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Τετάρτη 23 Αυγούστου 2017

Biogeochemical gradients and microbial communities in Winogradsky columns established with polluted wetland sediments

Abstract
A Winogradsky column is a miniature ecosystem established with enriched sediments that can be used to study the relationship between biogeochemical gradients, microbial diversity and pollutant transformation. Biogeochemical processes and microbial communities changed with time and depth in Winogradsky columns incubated with heavy-metal-polluted wetland sediments for 520 days. 16S rRNA surveys were complemented by geochemical analyses, including heavy metal proportioning, to evaluate gradients in the mostly anoxic columns. Oxygen was depleted below the water–sediment interface (WSI), while NH4+, Fe2+, S2− and acetate increased by one order of magnitude at the bottom. Microbial niche differentiation occurred mainly by depth and from the light-exposed surface to the interior of the columns. Chemical gradients resulting from nutrient uptake by algae, and from iron and sulphate reduction mainly drove diversification. Heavy-metal proportioning did not significantly influence microbial diversity as Cu and Zn were immobilised at all depths. Proteobacteria were abundant in the top water and the WSI layers, whereas Firmicutes and Bacteroida dominated down-core. Together with low diversity and richness of communities at the WSI and column bottom, changes in the bacterial community coincided with algal-derived carbon sources and cellulose fermentation, respectively. We expect this study to be the starting point for the use Winogradsky columns to study microbial and geochemical dynamics in polluted sediments.

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Novel sequence types of extended-spectrum and acquired AmpC beta-lactamase producing Escherichia coli and Escherichia clade V isolated from wild mammals

Abstract
The closer contact with wildlife due to the growing human population and the destruction of natural habitats emphasizes the need of gaining insight into the role of animals as source of antimicrobial resistance. Here, we aim at characterizing the antimicrobial resistance genes and phylogenetic distribution of commensal Escherichia coli from 62 wild mammals. Isolates exhibiting resistance to ≥1 antibiotic were detected in 25.8% of the animals and 6.4% carried an extended-spectrum beta-lactamase (ESBL)/AmpC-producing E. coli. Genetic mechanisms involved in third-generation cephalosporin resistance were as follows: (i) hyperproduction of chromosomal AmpC (hedgehog), (ii) production of acquired CMY-2 β-lactamase (hedgehog), (iii) production of SHV-12 and CTX-M-14 ESBLs (n = 2, mink and roe-deer). ESBL genes were transferable by conjugation, and blaCMY-2 was mobilized by a 95kb IncI1 plasmid. The distribution of the phylogenetic groups in the E. coli collection studied was B1 (44.6%), B2 (24.6%), E (15.4%), A (4.6%) and F (3.1%). Five isolates (7.7%) were cryptic Escherichia clades (clade IV, 4 mice; clade V, 1 mink). ESBL/AmpC-E. coli isolates showed different sequence types (STs): ST1128/B1, ST4564/B1 (new), ST4996/B1 (new) and a non-registered ST. This study contributes to better understand the E. coli population and antimicrobial resistance flow in wildlife and reports new AmpC-E. coli STs and a first described ESBL-producing Escherichia clade V isolate.

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Mineral trioxide aggregate and other bioactive endodontic cements: An updated overview- Part I: Vital pulp therapy

Abstract

Mineral trioxide aggregate (MTA) is a bioactive endodontic cement (BEC) mainly comprised of calcium and silicate elements. The cement was introduced by Torabinejad in the 1990s and has been approved by the Food and Drug Administration (FDA) to be used in the U.S. in 1997. A number of new Bioactive Endodontic Cements (BECs) have also been introduced to the market, including BioAggregate, Biodentine, BioRoot RCS, calcium enriched mixture (CEM) cement, CAPSEAL, Endo-CPM, Endocem, EndoSequence, EndoBinder, EndoSeal MTA, iRoot, MicroMega MTA, MTA Bio, MTA Fillapex, MTA Plus, Neo MTA Plus, Ortho MTA, Quick-Set, Retro MTA, Tech Biosealer, and TheraCal. It has been claimed that these materials have properties similar to those of MTA without its drawbacks. In this article, chemical composition and the application of MTA and other BECs for vital pulp therapy (VPT) including indirect pulp cap, direct pulp cap, partial pulpotomy, pulpotomy, and partial pulpectomy, have been reviewed and compared. Based on selected key words all papers regarding chemical composition and VPT applications of BECs had been reviewed.

Most of the materials had calcium and silicate in their composition. Instead of referring to the cements based on their chemical compositions, we suggest the term "bioactive endodontic cements (BECs)," which seems more appropriate for these materials because, in spite of differences in their chemical compositions, bioactivity is a common property for all of them. Numerous articles were found regarding use of BECs as VPT agents for indirect pulp capping, partial pulpotomy, and cervical pulpotomy. Most of these investigations used MTA for VPT.

In most studies, newly introduced materials have been compared to MTA. Some of the BECs have shown promising results; however, the number of their studies compared to investigations on MTA is very limited. Most studies have had several methodological shortcomings. Future investigations with rigorous methods and materials are needed.

This article is protected by copyright. All rights reserved.



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Understanding Resistance Mechanisms and Expanding the Therapeutic Utility of PARP Inhibitors.

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Understanding Resistance Mechanisms and Expanding the Therapeutic Utility of PARP Inhibitors.

Cancers (Basel). 2017 Aug 22;9(8):

Authors: Lim JSJ, Tan DSP

Abstract
Poly-(ADP-ribose) polymerase (PARP) inhibitors act through synthetic lethality in cells with defects in homologous recombination (HR) DNA repair caused by molecular aberrations such as BRCA mutations, and is approved for treatment in ovarian cancer, with promising clinical activity against other HR defective tumors including breast and prostate cancers. Three PARP inhibitors have been FDA approved, while another two have shown promising activity and are in late stage development. Nonetheless, both primary and secondary resistance to PARP inhibition have led to treatment failure, and the development of predictive biomarkers and the ability to identify and overcome mechanisms of resistance is vital for optimization of its clinical utility. Additionally, there has been evidence that PARP inhibition may have a therapeutic role beyond HR deficient tumors which warrants further investigation, both as single agent and in combination with other therapeutic modalities like cytotoxic chemotherapy, radiation, targeted therapy and immunotherapy. With new strategies to overcome resistance and expand its therapeutic utility, PARP inhibitors are likely to become a staple in our armamentarium of drugs in cancer therapeutics.

PMID: 28829366 [PubMed]



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Expression and characterization of the zebrafish orthologue of the human FOLR1 gene during embryogenesis.

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Expression and characterization of the zebrafish orthologue of the human FOLR1 gene during embryogenesis.

Gene Expr Patterns. 2017 Aug 18;:

Authors: Jones RN, Erhard SA, Malham MR, Gen AY, Sullivan K, Olsen KW, Dale RM

Abstract
It has been well established that many types of rapidly dividing normal and diseased cells require an increased amount of folate for DNA replication and repair as well as cellular metabolism. Thus one of folate's cognate receptors, Folate Receptor 1 (FOLR1) is usually up-regulated in rapidly dividing cells, including many types of cancerous tumors. Because zebrafish have become a model organism for understanding conserved vertebrate cellular pathways and human disease, there has been an increased need to identify and elucidate orthologous zebrafish genes that are central to known human maladies. The cells of all early animal embryos go through a phase of rapid division (cleavage) where particular cell cycle checkpoints are skipped until a specification event occurs directing these embryonic stem cells to their fated germ layer cell type. Interestingly, this rapid cell division that ignores cell cycle checkpoints is also observed in many cancers. Developing blastula and tumor cells both require folr1 expression to obtain folate. In this report we have identified the expression pattern of the zebrafish gene zgc:165502, located on chromosome 15. Using computational and comparative methods and molecular biology techniques such as reverse transcription polymerase chain reaction (RT-PCR) and whole mount in situ hybridization (WISH) during embryogenesis, we demonstrate that zgc:165502 is the zebrafish orthologue of the human FOLR1 gene. Understanding when and where FOLR1 orthologues are expressed in different biomedical model organisms such as the zebrafish will help researchers design better experiments to study the endogenous FOLR1 activity.

PMID: 28826993 [PubMed - as supplied by publisher]



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Multi-modal sensor based weight drop spinal cord impact system for large animals

Publication date: Available online 23 August 2017
Source:The Spine Journal
Author(s): Hyeongbeom Kim, Jong-Wan Kim, Jung-Keun Hyun, Ilyong Park
Background ContextA conventional weight drop spinal cord (SC) impact system for large animals is composed of a high-speed video camera, a vision system, and other things. However, a camera with high speed at over 5,000 frames per second (FPS) is very expensive. In addition, the utilization of the vision system involves complex pattern recognition algorithms and accurate arrangement of the camera and the target.PurposeThe purpose of this study was to develop a large animal spinal cord injury modeling system using a multi-modal sensor instead of a high-speed video camera and vision system. Another objective of this study was to demonstrate the possibility of the developed system to measure the impact parameters in the experiments using different stiffness materials and an in-vivo porcine SC.Study DesignA multi-modal sensor based spinal cord injury impact system was developed for large animals. The experiments to measure SC impact parameters were then performed using three different stiffness materials and a Yucatan miniature pig to verify the performance of system developed.MethodsA comparative experiment was performed using three different stiffness materials such as high density (HD) sponge, rubber, and clay to demonstrate the system and perform measurement for impact parameters such as impact velocity, impulsive force, and maximally compressed displacement reflecting physical properties of materials. In the animal experiment, a female Yucatan miniature pig of 60 kg weight was used. Impact conditions for all experiments were fixed at freefalling object mass of 50 g and height of 20 cm.ResultsIn the impact test, measured impact velocities were almost the same for the three different stiffness materials at 1.84 ± 0.0153 m/s. Impulsive forces for the three materials of rubber, HD sponge, and clay were 50.88 N, 32.35 N, and 6.68 N, respectively. Maximally compressed displacements for rubber, HD sponge, and clay were 1.93 mm, 3.35 mm, and 15.01 mm, respectively. In the pig experiment, impact velocity, impulsive force, and maximally compressed dural displacement were measured at 1.84 m/s, 13.35 N, and 3.04 mm, respectively. After 3 days from the experiment, paralysis was confirmed for the lower half body of the experimental pig.ConclusionsThrough experiments, it was verified that our proposed system could be utilized to measure the SC impact parameters and induce spinal cord injury for large animals.



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The synergistic effects of combining TLR ligand based adjuvants on the cytokine response are dependent upon p38/JNK signalling.

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The synergistic effects of combining TLR ligand based adjuvants on the cytokine response are dependent upon p38/JNK signalling.

