Dexamethasone potentiates in vitro blood-brain barrier recovery after primary blast injury by glucocorticoid receptor-mediated upregulation of ZO-1 tight junction protein

Owing to the frequent incidence of blast-induced traumatic brain injury (bTBI) in recent military conflicts, there is an urgent need to develop effective therapies for bTBI-related pathologies. Blood-brain barrier (BBB) breakdown has been reported to occur after primary blast exposure, making restoration of BBB function and integrity a promising therapeutic target. We tested the hypothesis that treatment with dexamethasone (DEX) after primary blast injury potentiates recovery of an in vitro BBB model consisting of mouse brain endothelial cells (bEnd.3). DEX treatment resulted in complete recovery of transendothelial electrical resistance and hydraulic conductivity 1 day after injury, compared with 3 days for vehicle-treated injured cultures. Administration of RU486 (mifepristone) inhibited effects of DEX, confirming that barrier restoration was mediated by glucocorticoid receptor signaling. Potentiated recovery with DEX treatment was accompanied by stronger zonula occludens (ZO)-1 tight junction immunostaining and expression, suggesting that increased ZO-1 expression was a structural correlate to BBB recovery after blast. Interestingly, augmented ZO-1 protein expression was associated with specific upregulation of the α⁺ isoform but not the α⁻ isoform. This is the first study to provide a mechanistic basis for potentiated functional recovery of an in vitro BBB model because of glucocorticoid treatment after primary blast injury.     

Direct insertion of an ultra‐slim upper endoscope for cholangioscopy in patients undergoing choledochoduodenostomy

Direct peroral cholangioscopy (POC) using an ultra‐slim upper endoscope is one modality of POC for intraductal endoscopic evaluation and treatment of the bile duct. Choledochoduodenostomy (CDS) is one modality of biliary bypass surgery that provides a new route to the bile duct. We carried out direct POC using an ultra‐slim upper endoscope without the use of accessories in 10 patients (four sump syndromes, three bile duct strictures and three intrahepatic duct stones) previously undergoing surgical CDS. Direct POC was successful in all patients. The use of an intraductal balloon catheter was required in one patient for advancement of the endoscope into the bile duct. Distal bile ducts with sump syndromes were cleared using baskets and water irrigation under direct POC. Cholangiocarcinoma was diagnosed in one patient with hilar bile duct stricture after cholangioscopic evaluation and a targeting forceps biopsy under direct POC. Intrahepatic duct stones were successfully extracted after intraductal fragmentation under direct POC. Oozing bleeding occurred during intraductal lithotripsy but stopped spontaneously. Direct POC using an ultra‐slim upper endoscope without the assistance of accessories can easily be carried out in patients undergoing CDS.     

Estimation of phase signal change in neuronal current MRI for evoke response of tactile detection with realistic somatosensory laminar network model

Magnetic field generated by neuronal activity could alter magnetic resonance imaging (MRI) signals but detection of such signal is under debate. Previous researches proposed that magnitude signal change is below current detectable level, but phase signal change (PSC) may be measurable with current MRI systems. Optimal imaging parameters like echo time, voxel size and external field direction, could increase the probability of detection of this small signal change. We simulate a voxel of cortical column to determine effect of such parameters on PSC signal. We extended a laminar network model for somatosensory cortex to find neuronal current in each segment of pyramidal neurons (PN). 60,000 PNs of simulated network were positioned randomly in a voxel. Biot–savart law applied to calculate neuronal magnetic field and additional phase. The procedure repeated for eleven neuronal arrangements in the voxel. PSC signal variation with the echo time and voxel size was assessed. The simulated results show that PSC signal increases with echo time, especially 100/80 ms after stimulus for gradient echo/spin echo sequence. It can be up to 0.1 mrad for echo time = 175 ms and voxel size = 1.48 × 1.48 × 2.18 mm³. With echo time less than 25 ms after stimulus, it was just acquired effects of physiological noise on PSC signal. The absolute value of the signal increased with decrease of voxel size, but its components had complex variation. External field orthogonal to local surface of cortex maximizes the signal. Expected PSC signal for tactile detection in the somatosensory cortex increase with echo time and have no oscillation.     

Epidemiologic Characteristics of Work-related Eye Injuries and Risk Factors Associated with Severe Eye Injuries: A Registry-based Multicentre Study

ABSTRACT

Purpose

Work-related eye injuries have been reported with a variety of epidemiologic and clinical characteristics. We aimed to identify epidemiologic characteristics of work-related eye injuries and risk factors associated with severe injury in a large metropolitan city.     

Clinicopathologic characteristics of paranasal sinus fungus ball: retrospective,multicenter study in Korea

European Archives of Oto-Rhino-Laryngology - Fungus ball (FB) is the most common type of fungal rhinosinusitis and the prevalence of FB has increased over the past 10 years. The aim of...     

Binding mode of conformations and structure-based pharmacophore development for farnesyltransferase inhibitors

Farnesyltransferase (FTase) is one of the prenyltransferase family enzymes that catalyse the transfer of 15-membered isoprenoid (farnesyl) moiety to the cysteine of CAAX motif-containing proteins including Rho and Ras family of G proteins. Inhibitors of FTase act as drugs for cancer, malaria, progeria and other diseases. In the present investigation, we have developed two structure-based pharmacophore models from protein–ligand complex (3E33 and 3E37) obtained from the protein data bank. Molecular dynamics (MD) simulations were performed on the complexes, and different conformers of the same complex were generated. These conformers were undergone protein–ligand interaction fingerprint (PLIF) analysis, and the fingerprint bits have been used for structure-based pharmacophore model development. The PLIF results showed that Lys164, Tyr166, TrpB106 and TyrB361 are the major interacting residues in both the complexes. The RMSD and RMSF analyses on the MD-simulated systems showed that the absence of FPP in the complex 3E37 has significant effect in the conformational changes of the ligands. During this conformational change, some interactions between the protein and the ligands are lost, but regained after some simulations (after 2 ns). The structure-based pharmacophore models showed that the hydrophobic and acceptor contours are predominantly present in the models. The pharmacophore models were validated using reference compounds, which significantly identified as HITs with smaller RMSD values. The developed structure-based pharmacophore models are significant, and the methodology used in this study is novel from the existing methods (the original X-ray crystallographic coordination of the ligands is used for the model building). In our study, along with the original coordination of the ligand, different conformers of the same complex (protein–ligand) are used. It concluded that the developed methodology is significant for the virtual screening of novel molecules on different targets.     

Dying is the Most Grown-Up Thing We Ever Do: But Do Health Care Professionals Prevent Us from Taking It Seriously?

This paper takes a somewhat slant perspective on flourishing and care in the context of suffering, death and dying, arguing that care in this context consists principally of ‘acts of work and courage that enable flourishing’. Starting with the perception that individuals, society and health care professionals have become dulled to death and the process of dying in Western advanced health systems, it suggests that for flourishing to occur, both of these aspects of life need to be faced more directly. The last days of life need to be ‘undulled’. Reflections upon the experiences of the author as carer and daughter in the face of her mother’s experience of death are used as basis for making suggestions about how care systems and professionals might better assist people in dealing with ‘the most grown up thing’ humans ever do, which is to die.