Valproic acid inhibits adhesion of vincristine- and cisplatin-resistant neuroblastoma tumour cells to endothelium

Drug resistance to chemotherapy is often associated with increased malignancy in neuroblastoma (NB). In pursuit of alternative treatments for chemoresistant tumour cells, we tested the response of multidrug-resistant SKNSH and of vincristine (VCR)-, doxorubicin (DOX)-, or cisplatin (CDDP)-resistant UKF-NB-2, UKF-NB-3 or UKF-NB-6 NB tumour cell lines to valproic acid (VPA), a differentiation inducer currently in clinical trials. Drug resistance caused elevated NB adhesion (UKF-NB-2VCR, UKF-NB-2DOX, UKF-NB-2CDDP, UKF-NB-3VCR, UKF-NB-3CDDP, UKF-NB-6VCR, UKF-NB-6CDDP) to an endothelial cell monolayer, accompanied by downregulation of the adhesion receptor neural cell adhesion molecule (NCAM). Based on the UKF-NB-3 model, N-myc proteins were enhanced in UKF-NB-3VCR and UKF-NB-3CDDP, compared to the drug naïve controls. p73 was diminished, whereas the p73 isoform deltaNp73 was upregulated in UKF-NB-3VCR and UKF-NB-3CDDP. Valproic acid blocked adhesion of UKF-NB-3VCR and UKF-NB-3CDDP, but not of UKF-NB-3DOX, and induced the upregulation of NCAM surface expression, NCAM protein content and NCAM coding mRNA. Valproic acid diminished N-myc and enhanced p73 protein level, coupled with downregulation of deltaNp73 in UKF-NB-3VCR and UKF-NB-3CDDP. Valproic acid also reverted enhanced adhesion properties of drug-resistant UKF-NB-2, UKF-NB-6 and SKNSH cells, and therefore may provide an alternative approach to the treatment of drug-resistant NB by blocking invasive processes

Mechanical Strain Stabilizes Reconstituted Collagen Fibrils against Enzymatic Degradation by Mammalian Collagenase Matrix Metalloproteinase 8 (MMP-8)

Collagen, a triple-helical, self-organizing protein, is the predominant structural protein in mammals. It is found in bone, ligament, tendon, cartilage, intervertebral disc, skin, blood vessel, and cornea. We have recently postulated that fibrillar collagens (and their complementary enzymes) comprise the basis of a smart structural system which appears to support the retention of molecules in fibrils which are under tensile mechanical strain. The theory suggests that the mechanisms which drive the preferential accumulation of collagen in loaded tissue operate at the molecular level and are not solely cell-driven. The concept reduces control of matrix morphology to an interaction between molecules and the most relevant, physical, and persistent signal: mechanical strain.The investigation was carried out in an environmentally-controlled microbioreactor in which reconstituted type I collagen micronetworks were gently strained between micropipettes. The strained micronetworks were exposed to active matrix metalloproteinase 8 (MMP-8) and relative degradation rates for loaded and unloaded fibrils were tracked simultaneously using label-free differential interference contrast (DIC) imaging. It was found that applied tensile mechanical strain significantly increased degradation time of loaded fibrils compared to unloaded, paired controls. In many cases, strained fibrils were detectable long after unstrained fibrils were degraded.In this investigation we demonstrate for the first time that applied mechanical strain preferentially preserves collagen fibrils in the presence of a physiologically-important mammalian enzyme: MMP-8. These results have the potential to contribute to our understanding of many collagen matrix phenomena including development, adaptation, remodeling and disease. Additionally, tissue engineering could benefit from the ability to sculpt desired structures from physiologically compatible and mutable collagen

Bedside vital parameters that indicate early deterioration

Purpose: The purpose of this paper is to determine associations between initially recorded deviations in individual bedside vital parameters that contribute to total Modified Early Warning Score (MEWS) levels 2 or 3 and further clinical deterioration (MEWS level=4). Design/methodology/approach: This was a prospective study in which 27,504 vital parameter values, corresponding to a total MEWS level⩾2, belonging to 1,315 adult medical and surgical inpatient patients admitted to a 90-bed study setting at a university hospital, were subjected to binary logistic and COX regression analyses to determine associations between vital parameter values initially corresponding to total MEWS levels 2 or 3 and later deterioration to total MEWS level ⩾4, and to evaluate corresponding time intervals. Findings: Respiratory rate, heart rate and patient age were significantly (p=0.012, p<0.001 and p=0.028, respectively) associated with further deterioration from a total MEWS level 2, and the heart rate also (p=0.009) from a total MEWS level 3. Within 24 h from the initially recorded total MEWS levels 2 or 3, 8 and 17 percent of patients, respectively, deteriorated to a total MEWS level=4. Patients initially scoring MEWS 2 had a 27 percent 30-day mortality rate if they later scored MEWS level=4, and 8.7 percent if they did not. Practical implications: It is important to observe all patients closely, but especially elderly patients, if total MEWS levels 2 or 3 are tachypnoea and/or tachycardia related. Originality/value: Findings might contribute to patient safety by facilitating appropriate clinical and organizational decisions on adequate time spans for early warning scoring in general ward patients

European Society of Anaesthesiology and European Board of Anaesthesiology guidelines for procedural sedation and analgesia in adults