Cytokine. 2017 Aug 18;:

Authors: Fischetti L, Zhong Z, Pinder CL, Tregoning JS, Shattock RJ

Abstract
Toll like receptor (TLR) ligands are important adjuvant candidates, causing antigen presenting cells to release inflammatory mediators, leading to the recruitment and activation of other leukocytes. The aim of this study was to define the response of human blood derived dendritic cells and macrophages to three TLR ligands acting singly or in combination, Poly I:C (TLR3), GLA (TLR4) and R848 (TLR7/8). Combinations of TLR agonists have been shown to have a synergistic effect on individual cytokines, here we look at the global inflammatory response measuring both cytokines and chemokines. Using a custom Luminex assay we saw dose responses in several mediators including CCL3 (MIP1α), IL-1α, IL-1β, IL-12, CXCL10 (IP-10) and IL-6, all of which were significantly increased by the combination of R848 and GLA, even when low dose GLA was added. The synergistic effect was inhibited by specific MAP kinase inhibitors blocking the kinases p38 and JNK but not MEK1. Combining TLR adjuvants also had a synergistic effect on cytokine responses in human mucosal tissue explants. From this we conclude that the combination of R848 and GLA potentiates the inflammatory profile of antigen presenting cells. Since the pattern of inflammatory mediators released can alter the quality and quantity of the adaptive immune response to vaccination, this study informs vaccine adjuvant design.

PMID: 28826648 [PubMed - as supplied by publisher]



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The Pharmacogenetics Laboratory of the Department of Pharmacology and Toxicology at the American University of Beirut Faculty of Medicine

Pharmacogenomics, Ahead of Print.


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DNA methylation profiling opens a new phase in the search of targeted therapy against Ewing sarcoma

Pharmacogenomics, Ahead of Print.


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miRNA profiling for diagnosis, prognosis and stratification of cancer treatment in cholangiocarcinoma

Pharmacogenomics, Ahead of Print.


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Re: Guest Editorial Ann Kinnear Women and Birth 30 (2017) 168

Publication date: Available online 23 August 2017
Source:Women and Birth
Author(s): Wendy Cross




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Resistance of Staphylococcus aureus to antimicrobial agents in Ethiopia: a meta-analysis

Emergence of antimicrobial resistance by Staphylococcus aureus has limited treatment options against its infections. The purpose of this study was to determine the pooled prevalence of resistance to different ant...

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The Perth Emergency Laparotomy Audit

Background

Emergency laparotomies (ELs) are associated with high mortality and substantial outcome variation. There is no prospective Australian data on ELs. The aim of this study was to audit outcome after ELs in Western Australia.

Methods

A 12-week prospective audit was completed in 10 hospitals. Data collected included patient demographics, the clinical pathway, preoperative risk assessment and outcomes including 30-day mortality and length of stay.

Results

Data were recorded for 198 (76.2%) of 260 patients. The 30-day mortality was 6.5% (17/260) in participating hospitals, and 5.4% (19 of 354) across Western Australia. There was minimal variation between the three tertiary hospitals undertaking 220 of 354 (62.1%) ELs. The median and mean post-operative lengths of stay, excluding patients who died, were 8 and 10 days, respectively. In the 48 patients with a prospectively documented risk of ≥10%, both a consultant surgeon and anaesthetist were present for 68.8%, 62.8% were admitted to critical care and 45.8% commenced surgery within 2 h. The mortality in those retrospectively (62; 31%) and prospectively risk-assessed was 9.5% and 5.2%, respectively.

Conclusion

This prospective EL audit demonstrated low 30-day mortality with little inter-hospital variation. Individual hospitals have scope to improve their standards of care. The importance of prospective risk assessment is clear.



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Biomarkers, imaging and multifocality in intraductal papillary mucinous neoplasms: relevant for decision making?

Future Oncology, Ahead of Print.


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PDL-1/PD1 inhibitors: antibody or antinobody?

Future Oncology, Ahead of Print.


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Do all aromatase inhibitors have similar efficacy and safety?

Future Oncology, Ahead of Print.


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Single Dose of the CXCR4 Antagonist BL-8040 Induces Rapid Mobilization for the Collection of Human CD34+ Cells in Healthy Volunteers

Purpose: The potential of the high affinity CXCR4 antagonist BL-8040 as a monotherapy mobilizing agent and its derived graft composition and quality were evaluated in a phase I clinical study in healthy volunteers (NCT02073019). <p>Experimental Design: The first part of the study was a randomized, double-blind, placebo-controlled dose escalation phase. The second part of the study was an open label phase, in which 8 subjects received a single injection of BL-8040 (1mg/kg) and approximately 4hrs later underwent a standard leukapheresis procedure. The engraftment potential of the purified mobilized CD34+ cells was further evaluated by transplanting the cells into NSG immune deficient mice.</p> <p>Results: BL-8040 was found safe and well tolerated at all doses tested (0.5-1 mg/kg). The main treatment related AEs were mild to moderate. Transient injection site and systemic reactions were mitigated by methylprednisolone, paracetamol and promethazine pre-treatment. In the first part of the study BL-8040 triggered rapid and substantial mobilization of WBCs and CD34+ cells in all tested doses. 4hrs post dose, the count rose to a mean of 8, 37, 31 and 35cells/µL (placebo, 0.5, 0.75 and 1mg/kg, respectively). FACS analysis revealed substantial mobilization of immature dendritic, T, B and NK cells. In the second part the mean CD34+/kg collected were 11.6 x106 cells/kg. The graft composition was rich in immune cells.</p> <p>Conclusion: The current data demonstrate that BL-8040 is a safe and effective monotherapy strategy for the collection of large amounts of CD34+ cells and immune cells in a one-day procedure for allogeneic HSPC transplantation.<br />



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Sequential, Multiple Assignment, Randomized Trial Designs in Immuno-Oncology Research

Clinical trials investigating immune checkpoint inhibitors have led to the approval of anti-CTLA-4 (cytotoxic T-lymphocyte antigen-4), anti-PD-1 (programmed death-1) and anti-PD-L1 (PD-ligand 1) drugs by the United States Food & Drug Administration (FDA) for numerous tumor types. In the treatment of metastatic melanoma, combinations of checkpoint inhibitors are more effective than single agent inhibitors, but combination immunotherapy is associated with increased frequency and severity of toxicity. There are questions about the use of combination immunotherapy or single agent anti-PD-1 as initial therapy and the number of doses of either approach required to sustain a response. In this paper, we describe a novel use of sequential multiple assignment randomized trial (SMART) design to evaluate immune checkpoint inhibitors to find treatment regimens that adapt within individual based on intermediate response and lead to the longest overall survival. We provide a hypothetical example SMART design for BRAF wild-type metastatic melanoma as a framework for investigating immunotherapy treatment regimens. We compare implementing a SMART design to implementing multiple traditional randomized clinical trials. We illustrate the benefits of a SMART over traditional trial designs and acknowledge the complexity of a SMART.  SMART designs may be an optimal way to find treatment strategies that yield durable response, longer survival, and lower toxicity.



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Liver Transplantation for the Treatment of Complicated Iatrogenic Biliary Injuries: A National Review from the UNOS Dataset.

Background: Liver transplantation (LT) is rarely indicated in the management of iatrogenic bile duct injuries (IBDI), but occasionally it becomes the only remaining therapy. The purpose of this study is to evaluate potential complications of IBDI and their impact on perioperative mortality, graft and patient survival after LT. Methods: The UNOS database was queried for all LT performed in the United States between 1994 and 2014. Of the 101 238 liver transplants performed, 61 were related to IBDI. We performed a case matched analysis in a 5:1 ratio. Results: The median age for patients with IBDI was 50.16+11.7 years with a mean MELD score of 22.6 + 9.8. Patients receiving liver transplantation for IBDI were more likely women (54.1%, p 0.001), had lower incidence of hepatitis C virus infection (4.9%, p 0.001) and longer cold ischemic time (p 0.001). The mean BMI was 25.5+ 5.2) in patients transplanted for IBDI. IBDI was recognized as the strongest independent predictor associated with 8-fold increased risk of early graft loss (p 0.001, OR 8.4) and a 2.9-fold increased risk of 30-day mortality after LT in a case matched analysis (p 0.03). Conclusions: IBDI is an uncommon but challenging indication for liver transplantation. These patients have significantly increased rates of early graft loss. IBDI is an independent factor related to increased risk of perioperative death after LT. Further studies are needed to determine the causes of perioperative complications and identify potential modifiable factors to improve outcomes in patients undergoing transplantation for IBDI. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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White-nose syndrome increases torpid metabolic rate and evaporative water loss in hibernating bats

Fungal diseases of wildlife typically manifest as superficial skin infections but can have devastating consequences for host physiology and survival. White-nose syndrome (WNS) is a fungal skin disease that has killed millions of hibernating bats in North America since 2007. Infection with the fungus Pseudogymnoascus destructans causes bats to rewarm too often during hibernation, but the cause of increased arousal rates remains unknown. Based on data from studies of captive and free-living bats, two mechanistic models have been proposed to explain disease processes in WNS. Key predictions of both models are that WNS-affected bats will show (1) higher metabolic rates during torpor (TMR), and (2) higher rates of evaporative water loss (EWL). We collected bats from a WNS-negative hibernaculum, inoculated one group with P. destructans and sham-inoculated a second group as controls. After four months of hibernation, we used respirometry to measure TMR and EWL. Both predictions were supported and our data suggest that infected bats were more affected by variation in ambient humidity than controls. Furthermore, disease severity, as indicated by the area of the wing with UV fluorescence, was positively correlated with EWL but not TMR. Our results provide the first direct evidence that heightened energy expenditure during torpor, and higher EWL, independently contribute to WNS pathophysiology with implications for the design of potential treatments for the disease.



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The Differential Role of Reactive Oxygen Species in Early and Late Stages of Cancer

The large doses of vitamin C and E and β-carotene used to reduce reactive oxygen species (ROS) production and oxidative damages in cancerous tissue, have produced disappointing and contradictory results. This therapeutic conundrum was attributed to the double-faced role of ROS, notably, their ability to induce either proliferation or apoptosis of cancer cells. However, for a ROS-inhibitory approach to be effective, it must targets ROS when they induce proliferation rather than apoptosis. Based on recent advances in redox biology, this review underlined a differential regulation of pro- and antioxidant system, respective to the stage of cancer. At early precancerous and neoplastic stages, antioxidant activity decreases and ROS appear to promote cancer initiation via inducing oxidative damage and base pair substitution mutations in pro-oncogenes and tumor suppressor genes, such as RAS and TP53, respectively. Whereas in late stages of cancer progression, tumor cells escape apoptosis by producing high levels of intracellular antioxidants, like NADPH and GSH, via the pentose phosphate pathway to buffer the excessive production of ROS and related intra-tumor oxidative injuries. Therefore, antioxidants should be prohibited in patients with advanced stages of cancer and/or undergoing anticancer therapies. Interestingly, the biochemical and biophysical properties of some polyphenols allow them to selectively recognize tumor cells. This characteristic was exploited to design and deliver nanoparticles coated with low doses of polyphenols and containing chemotherapeutic drugs into tumor-bearing animals. First results are encouraging, which may revolutionize the conventional use of antioxidants in cancer.



