Bioresorbable Film for the Prevention of Adhesion to the Anterior Spine After Anterolateral Discectomy

Background context The development of scar tissue and adhesions postoperatively is a natural consequence of healing but can be associated with medical complications and render reoperation difficult. Many biocompatible products have been evaluated as barriers or deterrents to adhesions. Purpose To evaluate the efficacy of a bioresorbable polylactide film as a barrier to adhesion formation after anterolateral discectomy. Study design Experimental study. Methods Seven, skeletally mature female sheep underwent a retroperitoneal approach to the anterolateral lumbar spine. A discectomy was performed at two levels with an intervening unoperated disc site. One site was treated with a polylactide film barrier (Hydrosorb Shield; MacroPore Biosurgery, San Diego, CA) affixed with tacks manufactured from the same material. The second site was left untreated. Treatment and control sites were randomly assigned. Postmortem analysis included scar tenacity scoring on five spines and histological evaluation on two spines. Results The application of the Hydrosorb film barrier allowed a definite dissection plane during scar tenacity scoring and there was a significant difference in the development of adhesions to the disc between the control and treated sites. Histological evaluation revealed evidence of barrier formation to scar tissue and no significant adverse inflammatory reactions. Conclusions Hydrosorb Shield appears to be an effective postoperative barrier to scar tissue adhesion after anterolateral discectomy. The use of polylactide tacks was beneficial to affix the barrier film in place. Safety issues associated with delayed healing or adverse response to the film or tacks were not observed. Hydrosorb film may be useful as an antiadhesion barrier facilitating dissection during surgical revision in anterior approaches to the spine. Further studies are indicated to evaluate the performance of the bioresorbable material as an antiadhesion barrier in techniques of spinal fusion and disc replacement

Mars Pathfinder mission operations concepts

The Mars Pathfinder Project plans a December 1996 launch of a single spacecraft. After jettisoning a cruise stage, an entry body containing a lander and microrover will directly enter the Mars atmosphere and parachute to a hard landing near the sub-solar latitude of 15 degrees North in July 1997. Primary surface operations last for 30 days. Cost estimates for Pathfinder ground systems development and operations are not only lower in absolute dollars, but also are a lower percentage of total project costs than in past planetary missions. Operations teams will be smaller and fewer than typical flight projects. Operations scenarios have been developed early in the project and are being used to guide operations implementation and flight system design. Recovery of key engineering data from entry, descent, and landing is a top mission priority. These data will be recorded for playback after landing. Real-time tracking of a modified carrier signal through this phase can provide important insight into the spacecraft performance during entry, descent, and landing in the event recorded data is never recovered. Surface scenarios are dominated by microrover activity and lander imaging during 7 hours of the Mars day from 0700 to 1400 local solar time. Efficient uplink and downlink processes have been designed to command the lander and microrover each Mars day

Repeated administration of phytocannabinoid Δ9-THC or synthetic cannabinoids JWH-018 and JWH-073 induces tolerance to hypothermia but not locomotor suppression in mice, and reduces CB1 receptor expression and function in a brain region-specific manner

These studies probed the relationship between intrinsic efficacy and tolerance / cross-tolerance between Δ9-THC and synthetic cannabinoid drugs of abuse (SCBs) by examining in vivo effects and cellular changes concomitant with their repeated administration in mice. Dose-effect relationships for hypothermic effects were determined in order to confirm that SCBs JWH-018 and JWH-073 are higher efficacy agonists than Δ9-THC in mice. Separate groups of mice were treated with saline, sub-maximal hypothermic doses of JWH-018 or JWH-073 (3.0 mg/kg or 10.0 mg/kg, respectively) or a maximally hypothermic dose of 30.0 mg/kg Δ9-THC once per day for 5 consecutive days while core temperature and locomotor activity were monitored via biotelemetry. Repeated administration of all drugs resulted in tolerance to hypothermic effects, but not locomotor effects, and this tolerance was still evident 14 days after the last drug administration. Further studies treated mice with 30.0 mg/kg Δ9-THC once per day for 4 days, then tested with SCBs on day 5. Mice with a Δ9-THC history were cross-tolerant to both SCBs, and this cross-tolerance also persisted 14 days after testing. Select brain regions from chronically treated mice were examined for changes in CB1 receptor expression and function. Expression and function of hypothalamic CB1Rs were reduced in mice receiving chronic drugs, but cortical CB1R expression and function were not altered. Collectively, these data demonstrate that repeated Δ9-THC, JWH-018 and JWH-073 can induce long-lasting tolerance to some in vivo effects, which is likely mediated by region-specific downregulation and desensitization of CB1Rs

Periodontitis is associated with significant hepatic fibrosis in patients with non-alcoholic fatty liver disease

This work was funded by the Diabetes Research and Wellness Fund. WA is in receipt of an MRC New Investigator Award

Electronic cigarette use was not associated with quitting of conventional cigarettes in youth smokers

postprin

Cellular Growth Kinetics Distinguish a Cyclophilin Inhibitor from an HSP90 Inhibitor as a Selective Inhibitor of Hepatitis C Virus

