A trivalent approach for determining in vitro toxicology: Examination of oxime K027

Unforeseen toxic effects contribute to compound attrition during preclinical evaluation and clinical trials. Consequently, there is a need to correlate in vitro toxicity to in vivo and clinical outcomes quickly and effectively. We propose an expedited evaluation of physiological parameters in vitro that will improve the ability to predict in vivo toxicity of potential therapeutics. By monitoring metabolism, mitochondrial physiology and cell viability, our approach provides insight to the extent of drug toxicity in vitro. To implement our approach, we used human hepatocellular carcinoma cells (HepG2) and neuroblastoma cells (SH‐SY5Y) to monitor hepato‐ and neurotoxicity of the experimental oxime K027. We utilized a trivalent approach to measure metabolism, mitochondrial stress and induction of apoptosis in 96‐well formats. Any change in these three areas may suggest drug‐induced toxicity in vivo. K027 and pralidoxime, an oxime currently in clinical use, had no effect on glycolysis or oxygen consumption in HepG2 and SH‐SY5Y cells. Similarly, these oximes did not induce oxidant generation nor alter mitochondrial membrane potential. Further, K027 and pralidoxime failed to activate effector caspases, and these oximes did not alter viability. The chemotherapeutic agent, docetaxel, negatively affected metabolism, mitochondrial physiology and viability. Our studies present a streamlined high‐throughput trivalent approach for predicting toxicity in vitro, and this approach reveals that K027 has no measurable hepatotoxicity or neurotoxicity in vitro, which correlates with their in vivo data. This approach could eliminate toxic drugs from consideration for in vivo preclinical evaluation faster than existing toxicity prediction panels and ultimately prevent unnecessary experimentation. Copyright © 2014 John Wiley & Sons, Ltd.     

Increased plasma levels of soluble vascular cellular adhesion molecule-1 in patients with chest pain and angiographically normal coronary arteries

AIMS: To assess plasma levels of vascular cellular adhesion molecule-1, a marker of endothelial dysfunction, in patients presenting with coronary syndromes submitted to coronary angiography. METHODS AND RESULTS: Plasma levels of soluble vascular cellular adhesion molecule-1 were measured by enzymatic immunoabsorbent assay in eight patients with angina-like chest pain and angiographically normal coronary arteries; in 14 patients with stable angina and in 18 patients with unstable angina, both with coronary lesions by angiography, and in 10 healthy volunteers. Levels of soluble vascular cellular adhesion molecule-1 were higher in unstable angina patients (1777+/-161 SE pg ml(-1)) compared to patients with stable angina (1178+/-206 SE pg ml(-1), P<0.05). Moreover, patients with angina-like chest pain and normal coronary arteries had significantly higher soluble vascular cellular adhesion molecule-1 levels (2307+/-295 SE pg ml(-1)) compared to stable angina patients (P<0.05), but similar levels compared to unstable angina patients. Patient groups had higher values of soluble vascular cellular adhesion molecule-1 compared to the control group (734+/-97 SE pg ml(-1)). CONCLUSIONS: Increased levels of soluble vascular cellular adhesion molecule-1 are associated with coronary artery disease in patients with anatomically established lesions. In patients free of flow-limiting lesions and angina-like chest pain, high levels of this marker may indicate endothelial dysfunction.     

Barriers to physical activity during the COVID-19 pandemic in adults: a cross-sectional study

Sport Sciences for Health - Social isolation due to the coronavirus disease 2019 (COVID-19) pandemic has reduced physical activity levels in both men and women. The identification of barriers to...     

Cervical lymph node metastasis in squamous cell carcinoma of the buccal mucosa: a retrospective study on pattern of involvement and clinical analysis

Background The study was performed with an aim to map the pattern of metastasis of squamous cell carcinomas of buccal mucosa to various cervical lymph node levels and analyze its correlation with primary tumor size and histo-pathological grading. Material and Methods 254 patients with squamous cell carcinoma of the buccal mucosa treated with surgery first approach were analyzed retrospectively. The tumor size was noted from pre-operative CT Scans and were divided into early and advanced tumors. The resected specimen was studied to note the histo-pathological grading of the squamous cell carcinoma and the metastatic deposits at various lymph node levels. Results Out of 254 patients (149 females, 105 males), 145 patients showed histo-pathologically proven metastatic deposits in one or more lymph nodes out of which there were 56 patients showing occult metastasis. 78/145 patients showed metastatic involvement of level IB and/or IA lymph nodes, 31 showed involvement of level II and/or I lymph nodes, 27 showed involvement of level III with or without involvement of level I and II and 9 showed metastasis to level IV and V lymph nodes with or without level I, II or III lymph nodes. Cervical lymph node metastasis had statistically significant association with tumor size with advanced tumors showing worse pattern of metastatic spread beyond level I and II lymph nodes. As the degree of differentiation of squamous cell carcinoma reduced, they were more prone for cervical metastasis with moderately and poorly differentiated squamous cell carcinoma showing higher involvement of level III, IV and V lymph nodes. Conclusions The majority of buccal mucosa cases showed metastasis to level I, II and III lymph nodes out of which level IB and/or IA was most frequently involved. Metastasis to level IV and V lymph nodes was rare and was seen especially in patients with advanced primary tumor and poor histo-pathologic differentiation. Key words:Oral squamous cell carcinoma (OSCC), cervical lymph node metastasis, histologic differentiation, locally advanced disease.     