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Fluorescence quenching by metal centered porphyrins and poryphyrin enzymes

Fluorescence spectroscopy and microscopy has been used extensively to monitor biomolecules, especially reactive oxygen species (ROS) and more recently reactive sulfide (RSS) species. Nearly all fluorophores are either excited by or emit light between 450 and 550 nm which is similar to the absorbance of heme proteins and metal-centered porphyrins. Here we examined the effects of catalase (Cat), reduced and oxidized hemoglobin (Hb and metHb), albumin (alb), manganese (III) Tetrakis (4-Benzoic Acid) porphyrin chloride (MnTBAP), iron proto-porphyrin IX (hemin) and copper proto-porphyrin IX (CuPPIX) on the fluorescence properties of fluorescein. We also examined the effects of catalase and MnTBAP on fluorophores for ROS (dichlorofluorescein, DCF), polysulfides (3',6'-Di(O-thiosalicyl)fluorescein, SSP4) and H2S (7-azido-4-methylcoumarin, AzMC) previously activated by H2O2, a mixed polysulfide (H2Sn, n=1-7) and H2S, respectively. All except albumin concentration-dependently inhibited fluorophore fluorescence and absorbed light between 450 and 550 nm suggesting that the inhibitory effect was physical not catalytic. Catalase inhibition of fluorescein fluorescence was unaffected by sodium azide, dithiothreitol, diamide, TCEP or iodoacetate, supporting a physical inhibitory mechanism. Catalase and TBAP augmented then inhibited DCF fluorescence, but only inhibited SSP4 and AzMC fluorescence indicative of a substrate-specific catalytic oxidation of DCF and nonspecific fluorescence inhibition of all three fluorophores. These results suggest caution must be exercised when using any fluorescent tracers in the vicinity of metal-centered porphyrins.



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Cyclical Blood Flow Restriction Resistance Exercise: A Potential Parallel to Remote Ischemic Preconditioning?

Remote ischemic preconditioning (RIPC) is characterized by the cyclical application of limb blood flow restriction and reperfusion, and has been shown to protect vital organs during a subsequent ischemic insult. Blood flow restriction exercise (BFRE) similarly combines bouts of blood flow restriction with low-intensity exercise and thus could potentially emulate the protection demonstrated by RIPC. One concern with BFRE, however, is the potential for an augmented rise in sympathetic outflow, due to greater activation of the exercise pressor reflex. Due to the use of lower workloads, however, we hypothesized that BFRE would elicit an attenuated increase in sympathetic outflow (assessed via plasma norepinephrine (NE) and mean arterial pressure (MAP)), and middle cerebral artery velocity (MCAv) when compared with conventional exercise (CE). Fifteen subjects underwent two leg-press exercise interventions: 1.BFRE-220 mmHg bilateral thigh occlusion at 20% 1 rep-max (1RM), and; 2.CE-65% 1RM without occlusion. Each condition consisted of 4 x 5-min cycles of exercise, with 3 x 10-reps in each cycle. 5-min of rest and reperfusion (for BFRE) followed each cycle. MAP increased with exercise (P<0.001), and was 4-5 mmHg higher with CE vs. BFRE (P≤0.09). Mean MCAv also increased with exercise (P<0.001) and was higher with CE compared to BFRE during the first bout of exercise only (P=0.07). Plasma [NE] increased with CE only (P<0.001), and was higher than BFRE throughout exercise (P≤0.02). The attenuated sympathetic response combined with similar cerebrovascular responses suggest that cyclical BFRE could be explored as an alternative to CE in the clinical setting.



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Obesity-induced vascular inflammation involves elevated arginase activity

Obesity-induced vascular dysfunction involves pathological remodeling of the visceral adipose tissue (VAT) and increased inflammation. Our previous studies showed that arginase 1 (A1) in endothelial cells (EC) is critically involved in obesity-induced vascular dysfunction. We tested the hypothesis that EC A1 activity also drives obesity-related VAT remodeling and inflammation. Our studies utilized wild-type and EC-A1 knockout (KO) mice made obese by high fat/high sucrose (HFHS) diet. HFHS diet induced increases in body weight, fasting blood glucose, and VAT expansion. This was accompanied by increased arginase activity and A1 expression in vascular EC and increased expression of tumor necrosis factor α (TNFα), monocyte chemoattractant protein-1 (MCP-1), interleukin-10 (IL-10), vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) mRNA and protein in both VAT and EC. HFHS also markedly increased circulating inflammatory monocytes and VAT infiltration by inflammatory macrophages, while reducing reparative macrophages. Additionally, adipocyte size and fibrosis increased and capillary density decreased in VAT. These effects of HFHS, except for weight gain and hyperglycemia, were prevented or reduced in mice lacking EC-A1 or treated with the arginase inhibitor ABH (2-(S)-amino-6-boronohexanoic acid). In mouse aortic EC, exposure to high glucose (25 mM) and Na palmitate (200 μM) reduced NO production, increased A1, TNFα, VCAM-1, ICAM-1 and MCP-1 mRNA, and monocyte adhesion. Knockout of EC-A1 or ABH prevented these effects. Summary- HFHS diet-induced VAT inflammation is mediated by EC A1 expression/activity. Limiting arginase activity is a possible therapeutic means of controlling obesity-induced vascular and VAT inflammation.



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Combining Remote Ischemic Preconditioning and Aerobic Exercise: A Novel Adaptation of Blood Flow Restriction Exercise

Remote ischemic preconditioning (RIPC) can attenuate tissue damage sustained by ischemia-reperfusion injury. Blood flow restriction exercise (BFRE) restricts blood flow to exercising muscles. We implemented a novel approach to BFRE with cyclical bouts of blood flow restriction-reperfusion, reflecting the RIPC model. A concern about BFRE, however, is potential amplification of the exercise pressor reflex, which could be unsafe in at-risk populations. We hypothesized that cyclical BFRE would elicit greater increases in sympathetic outflow and arterial pressure than conventional exercise (CE), performed at the same relative intensity. We also assessed the cerebrovascular responses, due to potential implementation of BFRE in stroke rehabilitation. Fourteen subjects performed treadmill exercise at 65-70% HRmax with and without intermittent BFR (4x5-min intervals of bilateral thigh-cuff pressure followed by 5-min reperfusion periods). Mean arterial pressure (MAP), plasma norepinephrine (NE), and middle and posterior cerebral artery velocities (MCAv and PCAv) were compared between trials. As expected, BFRE elicited higher [NE] compared to CE (1249±170 vs 962±114 pg/ml; P=0.06). Unexpectedly, however, there were no differences in MAP between conditions (overall P=0.33), and MAP was 4-5 mmHg lower with BFRE vs. CE during the reperfusion periods (P≤0.05 for reperfusion periods 3 and 4). There were no differences in MCAv or PCAv between trials (P≥0.22), suggesting equivalent cerebro-metabolic demand. The exaggerated sympatho-excitatory response with BFRE was not accompanied by higher MAP, likely due to the cyclical reperfusions. This cyclical BFRE paradigm could be adapted to cardiac- or stroke-rehabilitation, where exercising patients could benefit from the cardio- and cerebro-protection associated with RIPC.



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Acute Limb Ischemia

Acute limb ischemia is a medical emergency with significant morbidity and mortality. Rapid diagnosis is required because it is a time-sensitive condition. Timely treatment is necessary to restore blood flow to the extremity and prevent complications. The differential diagnosis of acute limb ischemia is broad. Classification of severity of acute limb ischemia is based on clinical variables. A suspicion of acute ischemia based on history and physical examination warrants heparin administration and vascular surgery consultation. The decision for endovascular thrombolysis or standard surgery depends on etiology, duration, and location of vascular occlusion. This review evaluates the diagnostic approach and management for acute limb ischemia.

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Penetrating Vascular Injury

Penetrating vascular injury is becoming increasingly common in the United States and abroad. Much of the current research and treatment is derived from wartime and translation to the civilian sector has been lacking. Penetrating vascular injury can be classified as extremity, junctional, or noncompressible. Diagnosis can be obvious but at other times subtle and difficult to diagnose. Although there are numerous modalities, computed tomography angiography is the diagnostic study of choice. It is hoped that care will be improved by using an algorithmic approach integrating experience from military and civilian research.

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Cerebral Venous Thrombosis

Headache is a common emergency department chief complaint. Although most are benign, emergency physicians must rapidly identify and manage the uncommon, sometimes subtle, presentation of headache from a life-threatening cause. Cerebral venous thrombosis imparts significant morbidity and mortality, and can be a challenging diagnosis. It most commonly occurs in those under 50 years of age with thrombosis of the cerebral veins/sinuses. Diagnosis is frequently delayed. The disease can present with 1 or more clinical syndromes, including intracranial hypertension with headaches, focal neurologic deficits, seizures, and encephalopathy. Diagnosis requires imaging. Treatment includes stabilization, management of complications, and anticoagulation.

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Extracranial Cervical Artery Dissections

Cervical artery dissections (CeAD) include both internal carotid and vertebral artery dissections. They are rare but important causes of stroke, especially in younger patients. CeAD should be considered in patients with strokelike symptoms, a new-onset headache and/or neck pain, and/or other risk factors. Early imaging with computed tomography (CT) or magnetic resonance imaging (MRI) is key to making the diagnosis. Treatment may vary depending on the extent of the dissection, timing of the dissection, and other comorbidities. The overall prognosis is good, but does depend on the initial severity of symptoms.

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Subarachnoid Hemorrhage

Subarachnoid hemorrhage (SAH) is a neurologic emergency due to bleeding into the subarachnoid space. Mortality can reach 50%. The clinical presentation is most often in the form of headache, classically defined as maximal at onset and worst of life. The most common cause is traumatic; approximately 80% of nontraumatic SAH are due to aneurysmal rupture, with the remainder from idiopathic peri-mesencephalic hemorrhage or other less common causes. Noncontrast brain computed tomography (CT) performed within 6 hours of symptom onset has sensitivity approaching 100%. Lumbar puncture may be considered after this period for definitive diagnosis if initial CT is normal.

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Vascular Access Complications

Millions of central venous and arterial catheters are placed across the United States annually as mechanisms of obtaining advanced hemodynamic monitoring and facilitating acute resuscitation. Although presumably life saving or sustaining in many circumstances, current literature identifies the preprocedural and postprocedural complications of infection, thrombosis, embolism, and iatrogenic injury as resulting in patient morbidity and mortality. Today, through the application of aseptic technique, performance of operator training, and the utilization of ultrasound, emergency physicians may limit vascular access complications and improve patient outcomes.

http://ift.tt/2wGK51q

Deep Venous Thrombosis

Deep venous thrombosis (DVT) is a frequently encountered condition that is often diagnosed and treated in the outpatient setting. Risk stratification is helpful and recommended in the evaluation of DVT. An evidence-based diagnostic approach is discussed here. Once diagnosed, the mainstay of DVT treatment is anticoagulation. The specific type and duration of anticoagulation depend upon the suspected etiology of the venous thromboembolism, as well as risks of bleeding and other patient comorbidities. Both specific details and a standardized approach to this vast treatment landscape are presented.

http://ift.tt/2vh4V3Z

Plasmodium falciparum malaria parasite var gene expression is modified by host antibodies: longitudinal evidence from controlled infections of Kenyan adults with varying natural exposure

The PfEMP1 family of Plasmodium falciparum antigens play a key role in pathogenesis of severe malaria through their insertion into the surface of parasite infected erythrocytes, and adhesion to host cells. Previo...

http://ift.tt/2g7hoEM

Spondylodiscitis due to Parvimonas micra diagnosed by the melting temperature mapping method: a case report

It has been suggested that more than 100 bacterial species can be identified using only seven universal bacterial primer sets in the melting temperature (Tm) mapping method and that these findings can be obtai...

http://ift.tt/2g7gWX6

Revisiting the in vivo GlnR-binding sites at the genome scale in Bacillus subtilis

In Bacillus subtilis, two major transcriptional factors, GlnR and TnrA, are involved in a sophisticated network of adaptive responses to nitrogen availability. GlnR was reported to repress the transcription of th...

http://ift.tt/2wGG5xZ

Congenital Syphilis Masquerading as Leukemia

AJP Rep 2017; 07: e167-e170
DOI: 10.1055/s-0037-1603955

As of late, the incidence of congenital syphilis in the United States is increasing. Each new case represents a failure of preventing, diagnosing, and treating syphilis in pregnant women. Pediatricians should confirm that all women have received adequate screening for and management of syphilis during pregnancy. Congenital syphilis is easily treatable but may be a diagnostic challenge with high morbidity and mortality.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Article in Thieme eJournals:
Table of contents  |  Abstract  |  open access Full text



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Atypical mitoses in pleomorphic lipomas

In our recent article published in this journal, we evaluated the presence and frequency of lipoblasts in spindle cell and pleomorphic lipomas (SCL/PL). Overall, lipoblasts were found in 66% of PL. These cases, which mostly occurred in the typical clinical setting of PL, were also molecular genetically tested to exclude MDM2 and CDK4 amplifications, and stained for CD34 and Retinoblastoma protein in order to further validate the diagnosis [1]. (See Fig..)

