In silico panning for a non-competitive peptide inhibitor

BACKGROUND: Peptide ligands have tremendous therapeutic potential as efficacious drugs. Currently, more than 40 peptides are available in the market for a drug. However, since costly and time-consuming synthesis procedures represent a problem for high-throughput screening, novel procedures to reduce the time and labor involved in screening peptide ligands are required. We propose the novel approach of 'in silico panning' which consists of a two-stage screening, involving affinity selection by docking simulation and evolution of the peptide ligand using genetic algorithms (GAs). In silico panning was successfully applied to the selection of peptide inhibitor for water-soluble quinoprotein glucose dehydrogenase (PQQGDH). RESULTS: The evolution of peptide ligands for a target enzyme was achieved by combining a docking simulation with evolution of the peptide ligand using genetic algorithms (GAs), which mimic Darwinian evolution. Designation of the target area as next to the substrate-binding site of the enzyme in the docking simulation enabled the selection of a non-competitive inhibitor. In all, four rounds of selection were carried out on the computer; the distribution of the docking energy decreased gradually for each generation and improvements in the docking energy were observed over the four rounds of selection. One of the top three selected peptides with the lowest docking energy, 'SERG' showed an inhibitory effect with K(i )value of 20 μM. PQQGDH activity, in terms of the V(max )value, was 3-fold lower than that of the wild-type enzyme in the presence of this peptide. The mechanism of the SERG blockage of the enzyme was identified as non-competitive inhibition. We confirmed the specific binding of the peptide, and its equilibrium dissociation constant (K(D)) value was calculated as 60 μM by surface plasmon resonance (SPR) analysis. CONCLUSION: We demonstrate an effective methodology of in silico panning for the selection of a non-competitive peptide inhibitor from small virtual peptide library. This study is the first to demonstrate the usefulness of in silico evolution using experimental data. Our study highlights the usefulness of this strategy for structure-based screening of enzyme inhibitors

Physiological myocardial 18F-FDG uptake pattern in oncologic PET/CT: comparison with findings in cardiac sarcoidosis

Objective(s): Physiological myocardial 18F-fluorodeoxyglucose (18F-FDG) uptake in oncologic positron emission tomography (PET)/computed tomography (CT) is commonly observed with multiple variations under clinical fasting conditions. The purpose of the present study was to evaluate physiological myocardial 18F-FDG uptake pattern by comparing with the results in cardiac sarcoidosis.Methods: A total of 174 examinations in 174 patients without cardiac disease and 27 examinations in 17 patients with cardiac sarcoidosis were performed. The polar map images generated from 18F-FDG PET/CT data were visually assessed as “basal-ring,” “focal,” and “focal on diffuse” patterns. Semi-quantitative analysis was also performed using the regional relative 18F-FDG uptake (% uptake).Results: On visual analysis, the “focal on diffuse” pattern was the most common in both examinations (43% and 59%, respectively). The physiological % uptake in the lateral and basal septal walls tended to be higher. Subgroup analysis showed significantly higher uptake in the mid-wall and left circumflex territory. In cardiac sarcoidosis patients, there was a significant difference only between segments 2 and 15 (p=0.04). No significant differences were observed between the base-mid-apical territory and coronary artery branch territory.Conclusion: High 18F-FDG uptake in the basal septal walls is likely to be observed as both physiological uptake in patients without cardiac disease and pathological uptake in patients with cardiac sarcoidosis

Prevention of long‐lasting atrial fibrillation through antitachycardia pacing in DDDR pacemakers

Objective The MINERVA trial showed that in pacemaker patients with atrial fibrillation (AF) history, DDDRP pacing combining three algorithms - (a) atrial antitachycardia pacing with Reactive ATP enabled, (b) atrial preventive pacing and (c) managed ventricular pacing (MVP)-may effectively delay progression to persistent/permanent AF compared with standard DDDR pacing. We performed a comparative non-randomised evaluation to evaluate if Reactive ATP can be the main driver of persistent/permanent AF reduction independently on preventive pacing. Methods Thirty-one centres included consecutive dual-chamber pacemaker patients with AF history. Reactive ATP was programmed in all patients while preventive atrial pacing was not enabled. These patients were compared with the three groups of MINERVA randomised trial (Control DDDR, MVP, and DDDRP). The main endpoint was the incidence of AF longer than 7 consecutive days. Results A total of 146 patients (73 years old, 54% male) were included and followed for a median observation period of 31 months. The 2-year incidence of AF > 7 days was 12% in the Reactive ATP group, very similar to that found in the DDDRP arm of the MINERVA trial (13.8%, P = .732) and significantly lower than AF incidence found in the MINERVA Control DDDR arm (25.8%, P = .012) and in the MINERVA MVP arm (25.9%, P = .025). Conclusions In a real-world population of dual-chamber pacemaker patients with AF history, the use of Reactive ATP is associated with a low incidence of persistent AF, highlighting that the positive results of the MINERVA trial were related to the effectiveness of Reactive ATP rather than to preventive pacing

Comparative evaluation of 18F-FLT and 18F-FDG for detecting cardiac and extra-cardiac thoracic involvement in patients with newly diagnosed sarcoidosis

