Oxime K074 – in vitro and in silico reactivation of acetylcholinesterase inhibited by nerve agents and pesticides

Abstract

Oxime K074 was formerly considered to be a lead structure for design of novel oximes for reactivation of tabun-inhibited acetylcholinesterase (AChE). In this study, we are summarizing its reactivation activity in case of other nerve agents (sarin, cyclosarin, VX and Russian VX) and pesticides (chlorpyrifos, methylchlorpyrifos and DDVP). For this purpose, standard in vitro method using rat brain homogenate was used. As resulted, oxime K074 was able to reactivate brain ChE (cholinesterases) inhibited by all used nerve agents and pesticides excluding cyclosarin-inhibited ChE. Only slight modification in structure of sarin (isopropyl moiety) and cyclosarin (cyclohexyl moiety) caused extraordinary differences in the reactivation of acetylcholinesterase inhibited by these nerve agents. Obtained molecular docking results suggest that the oxime K074 interacts very well with the inhibitors addressed in this work, and the data obtained by the QM/MM approach showed a good correlation with our experimental results of reactivation rate (%) by the oxime K074.     

Proposed rituximab biosimilar BCD-020 versus reference rituximab for treatment of patients with indolent non-Hodgkin lymphomas: An international multicenter randomized trial

BCD-020 is a proposed rituximab biosimilar, which has shown high similarity to rituximab in quality and nonclinical studies in vitro and in vivo. International multicenter clinical trial was conducted to compare efficacy and safety of BCD-020 and reference rituximab in adult (older than 18 years) patients with indolent lymphomas (follicular lymphoma grade 1-2, splenic marginal zone lymphoma, and nodal marginal zone lymphoma). Pharmacokinetics, pharmacodynamics, and immunogenicity were also studied. Patients with no previous biologic treatment for lymphoma were randomly assigned 1:1 to receive BCD-020 or comparator 375 mg/m² for 4 weeks. Primary study outcome was day 50 overall response rate defined as complete or partial remission. Equivalence range was −20% to 20% for 95% CI for overall response rates difference. Secondary outcomes included adverse events, pharmacokinetics, pharmacodynamics, and immunogenicity. One hundred seventy-four patients were enrolled, 89 in BCD-020 arm and 85 in comparator arm. The overall response rate was 44.71% in BCD-020 arm and 41.89% in comparator arm. Limits of 95% confidence interval (CI) for difference of overall response rates between arms were (−12.62%-18.24%) showing equivalent efficacy. Sixty-one (68.54%) and 59 (69.41%) patients had at least one adverse event in BCD-020 arm or comparator arm, respectively. No unexpected adverse reactions were reported. Antidrug antibodies with no neutralizing activity were detected in two patients in comparator arm on day 14 further declining below detection threshold. Rituximab concentrations had equivalent pattern after intravenous administration of both drugs. Both drugs caused depletion of B-cells without significant influence on other blood cell lineages. In this study, we showed equivalent efficacy of BCD-020 and reference rituximab when used in patients with CD20-positive indolent lymphomas. We also confirmed pharmacokinetic equivalence of BCD-020 and reference rituximab. Safety profile, pharmacodynamics, and immunogenicity of BCD-020 were also comparable with those of reference rituximab.     

Surgery or Conservative Treatment of Forearm in Patients Diagnosed with Pediatric Floating Elbow? Retrospective Analysis of 60 Consecutive Cases

BackgroundThe coexistence of supracondylar humerus fracture and forearm fracture is a rare trauma (3–13%) and it is called floating elbow. The aim of this study is to clinically compare the treatment outcomes of the patients diagnosed with floating elbow who underwent surgical treatment and who were followed up forearm with immobilization with splint.Materials and MethodsWhen scanned retrospectively, 60 patients who were treated with the diagnosis of floating elbow due to traumatic causes and followed up for at least 1 year were included in our study. Surgical treatment was performed on 42 patients for forearm fracture. Eighteen patients followed up with immobilization with a long arm splint. The results were evaluated according to the criteria modified by Templeton and Graham, in comparison with the patient’s intact side.ResultsIn the patients whose forearms were followed up conservatively, the mean age was 5.67 ± 2.25 years, and the mean follow-up period was 62.17 ± 45.91 months. In the patients who underwent surgery for the forearm, the mean age was 8.79 ± 2.01 years, and the mean follow-up was 47.14 ± 34.25 months. Eighteen patients whose forearms followed up conservatively, 12 had excellent and good clinical results and 6 had poor and moderate clinical results. Excellent and good clinical results in 27 patients who underwent surgical treatment for their forearms, moderate and poor clinical results obtained in 15 of them. There was no significant difference between the two groups (p = 0.357).ConclusionsIn conclusion, satisfactory clinical and radiological outcomes can be obtained with immobilization of the forearm fracture with splint, if acceptable reduction can be provided for the forearm following fixation of the supracondylar humerus fracture with the K-wire for treatment of floating elbow injury.     