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Renal collision tumor composed of oncocytoma and mucinous tubular and spindle cell carcinoma: case report of an unprecedented entity

Primary renal collision tumors composed of two histologically distinct components are rare with only isolated case reports in the medical literature. Oncocytoma is a benign renal neoplasm, which is thought to originate from distal tubular epithelial cells. Mucinous tubular and spindle cell carcinoma (MTSCC) of kidney is a rare, relatively recently described renal neoplasm that was first included in the 2004 World Health Organization RCC classification as a distinct entity. Current studies suggest the tumor originates from the proximal nephron, although it is still controversial.

http://ift.tt/2g76hf3

Postablation neuroma of the myometrium – a report of 5 cases

When hysterectomy is performed for chronic pelvic pain, routine pathology examination often provides no explanation. However, analysis of small uterine nerves using immunostains may help to address this deficiency. Small uterine nerves tend to be sparse or absent in wide areas of normal myometrium. Some studies of uterine nerves have suggested that endometriosis, adenomyosis, and fibroids are not inherently painful, with increased small nerves in the inner uterine wall associated with the history of pelvic pain.

http://ift.tt/2iqUokV

Utility of Sox10 Labeling in Metastatic Breast Carcinomas

Sox10 labeling by immunohistochemistry has been primarily reported in tumors of neural crest origin, such as nerve sheath tumors and melanoma. However, Sox10 also labels primary breast carcinomas, particularly those with the basal-like, triple negative phenotype. However, the utility of Sox10 labeling in metastatic breast carcinomas has not been reported. Here, we prospectively evaluated Sox10 labeling in surgically resected metastatic breast carcinomas from 26 patients sampled on tissue microarrays.

http://ift.tt/2g6RBwh

PD-L1 in Breast Cancer: Comparative Analysis of Three Different Antibodies

The Programmed cell death-1 and its ligand-1 (PD-L1) interaction serve as a regulatory check against excessive immune response to antigen and autoimmunity. We compared the performance of three different PD-L1 antibodies (Ventana SP263, Dako 22C3 and BioCare RbMCAL10 antibodies) in 136 invasive ductal carcinoma specimens including 43 primary, 48 locally metastatic and 46 distantly metastatic disease. PD-L1 expression was correlated with clinicopathologic parameters including tumor size, grade, lymphovascular invasion, estrogen receptor (ER), progesterone receptor (PgR), HER2, Ki67, molecular type, TN status.

http://ift.tt/2g6QmNY

Lipofuscin Accumulation in Cortisol-Producing Adenomas With and Without PRKACA Mutations

Horm Metab Res
DOI: 10.1055/s-0043-116385

The adrenal cortex accumulates lipofuscin granules with age. Lipofuscin accumulation is also seen in adrenocortical tumors associated with Cushing syndrome (CS), particularly those with PRKAR1A mutations, such as in primary pigmented nodular adrenocortical disease (PPNAD). We investigated the presence of lipofuscin in cortisol-producing adenomas (CPAs) responsible for CS with and without the PRKACA (pLeu206Arg) somatic mutation. Ten paraffin-embedded sections of CPAs from cases with overt CS with (n=4) and without (n=6) a PRKACA mutation were microscopically examined through three detection methods, the hematoxylin-Eosin (H & E) staining, the Fontana Masson (FM) staining using light microscopy, and lipofuscin autofluorescence, using confocal laser scanning microscopy (CLSM). Sections were examined quantitatively according to the intensity of the pigmentation, as well as qualitatively based on the total number of granular pigments at all visual fields per tissue slide. Tissues from CPAs were compared to peritumoral adjacent tissues (n=5), to Conn adenomas (n=4), and PPNAD (n=3). CPAs had significantly higher number of lipofuscin-pigment granules compared to peritumoral adrenal tissue and Conn adenomas (46.9±9.5 vs. 3.8±4.8, p=0.0001). The presence of the PRKACA mutation did not increase the chances of pigmentation in the form of lipofuscin granules within CPAs associated with CS. Thus, all CPAs leading to CS accumulate lipofuscin, which presents like pigmentation sometimes seen macroscopically but always detected microscopically. PPNAD caused by PRKAR1A mutations is the best known adrenal lesion leading to CS associated with intense lipofuscin pigmentation and this was confirmed here; CPAs harboring PRKACA mutations did not have statistically significantly more pigmentation than CPAs without mutation, but a larger study might have shown a difference.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text



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Artificial Syndrome of Inappropriate Antidiuresis Model as Potential Use for Diagnostic and Therapeutic Strategies

Horm Metab Res
DOI: 10.1055/s-0043-113450

Hyponatremia is the most frequent electrolyte disorder with the syndrome of inappropriate antidiuresis (SIADH) being its predominant cause. Physiological studies in patients with SIADH are difficult to interpret due to usually several comorbidities and polymedication. Therefore, a SIADH model in healthy volunteers would be very helpful to allow insight in this complex disease and to test new therapeutic approaches. The aim of the study was to create a SIADH model with evaluation of subsequent physiological changes.The prospective interventional study on 14 healthy volunteers was carried out at the University Hospital Basel. The intervention was done by induction of hypotonic hyponatremia through hydration and administration of desmopressin. Clinical and laboratory parameters in a SIADH model were the main outcome of the measure.14 participants (64% males), BMI 23.1 kg/m2 (±2.4), aged 28.6 years (±9), completed the study. Through the intervention, serum sodium level decreased from 140 mmol/l (±1.3) to 132 mmol/l (±2.0) and serum osmolality from 286 mmol/kg (±4.7) to 267 mmol/kg (±3.5). Simultaneously urine osmolality increased to 879 mmol/kg (±97.7) and urine sodium to 213 mmol/l (±51.5) verifying the artificial SIADH model. A significant decrease of copeptin (5 pmol/l (±1.9) to 2.6 pmol/l (±0.5), p 0.002), aldosterone (314.7 pmol/l (±154.1) to 86.7 pmol/l (±23.6), p 0.019), and renin (21.2 ng/l (±26.7) to 3.6 ng/l (3.2), p 0.035) were noted, while NT-proBNP and MR-proANP significantly increased (31.7 ng/l (±18.6) to 50.5 ng/l (±33.0), p 0.001; 48.4 pmol/l (±16.8) to 56.8 pmol/l (±9.0), p 0.003).In conclusion, we were able to induce an artificial SIADH in healthy volunteers and study the changes of various hormonal biomarkers involved. This SIADH model could be helpful in evaluating diagnostic and therapeutic approaches.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text



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Aldosterone Hypothesis for Cognitive Impairment in Diabetes Mellitus

Horm Metab Res
DOI: 10.1055/s-0043-115226

Increased plasma aldosterone concentration is significantly associated with dementia, which is accentuated by diabetes mellitus (DM). Angiotensin II (AngII) deteriorates cognitive function through neuronal degradation. Lipoproteins, a major source of cholesterol for aldosterone biosynthesis, undergo glycoxidative modifications in the presence of hyperglycemia. We hypothesize that there would be a pathophysiological link between diabetically-modified lipoproteins, angiotensin II, and increased plasma aldosterone concentration for induction of cognitive impairment. Glycoxidized lipoproteins produce significantly more aldosterone from AngII-sensitized adrenocortical cells compared to their native counterparts. The elucidation of signaling mechanisms revealed that modified lipoproteins follow the similar signaling mechanism like AngII for adrenocortical aldosterone release via ERK1/2 and Janus kinase-2 (Jak-2)-mediated pathways. The enhanced aldosterone release from AngII-sensitized adrenocortical cells induced by glycoxidatively modified lipoproteins may play a crucial role in cognitive dysfunction in diabetic individuals along with AngII via a prevailing mode of signaling cascade involving ERK1/2- and Jak-2-dependent pathways.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text



http://ift.tt/2wzXgC9

A systematic review of the patient and carer related factors affecting the experience of pain for advanced cancer patients cared for at home

Effective pain management is a priority in the palliative care of advanced cancer patients. A body of research is emerging examining the factors that influence the management and experience of pain for such individuals. Identifying such factors should allow for the development of targeted interventions to improve pain management in the home while ultimately reducing unnecessary suffering for the patient.

http://ift.tt/2xtXMy2

Development and Validation of a Family Meeting Assessment Tool (FMAT)

A cornerstone procedure in Palliative Medicine is to perform family meetings. Learning how to lead a family meeting is an important skill for physicians and others who care for patients with serious illnesses and their families. There is limited evidence on how to assess best practice behaviors during end of life family meetings.

http://ift.tt/2wA1h9V

Fat accumulates preferentially in the right liver lobe than the left in non-diabetic subjects

To examine the distribution of liver fat (LFAT) in non-diabetic subjects and test whether the fat in the right as compared to the left lobe correlates better with components of the metabolic syndrome or not.

http://ift.tt/2wpkNVR

Hepatocellular carcinoma metastasis to sphenoid and cavernous sinus: an unexpected cause of ptosis



http://ift.tt/2w5wBtK

Intramural duodenal hematoma post EUS-guided placement of fiducial radiopaque markers



http://ift.tt/2xe2qkn

E-health in inflammatory bowel diseases: more challenges than opportunities?

