Discovery and validation of SIRT2 inhibitors based on tenovin-6 : use of a 1H-NMR method to assess deacetylase activity

The search for potent and selective sirtuin inhibitors continues as chemical tools of this type are of use in helping to assign the function of this interesting class of deacetylases. Here we describe SAR studies starting from the unselective sirtuin inhibitor tenovin-6. These studies identify a sub-micromolar inhibitor that has increased selectivity for SIRT2 over SIRT1 compared to tenovin-6. In addition, a H-1-NMR-based method is developed and used to validate further this class of sirtuin inhibitors. A thermal shift analysis of SIRT2 in the presence of tenovin-6, -43, a control tenovin and the known SIRT2 inhibitor AGK2 is also presented.Publisher PDFPeer reviewe

An Objective Pain Score for Chronic Pain Clinic Patients

Objectives. Although numerous studies have looked at the numeric rating scale (NRS) in chronic pain patients and several studies have evaluated objective pain scales, no known studies have assessed an objective pain scale for use in the evaluation of adult chronic pain patients in the outpatient setting. Subjective scales require patients to convert a subjective feeling into a quantitative number. Meanwhile, objective pain scales utilize, for the most part, the patient’s behavioral component as observed by the provider in addition to the patient’s subjective perception of pain. This study aims to examine the reliability and validity of an objective Chronic Pain Behavioral Pain Scale for Adults (CBPS) as compared to the traditional NRS. Methods. In this cross-sectional study, patients were assessed before and after an interventional pain procedure by a researcher and a nurse using the CBPS and the NRS. Interrater reliability, concurrent validity, and construct validity were analyzed. Results. Interrater reliability revealed a fair-good agreement between the nurse’s and researcher’s CBPS scores, weighted kappa values of 0.59 and 0.65, preprocedure and postprocedure, respectively. Concurrent validity showed low positive correlation for the preprocedure measurements, 0.34 (95% CI 0.16–0.50) and 0.47 (95% CI 0.31–0.61), and moderate positive correlation for the postprocedure measurements, 0.68 (95% CI 0.56–0.77) and 0.67 (95% CI 0.55–0.77), for the nurses and researchers, respectively. Construct validity demonstrated an equally average significant reduction in pain from preprocedure to postprocedure, CBPS and NRS median (IQR) scores preprocedure (4 (2–6) and 6 (4–8)) and postprocedure (1 (0–2) and 3 (0–5)), p<0.001. Discussion. The CBPS has been shown to have interrater reliability, concurrent validity, and construct validity. However, further testing is needed to show its potential benefits over other pain scales and its effectiveness in treating patients with chronic pain over a long-term. This study was registered with ClinicalTrial.gov with National Clinical Trial Number NCT02882971

The prediction of difficult intubation in obese patients using mirror indirect laryngoscopy: A prospective pilot study

Background: The incidence of difficult laryngoscopy and intubation in obese patients is higher than in the general population. Classical predictors of difficult laryngoscopy and intubation have been shown to be unreliable. We prospectively evaluated indirect mirror laryngoscopy as a predictor of difficult laryngoscopy in obese patients. Materials and Methods: 60 patients with a body mass index (BMI) greater than 30, scheduled to undergo general anesthesia, were enrolled. Indirect mirror laryngoscopy was performed and was graded 1-4 according to Cormack and Lehane. A view of grade 3-4 was classified as predicting difficult laryngoscopy. Additional assessments for comparison were the Samsoon and Young modification of the Mallampati airway classification, Wilson Risk Sum Score, neck circumference, and BMI. The view obtained upon direct laryngoscopy after induction of general anesthesia was classified according to Cormack and Lehane as grade 1-4. Results: Sixty patients met the inclusion criteria; however, 8 (13.3%) patients had an excessive gag reflex, and examination of the larynx was not possible. 15.4% of patients who underwent direct laryngoscopy had a Cormack and Lehane grade 3 or 4 view and were classified as difficult. Mirror laryngoscopy had a tendency toward statistical significance in predicting difficult laryngoscopy in these patients. Conclusions: This study is consistent with previous studies, which have demonstrated that no one individual traditional test has proven to be adequate in predicting difficult airways in the obese population. However, the new application of an old test - indirect mirror laryngoscopy - could be a useful additional test to predict difficult laryngoscopy in obese patients

Discovery and validation of SIRT2 inhibitors based on tenovin-6:use of a ¹H-NMR method to assess deacetylase activity

The search for potent and selective sirtuin inhibitors continues as chemical tools of this type are of use in helping to assign the function of this interesting class of deacetylases. Here we describe SAR studies starting from the unselective sirtuin inhibitor tenovin-6. These studies identify a sub-micromolar inhibitor that has increased selectivity for SIRT2 over SIRT1 compared to tenovin-6. In addition, a H-1-NMR-based method is developed and used to validate further this class of sirtuin inhibitors. A thermal shift analysis of SIRT2 in the presence of tenovin-6, -43, a control tenovin and the known SIRT2 inhibitor AGK2 is also presented.</p