During antiviral drug discovery, it is critical to distinguish molecules that selectively interrupt viral replication from those that reduce virus replication by adversely affecting host cell viability. In this report we investigate the selectivity of inhibitors of the host chaperone proteins cyclophilin A (CypA) and heat-shock protein 90 (HSP90) which have each been reported to inhibit replication of hepatitis C virus (HCV). By comparing the toxicity of the HSP90 inhibitor, 17-(Allylamino)-17-demethoxygeldanamycin (17-AAG) to two known cytostatic compounds, colchicine and gemcitabine, we provide evidence that 17-AAG exerts its antiviral effects indirectly through slowing cell growth. In contrast, a cyclophilin inhibitor, cyclosporin A (CsA), exhibited selective antiviral activity without slowing cell proliferation. Furthermore, we observed that 17-AAG had little antiviral effect in a non-dividing cell-culture model of HCV replication, while CsA reduced HCV titer by more than two orders of magnitude in the same model. The assays we describe here are useful for discriminating selective antivirals from compounds that indirectly affect virus replication by reducing host cell viability or slowing cell growth

International Guideline on Dose Prioritization and Acceptance Criteria in Radiation Therapy Planning for Nasopharyngeal Carcinoma

Purpose: The treatment of nasopharyngeal carcinoma requires high radiation doses. The balance of the risks of local recurrence owing to inadequate tumor coverage versus the potential damage to the adjacent organs at risk (OARs) is of critical importance. With advancements in technology, high target conformality is possible. Nonetheless, to achieve the best possible dose distribution, optimal setting of dose targets and dose prioritization for tumor volumes and various OARs is fundamental. Radiation doses should always be guided by the As Low As Reasonably Practicable principle. There are marked variations in practice. This study aimed to develop a guideline to serve as a global practical reference. Methods and Materials: A literature search on dose tolerances and normal-tissue complications after treatment for nasopharyngeal carcinoma was conducted. In addition, published guidelines and protocols on dose prioritization and constraints were reviewed. A text document and preliminary set of variants was circulated to a panel of international experts with publications or extensive experience in the field. An anonymized voting process was conducted to rank the proposed variants. A summary of the initial voting and different opinions expressed by members were then recirculated to the whole panel for review and reconsideration. Based on the comments of the panel, a refined second proposal was recirculated to the same panel. The current guideline was based on majority voting after repeated iteration for final agreement. Results: Variation in opinion among international experts was repeatedly iterated to develop a guideline describing appropriate dose prioritization and constraints. The percentage of final agreement on the recommended parameters and alternative views is shown. The rationale for the recommendations and the limitations of current evidence are discussed. Conclusions: Through this comprehensive review of available evidence and interactive exchange of vast experience by international experts, a guideline was developed to provide a practical reference for setting dose prioritization and acceptance criteria for tumor volumes and OARs. The final decision on the treatment prescription should be based on the individual clinical situation and the patient's acceptance of optimal balance of risk. (C) 2019 Elsevier Inc. All rights reserved

Local Ca2+ Entry Via Orai1 Regulates Plasma Membrane Recruitment of TRPC1 and Controls Cytosolic Ca2+ Signals Required for Specific Cell Functions

Store-operated Ca2+ entry (SOCE) has been associated with two types of channels: CRAC channels that require Orai1 and STIM1 and SOC channels that involve TRPC1, Orai1, and STIM1. While TRPC1 significantly contributes to SOCE and SOC channel activity, abrogation of Orai1 function eliminates SOCE and activation of TRPC1. The critical role of Orai1 in activation of TRPC1-SOC channels following Ca2+ store depletion has not yet been established. Herein we report that TRPC1 and Orai1 are components of distinct channels. We show that TRPC1/Orai1/STIM1-dependent ISOC, activated in response to Ca2+ store depletion, is composed of TRPC1/STIM1-mediated non-selective cation current and Orai1/STIM1-mediated ICRAC; the latter is detected when TRPC1 function is suppressed by expression of shTRPC1 or a STIM1 mutant that lacks TRPC1 gating, STIM1(684EE685). In addition to gating TRPC1 and Orai1, STIM1 mediates the recruitment and association of the channels within ER/PM junctional domains, a critical step in TRPC1 activation. Importantly, we show that Ca2+ entry via Orai1 triggers plasma membrane insertion of TRPC1, which is prevented by blocking SOCE with 1 µM Gd3+, removal of extracellular Ca2+, knockdown of Orai1, or expression of dominant negative mutant Orai1 lacking a functional pore, Orai1-E106Q. In cells expressing another pore mutant of Orai1, Orai1-E106D, TRPC1 trafficking is supported in Ca2+-containing, but not Ca2+-free, medium. Consistent with this, ICRAC is activated in cells pretreated with thapsigargin in Ca2+-free medium while ISOC is activated in cells pretreated in Ca2+-containing medium. Significantly, TRPC1 function is required for sustained KCa activity and contributes to NFκB activation while Orai1 is sufficient for NFAT activation. Together, these findings reveal an as-yet unidentified function for Orai1 that explains the critical requirement of the channel in the activation of TRPC1 following Ca2+ store depletion. We suggest that coordinated regulation of the surface expression of TRPC1 by Orai1 and gating by STIM1 provides a mechanism for rapidly modulating and maintaining SOCE-generated Ca2+ signals. By recruiting ion channels and other signaling pathways, Orai1 and STIM1 concertedly impact a variety of critical cell functions that are initiated by SOCE