Patients with inflammatory bowel disease need close monitoring for an optimal disease management. For this, e-health technologies are promising tools. But the current evidence for the implementation of ehealth in inflammatory bowel disease is weak. For this a critical evaluation of the existing evidence is presented. Furthermore some essential conditions need to be full-filled. We need a robust digital infrastructure that is workable for the patient and the healthcare provider. Important legal issues need to be solved to protect the patient.

http://ift.tt/2w0qjNT

Esophageal perforation and dissection due to echocardiography: endoscopic treatment using an Over-the-Scope clip



http://ift.tt/2xe2UHg

Long-term outcome of EUS-guided choledochoduodenostomy using a lumen-apposing metal stent for malignant distal biliary obstruction: a prospective multicenter study

EUS-guided choledochoduodenostomy (EUS-CDS) using conventional tubular stents has been successfully performed. However, EUS-CDS carries a high risk of bile leakage with attendant adverse events. This study aimed to prospectively evaluate the long-term outcome of EUS-CDS using a dedicated lumen-apposing metal stent (LAMS).

http://ift.tt/2wpdQo5

Metallic coil and N-butyl-2-cyanoacrylate for closure of pancreatic duct leak (with video)

Pancreatic fistula is a challenging yet common adverse event of partial pancreatectomy. Our objective is to determine the feasibility of endoscopic closure of a pancreatic fistula using a combination of a metallic coil and N-butyl-2-cyanoacrylate (NBCA) glue.

http://ift.tt/2w5aung

EUS-guided drainage of post-surgical fluid collections using lumen-apposing metal stents: a multicenter study

Post-surgical fluid collections (PSFCs) are traditionally drained either percutaneously or surgically. Endoscopic drainage offers several advantages compared to either percutaneous or surgical approaches including avoiding repeat surgery, or the need to have a percutaneous drain in place for weeks. There are very little data regarding use of lumen apposing metal stents (LAMSs) in the drainage of PSFCs. We aim to study the technical and clinical success and adverse events of using LAMSs in the drainage of PSFCs.

http://ift.tt/2wonMxY

Diagnosis of sessile serrated adenoma after educational training in a large, community-based, integrated healthcare setting

Sessile serrated adenomas (SSAs) are precursors of 15% to 30% of colorectal cancers but are frequently underdiagnosed. We sought to measure the SSA detection rate (SDR) and predictors of SSA detection after educational training for community gastroenterologists and pathologists.

http://ift.tt/2w56mnf

Esophageal triamcinolone acetonide-filling method: a novel procedure to prevent stenosis after extensive esophageal endoscopic submucosal dissection (with videos)

Endoscopic submucosal dissection (ESD) for extensive esophageal carcinomas may cause severe stenosis requiring endoscopic balloon dilations (EBD). A standard preventing method has not been established. We propose the esophageal triamcinolone acetonide (TA)-filling method as a novel local-steroid administration procedure.

http://ift.tt/2xtV77w

A biodegradable noncovered self-expandable stent to treat pancreatic duct strictures in chronic pancreatitis; a proof of principle

In chronic pancreatitis (CP), fibrotic pancreatic duct (PD) strictures pose a therapeutic challenge, as endoscopic dilatation requires multiple procedures, with suboptimal results. Biodegradable self-expandable stents (BD-SESs) may serve as an alternative in this setting.

http://ift.tt/2wzBTkl

A Systematic Review for the Development of a Core Outcome Set for Ulcerative Colitis Clinical Trials

Advances in drug development for ulcerative colitis (UC) have been paralleled by innovations in trial design. Development of a core outcome set (COS) to standardize outcome definitions and reporting in clinical trials is desirable. We aim to systematically review the efficacy and safety outcomes reported in UC placebo-controlled RCTs.

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The Blind Firing Squad



http://ift.tt/2w5c1tx

Compliance parameters and diagnostic yield



http://ift.tt/2wpdIVe

Unsuspected Critical Illness Among Emergency Department Patients Presenting for Acute Alcohol Intoxication

Emergency department (ED) visits for acute alcohol intoxication are common, but this population is at risk for decompensation and occult critical illness. The purpose of this study is to describe the incidence and predictors of unsuspected critical illness among patients with acute alcohol intoxication.

http://ift.tt/2itQwzM

Performance of Serum Creatinine and Kidney Injury Biomarkers for Diagnosing Histologic Acute Tubular Injury

The diagnosis of acute kidney injury (AKI), which is currently defined as an increase in serum creatinine (Scr) concentration, provides little information on the condition's actual cause. To improve phenotyping of AKI, many urinary biomarkers of tubular injury are being investigated. Because AKI cases are not frequently biopsied, the diagnostic accuracy of concentrations of Scr and urinary biomarkers for histologic acute tubular injury is unknown.

http://ift.tt/2g7gOXE

Arsenic Exposure From Drinking Water and the Incidence of CKD in Low to Moderate Exposed Areas of Taiwan: A 14-Year Prospective Study

Arsenic exposure is associated with decreased kidney function. The association between low to moderate arsenic exposure and kidney disease has not been fully clarified.

http://ift.tt/2irkrbw

Recommendations for the optimal radiation dose in patients with primary cutaneous anaplastic large cell lymphoma: A report of the Dutch Cutaneous Lymphoma Group

Radiotherapy is the first choice of treatment in primary cutaneous anaplastic large cell lymphoma (C-ALCL), but the optimal dose has yet to be defined. Based on the evaluation of 114 radiation fields in 78 C-ALCL patients, we recommend a dose of 20 Gy for the initial treatment of solitary or localized skin lesions and a dose of 8 Gy for initial treatment of multifocal lesions and for recurrent lesions.

http://ift.tt/2vpQrhJ

Identification of patients with localized Ewing sarcoma at higher risk for local failure: A report from the Children’s Oncology Group

Our analysis of local tumor control outcomes in 956 Ewing sarcoma patients demonstrates age ≥18 years and use of definitive radiotherapy, primarily for pelvis and extremity tumors, are associated with the highest risk of local failure. Local tumor control is excellent and similar between surgery and definitive radiotherapy for axial non-spine, spine, and soft tissue extraskeletal tumors.

http://ift.tt/2v7o24C

Low plasma vitamin A concentration is associated with tuberculosis in Moroccan population: a preliminary case control study

Vitamin A plays numerous roles in immune system. Its deficiency alters both the innate and adaptive immunity. Previous results reported that the micronutrients deficiency, particularly vitamin A, is observed i...

http://ift.tt/2wp0qIv

O161 The effect of food intake on patients with postural orthostatic tachycardia syndrome

The aim of this study was to determine the effect of food intake on heart rate (HR) and blood pressure (BP) in patients with postural orthostatic tachycardia syndrome (POTS).

http://ift.tt/2wz4h6h

S31 Structurally informed analyses of functional connectivity in stroke

Stroke is the leading cause of disability in industrialized countries, has a big impact on quality of life, and is of high socioeconomic relevance. Despite great advances of acute therapy – like thrombolysis and mechanical thrombectomy – approximately 50% of stroke survivors suffer from permanent neurological deficits, mostly because of structural and functional neural network failure.

http://ift.tt/2xdEwFS

O96 Large inter- and intra-rater variation on diagnostic criteria for amyotrophic lateral sclerosis

To study inter- and intra-rater agreement on diagnostic criteria for amyotrophic lateral sclerosis (ALS).

http://ift.tt/2wzeO1p

S196 New approach to presurgical evaluation in epilepsy surgery

In order to investigate and map the precise epileptic mechanism(network) and seizure onset zone during the planning of epilepsy surgery we use more and more complex imaging and electrophysiological studies. The analysis and evaluation of the ever growing datasets needs such a complex platform which can integrate the spatial information derived from the preoperative structural and functional imaging data with the electrophysiological data coming from the implanted intracranial electrodes.

http://ift.tt/2g5WhT6

O127 Neurophysiological localisation of ulnar neuropathy at the elbow: Validation of diagnostic criteria developed by a taskforce of the Danish society of clinical neurophysiology

This study validates consensus criteria for localisation of ulnar neuropathy at elbow (UNE) developed by a taskforce of the Danish Society of Clinical Neurophysiology and compares them to the existing criteria from the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM). The Danish criteria are based on combinations of conduction slowing in the elbow and forearm segments stated in Z-scores, and difference between the segments in m/s. Examining fibres to several muscles and sensory fibres can increase the certainty of the localisation.

http://ift.tt/2wz92wI

S63 Etiology of clinically established trigeminal neuralgia: Role of MRI

Neurovascular compression (NVC) is the commonest cause of trigeminal neuralgia (TN). The use of MRI for diagnosis and presurgical assessment is problematic, because NVC is commonly reported in asymptomatic subjects or affecting asymptomatic nerves TN patients. We reviewed the literature to evaluate the role of MRI in the diagnostics of TN.

http://ift.tt/2w4NUeI

O177 Novel method of intraoperative ocular movement monitoring using a piezoelectric device: Experimental study of OMNAPP (ocular motor nerve activating piezoelectric potentials) and clinical application for skull base surgeries

Intraoperative monitoring for the extraocular motor nerves (eOMNs) using electromyograms are not widely accepted due to their inherent invasiveness. We established a novel system for the intraoperative monitoring of eOMNs using a piezoelectric device capable of detecting imperceptible vibrations induced by ocular movement, with sensors placed on the eyelids alone.

http://ift.tt/2wz91c8

S111 Brain reorganization following the use of robotic hand prosthesis in four amputees

The amputation of a hand (as of any other body part) is followed by a cascade of plastic changes on the motor and somatosensory pathways; such changes are probably contributing to the Phantom limb syndrome, a distressing situation affecting the vast majority of amputees. Although many effort, a clear explanation of the phantom syndrome is still missing and it could be considered the result of multiple contributing mechanisms acting both at peripheral and central nervous system. The typical feature of cortical plastic reorganization following limb amputations is the invasion of the "deafferented" cortex by neighbouring areas in both the primary somatosensory and the motor cortices.

http://ift.tt/2wzhbBe

O79 vibro-tactile evoked potentials (EPS) for assessment of consciousness and communication for people with disorders of consciousness

The correct classification of patients in unresponsive wakefulness state (UWS) or minimally conscious state (MCS) is a challenge and misclassifications often occurre. In this publication we present a vibro-tactile EPs Brain-Computer Interface that serves for assessment of consciousness in and for communication.

http://ift.tt/2xtACrr

S47 Changes in voltage gated channels in regenerated axons distal and proximal to a nerve lesion

We compare function of regenerated motor axons and changes in the parent axons of young and aged mice after a sciatic nerve lesion with focus on voltage gated sodium channels (VGSC).

http://ift.tt/2wzp21P

S169 Sleep spindles and epilepsy

Sleep spindles (SSPs) are well known EEG phenomena characteristic to slow wave sleep (SWS). It has been demonstrated that SSPs participate in memory consolidation process during sleep. There are evidences of the participation of SSPs in various types of epilepsy ranging from idiopathic generalized to focal ones.Here we report the results of our investigation in human focal epilepsy patients implanted with cortical and thalamic macro-, and microelectrodes. Intracortical generators of SSPs in humans were explored and participation of different thalamic output systems was hypothesized.

http://ift.tt/2wzeaAM

O152 Investigating effective connectivity in the motor network with TMS-evoked cortical potentials

Our purpose was to learn what the spatial distribution of transcranial magnetic stimulation (TMS)-evoked potentials can reveal about connectivity originating from premotor, supplementary, and primary motor cortices.

http://ift.tt/2xtmJtF

O135 Sensory evoked potentials and central motor conduction times in children with dystonia help predict outcomes from Deep Brain Stimulation (DBS)

Deep Brain Stimulation (DBS) of the Globus Pallidus Internus produces dramatic benefits in primary dystonia. Improvements in patients with secondary dystonia are smaller and vary markedly between individuals. Predictive markers are lacking. This study tests the hypothesis that Somatosensory Evoked Potentials (SEPs) and Central Motor Conduction Times (CMCT) may predict outcome from DBS in childhood dystonia.