A Comparison of the Reactivating and Therapeutic Efficacy of Two Newly Developed Oximes (K727 and K733) with Oxime K203 and Trimedoxime in Tabun‐Poisoned Rats and Mice

The reactivating and therapeutic efficacy of three original bispyridinium oximes (K727, K733 and K203) and one currently available oxime (trimedoxime) was evaluated in tabun‐poisoned rats and mice. The oxime‐induced reactivation of tabun‐inhibited acetylcholinesterase was measured in diaphragm and brain of tabun‐poisoned rats. The results showed that the reactivating efficacy of two recently developed oximes (K727 and K733) does not achieve the level of the reactivation of tabun‐inhibited acetylcholinesterase induced by oxime K203 and trimedoxime. While all oximes studied were able to increase the activity of tabun‐inhibited acetylcholinesterase in diaphragm, oxime K733 was not able to reactivate tabun‐inhibited acetylcholinesterase in the brain. The therapeutic efficacy of all oximes studied roughly corresponds to their reactivating efficacy. While both recently developed oximes were able to reduce acute toxicity of tabun less than 1.5‐fold, another original oxime K203 and commonly used trimedoxime reduced the acute toxicity of tabun almost two times. In conclusion, the reactivating and therapeutic potency of both newly developed oximes does not prevail the effectiveness of oxime K203 and trimedoxime, and therefore, they are not suitable for their replacement of commonly used oximes for the antidotal treatment of acute tabun poisoning.     

Robot-Assisted Radical Prostatectomy After Previous Prostate Surgery

Background and Objectives:

Our objective is to clarify the effect of previous transurethral resection of the prostate (TURP) or open prostatectomy (OP) on surgical, oncological, and functional outcomes after robot-assisted radical prostatectomy (RARP).

Methods:

Between August 1, 2009, and March 31, 2013, 380 patients underwent RARP. Of these, 25 patients had undergone surgery for primary bladder outlet obstruction (TURP, 20 patients; OP, 5 patents) (group 1). A match-paired analysis was performed to identify 36 patients without a history of prostate surgery with equivalent clinicopathologic characteristics to serve as a control group (group 2). Patients followed up for 12 months were assessed.

Results:

Both groups were similar with respect to preoperative characteristics, as mean age, body mass index, median prostate-specific antigen, prostate volume, clinical stage, the biopsy Gleason score, D''Amico risk, the American Society of Anesthesiologists (ASA) classification score, the International Prostate Symptom Score, continence, and potency status. RARP resulted in longer console and anastomotic time, as well as higher blood loss compared with surgery-naive patients. We noted a greater rate of urinary leakage (pelvic drainage, >4 d) in group 1 (12% vs 2,8%). The anastomotic stricture rate was significantly higher in group 1 (16% vs 2.8%). No difference was found in the pathologic stage, positive surgical margin, and nerve-sparing procedure between the groups. Biochemical recurrence was observed in 12% (group 1) and 11.1% (group 2) of patients, respectively. No significant difference was found in the continence and potency rates.

Conclusions:

RARP after TURP or OP is a challenging but oncologically promising procedure with a longer console and anastomosis time, as well as higher blood loss and higher anastomotic stricture rate.     