Procedural sedation and analgesia (PSA) has become a widespread practice given the increasing demand to relieve anxiety, discomfort and pain during invasive diagnostic and therapeutic procedures. The role of, and credentialing required by, anaesthesiologists and practitioners performing PSA has been debated for years in different guidelines. For this reason, the European Society of Anaesthesiology (ESA) and the European Board of Anaesthesiology have created a taskforce of experts that has been assigned to create an evidence-based guideline and, whenever the evidence was weak, a consensus amongst experts on: the evaluation of adult patients undergoing PSA, the role and competences required for the clinicians to safely perform PSA, the commonly used drugs for PSA, the adverse events that PSA can lead to, the minimum monitoring requirements and post-procedure discharge criteria. A search of the literature from 2003 to 2016 was performed by a professional librarian and the retrieved articles were analysed to allow a critical appraisal according to the Grading of Recommendations Assessment, Development and Evaluation method. The Taskforce selected 2248 articles. Where there was insufficiently clear and concordant evidence on a topic, the Rand Appropriateness Method with three rounds of Delphi voting was used to obtain the highest level of consensus among the taskforce experts.These guidelines contain recommendations on PSA in the adult population. It does not address sedation performed in the ICU or in children and it does not aim to provide a legal statement on how PSA should be performed and by whom. The National Societies of Anaesthesiology and Ministries of Health should use this evidence-based document to help decision-making on how PSA should be performed in their countries. The final draft of the document was available to ESA members via the website for 4 weeks with the facility for them to upload their comments. Comments and suggestions of individual members and national Societies were considered and the guidelines were amended accordingly. The ESA guidelines Committee and ESA board finally approved and ratified it before publication

European Society of Anaesthesiology and European Board of Anaesthesiology guidelines for procedural sedation and analgesia in adults

© 2017 European Society of Anaesthesiology. All rights reserved.Procedural sedation and analgesia (PSA) has become a widespread practice given the increasing demand to relieve anxiety, discomfort and pain during invasive diagnostic and therapeutic procedures. The role of, and credentialing required by, anaesthesiologists and practitioners performing PSA has been debated for years in different guidelines. For this reason, the European Society of Anaesthesiology (ESA) and the European Board of Anaesthesiology have created a taskforce of experts that has been assigned to create an evidence-based guideline and, whenever the evidence was weak, a consensus amongst experts on: the evaluation of adult patients undergoing PSA, the role and competences required for the clinicians to safely perform PSA, the commonly used drugs for PSA, the adverse events that PSA can lead to, the minimum monitoring requirements and post-procedure discharge criteria. A search of the literature from 2003 to 2016 was performed by a professional librarian and the retrieved articles were analysed to allow a critical appraisal according to the Grading of Recommendations Assessment, Development and Evaluation method. The Taskforce selected 2248 articles. Where there was insufficiently clear and concordant evidence on a topic, the Rand Appropriateness Method with three rounds of Delphi voting was used to obtain the highest level of consensus among the taskforce experts.These guidelines contain recommendations on PSA in the adult population. It does not address sedation performed in the ICU or in children and it does not aim to provide a legal statement on how PSA should be performed and by whom. The National Societies of Anaesthesiology and Ministries of Health should use this evidence-based document to help decision-making on how PSA should be performed in their countries. The final draft of the document was available to ESA members via the website for 4 weeks with the facility for them to upload their comments. Comments and suggestions of individual members and national Societies were considered and the guidelines were amended accordingly. The ESA guidelines Committee and ESA board finally approved and ratified it before publication.info:eu-repo/semantics/publishedVersio

The European Board of Anaesthesiology recommendations for safe medication practice : First update

These European Board of Anaesthesiology (EBA) recommendations for safe medication practice replace the first edition of the EBA recommendations published in 2011. They were updated because evidence from critical incident reporting systems continues to show that medication errors remain a major safety issue in anaesthesia, intensive care, emergency medicine and pain medicine, and there is an ongoing need for relevant up-to-date clinical guidance for practising anaesthesiologists. The recommendations are based on evidence wherever possible, with a focus on patient safety, and are primarily aimed at anaesthesiologists practising in Europe, although many will be applicable elsewhere. They emphasise the importance of correct labelling practice and the value of incident reporting so that lessons can be learned, risks reduced and a safety culture developed

The Japan-United States Infrared Interferometry Experiment (JUStIInE): balloon-borne pathfinder for a space-based far-IR interferometer

The balloon-borne Japan-United States Infrared Interferometry Experiment (JUStIInE) is a pathfinder for the first space-based far-IR interferometer. JUStIInE will mature the system-level technology readiness of spatio-spectral far-IR interferometry and demonstrate this technique with scientific observations. Operating at wavelengths from 30 to 90 µm, JUStIInE will provide unprecedented sub-arcsecond angular resolution and spectroscopic data. Our plan is to develop a cryogenic Michelson beam combiner and integrate it with an existing and tested telescope optical system and gondola from the Japanese Far-infrared Interferometric Telescope Experiment (FITE). With two JUStIInE balloon flights we plan to collect, calibrate, analyze, and publish scientific results based on the first far-IR spatio-spectral observations of young stellar objects, evolved stars, and the active galactic nucleus of NGC 1068. The NASA Astrophysics Roadmap envisages a future in which interferometry is applied across the electromagnetic spectrum, starting in the far-infrared. The Far-IR Probe recommended in the 2021 Decadal Survey presents an opportunity to take that important step. A Far-IR Probe mission based on this concept will enable us to understand terrestrial planet formation and spectroscopically study individual distant galaxies to understand the astrophysical processes that govern their evolution