http://ift.tt/2xdAblY

S119 Axonal excitability studies in diabetic neuropathy

Diabetic polyneuropathy (DPN) is a complication of diabetes involving complex mechanisms. The introduction of automated threshold-tracking has led to a number of abnormal axonal excitability findings associated with diabetes without neuropathy (DWN) and DPN.The first abnormality described was a striking resistance to ischaemia in DWN. Superexcitability measurements showed that this ischaemic resistance was not due to a depolarized resting potential, but was related to the mean blood glucose over 24h, indicating a rapid effect of glucose on nerve metabolism.

http://ift.tt/2v72chs

S103 Polysomnographic features of narcolepsy types 1 and 2, and of idiopathic hypersomnia: Strengths and limitations

Current diagnostic criteria of narcolepsy types 1 (NT1), type 2 (NT2) and idiopathic hypersomnia (IH), including clinical, electrophysiological and biologic criteria are listed in the International classification of sleep disorders, 3rd edition (ICSD-3). Electrophysiological criteria have been recently weakened with the demonstration that the multiple sleep latency test (MSLT) has poor test/retest reliability. Thus the search for additional electrophysiological criteria for these central disorders of hypersomnolence.

http://ift.tt/2xdFAJw

S88 Optimizing the use of electrophysiology in the diagnosis of CIDP

Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common chronic inflammatory neuropathy. It is heterogeneous in its clinical presentation and electrophysiology has a vital role in achieving the diagnosis, to avoid patients missing out on treatment. The electrophysiology of CIDP consists of features of demyelination. Although commonly seemingly straightforward, the electrodiagnosis can be difficult due to inadequate use of existing criteria as well as of normative values and inconsistent interpretation of findings in relation to the clinical context.

http://ift.tt/2vZCZVm

S71 Motor unit number index (MUNIX)

Loss of motor units (MUs) is the primary disease process in degenerative motor neuron diseases like amyotrophic lateral sclerosis (ALS). Reinnervation can compensate for MU loss. The net result is a reduced number of MUs, and increased MU size. The assessment of the number and size of MUs will be essential to study disease progression, and to study the efficacy of treatment.

http://ift.tt/2xdFn9d

S55 Epileptogenicity biomarkers and effective connectivity in stereo-EEG

By analyzing the responses to intracranial electrical stimulation we aim at im-proving the localization of the seizure onset zone (SOZ) and the connectivity between different areas.

http://ift.tt/2xdzJ7c

Volume Segmentation and Analysis of Biological Materials Using SuRVoS (Super-region Volume Segmentation) Workbench

Segmentation of three-dimensional data from many imaging techniques is a major bottleneck in analysis of complex biological systems. Here, we describe the use of SuRVoS Workbench to semi-automatically segment volumetric data at various length-scales using example datasets from cryo-electron tomography, cryo soft X-ray tomography, and phase contrast X-ray tomography techniques.

http://ift.tt/2wFzDHP

A novel aliasing-free subband information fusion approach for wideband sparse spectral estimation

Wideband sparse spectral estimation is generally formulated as a multi-dictionary/multi-measurement (MD/MM) problem which can be solved by using group sparsity techniques. In this paper, the MD/MM problem is r...

http://ift.tt/2irJGKR

Low-Income Extraverts Spend More on Status Than Introverted Peers

The types of goods and services that low-income individuals buy may depend, at least in part, on their personality traits, according to new research published in Psychological Science, a journal of the Association for Psychological Science.

"Our findings suggest that extraverts compensate for having low income by spending more on items and experiences that reflect higher status," says researcher Blaine Landis of University College London, first author on the research. "In other words, individuals' spending patterns may reflect personality differences in how they respond to having low income."

Landis and UCL colleague Joe Gladstone were interested in understanding how personality differences might play a role in the experiences of those living on a low income.

"Past research tends to treat the experience of low income and relative deprivation as a condition that affects everyone equally, and we wanted to explore whether this was indeed the case," explains Landis.

Studies investigating so-called "compensatory consumption" indicate that people purchase items or services as a means of compensating for self-perceived shortcomings. Landis and Gladstone hypothesized that the more individuals are focused on their relative social and economic status, the more likely they will be to purchase goods and services intended to boost their status.

Specifically, the researchers expected that people who rate high on the personality trait extraversion – those who are sociable and assertive – would spend more of their money on status items compared with their less extraverted peers.

To test this hypothesis, the researchers worked with a retail bank to recruit 718 bank customers for participation in the study. The participants provided information about their age, employment status, income, savings, debt, and cash withdrawals and they consented to have their responses linked to their actual bank account data from the previous 12 months.

The participants also completed a brief, validated measure of five core personality traits (openness to experience, conscientiousness, extraversion, agreeableness, and neuroticism).

Landis and Gladstone examined each individual's spending, using independent ratings from a group of online participants to calculate the status of purchases in each spending category automatically assigned by the bank. High-status categories included spending on foreign air travel, electronics, and art institutions, while low-status categories including purchases related to pawnbrokers, salvage yards, and discount stores.

The data showed that low-income participants seemed to spend their income in different ways depending on their level of extraversion. As expected, low-income participants who rated high on trait extraversion spent more on high-status items compared with participants who were less extraverted.

"These people had the same financial resources and/or budget available to them, but our data show that they spent this money in very different ways," observes Landis.

This pattern held even after the researchers accounted for other potential factors, such as age, employment status, and relative levels of savings and debt. And the relationship between personality and spending was the same regardless of whether the researchers looked at overall spending on high-status categories or status spending as a proportion of total spending.

However, the data indicated that personality-related differences in spending seemed to diminish as participants' income increased.

The researchers note that being able to obtain and analyze objective spending data using bank account records lend weight to the real-world applications of these findings, but they acknowledge the possibility that the customers who consented to participate may not be representative of the broader population.

These findings provide initial evidence that income and personality interact to influence spending behavior and, Landis and Gladstone note, they may have implications for researchers and policymakers who are trying to design policies aimed at providing assistance to low-income populations.



http://ift.tt/2v643Da

Preparation and Metabolic Assay of 3-dimensional Spheroid Co-cultures of Pancreatic Cancer Cells and Fibroblasts

56081fig1.jpg

Here, a method is described for the preparation of 3-dimensional (3D) spheroid co-culture of pancreatic cancer cells and fibroblasts, followed by measurement of metabolic functions using an extracellular flux analyzer.

http://ift.tt/2xd781M

Neratinib Approved by FDA for HER2-Positive Breast Cancer

FDA has approved neratinib for patients with early-stage HER2-positive breast cancer who have finished at least 1 year of adjuvant therapy with trastuzumab.



http://ift.tt/2wFDF2L

Ninjacof and Ninjacof A: Recall - Potential Burkholderia Cepacia Contamination

Audience: Consumer, Pharmacy [Posted 08/23/2017] ISSUE: Centurion Labs is voluntarily recalling 1 lot of Ninjacof (Lot# 200N1601) and 1 lot of Ninjacof A (Lot# 201NA1601) manufactured by Vilvet and distributed by Centurion Labs to the retail level...

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Calcineurin Dysregulation Underlies Spinal Cord Injury-Induced K+ Channel Dysfunction in DRG Neurons

Dysfunction of the fast-inactivating Kv3.4 potassium current in dorsal root ganglion (DRG) neurons contributes to the hyperexcitability associated with persistent pain induced by spinal cord injury (SCI). However, the underlying mechanism is not known. In light of our previous work demonstrating modulation of the Kv3.4 channel by phosphorylation, we investigated the role of the phosphatase calcineurin (CaN) using electrophysiological, molecular, and imaging approaches in adult female Sprague Dawley rats. Pharmacological inhibition of CaN in small-diameter DRG neurons slowed repolarization of the somatic action potential (AP) and attenuated the Kv3.4 current. Attenuated Kv3.4 currents also exhibited slowed inactivation. We observed similar effects on the recombinant Kv3.4 channel heterologously expressed in Chinese hamster ovary cells, supporting our findings in DRG neurons. Elucidating the molecular basis of these effects, mutation of four previously characterized serines within the Kv3.4 N-terminal inactivation domain eliminated the effects of CaN inhibition on the Kv3.4 current. SCI similarly induced concurrent Kv3.4 current attenuation and slowing of inactivation. Although there was little change in CaN expression and localization after injury, SCI induced upregulation of the native regulator of CaN 1 (RCAN1) in the DRG at the transcript and protein levels. Consistent with CaN inhibition resulting from RCAN1 upregulation, overexpression of RCAN1 in naive DRG neurons recapitulated the effects of pharmacological CaN inhibition on the Kv3.4 current and the AP. Overall, these results demonstrate a novel regulatory pathway that links CaN, RCAN1, and Kv3.4 in DRG neurons. Dysregulation of this pathway might underlie a peripheral mechanism of pain sensitization induced by SCI.

SIGNIFICANCE STATEMENT Pain sensitization associated with spinal cord injury (SCI) involves poorly understood maladaptive modulation of neuronal excitability. Although central mechanisms have received significant attention, recent studies have identified peripheral nerve hyperexcitability as a driver of persistent pain signaling after SCI. However, the ion channels and signaling molecules responsible for this change in primary sensory neuron excitability are still not well defined. To address this problem, this study used complementary electrophysiological and molecular methods to determine how Kv3.4, a voltage-gated K+ channel robustly expressed in dorsal root ganglion neurons, becomes dysfunctional upon calcineurin (CaN) inhibition. The results strongly suggest that CaN inhibition underlies SCI-induced dysfunction of Kv3.4 and the associated excitability changes through upregulation of the native regulator of CaN 1 (RCAN1).



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Ninjacof and Ninjacof A: Recall - Potential Burkholderia Cepacia Contamination

Audience: Consumer, Pharmacy [Posted 08/23/2017] ISSUE: Centurion Labs is voluntarily recalling 1 lot of Ninjacof (Lot# 200N1601) and 1 lot of Ninjacof A (Lot# 201NA1601) manufactured by Vilvet and distributed by Centurion Labs to the retail level...

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NAD+-dependent HDAC inhibitor stimulates Monascus pigment production but inhibit citrinin

Monascus species are edible fungi due to the production of food colorant and other beneficial compounds. Hence, it has been an attractive thesis to improve their productivities. Increasin...

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Contents: (Adv. Healthcare Mater. 16/2017)



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In Vivo Recordings: A Ferroelectric Ceramic/Polymer Composite-Based Capacitive Electrode Array for In Vivo Recordings (Adv. Healthcare Mater. 16/2017)

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A new implantable capacitive electrocorticography electrode array is developed by Yuan Lin and co-workers in article number 1700305. The high permittivity barium titanate/polyimide nanocomposite acts as the ultrathin dielectric layer, endowing the electrode array with electrical safety and high conformability with the biological tissue. This work shows the potentials of capacitive electrode array in the field of brain/computer interfaces.



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Biofabrication: ‘Printability' of Candidate Biomaterials for Extrusion Based 3D Printing: State-of-the-Art (Adv. Healthcare Mater. 16/2017)

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3D bioprinting has the potential to replicate complex tissue architecture and biomanufacture physiologically relevant multicellular constructs on demand. In article number 1700264, Stuart Kyle, Iain S. Whitaker, and co-workers review a new generation of bioinks with suitable biocompatibility and high shape/print fidelity, that have the potential to match or exceed the physical, chemical and biological properties of human tissue, when combined with the appropriate cell source.