Ortoreksja – patologiczna kontrola nad odżywianiem. Zagrożenie dla dzieci i młodzieży

Eating disorders are serious threat to children and adolescents living in western countries. Parental influence as well as sociocultural standards, shapes specific attitudes towards selection, preparing and consuming food among juveniles. Orthorexia is a form of eating disorder, which is based on concentration over quality of consumed food. The paper provides symptomatology of orthorerxia along with various risk factors that may cause children and adolescents to develop disturbed eating behaviours.     

Effects of nonsurgical periodontal therapy on C-reactive protein and serum lipids in Jordanian adults with advanced periodontitis

Kamil W, Al Habashneh R, Khader Y, Al Bayati L, Taani D. Effects of nonsurgical periodontal therapy on C‐reactive protein and serum lipids in Jordanian adults with advanced periodontitis. J Periodont Res 2011; 46: 616–621. © 2011 John Wiley & Sons A/S Background and Objective: Data on whether periodontal therapy affects serum CRP levels are inconclusive. The aim of this study was to determine if nonsurgical periodontal therapy has any effect on CRP and serum lipid levels in patients with advanced periodontitis. Material and Methods: Thirty‐six systemically healthy patients, ≥ 40 years of age and with advanced periodontitis, were recruited for the study. Patients were randomized consecutively to one of two groups: the treatment group (n = 18) or the control group (n = 18). Treated subjects received nonsurgical periodontal therapy, which included oral hygiene instructions and subgingival scaling and root planing. Systemic levels of inflammatory markers [C‐reactive protein (CRP) and the lipid profile] were measured at baseline and 3 mo after periodontal therapy. Results: Nonsurgical periodontal therapy in the treatment group resulted in a significant reduction in the serum CRP level. The average CRP level decreased from 2.3 mg/dL at baseline to 1.8 mg/dL (p < 0.005) after 3 mo of periodontal therapy. The average reduction (95% confidence interval) in CRP was 0.498 (95% confidence interval = 0.265–0.731). In the treatment group, the reduction in CRP was significantly, linearly and directly correlated with the reduction in the plaque index, the gingival index and the percentage of sites with pocket depth ≥ 7 mm (Pearson correlation coefficient = 0.746, 0.425 and 0.621, respectively). Nonsurgical periodontal therapy had no effect on the lipid parameters. Conclusion: This study demonstrated that nonsurgical periodontal therapy results in a significant reduction in the serum CRP level. The effect of this outcome on systemic disease is still unknown.     

Multicenter Validation of the Revised Assessment of Bleeding and Transfusion (RABT) Score for Predicting Massive Transfusion

World Journal of Surgery - Massive transfusion (MT) is a lifesaving treatment for hemorrhaging patients. Predicting the need for MT is crucial to improve survival. The aim of our study was to...     

Elevated Numbers of Circulating Very Small Embryonic-Like Stem Cells (VSELs) and Intermediate CD14++CD16+ Monocytes in IgA Nephropathy

IgA nephropathy (IgAN) is recognized as most frequent form of primary glomerulonephritis worldwide. IgAN is associated with renal degradation occurring due to irreversible pathological changes leading to glomerulosclerosis and interstitial fibrosis. It remains poorly understood whether and to what extent these changes are followed by the activation of regenerative mechanisms. Therefore, in this study we aimed to evaluate regenerative potential of IgAN patients by quantitating the frequencies of several stem cell types, namely circulating very small embryonic-like stem cells (VSELs), hematopoietic stem cells (HSCs), endothelial progenitor cells (EPCs) as well as different monocyte subsets with varying maturation and angiopoietic potential. Moreover, we analyzed whether changes in stem cell and monocyte frequencies were related to alterations of several chemotactic factors (stromal derived-factor (SDF-1), angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2)) and a marker of monocyte/macrophage activation, namely soluble form of CD163 receptor (sCD163). We showed that IgAN patients presented with enhanced levels of VSELs, but not other stem cell types. We also demonstrated significantly elevated numbers of intermediate monocytes known for their M2-like properties as well as high angiopoietic potential and CD163 expression. This finding was accompanied by detection of elevated sCD163 plasma levels in IgAN patients. Taking together, we demonstrated here that IgAN is associated with selective mobilization of VSELs and increased maturation of monocytes towards M2-like and angiopoietic phenotype. These findings contribute to better understanding of the role of regenerative mechanisms in the pathogenesis of chronic inflammation in the course of IgAN.