Abstract Background 18F-FDG PET has been used in sarcoidosis for diagnosis and determination of the extent of the disease. However, assessing inflammatory lesions in cardiac sarcoidosis using 18F-FDG can be challenging because it accumulates physiologically in normal myocardium. Another radiotracer, 3′-deoxy-3′-18F-fluorothymidine (18F-FLT), has been investigated as a promising PET tracer for evaluating tumor proliferative activity. In contrast to 18F-FDG, 18F-FLT uptake in the normal myocardium is low. The purpose of this retrospective study was to compare the uptake of 18F-FLT and 18F-FDG in the evaluation of cardiac and extra-cardiac thoracic involvement in patients with newly diagnosed sarcoidosis. Data for 20 patients with newly diagnosed sarcoidosis were examined. 18F-FLT and 18F-FDG PET/CT studies had been performed at 1 h after each radiotracer injection. The patients had fasted for at least 18 h before 18F-FDG PET/CT but were given no special dietary instructions regarding the period before 18F-FLT PET/CT. Uptake of 18F-FLT and 18F-FDG was examined visually and semiquantitatively using maximal standardized uptake value (SUVmax). Results Two patients had cardiac sarcoidosis, 7 had extra-cardiac thoracic sarcoidosis, and 11 had both cardiac and extra-cardiac thoracic sarcoidosis. On visual analysis for diagnosis of cardiac sarcoidosis, 4/20 18F-FDG scans were rated as inconclusive because the 18F-FDG pattern was diffuse, whereas no FLT scans were rated as inconclusive. The sensitivity of 18F-FDG PET/CT for detection of cardiac sarcoidosis was 85%; specificity, 100%; and accuracy, 90%. The corresponding values for 18F-FLT PET/CT were 92, 100, and 95%, respectively. Using semiquantitative analysis of cardiac sarcoidosis, the mean 18F-FDG SUVmax was significantly higher than the mean 18F-FLT SUVmax (P < 0.005). Both 18F-FDG and 18F-FLT PET/CT studies detected all 24 extra-cardiac lesions. Using semiquantitative analysis of extra-cardiac sarcoidosis, the mean 18F-FDG SUVmax was significantly higher than the mean 18F-FLT SUVmax (P < 0.001). Conclusions The results of this preliminary study suggest that 18F-FLT PET/CT can detect cardiac and extra-cardiac thoracic involvement in patients with newly diagnosed sarcoidosis as well as 18F-FDG PET/CT, although uptake of 18F-FLT in lesions was significantly lower than that of 18F-FDG. However, 18F-FLT PET/CT may be easier to perform since it requires neither prolonged fasting nor a special diet prior to imaging

Predictive ability of pulse oximetry-derived indices for hypotension after spinal anaesthesia for caesarean section: protocol for a systematic review and meta-analysis

Introduction In general, caesarean sections are performed under spinal anaesthesia. Hypotension after spinal anaesthesia adversely affects both the mother and fetus. Although several studies have used pulse oximetry-derived indices, such as pulse perfusion index (PI) and Pleth variability index (PVI), to predict hypotension after spinal anaesthesia, the predictive ability of the PI and PVI remain controversial.Methods and analysis We prepared this protocol following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines. We will conduct searches of MEDLINE, Embase, Web of Science, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Clinicaltrial.gov, European Union Clinical Trials Register (EU-CTR), WHO International Clinical Trials Registry Platform (ICTRP) and University Hospital Medical Information Network Clinical Trials Registry (UMIN) from inception until 8 October 2022. We will include retrospective and prospective observational studies and randomised controlled trials that evaluated the predictive ability of PI and PVI for hypotension after spinal anaesthesia for caesarean section, published in any language. We will exclude case reports, case series and animal studies. Two authors will independently scan and select eligible studies and perform data extraction and assessment of risk of bias. We will estimate predictive ability of PI and PVI as indices of hypotension after spinal anaesthesia for caesarean section using the Reitsma-type bivariate random-effects synthesis model and the hierarchical summary receiver operating characteristic curve. We will assess the quality of evidence using the Grading of Recommendation Assessment, Development and Evaluation approach.Ethics and dissemination Ethics approval is not required as the systematic review will use existing published data. The results will be submitted for publication in a peer-reviewed journal.PROSPERO registration number CRD42022362596

Association of abnormal carbon dioxide levels with poor neurological outcomes in aneurysmal subarachnoid hemorrhage: a retrospective observational study

Abstract Background In patients with aneurysmal subarachnoid hemorrhage (SAH), an association between hypocapnia and poor clinical outcomes has been reported. However, the optimal arterial carbon dioxide tension (PaCO2) remains unknown. The present retrospective study aimed to examine the association of abnormal PaCO2 levels with neurological outcomes and investigate the optimal target PaCO2 level in patients with SAH. Methods We retrospectively selected consecutive adult patients hospitalized in the intensive care unit (ICU) for SAH between January 2009 and April 2017. Univariate and multivariate analyses were performed to identify the independent predictors of unfavorable neurological outcomes (i.e., modified Rankin scale score of 3–6 on hospital discharge). Results Among 158 patients with SAH, 73 had unfavorable neurological outcomes. During the first 2 weeks in the ICU, the median number of PaCO2 measurements per patient was 43. The factors significantly associated with unfavorable neurological outcomes were age, Hunt and Kosnik grade, maximum lactate levels during the first 24 h, and maximum (odds ratio [OR], 1.12; 95% confidence interval [CI], 1.03–1.21; p < 0.01) and minimum PaCO2 levels (OR, 0.81; 95% CI, 0.72–0.92; p < 0.01). Receiver operating characteristic curve analysis revealed that the cutoff range of PaCO2 was 30.2–48.3 mmHg. Unfavorable neurological outcomes were noted in 78.8% of patients with PaCO2 levels outside this range and in 22.8% of patients with PaCO2 levels within this range. Conclusions Both the maximum and minimum PaCO2 levels during ICU management in patients with SAH were significantly associated with unfavorable neurological outcomes. Further prospective studies are required to validate our findings and explore their clinical implications. Our findings may provide a scientific rationale for these future prospective studies