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Masthead: (Adv. Healthcare Mater. 16/2017)



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Supercritical Fluids: Supercritical Fluid Technology: An Emphasis on Drug Delivery and Related Biomedical Applications (Adv. Healthcare Mater. 16/2017)

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The supercritical fluid technology produces polymeric carriers in various forms in a non-toxic, cost-effective, and environmental-friendly manner. In article number 1700433, Yu Shrike Zhang, Ai-Zheng Chen, and co-workers provide an overview of the history, principle, and preparation methods involving this versatile technology and its use in fabrication of polymeric carriers for applications in biomedicine with a focus on drug delivery.



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Capturing “Extraordinary” Soft-Assembled Charge-Like Polypeptides as a Strategy for Nanocarrier Design

The rational design of nanomedicines is a challenging task given the complex architectures required for the construction of nanosized carriers with embedded therapeutic properties and the complex interface of these materials with the biological environment. Herein, an unexpected charge-like attraction mechanism of self-assembly for star-shaped polyglutamates in nonsalty aqueous solutions is identified, which matches the ubiquitous "ordinary–extraordinary" phenomenon previously described by physicists. For the first time, a bottom-up methodology for the stabilization of these nanosized soft-assembled star-shaped polyglutamates is also described, enabling the translation of theoretical research into nanomaterials with applicability within the drug-delivery field. Covalent capture of these labile assemblies provides access to unprecedented architectures to be used as nanocarriers. The enhanced in vitro and in vivo properties of these novel nanoconstructs as drug-delivery systems highlight the potential of this approach for tumor-localized as well as lymphotropic delivery.

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An "extraordinary" mechanism for charge-like association enables self-assembled anionic polypeptidic nanocarriers to be constructed. Covalent capture of these highly dynamic assemblies allows unprecedented architectures to be accessed. Their evaluation in relevant biological settings reveals a dramatically enhanced cell uptake, blood half-life, and accumulation in lymph nodes, promising features for drug delivery in cancer treatment and immunotherapy.



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BioEssays 9∕2017

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Cell size impacts cellular and organismal function through metabolism: The cover illustrates that cell size is intimately connected to mitochondrial metabolism and cellular fitness. In article 1700058, Mikael Björklund and co-workers discuss how metabolism is often cell-size dependent due to biophysical constrains imposed by cell size and shape. As cell size defines cellular fitness, this has potential implications on organismal health as demonstrated by polyploid animal models.



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BioEssays – Next Issue



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Good supervision



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BioEssays 9∕2017



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Cancer: Towards a general theory of the target

General theories (GT) are reductionist explications of apparently independent facts. Here, in reviewing the literature, I develop a GT to simplify the cluttered landscape of cancer therapy targets by revealing they cluster parsimoniously according to only a few underlying principles. The first principle is that targets can be only exploited by either or both of two fundamentally different approaches: causality-inhibition, and 'acausal' recognition of some marker or signature. Nonetheless, each approach must achieve both of two separate goals, efficacy (reduction in cancer burden) and selectivity (sparing of normal cells); if the mechanisms are known, this provides a definition of rational treatment. The second principle is target fragmentation, whereby the target may perform up to three categoric functions (cytoreduction, modulation, cytoprotection), potentially mediated by physically different target molecules, even on different cell types, or circulating freely. This GT remains incomplete until the minimal requirements for cure, or alternatively, proof that cure is impossible, become predictable.

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A reductionist General Theory of Cancer Targets is presented, proposing that all good targets are based either on causality-inhibition, or recognition; essential tasks (efficacy and selectivity) emerge differently in each case. Sophisticated hybrids may provide additional benefit. General theory analysis, including target fragmentation concepts, provides deeper insights into therapeutic mechanisms.



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BioEssays 8∕2017

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Precarious maintenance of simple DNA repeats in eukaryotes:In article number 1700077, Sergei M. Mirkin and co-workers present a model for replication fork uncoupling at expandable (GAA)n repeats responsible for Friedreich's ataxia. Lagging strand synthesis by DNA polymerase δ (blue oval) is stalled when the repetitive 5‵-flap of an Okazaki fragment (green strand) folds forward forming a triplex with the downstream duplex. This may prompt Pol δ to switch templates to the nascent leading strand, resulting in repeat expansions.



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BioEssays 9∕2017



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Using a Split-belt Treadmill to Evaluate Generalization of Human Locomotor Adaptation

We describe a protocol for investigating human locomotor adaptation using the split-belt treadmill, which has two belts that can drive each leg at a different speed. We specifically focus on a paradigm designed to test the generalization of adapted locomotor patterns to different walking contexts (e.g., gait speeds, walking environments).

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ERK/MAPK Signaling Is Required for Pathway-Specific Striatal Motor Functions

The ERK/MAPK intracellular signaling pathway is hypothesized to be a key regulator of striatal activity via modulation of synaptic plasticity and gene transcription. However, prior investigations into striatal ERK/MAPK functions have yielded conflicting results. Further, these studies have not delineated the cell-type-specific roles of ERK/MAPK signaling due to the reliance on globally administered pharmacological ERK/MAPK inhibitors and the use of genetic models that only partially reduce total ERK/MAPK activity. Here, we generated mouse models in which ERK/MAPK signaling was completely abolished in each of the two distinct classes of medium spiny neurons (MSNs). ERK/MAPK deletion in D1R-MSNs (direct pathway) resulted in decreased locomotor behavior, reduced weight gain, and early postnatal lethality. In contrast, loss of ERK/MAPK signaling in D2R-MSNs (indirect pathway) resulted in a profound hyperlocomotor phenotype. ERK/MAPK-deficient D2R-MSNs exhibited a significant reduction in dendritic spine density, markedly suppressed electrical excitability, and suppression of activity-associated gene expression even after pharmacological stimulation. Our results demonstrate the importance of ERK/MAPK signaling in governing the motor functions of the striatal direct and indirect pathways. Our data further show a critical role for ERK in maintaining the excitability and plasticity of D2R-MSNs.

SIGNIFICANCE STATEMENT Alterations in ERK/MAPK activity are associated with drug abuse, as well as neuropsychiatric and movement disorders. However, genetic evidence defining the functions of ERK/MAPK signaling in striatum-related neurophysiology and behavior is lacking. We show that loss of ERK/MAPK signaling leads to pathway-specific alterations in motor function, reduced neuronal excitability, and the inability of medium spiny neurons to regulate activity-induced gene expression. Our results underscore the potential importance of the ERK/MAPK pathway in human movement disorders.



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Why New Spinal Cord Plasticity Does Not Disrupt Old Motor Behaviors

When new motor learning changes the spinal cord, old behaviors are not impaired; their key features are preserved by additional compensatory plasticity. To explore the mechanisms responsible for this compensatory plasticity, we transected the spinal dorsal ascending tract before or after female rats acquired a new behavior—operantly conditioned increase or decrease in the right soleus H-reflex—and examined an old behavior—locomotion. Neither spinal dorsal ascending tract transection nor H-reflex conditioning alone impaired locomotion. Nevertheless, when spinal dorsal ascending tract transection and H-reflex conditioning were combined, the rats developed a limp and a tilted posture that correlated in direction and magnitude with the H-reflex change. When the right H-reflex was increased by conditioning, the right step lasted longer than the left and the right hip was higher than the left; when the right H-reflex was decreased by conditioning, the opposite occurred. These results indicate that ascending sensory input guides the compensatory plasticity that normally prevents the plasticity underlying H-reflex change from impairing locomotion. They support the concept of the state of the spinal cord as a negotiated equilibrium that reflects the concurrent influences of all the behaviors in an individual's repertoire; and they support the new therapeutic strategies this concept introduces.

SIGNIFICANCE STATEMENT The spinal cord provides a reliable final common pathway for motor behaviors throughout life. Until recently, its reliability was explained by the assumption that it is hardwired; but it is now clear that the spinal cord changes continually as new behaviors are acquired. Nevertheless, old behaviors are preserved. This study shows that their preservation depends on sensory feedback from the spinal cord to the brain: if feedback is removed, the acquisition of a new behavior may disrupt an old behavior. In sum, when a new behavior changes the spinal cord, sensory feedback to the brain guides further change that preserves old behaviors. This finding contributes to a new understanding of spinal cord function and to development of new rehabilitation therapies.



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Structural Basis of Large-Scale Functional Connectivity in the Mouse

Translational neuroimaging requires approaches and techniques that can bridge between multiple different species and disease states. One candidate method that offers insights into the brain's functional connectivity (FC) is resting-state fMRI (rs-fMRI). In both humans and nonhuman primates, patterns of FC (often referred to as the functional connectome) have been related to the underlying structural connectivity (SC; also called the structural connectome). Given the recent rise in preclinical neuroimaging of mouse models, it is an important question whether the mouse functional connectome conforms to the underlying SC. Here, we compared FC derived from rs-fMRI in female mice with the underlying monosynaptic structural connectome as provided by the Allen Brain Connectivity Atlas. We show that FC between interhemispheric homotopic cortical and hippocampal areas, as well as in cortico-striatal pathways, emerges primarily via monosynaptic structural connections. In particular, we demonstrate that the striatum (STR) can be segregated according to differential rs-fMRI connectivity patterns that mirror monosynaptic connectivity with isocortex. In contrast, for certain subcortical networks, FC emerges along polysynaptic pathways as shown for left and right STR, which do not share direct anatomical connections, but high FC is putatively driven by a top-down cortical control. Finally, we show that FC involving cortico-thalamic pathways is limited, possibly confounded by the effect of anesthesia, small regional size, and tracer injection volume. These findings provide a critical foundation for using rs-fMRI connectivity as a translational tool to study complex brain circuitry interactions and their pathology due to neurological or psychiatric diseases across species.

SIGNIFICANCE STATEMENT A comprehensive understanding of how the anatomical architecture of the brain, often referred to as the "connectome," corresponds to its function is arguably one of the biggest challenges for understanding the brain and its pathologies. Here, we use the mouse as a model for comparing functional connectivity (FC) derived from resting-state fMRI with gold standard structural connectivity measures based on tracer injections. In particular, we demonstrate high correspondence between FC measurements of cortico-cortical and cortico-striatal regions and their anatomical underpinnings. This work provides a critical foundation for studying the pathology of these circuits across mouse models and human patients.



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Altered Balance of Receptive Field Excitation and Suppression in Visual Cortex of Amblyopic Macaque Monkeys

In amblyopia, a visual disorder caused by abnormal visual experience during development, the amblyopic eye (AE) loses visual sensitivity whereas the fellow eye (FE) is largely unaffected. Binocular vision in amblyopes is often disrupted by interocular suppression. We used 96-electrode arrays to record neurons and neuronal groups in areas V1 and V2 of six female macaque monkeys (Macaca nemestrina) made amblyopic by artificial strabismus or anisometropia in early life, as well as two visually normal female controls. To measure suppressive binocular interactions directly, we recorded neuronal responses to dichoptic stimulation. We stimulated both eyes simultaneously with large sinusoidal gratings, controlling their contrast independently with raised-cosine modulators of different orientations and spatial frequencies. We modeled each eye's receptive field at each cortical site using a difference of Gaussian envelopes and derived estimates of the strength of central excitation and surround suppression. We used these estimates to calculate ocular dominance separately for excitation and suppression. Excitatory drive from the FE dominated amblyopic visual cortex, especially in more severe amblyopes, but suppression from both the FE and AEs was prevalent in all animals. This imbalance created strong interocular suppression in deep amblyopes: increasing contrast in the AE decreased responses at binocular cortical sites. These response patterns reveal mechanisms that likely contribute to the interocular suppression that disrupts vision in amblyopes.