A Ubiquitous Reflective E-Portfolio Architecture

BackgroundIn nurse and in medicine courses, the use of reflective portfolios as a pedagogical tool is becoming a common practice; in the last years, this practice has gradually migrated from paper-based to electronic-based portfolios. Current approaches for reflective e-portfolios, however, do not widely operate at outdoor sites, where data networks are limited or nonexistent. Considering that many of the activities related to nurse and medicine courses relate to professional practices conducted in such conditions, these network shortcomings restrict the adoption of e-portfolios.PurposeThe present study describes the requirements specification, design, implementation, and evaluation of the Ubiquitous Reflective E-Portfolio Architecture, a solution proposed to support the development of systems based on mobile and wired access for both online and offline operation.MethodsWe have implemented a prototype named Professional Practice Module to evaluate the Ubiquitous Reflective E-Portfolio Architecture; the module was based on requirements observed during the professional practice, the paper-based portfolio in use, and related learning meetings in the Medicine Course of a Brazilian University. The evaluation of the system was carried out with a learning group of 2nd year students of the medicine course, who answered to extensive evaluation questionnaires.ResultsThe prototype proved to be operational in the activities of the professional practice of the Medicine Course object of the study, including homework tasks, patient care, data sharing, and learning meetings. It also demonstrated to be versatile with respect to the availability of the computer network that, many times, was not accessible. Moreover, the students considered the module useful and easy to use, but pointed out difficulties about the keyboard and the display sizes of the netbook devices, and about their operational system. Lastly, most of the students declared preference for the electronic Professional Practice Module in internal and in group activities, and for the paper-based version while in patient attendance.ConclusionsThere is evidence that the environment where the professional practice takes place influences the usage of the e-portfolio. Mobile devices were able to support students in their professional practice; however, these devices present characteristics that must be judiciously selected, otherwise, they may limit the execution of important tasks. The main shortcoming identified during the evaluation tests was about the use of the module, and of the access device, during patient attendance. For this reason, we have envisioned a new version of the Professional Practice Module that shall follow a twofold requisite: by one side, it will include all the features of the module, to be used at the university or in the students’ homes; from the other side, it will include only the features that are essential for the practice of patient attendance.     

Successful Treatment of Carbapenemase-Producing Pandrug-Resistant Klebsiella pneumoniae Bacteremia

New antibiotic options are urgently needed for the treatment of carbapenem-resistant Enterobacteriaceae infections. We report a 64-year-old female with prolonged hospitalization following an intestinal transplant who developed refractory bacteremia due to a serine carbapenemase-producing pandrug-resistant isolate of Klebsiella pneumoniae. After failing multiple antimicrobial regimens, the patient was successfully treated.     

Edentulousness in relation to remodeling of the gonial angles and incisures in dentate and edentate mandibles: morphometric study using the Image J software

Purpose

The human mandible is subject to stimuli during its growth phase and also in adulthood. One of these stimuli may be absence of teeth, which gives rise to mandibular remodeling. Morphological changes may occur in different areas of this bone, such as in the gonial, condylar and ramus regions.

Objective

To investigate the influence of edentulousness on remodeling of the gonial angle of the mandible and the angle formed by the mandibular incisure.

Materials and method

Eighty-five dry mandibles from adults were examined: 42 from males and 43 from females. The mandibles were photographed using a camera coupled to a static support that was positioned 20 cm from the object to be photographed. The images were digitized and transferred to the Image J 1.42q software, in which the gonial angle of the mandible and the mandibular incisure angle were measured.

Results

There were no differences in the mandibular and mandibular incisure angles in relation to presence or absence of teeth, or between the right and left sides. The mandibular incisure angle was greater in the women.

Conclusion

Edentulousness did not cause remodeling of the gonial angle of the mandible or in the mandibular incisure angle.