambulatory laparoscopic cholecystectomy.
We have characterized the dissolved state of microcrystalline cellulose (MCC) in cold alkali [2.0 M NaOH(aq)] solutions using a combination of small angle X-ray (SAXS) and static light scattering (SLS), 1 H NMR, NMR self-diffusion, and rheology experiments. NMR and SAXS data demonstrate that the cellulose is fully molecularly dissolved. SLS, however, shows the presence of large concentration fluctuations in the solution, consistent with significant attractive cellulose-cellulose interactions. The scattering data are consistent with fractal cellulose aggregates of micrometre size having a mass fractal dimension D $ 1:5. At 25 C the solution structure remains unchanged on the time scale of weeks. However, upon heating the solutions above 35 C additional aggregation occurs on the time scale of minutes. Decreasing or increasing the NaOH concentration away from the ''optimum'' 2 M also leads to additional aggregation. This is seen as an increase of the SAXS intensity at lower q values. Addition of urea (1.8 and 3.6 M, respectively) does not significantly influence the solution structure. With these examples, we will discuss how scattering methods can be used to assess the quality of solvents for cellulose.
BackgroundEmergency abdominal surgery carries a 15% to 20% short-term mortality rate. Postoperative medical complications are strongly associated with increased mortality. Recent research suggests that timely recognition and effective management of complications may reduce mortality. The aim of the present trial is to evaluate the effect of postoperative intermediate care following emergency major abdominal surgery in high-risk patients.Methods and designThe InCare trial is a randomised, parallel-group, non-blinded clinical trial with 1:1 allocation. Patients undergoing emergency laparotomy or laparoscopic surgery with a perioperative Acute Physiology and Chronic Health Evaluation II score of 10 or above, who are ready to be transferred to the surgical ward within 24 h of surgery are allocated to either intermediate care for 48 h, or surgical ward care. The primary outcome measure is all-cause 30-day mortality. We aim to enrol 400 patients in seven Danish hospitals. The sample size allows us to detect or refute a 34% relative risk reduction of mortality with 80% power.DiscussionThis trial evaluates the benefits and possible harm of intermediate care. The results may potentially influence the survival of many high-risk surgical patients. As a pioneer trial in the area, it will provide important data on the feasibility of future large-scale randomised clinical trials evaluating different levels of postoperative care.Trial registrationClinicaltrials.gov identifier: NCT01209663
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