SIGNIFICANCE STATEMENT Amblyopia is a developmental visual disorder that alters both monocular vision and binocular interaction. Using microelectrode arrays, we examined binocular interaction in primary visual cortex and V2 of six amblyopic macaque monkeys (Macaca nemestrina) and two visually normal controls. By stimulating the eyes dichoptically, we showed that, in amblyopic cortex, the binocular combination of signals is altered. The excitatory influence of the two eyes is imbalanced to a degree that can be predicted from the severity of amblyopia, whereas suppression from both eyes is prevalent in all animals. This altered balance of excitation and suppression reflects mechanisms that may contribute to the interocular perceptual suppression that disrupts vision in amblyopes.



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Sound-Evoked Activity Influences Myelination of Brainstem Axons in the Trapezoid Body

Plasticity of myelination represents a mechanism to tune the flow of information by balancing functional requirements with metabolic and spatial constraints. The auditory system is heavily myelinated and operates at the upper limits of action potential generation frequency and speed observed in the mammalian CNS. This study aimed to characterize the development of myelin within the trapezoid body, a central auditory fiber tract, and determine the influence sensory experience has on this process in mice of both sexes. We find that in vitro conduction speed doubles following hearing onset and the ability to support high-frequency firing increases concurrently. Also in this time, the diameter of trapezoid body axons and the thickness of myelin double, reaching mature-like thickness between 25 and 35 d of age. Earplugs were used to induce ~50 dB elevation in auditory thresholds. If introduced at hearing onset, trapezoid body fibers developed thinner axons and myelin than age-matched controls. If plugged during adulthood, the thickest trapezoid body fibers also showed a decrease in myelin. These data demonstrate the need for sensory activity in both development and maintenance of myelin and have important implications in the study of myelin plasticity and how this could relate to sensorineural hearing loss following peripheral impairment.

SIGNIFICANCE STATEMENT The auditory system has many mechanisms to maximize the dynamic range of its afferent fibers, which operate at the physiological limit of action potential generation, precision, and speed. In this study we demonstrate for the first time that changes in peripheral activity modifies the thickness of myelin in sensory neurons, not only in development but also in mature animals. The current study suggests that changes in CNS myelination occur as a downstream mechanism following peripheral deficit. Given the required submillisecond temporal precision for binaural auditory processing, reduced myelination might augment sensorineural hearing impairment.



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Place and Grid Cells in a Loop: Implications for Memory Function and Spatial Coding

Place cells in the hippocampus and grid cells in the medial entorhinal cortex have different codes for space. However, how one code relates to the other is ill understood. Based on the anatomy of the entorhinal-hippocampal circuitry, we constructed a model of place and grid cells organized in a loop to investigate their mutual influence in the establishment of their codes for space. Using computer simulations, we first replicated experiments in rats that measured place and grid cell activity in different environments, and then assessed which features of the model account for different phenomena observed in neurophysiological data, such as pattern completion and pattern separation, global and rate remapping of place cells, and realignment of grid cells. We found that (1) the interaction between grid and place cells converges quickly; (2) the spatial code of place cells does not require, but is altered by, grid cell input; (3) plasticity in sensory inputs to place cells is key for pattern completion but not pattern separation; (4) grid realignment can be explained in terms of place cell remapping as opposed to the other way around; (5) the switch between global and rate remapping is self-organized; and (6) grid cell input to place cells helps stabilize their code under noisy and/or inconsistent sensory input. We conclude that the hippocampus-entorhinal circuit uses the mutual interaction of place and grid cells to encode the surrounding environment and propose a theory on how such interdependence underlies the formation and use of the cognitive map.

SIGNIFICANCE STATEMENT The mammalian brain implements a positional system with two key pieces: place and grid cells. To gain insight into the dynamics of place and grid cell interaction, we built a computational model with the two cell types organized in a loop. The proposed model accounts for differences in how place and grid cells represent different environments and provides a new interpretation in which place and grid cells mutually interact to form a coupled code for space.



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Are heart toxicities in breast cancer patients important for radiation oncologists? A practice pattern survey in German speaking countries

Abstract

Background

To assess the personal beliefs of radiation oncologists regarding heart sparing techniques in breast cancer patients.

Methods

Between August 2015 and September 2015, a survey was sent to radiation oncology departments in Germany, Austria and Switzerland. 82 radiation oncology departments answered the questionnaire: 16 university clinics and 66 other departments. Most (87.2%) of the participants had >10 years of radiation oncology experience.

Results

89.2% of the participants felt that there is enough evidence to support heart sparing for breast cancer patients. The most important dose parameter was considered the mean heart dose (69.1%). The personal "safe" dose to the heart was considered to be 5 Gy (range: 0–40 Gy). The main impediment in offering all breast cancer patients heart-sparing techniques seems to be the fact that these techniques are time/ resource consuming (46.5% of the participants).

Conclusions

Most radiation oncologists believe that there is enough evidence to support heart sparing for breast cancer patients. But translating this belief into a wide practice will need better dosimetric and clinical data on what patients are expected to profit most, specific guidelines for which patients' heart sparing techniques should be performed, as well as recognition of the time/resource consumption of these techniques.



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Vitamin D supplementation in cutaneous malignant melanoma outcome (ViDMe): a randomized controlled trial

Abstract

Background

Previous studies have investigated the protective effect of vitamin D serum levels, at diagnosis and during the follow-up period after treatment, on melanoma outcome. In the present study we assess whether vitamin D supplementation, in the follow-up period after diagnosis and surgical resection of the primary tumor, has a protective effect on relapse of cutaneous malignant melanoma and whether this protective effect correlates with vitamin D levels in serum and Vitamin D Receptor immunoreactivity in the primary tumor.

Methods/design

This study is a multicenter randomized double blind placebo- controlled phase III trial. Patients between the age of 18 and 80 years diagnosed and treated surgically for a melanoma stage IB-III are eligible for randomization in a 1:1 ratio to active treatment or placebo. The study drug is taken each month and consists of either 100,000 International Unit cholecalciferol or arachidis oleum raffinatum used as a placebo. The primary endpoint is relapse free survival. The secondary endpoints are 25 hydroxyvitamin D3 serum levels at diagnosis and at 6 month intervals, melanoma subtype, melanoma site and stage of melanoma at diagnosis according to the 2009 American Joint Committee on Cancer melanoma staging and classification. At randomization a bloodsample is taken for DNA analysis. The study is approved by the local Ethics Committees.

Discussion

If we can confirm our hypothesis that vitamin D supplementation after removal of the tumor has a protective effect on relapse of cutaneous malignant melanoma we may reduce the burden of CMM at several levels. Patients, diagnosed with melanoma may have a better clinical outcome and improved quality of life. There will be a decrease in health care costs related to treatment of metastatic disease and there will be a decrease in loss of professional years, which will markedly reduce the economic burden of the disease.

Trial registration

Clinical Trial.gov, NCT01748448, 05/12/2012



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Clinical decision-making and health-related quality of life during first-line and maintenance therapy in patients with advanced non-small cell lung cancer (NSCLC): findings from a real-world setting

Abstract

Background

Maintenance therapy (MT) with pemetrexed has been shown to improve overall and progression-free survival of patients with non-squamous non-small cell lung cancer (NSCLC), without impairing patients' health-related quality of life (HRQOL) substantially. Comprehensive data on HRQOL under real-life conditions are necessary to enable informed decision-making. This study aims to (1) assess HRQOL during first-line chemotherapy and subsequent MT and (2) record patients' and physicians' reasons leading to clinical decisions on MT.

Methods

Patients treated for NSCLC at three Austrian medical centres were included. HRQOL was assessed at every chemotherapy cycle using the EORTC QLQ-C30/+LC13 questionnaire. Semi-structured interviews were conducted before MT initiation and at the time of discontinuation to evaluate patients' and physicians' reasons for treatment decisions. Longitudinal QOL analysis was based on linear mixed models.

Results

Sixty-one (73%) out of 84 patients were considered for MT. Thirty-six patients (43%) received MT and 29 (35%) discontinued therapy. Decisions on MT initiation (in 20 cases by the physician vs 4 by the patient) and discontinuation (19 vs 10) were mainly voiced by the physician. Treatment toxicity of first-line chemotherapy was the main reason for rejection of MT in patients with stable disease and was more often indicated by patients than clinicians. HRQOL data were collected from 83 patients at 422 assessment time points and indicated significantly lower symptom severity during MT compared with first-line therapy for nausea and vomiting (p = 0.006), sleep disturbances (p < 0.001), appetite loss (p = 0.043), constipation (p = 0.017) and chest pain (p = 0.022), and a deterioration in emotional functioning (p = 0.023) and cognitive functioning (p = 0.044) during MT.

Conclusions

Our results indicate that HRQOL and symptom burden improve between first-line treatment to MT in some respects, although some late toxicity persists. Discrepancies between patients' and physicians' perception of reasons for rejecting MT were evident. Thus, the integration of patient-reported outcomes, such as HRQOL, is required to enable shared decision-making and personalised healthcare based on mutual understanding of treatment objectives.



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Phenotypic change in trigeminal ganglion neurons associated with satellite cell activation via extracellular signal-regulated kinase phosphorylation is involved in lingual neuropathic pain

Abstract

Iatrogenic trigeminal nerve injuries remain a common and complex clinical problem. Satellite glial cell (SGC) activation, associated phosphorylation of extracellular signal-regulated kinase (ERK) and neuropeptide expression in the trigeminal ganglion (TG) are known to be involved in trigeminal neuropathic pain related to trigeminal nerve injury. However, the involvement of these molecules in orofacial neuropathic pain mechanisms is still unknown. Phosphorylation of ERK1/2 in lingual nerve crush (LNC) rats was observed in SGCs. To evaluate the role of neuron-SGC interactions under neuropathic pain, calcitonin gene-related peptide (CGRP)-immunoreactive (IR), phosphorylated ERK1/2 (pERK1/2)-IR and glial fibrillary acidic protein (GFAP)-IR cells in the TG were studied in LNC rats.

The number of CGRP-IR neurons and neurons encircled with pERK1/2-IR SGCs was significantly larger in LNC rats compared with sham rats. The percentage of large sized CGRP-IR neurons was significantly higher in LNC rats. The number of CGRP-IR neurons, neurons encircled with pERK1/2-IR SGCs and neurons encircled with GFAP-IR SGCs was decreased following CGRP receptor blocker CGRP8-37 or mitogen-activated protein kinase/ERK kinase 1 inhibitor PD98059 administration into the TG after LNC. Reduced thresholds to mechanical and heat stimulation to the tongue in LNC rats were also significantly recovered following CGRP8-37 or PD98059 administration.

The present findings suggest that CGRP released from TG neurons activates SGCs through ERK1/2 phosphorylation and TG neuronal activity is enhanced, resulting in the tongue hypersensitivity associated with lingual nerve injury. The phenotypic switching of large myelinated TG neurons expressing CGRP may account for the pathogenesis of tongue neuropathic pain.

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